Medical Physiology, 3rd Edition

Digestion and Absorption of Vitamins and Minerals

Intestinal absorption of fat-soluble vitamins follows the pathways of lipid absorption and transport

Table 45-3 summarizes characteristics of the fat-soluble vitamins A (see pp. 367–368), D (see pp. 1063–1067), E, and K (see pp. 440–442). As a class, these vitamins rely on the lipid-absorption process discussed in the preceding subchapter. Although individual fat-soluble vitamins, once digested and absorbed, have somewhat specific fates according to their chemical nature, they have numerous overlapping physical properties that determine their similar handling in the intestinal lumen as well as uptake and processing by enterocytes. In contrast to their water-soluble counterparts (discussed below), fat-soluble vitamins do not form classical coenzyme structures or prosthetic groups with soluble apolipoproteins. Fat-soluble vitamins can also be stored in fat depots in the body. Each of the fat-soluble vitamins is really a family of related compounds, some of which are esters.

TABLE 45-3






A (retinol)

Retinal pigment

Male: 1000 µg

Female: 800 µg

Follicular hyperkeratosis, night blindness

B1 (thiamine)

Coenzyme in decarboxylation of pyruvate and α-keto acids

Male: 1.5 mg

Female: 1.1 mg


B2 (riboflavin)

Component of coenzymes FAD and FMN, H carriers in mitochondria

Male: 1.7 mg

Female: 1.3 mg

Hyperemia of nasopharyngeal mucosa, normocytic anemia

B3 (niacin, nicotinic acid)

Component of coenzymes NAD and NADP, H carriers in mitochondria

Male: 19 mg

Female: 15 mg


B6 (pyridoxine)

Coenzyme in transamination for synthesis of amino acids

Male: 2 mg

Female: 1.6 mg

Stomatitis, glossitis, normocytic anemia

B12 (cobalamin; see pp. 935–937)

Coenzyme in reduction of ribonucleotides to deoxyribonucleotides. Promotes formation of erythrocytes, myelin

2 µg

Pernicious anemia (a megaloblastic anemia)

C (ascorbic acid)

Coenzyme in formation of hydroxyproline used in collagen

60 mg


D (1,25-dihydroxy-cholecalciferol; see pp. 1063–1067)

Ca2+ absorption

5–10 µg


E (α-tocopherol)

Antioxidant: thought to prevent oxidation of unsaturated fatty acids

Male: 10 mg

Female: 8 mg

Peripheral neuropathy

K (K1 = phylloquinone, K2 = various menaquinones)

Clotting: necessary for synthesis by liver of prothrombin and factors VII, IX, and X

Male: 70–80 µg

Female: 60–65 µg

Hemorrhagic disease

Folate (see pp. 933–935)

Backbone used to synthesize purines and thymine

Male: 200 µg

Female: 180 µg

Pregnancy: 400 µg

Megaloblastic anemia


Coenzyme in carboxylation reactions

30–100 µg*

Neurological changes

Pantothenic acid

Component of CoA; necessary for carbohydrate and fat metabolism involving acetyl CoA; amino-acid synthesis

4–7 mg*

Abdominal pain, vomiting, neurological signs

*Safe and allowable range.

FAD, flavin adenine dinucleotide; FMN, flavin mononucleotide; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate.

After ingestion, fat-soluble vitamins are released from their association with proteins by the acidity of gastric juice or by proteolysis. In addition, carboxyl ester hydrolases (found in pancreatic juice and in the mucosal brush border) liberate free vitamins from their esters. In the proximal small intestine, fat-soluble vitamins incorporate with other lipid products into emulsion droplets, vesicles, and mixed micelles, which ferry them to the enterocyte surface for uptake. The absorption efficiency of fat-soluble vitamins varies from 50% to 80% for A, D, and K to only 20% to 30% for vitamin E. Other ingestants—including dietary components and drugs and their carrier vehicles—can modify the absorption of fat-soluble vitamins. For example, high doses of vitamin A impair the absorption of vitamins E and K, whereas high doses of vitamin E enhance the absorption of vitamin A.

