Focusing on xerophthalmia, vitamin A deficiency

Preventing and treating vitamin A deficiency is the first step in preventing systemic and ocular complications, including xerophthalmia.

Reviewed by Alfred Sommer, MD, MHS

Xerophthalmia, a form of dry eye that results from vitamin A deficiency, was recognized medically as far back as 1520 BC. A treatment was devised that involved cooking beef liver, and then squeezing the “juice” of the liver on the affected eyes, according to Alfred Sommer, MD, MHS In 1977, George Wald theorized that the juice from the liver trickled down through the lacrimal sac and was absorbed, entered the blood stream, and ultimately reached the back of the eye.

Dr. Sommer, professor of ophthalmology, Johns Hopkins University, Baltimore, recounted his experience in 1978 in an Indonesian village during which he witnessed a similar ceremony performed on a child with nightblindness who was treated with goat’s liver and then given the liver to eat, which may be how the vitamin A entered the child’s circulation in the first place.

In the dark

A 19th-century treatment that was less humane advised keeping the affected person in a dark room for at least a month, which works temporarily because the retinal pigments have a chance to build up, Dr. Sommer explained. Nightblindness is diagnosed currently by observing a patient’s response to various levels of light, a method that grew out of an observation in malnourished Confederate soldiers during the American Civil War.

The soldiers refused to take night watch because they could not see in the dark, which was confirmed by the lack of a pupillary response when a candle was waved in front of their eyes, Dr. Sommer noted. Another manifestation of xerophthalmia is the presence of Bitot’s spots on conjunctiva, which are comprised of keratin.

“Vitamin A is necessary for development of normal, mucous-secreting conjunctival epithelium,” he explained.

The spots usually develop temporally, but severe cases involve the entire conjunctiva. In the late 19th century, cod liver oil, which is rich in vitamins A and D, was determined to be an effective cure for night blindness and Bitot’s spots.An unusual manifestation

Dr. Sommer described the case of a child who was vitamin A-deficient and had an unusual form of local necrosis.

“This manifestation often begins with a small ulcerative area that is hard to differentiate from an infection until the clinician realizes that nothing can be cultured from it and it is refractory to antibiotic treatment,” Dr. Sommer said. Slit-lamp examination revealed the presence of liquefied corneal stroma over an intact epithelium.

The World Health Organization recommended treatment of the necrosis with water-miscible vitamin A, which was unavailable and required formulation. Dr. Sommer instead administered an oily preparation of vitamin A orally (it was known that it did not work when injected, as had long been taught) until the water-miscible formulation became available.

The new formulation worked well when given intra-muscularly, but no better than the less expensive oily preparation given by mouth. Studies of locally necrotic corneal ulcers in children who died showed them to be strictly demarcated, absent of inflammatory cells, under an intact epithelium, and bordered by normal tissue.

“It did not fit any of the suggestions we had about the mechanism by which sterile corneal melting would develop,” Dr. Sommer said.

Because of the good results Dr. Sommer achieved with the cheap, available orally administered oily vitamin A, he compared it with the more expensive, less readily available water-miscible form administered intramuscularly.

“The rates at which corneal healing occurred were very similar in the two groups,” he said. “We confirmed in 1980 that both the clinical and the biochemical responses were identical in the two groups.”

At six to eight days after administration, the improved/cure rates were 94% and 97%. Early treatment of xerophthalmia is essential before the cornea is completely necrotic. The disease is associated with a mortality rate of about 25% despite hospital care.

Keratomalacia is the most severe form of xerophthalmia. The association between the corneal deterioration and Bitot’s spot was not recognized until the early 1900s, about the same time as the discovery of vitamin A.

This was a period when it was found that the so-called essential nutrients, i.e., fat, carbohydrates, and protein, were insufficient by themselves to sustain life, but, according to Dr. Sommer, life required “accessory factors,” as they were called by Hopkins, or “vital amines” by Funk, and fat-soluble A by McCollum and Davis.

It was not until 1917, that McCollum reported, “We feel confident that these cases of xerophthalmia … should be looked upon as a deficiency disease not hitherto recognized in its true relationship to diet.”

Dr. Sommer described a rat study in which pregnant rats were made vitamin A deficient and the pups were born severely deficient, to facilitate development of xerophthalmia and other manifestations of vitamin A deficiency. The deaths among the pups were charted. The results showed that xerophthalmia developed much later, after a number had died.

This death rate was evident when Dr. Sommer and colleagues studied xerophthalmia in Indonesia and found that children with mild vitamin A deficiency, but with normal looking eyes, died at a third of the rate of those with nightblindness, which was one-sixth the rate of the children with Bitot’s spots.

Further studies, and randomized trials, showed that by giving vitamin A by mouth twice a year to children in the developing world, would reduce childhood mortality by one-third.

“This changed the paradigm,” he noted. “Instead of vitamin A deficiency equaling xerophthalmia, as the vitamin A status declines other systemic functions are seriously impacted.”

The ocular manifestations, which had been considered the primary outcomes of vitamin A deficiency, develop relatively late. This recognition led to a program in 50 countries in which large-dose vitamin A capsules are distributed twice annually to all children younger than 5 years. This has been estimated to save about 350,000 lives annually.

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Disclosures:

Alfred Sommer, MD, MHS
E: asommer@jhsph.edu
Dr. Sommer has no financial interest in any aspect of this report.