4.1 Folic Acid (Pteroylglutamic Acid, PteGlu₁)

4.1.1 FOOD SOURCES

Dietary folates (folacins) are synthesized by bacteria and plants. They occur mostly as polyglutamates, which are not absorbed intact. All folacins, or polypteroylglutamates (PteGlu_n), are hydrolyzed to folic acid, or pteroylglutamic acid (PteGlu₁), during absorption. Pteroylglutamic acid (PteGlu₁) is absorbed at a faster rate than larger polymers (PteGlu_n). Only 25-50% of dietary folacin is nutritionally available; boiling destroys much of folate activity. Therefore, uncooked foods with a large portion of the monoglutamate form (PteGlu₁) - e.g., bananas, lima beans, liver and yeast - contain the highest availability of folacin. Average Canadian diets contain about 240 µg of folate a day. The daily requirement for folate is approximately 100 µg, although the recommended dietary allowance is 400 µg. Tissue stores of folate are only about 3 mg; therefore, malabsorption can deplete the body of folate within one month.

Polyglutamate forms of folate (PteGlu_n) hydrolyze sequentially down to the monoglutamate form (PteGlu₁). This hydrolysis takes place at the brush border by the enzyme folate conjugase (Figure 1). Folic acid (PteGlu₁) is absorbed from the intestinal lumen by a sodium-dependent carrier. Once in the intestinal epithelial cell, folic acid is methylated and reduced to the tetrahydro form (CH₃H₄PteGlu₁).

Interference with folic acid absorption at the brush-border carrier site occurs with drugs such as phenytoin and sulfasalazine. In addition, folic acid deficiency itself can impair folic acid absorption by producing "megaloblastic" changes in columnar epithelial cells of the gut - an abnormal epithelium.

4.2.1 FOOD SOURCES

Cobalamin refers to cobalt-containing compounds with a corrin ring: these have biological activity for humans. Vitamin B₁₂ is the generic term for all of these compounds with bioactivity in any species. Cobalamin is therefore the preferred term to distinguish those compounds that are active in humans from the many analogues produced by bacteria. Cobalamin enters animal tissues when the animal ingests bacteria-containing foods or from production in the animal's rumen. Microorganisms in the human colon synthesize cobalamin, but it is not absorbed. Thus, strict vegetarians who do not eat cobalamin- containing meats will develop cobalamin deficiency. The average Western diet contains 10-20 µg per day. The daily requirement for cobalamin is 1 µg. The human liver is the repository of approximately 5 mg of cobalamin. These large hepatic stores account for the delay of several years in the clinical appearance of deficiency after cobalamin malabsorption begins.

Once cobalamin is liberated from food, it is bound at acid pH to R proteins (so called because of their rapid movement during electrophoresis). R proteins are glycoproteins present in many body secretions, including serum, bile, saliva and gastric and pancreatic juices. Most of the gastric R protein is from swallowed saliva. The R proteins cannot mediate the absorption of cobalamin alone, and their physiologic function is incompletely understood. Rare cases of complete R-protein deficiency have occurred without obvious clinical effect on the patient.

The cobalamin/R protein complex leaves the stomach along with free intrinsic factor (Figure 2). In the duodenum, pancreatic proteases in the presence of bicarbonate (i.e., neutral pH) hydrolyze the R protein, thereby liberating free cobalamin. The cobalamin now combines with gastric intrinsic factor. A conformational change takes place, allowing the cobalamin/intrinsic-factor complex to be resistant to proteolytic digestion. This resistance allows the complex to safely traverse the small intestine and reach the ileum, its site of active absorption.

Since transfer of cobalamin from R protein to intrinsic factor depends upon pH, pancreatic insufficiency (with deficient bicarbonate production) or the Zollinger-Ellison syndrome (with excess hydrogen ion production) interferes with this process and may result in cobalamin deficiency.

In the ileum, the cobalamin/intrinsic-factor complex binds to a specific receptor located on the brush border. Free cobalamin does not bind to the ileal receptor. After passage across the enterocytes, cobalamin is transported in blood bound to circulating proteins known as transcobalamins.

Understanding the normal absorptive processes allows a classification of cobalamin malabsorption and deficiency (Table 1).

4.3.1 FOOD SOURCES

Iron is available for absorption from vegetables (nonheme iron) and from meats (heme iron). Heme iron is better absorbed (10-20%) and is unaffected by intraluminal factors or its dietary composition. Nonheme iron is poorly absorbed, with an efficiency of 1-6%, and absorption is largely controlled by luminal events. The average dietary intake of iron is 10-20 mg/day. Men absorb 1-2 mg/day, while menstruating women and iron-deficient patients absorb 3-4 mg/day. In acute blood loss, increased absorption of iron does not occur until three days later. Nonheme iron (in the ferric, Fe⁺⁺⁺ state), when ingested into a stomach unable to produce acid, forms insoluble iron complexes, which are not available for absorption (Figure 3). In the presence of gastric acid and such agents as ascorbic acid, however, ferrous iron (Fe⁺⁺) forms. The ferrous iron complexes bind to a mucopolysaccharide of about 200,000 MW_r and are transported as an insoluble complex into the duodenum and proximal jejunum. Here, with the assistance of ascorbic acid, glucose and cysteine, the iron is absorbed. Dietary factors such as phosphate, phytate and phosphoproteins can render the iron insoluble and so inhibit nonheme iron absorption.

Heme iron (ferrous, Fe⁺⁺) is ingested as myoglobin and hemoglobin. In the presence of gastric acid, the globin molecule is split off, and ferrous iron is liberated and transported with its phosphorin ring from the stomach into the duodenum and jejunum for absorption.

Both heme and nonheme iron are absorbed most rapidly in the duodenum. Some of the iron taken up is deposited as ferritin within the enterocyte, and the remainder is transferred to the plasma-bound transferrin. When the enterocyte defoliates, iron deposited as ferritin is lost into the intestinal lumen. This mechanism for loss is probably overwhelmed by the large amounts of iron ingested. The amount of iron entering the body depends largely upon two factors: (1) total body iron content and (2) the rate of erythropoiesis.