Enterocytes take up fat-soluble vitamins by simple diffusion or via transporters. After entry into the enterocyte, fat-soluble vitamins diffuse to the SER attached to carrier proteins—such as a cellular retinol-binding protein in the case of vitamin A, or retinol—or by other mechanisms. In the SER, the vitamins associate with lipid droplets that form nascent chylomicrons and VLDLs, which then translocate through the Golgi and secretory vesicles for exocytosis into lymph. During passage through the enterocyte, vitamin A and tiny amounts of vitamin D are esterified with LCFAs, but vitamin E and K are not.

Once in the systemic blood circulation, the fat-soluble vitamins A, D, E, and K enter the liver by receptor-mediated endocytosis of chylomicrons or remnant chylomicrons, as discussed on pages 966–968.

Fat-soluble vitamin deficiency occurs in various fat-malabsorption states, including those induced by malabsorptive bariatric surgery, imageN45-14 drugs that impair TAG hydrolysis (e.g., orlistat), drugs that bind bile acids (e.g., cholestyramine), and reduction of bile acids by impaired hepatobiliary function or by unabsorbable dietary fat substitutes. Fat-soluble vitamin deficiency can also result from impaired hepatic function. The consequences can include blindness and other irreversible eye disorders (deficiency of vitamin A); bone demineralization and resorption (deficiency of vitamin D); neurological, neuromuscular, and erythrocyte aberrations (deficiency of vitamin E); and both hemorrhagic and hypercoagulable states (disorders of vitamin K).


Bariatric Surgery

Contributed by Emile Boulpaep, Walter Boron

Bariatrics (from Greek baros [weight] + iater [physician]) is a branch of medicine that focuses on treating obesity. Bariatric surgery—or weight-loss surgery—includes a variety of procedures for treating morbid obesity but does not include procedures for removing body fat per se (e.g., liposuction).

Bariatric surgery is sometimes classified into three groups depending on whether the surgical procedure predominantly produces malabsorption, restriction (or reduction) of stomach size, or a mixed malabsorption/restriction. To the extent that the surgery results in malabsorption of fats, a consequence can be a deficiency of the fat-soluble vitamins. In patients who have undergone such surgery, vitamin D deficiency is common.

In addition, bariatric surgery patients are also commonly deficient in several water-soluble vitamins (e.g., cobalamin, thiamine, folate) and minerals (e.g., iron, zinc, magnesium). In the case of cobalamin or vitamin B12, the stomach contributes the IF that binds the cobalamin (see Fig. 45-16). Vitamin B12 must be given parenterally to avoid pernicious anemia (see imageN45-6).


Malone M. Recommended nutritional supplements for bariatric surgery patients. Ann Pharmacother. 2008;42:1851–1858.

Toh SY, Zarshenas N, Jorgensen J. Prevalence of nutrient deficiencies in bariatric patients. Nutrition. 2009;25(11–12):1150–1156 [Epub May 31, 2009].

Torpy JM, Writer MD, Burke AB. Bariatric surgery. JAMA. 2005;294(15):1986 [Accessed September 2014].

Treatment of fat-soluble vitamin deficiency includes administration of water-miscible emulsions of vitamins A and E, which can enter enterocytes without special handling in the intestinal lumen. These compounds then move into portal blood together with small amounts of the more polar forms of some of the vitamins, such as retinoic acid in the case of vitamin A and menadione in the case of vitamin K.

Dietary folate (PteGlu7) must be deconjugated by a brush-border enzyme before absorption by an anion exchanger at the apical membrane

Folate is also referred to as folic acid, or pteroylmonoglutamate (PteGlu1). As we discuss below, the reduced form of folate—tetrahydrofolate (THF)—is a cofactor in biochemical reactions involving the transfer of 1-carbon fragments. The recommended dietary allowance (RDA) for folate is 200 µg for men and 180 µg for women (see Table 45-3), but it is more than doubled in pregnant women (see p. 1143). THF is essential for the synthesis of thymine and purines, which are critical components of DNA. Thus, folate deficiency compromises DNA synthesis and cell division, an effect that is most clinically noticeable in the bone marrow, where the turnover of cells is rapid. Because RNA and protein synthesis are not impaired, large red blood cells called megaloblasts are produced. The resultant megaloblastic anemia can become quite severe if untreated. Megaloblastic cells also may be seen in other organs with rapid cell turnover, such as the small intestine. Folic acid supplementation during pregnancy also reduces the risk of neural tube defects.

The medicinal form of folate is PteGlu1, a monoglutamate. Fig. 45-15A shows the structure of PteGlu1 and also illustrates how folate can act as a methyl acceptor or donor in the interconversion of serine to glycine. Dietary folate exists in several forms, much of it as folate polyglutamate, or PteGlu7 (see Fig. 45-15B), which is widely available in the diet, particularly in spinach, beans, and liver. The intestinal absorption of PteGlu7 requires deconjugation by a brush-border peptidase to PteGlu1, which then enters the enterocyte via a transporter (see Fig. 45-15C). This deconjugation is catalyzed by folate conjugase, a zinc-activated exopeptidase present in the brush border. This enzyme removes glutamate residues from PteGlu7 in a stepwise fashion before absorption of PteGlu1. This stepwise hydrolysis of the polyglutamate chain of PteGlu7 is the rate-limiting step in folate digestion-absorption. Both folate deconjugation and folate absorption occur only in the proximal small intestine and are maximally active at a pH of 5.


FIGURE 45-15 Folate deconjugation and absorption. A, THF has three parts: the biologically active pteridine moiety, a p-aminobenzoate, and a glutamate. PteGlu1 is the oxidized form of folate and is biologically inactive. B, Dietary folate is similar to medicinal folate but has several glutamate residues. PteGlu7 is also oxidized and inactive. C, In the proximal small intestine, a brush-border peptidase sequentially removes all but the last of the glutamate residues from dietary folate. The enterocyte then absorbs the resulting PteGlu1 using a folate-OH exchanger. Once inside the enterocyte, the PteGlu1 exists across the basolateral membrane via an unknown transporter. The enterocyte may reduce some of the PteGlu1 to DHF and then to THF, the biologically active form of folate. The enterocyte may then methylate some of the THF to form N5-methyl-THF, as summarized in D. D, After the cell has reduced PteGlu1 to THF by adding the four highlighted hydrogens, it first converts THF to 5,10-methylene-THF, breaking down serine to glycine in the process. This 5,10-methylene-THF is the methyl donor in the conversion of the nucleotide dUMP to dTMP in the synthesis of DNA. A second reaction converts this 5,10-methylene-THF to N5-methyl-THF, which can then act as a methyl donor in the synthesis of methionine (see Fig. 45-16B). NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide (reduced form). imageN45-15



Contributed by Alisha Bouzaher

NADH and NAD+ are, respectively, the reduced and oxidized forms of nicotinamide adenine dinucleotide (NAD) and their close analogs are NADPH and NADP+, the reduced and oxidized forms of nicotinamide adenine dinucleotide phosphate (NADP). The coenzymes NADH and NADPH each consist of two nucleotides joined at their phosphate groups by a phosphoanhydride bond. NADPH is structurally distinguishable from NADH by the additional phosphate group residing on the ribose ring of the nucleotide, which allows enzymes to preferentially interact with either molecule.

Total concentrations of NAD+/NADH (10−5 M) are higher in the cell by ~10-fold compared to NADP+/NADPH (10−6 M). Ratios of the oxidized and reduced forms of these coenzymes offer perspective into the metabolic activity of the cell. The high NAD+/NADH ratio favors the transfer of a hydride from a substrate to NAD+ to form NADH, the reduced form of the molecule and oxidizing agent. Therefore, NAD+ is highly prevalent within catabolic reaction pathways where reducing equivalents (carbohydrate, fats, and proteins) transfer protons and electrons to NAD+. NADH acts as an energy carrier, transferring electrons from one reaction to another. Conversely, the NADP+/NADPH ratio is low, favoring the transfer of a hydride to a substrate oxidizing NADPH to NADP+. Thus, NADPH is utilized as a reducing agent within anabolic reactions, particularly the biosynthesis of fatty acids.


Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 6th ed. WH Freeman: New York; 2012.

Wikipedia. s.v. Nicotinamide adenine dinucleotide. [Last modified May 8]; 2015 [Accessed May 15, 2015].

PteGlu1 absorption is saturable, shows substrate specificity, and is markedly enhanced at an acid pH. Folate absorption represents an apical membrane anion-exchange process in which folate uptake is linked to the efflux of OH across the apical membrane (i.e., folate-OH exchange). The mechanism of folate movement out of the epithelial cell across the basolateral membrane is not understood.

The PteGlu1 taken up by the enterocyte is not biologically active. The enzyme difolate reductase acts on PteGlu1 to form first dihydrofolate (DHF) and then the biologically active derivative THF. The cell then converts THF to 5,10-methylene-THF (see Fig. 45-15D), the form of folate needed for DNA synthesis. The cell also can transform this 5,10-methylene-THF to N5-methyl-THF, which—as we discuss in the next section—can act as a methyl donor in the synthesis of methionine. The circulating, storage, and active forms of folate constitute various reduced (DHF and THF) and methylated derivatives of folate. The liver is the primary site at which dietary pteroylglutamates are reduced and methylated, although the intestinal epithelium may make a small contribution to these reactions.

Vitamin B12 (cobalamin) binds to haptocorrin in the stomach and then to intrinsic factor in the small intestine before endocytosis by enterocytes in the ileum

Cobalamin, or vitamin B12 (Fig. 45-16A), is synthesized only by microorganisms, not by mammalian cells. The primary source of cobalamin in humans is the ingestion of animal products—meat, fish, shellfish, eggs, and (to a limited extent) milk. Cobalamin is not present in vegetables or fruit. Therefore, strict vegetarians are at risk of developing dietary cobalamin deficiency.


FIGURE 45-16 Cobalamin and the role of intrinsic factor (IF) in the absorption of cobalamin. A, Cyanocobalamin. B, Methylation cycle. Cobalamin is the coenzyme for the enzyme homocysteine : methionine methyltransferase, which transfers a methyl group from N5-methyltetrahydrofolate to homocysteine, thereby forming methionine and THF. C, Steps 1 to 8 show the fate of dietary cobalamin (CBL). Steps 4 to 8 show the role of IF. In addition, bile carries cobalamin into the duodenum. D, The IF/cobalamin complex is thought to be endocytosed. The cobalamin is liberated within the enterocyte by mechanisms that have not been established. Within the enterocyte, cobalamin binds to transcobalamin II (TCII), which is required for cobalamin's exit from the enterocyte.

Cobalamin's primary function is to serve as a coenzyme for homocysteine : methionine methyltransferase (see Fig. 45-16B), which transfers a methyl group from methyltetrafolate to homocysteine, thereby converting homocysteine to methionine. Methionine is an essential amino acid and in an altered form serves as an important donor of methyl groups in several important enzymatic reactions. If cobalamin is deficient and methionine levels fall, then the body converts its stores of intracellular folate (e.g., PteGlu1, THF, 5,10-methylene-THF) into N5-methyl-THF (see Fig. 45-15D) in an effort to produce more methionine. As a result, levels of 5,10-methylene-THF (the form of folate needed for DNA synthesis) falls, an effect that explains why folate and cobalamin deficiencies cause identical hematological abnormalities (i.e., megaloblastic anemia). In addition, cobalamin deficiency causes various neurological and psychological abnormalities that are not part of the syndrome of folate deficiency. Some of these abnormalities may be linked to deficient activity of methylmalonyl-CoA mutase, another cobalamin-dependent coenzyme.

Cobalamin reaches the stomach bound to proteins in ingested food. In the stomach, pepsin and the low gastric pH release the cobalamin from the ingested proteins (see Fig. 45-16C). The now-free cobalamin binds to haptocorrin (formerly known as R-type binder), a glycoprotein secreted by the salivary and gastric glands. The parietal cells of the stomach secrete a second protein, intrinsic factor (IF), crucial for the absorption of cobalamin. However, cobalamin and IF do not interact in the acidic milieu of the stomach. Rather, gastric acidity enhances the binding of cobalamin to haptocorrin. When this cobalamin-haptocorrin complex reaches the duodenum, the haptocorrin is degraded by pancreatic proteases (see Fig. 45-16C).

After the release of cobalamin from the cobalamin-haptocorrin complex in the proximal small intestine—made alkaline by the secretion of image from the pancreas and duodenum—both dietary cobalamin and cobalamin derived from bile bind to IF. The cobalamin-IF complex is highly resistant to enzyme degradation. As noted above, the gastric parietal cells secrete IF, a 45-kDa glycoprotein. Acetylcholine, gastrin, and histamine stimulate gastric acid secretion (see p. 866), and they also stimulate IF secretion. IF secretion parallels proton secretion, but with three important differences. First, as in pepsinogen secretion, histamine triggers an IF release that peaks within minutes and then continues at a reduced rate. This secretory pattern is related to the secretion of preformed IF; histamine has no effect on IF synthesis. Second, although cAMP is important in IF secretion, a role for intracellular Ca2+ has not yet been established. Third, H2 histamine-receptor antagonists block IF secretion, but omeprazole, an inhibitor of the parietal-cell H-K pump, does not affect IF secretion.

The next step in the absorption of cobalamin is the binding of the cobalamin-IF complex to specific receptors on the apical membranes of enterocytes in the ileum. Cobalamin without IF neither binds to ileal receptors nor is absorbed. The binding of the cobalamin-IF complex is selective and rapid and requires Ca2+, but it is not energy dependent. The enterocyte next internalizes the cobalamin-IF complex in a process that is energy dependent but has not been well characterized. Inside the cell, cobalamin and IF dissociate; lysosomal degradation may play a role here. Within the enterocyte, cobalamin binds to another transport protein—transcobalamin II—which is required for cobalamin's exit from the enterocyte. The cobalamin exits the ileal enterocyte across the basolateral membrane bound to transcobalamin II, possibly by an exocytotic mechanism. The transcobalamin II–cobalamin complex enters the portal circulation, where it is delivered to the liver for storage and for secretion into the bile.

Total-body cobalamin stores are large (~5 mg), particularly when compared with the daily rate of cobalamin absorption and loss. (The daily cobalamin requirement for normal adults is only 2 micrograms.) The load of cobalamin presented to the small intestine is derived about equally from two sources: the diet and biliary secretions. The latter is the result of the enterohepatic circulation (see pp. 962–964) of cobalamin; after its absorption, cobalamin is delivered throughout the body, and the excess is secreted by the liver into the bile, where it once again can be reabsorbed by the small intestine and recirculated.

Cobalamin deficiency has many possible causes. As already mentioned, a strict vegetarian diet is deficient in cobalamin. In pernicious anemia, a disorder seen primarily in the elderly, the absence of gastric parietal cells results in the absence of gastric acid and IF secretion. Consequently, cobalamin absorption is markedly reduced, and cobalamin deficiency develops. Other causes of cobalamin deficiency include related problems in the intestine. Bacterial overgrowth in the small intestine as a result of stasis (e.g., multiple jejunal diverticulosis) can be associated with cobalamin deficiency as a consequence of bacterial binding and metabolism of cobalamin. Crohn disease affecting the ileum and ileal resection are other possible causes of cobalamin malabsorption and deficiency as a result of an absence of ileal receptors for the cobalamin-IF complex.

Ca2+ absorption, regulated primarily by vitamin D, occurs by active transport in the duodenum and by diffusion throughout the small intestine

The physiological importance and complex regulation of Ca2+ and vitamin D are discussed in Chapter 52. The Ca2+ load presented to the small intestine is derived from dietary sources and digestive secretions. Most of the dietary Ca2+ (~1000 mg/day) comes from milk and milk products (see Fig. 52-1). Not all of the ingested Ca2+ is bioavailable. For example, only very little of the Ca2+ present in leafy vegetables is absorbed because of the concomitant presence of oxalate, a salt that binds Ca2+ and reduces its availability for absorption. The small intestine absorbs ~500 mg/day of Ca2+, but also secretes ~325 mg/day of Ca2+. Thus, the net uptake is ~175 mg/day.

Active transcellular uptake of Ca2+ occurs only in the epithelial cells of the duodenum, but Ca2+ is absorbed by passive paracellular diffusion throughout the small intestine. More Ca2+ is absorbed in the jejunum and ileum by diffusion than in the duodenum by active transport; this difference arises largely because the duodenum has a smaller total surface area and because the flow of Ca2+-containing fluid through the duodenum is faster.

The active transport of Ca2+ across the villous epithelial cells of the duodenum is transcellular and is under the control of vitamin D—primarily via genomic effects (see pp. 71–72). Transcellular Ca2+ absorption involves three steps (Fig. 45-17). The uptake of Ca2+ across the apical membrane occurs via TRPV6 Ca2+ channels (see Table 6-2, family No. 5), driven by the electrochemical gradient between the lumen and the cell. Cytosolic Ca2+ then binds to a protein called calbindin, which buffers intracellular Ca2+. This step is important because it allows levels of unbound (i.e., free) intracellular Ca2+ to remain rather low despite large transcellular fluxes of Ca2+. A Ca pump and an Na-Ca exchanger on the basolateral membrane then extrude the Ca2+ from the cell into the interstitial fluid. The active form of vitamin D—1,25-dihydroxyvitamin D—stimulates all three steps of the transcellular pathway, but its most important effect is to enhance the second step by increasing the synthesis of calbindin.


FIGURE 45-17 Active Ca2+ uptake in the duodenum. The small intestine absorbs Ca2+ by two mechanisms. The passive paracellular absorption of Ca2+ occurs throughout the small intestine. This pathway is the predominant one but is not under the control of vitamin D. The second mechanism—the active transcellular absorption of Ca2+—occurs only in the duodenum. Ca2+ enters the cell across the apical membrane via a channel. Inside the cell, the Ca2+ is buffered by binding proteins such as calbindin and is also taken up into intracellular organelles such as the endoplasmic reticulum. The enterocyte then extrudes Ca2+ across the basolateral membrane via a Ca pump and an Na-Ca exchanger. Thus, the net effect is Ca2+ absorption. The active form of vitamin D (1,25-dihydroxyvitamin D) stimulates all three steps of transcellular Ca2+ absorption. NCX1, Na-Ca exchanger 1.

The passive absorption of Ca2+ throughout the small intestine occurs via the paracellular pathway, which is not under the control of vitamin D. Ca2+ absorption is also enhanced by low plasma [Ca2+] and during pregnancy and lactation. Absorption tends to diminish with aging.

Vitamin D itself is a fat-soluble vitamin that is absorbed mainly in the jejunum. Of course, the skin synthesizes vitamin D3 from cholesterol in a process that requires ultraviolet light (see p. 1064). Thus, dietary vitamin D (both vitamin D2 and D3) is most important in regions of the world that do not receive much sunlight and during long, dark winters.

Mg2+ absorption occurs by an active process in the ileum

Mg2+ is an important intracellular ion that is required as an enzyme cofactor—many enzymes using ATP actually require that the ATP be complexed with Mg2+—and is critical for neurotransmission and muscular contractions. Mg2+ deficiency can affect neuromuscular, cardiovascular, and gastrointestinal function. Mg2+ is also important for the proper secretion of, and end-organ response to, parathyroid hormone. Thus, Mg2+ depletion is typically associated with hypocalcemia.

Mg2+ is widely available in different foods but is present in particularly large amounts in green vegetables, cereals, and meats. The RDA for Mg2+ in young adults is ~350 mg/day for men and ~280 mg/day for women (Table 45-4). The Mg2+ load to the small intestine is derived from both dietary sources and digestive secretions.

TABLE 45-4

Essential Minerals





Bone mineralization (see pp. 1056–1058), intracellular signaling (see p. 60)

800–1200 mg


Possibly a cofactor in metabolism of carbohydrates, protein, lipids

50–200 µg


Enzyme cofactor (e.g., superoxide dismutase)

1.5–3 mg


Constituent of hemoglobin (see p. 647) and cytochromes (see p. 955)

Male: 10 mg

Female (childbearing age): 15 mg


Constituent of thyroid hormones (see p. 1006)

150 µg


Complexes with ATP (see p. 82)

Male: ~350 mg

Female: ~280 mg



2–5 mg


Cofactor in carbon, nitrogen, and sulfur metabolism

75–250 µg


Bone mineralization (see pp. 1056–1058)

800–1000 mg



Male: 70 µg

Female: 55 µg


Antioxidant, component of transcription factors (see p. 82), enzyme cofactor imageN18-3

Male: 15 mg

Female: 12 mg

Mg2+ absorption by the gastrointestinal tract is not yet well understood, but it appears to differ substantially from the absorption of the other key divalent cation, Ca2+, in three important respects. First, an active transport process for Mg2+ absorption appears to exist in the ileum, rather than in the duodenum, as is the case for Ca2+. Second, 1,25-dihydroxyvitamin D does not consistently increase Mg2+ absorption. Third, patients with increased intestinal Ca2+ absorption (e.g., absorptive hypercalciuria) have normal Mg2+ absorption. Along with active Mg2+ absorption in the ileum, passive absorption of Mg2+ occurs in the rest of the small intestine.

Heme and nonheme iron are absorbed in the duodenum by distinct cellular mechanisms

Iron plays several critical roles in human physiology, both in the heme groups of the cytochromes and as a key component of the oxygen-carrying heme moieties of hemoglobin and myoglobin. The most important complication of iron depletion is anemia. Iron overload produces hemochromatosis, a not-uncommon genetic disease (Box 45-6).

Box 45-6


Hereditary hemochromatosis (HH) is a relatively common inherited disorder (3 to 5 persons in 1000 of northwestern European ancestry are homozygous) in which the body absorbs excessive iron from the diet. This autosomal recessive disease becomes clinically significant only in homozygotes. If left untreated, HH can be fatal. The excess iron is stored in the liver, where it reaches toxic concentrations. Cirrhosis eventually results, greatly increasing the risk of hepatoma. Iron also ultimately accumulates in other organ systems, causing pancreatic damage (diabetes mellitus), bronze pigmentation of the skin, pituitary and gonadal failure, arthritis, and cardiomyopathy. The disease hardly ever becomes apparent before the individual enters the third decade of life. Women are relatively protected as long they are premenopausal, because their monthly menstrual flow keeps total-body iron stores at relatively normal levels.

The diagnosis can be made by detection of elevated iron and transferrin-saturation levels and elevated ferritin level. A liver biopsy is confirmatory.

Treatment, reminiscent of the medieval approach to disease, is to remove (by phlebotomy) one or even several units of blood (1 unit = 500 mL) from the patient on a regular basis until the iron overload is corrected, as evidenced by normal plasma ferritin levels. Afterward, most patients require phlebotomy only once every few months to maintain low iron stores.

The HFE gene that is associated with HH is related to the major histocompatibility complex (MHC) class I family. More than 80% of patients with HH are homozygous for a missense mutation (C282Y) in HFE. However, the role of this mutated gene in hemochromatosis is not yet clear because the penetrance of hemochromatosis in individuals with the C282Y allele is very low (<5%).

Attention has focused on hepcidin, a hepatic peptide hormone that is the primary regulator of body iron stores. In response to elevated iron stores, Kupffer cells increase their production of hepcidin; the hepcidin binds to basolateral FPN1 in duodenal enterocytes, which leads to FPN1 internalization, ubiquitination, and degradation. The result is a decrease in Fe2+ absorption (see Fig. 45-18). Hemochromatosis may represent a defect in the regulation of hepcidin. It is possible that a mutated HFE gene causes an inappropriately low hepatic hepcidin expression, thus resulting in hemochromatosis.

The relationship between hepcidin and iron absorption has also been identified in the anemia of inflammation, caused by a reduction in duodenal iron absorption. In this setting, the cytokine interleukin-6 stimulates hepcidin expression and thus decreased iron absorption.

Dietary iron takes two major forms: iron that is part of a heme moiety and iron that is not. These two types of dietary iron are absorbed by distinctly different mechanisms (Fig. 45-18). Overall iron absorption is low; 10% to 20% of ingested iron is absorbed. Heme iron is absorbed more efficiently than nonheme iron. Body stores of iron depend almost exclusively on iron absorption because no regulated pathway for iron excretion exists. Except in menstruating women, who require ~50% more iron in their diets, very little iron is lost from the body. Dietary iron comes primarily from meat—especially liver and fish—as well as vegetables. The RDA for iron in young adults is ~10 mg/day for men and ~15 mg/day for women (see Table 45-4).


FIGURE 45-18 Absorption of nonheme and heme iron in the duodenum. The absorption of nonheme iron occurs almost exclusively in the form of Fe2+, which crosses the duodenal apical membrane via DMT1, driven by a H+ gradient that is maintained by Na-H exchange. Heme enters the enterocyte by an unknown mechanism. Inside the cell, heme oxygenase releases Fe3+, which is then reduced to Fe2+. Cytoplasmic Fe2+ then binds to mobilferrin for transit across the cell to the basolateral membrane. Fe2+ probably exits the enterocyte via basolateral ferroportin. The ferroxidase activity of hephaestin converts Fe2+ to Fe3+ for carriage in the blood plasma bound to transferrin.

Nonheme Iron

Nonheme iron may be either ferric (Fe3+) or ferrous (Fe2+). Ferric iron tends to form salt complexes with anions quite easily and thus is not readily absorbed; it is not soluble at pH values >3. Ferrous iron does not complex easily and is soluble at pH values as high as 8. Ascorbic acid (vitamin C) forms soluble complexes with iron and reduces iron from the ferric to the ferrous state, thereby enhancing iron absorption. Tannins, present in tea, form insoluble complexes with iron and lower its absorption.

Iron movement does not occur passively but requires one or more proteins for facilitation of movement into and out of cells (especially enterocytes, hepatocytes, and macrophages) as well as for intracellular binding. The absorption of nonheme iron is restricted to the duodenum. The enterocyte takes up nonheme iron across the apical membrane via the divalent metal cotransporter DMT1 (SLC11A2), which cotransports Fe2+ and H+ into the cell (see p. 123). DMT1, as well as the oligopeptide cotransporter that we discussed above, is unusual in being energized by the inwardly directed H+ gradient. DMT1 also efficiently absorbs a host of other divalent metals, including several that are highly toxic (e.g., Cd2+, Pb2+). In the case of dietary ferric iron, the ferric reductase Dcytb (duodenal cytochrome b) presumably reduces Fe3+ to Fe2+ at the extracellular surface of the apical membrane before uptake via DMT1.

Fe2+ moves into the cytoplasm of the enterocyte, where it binds to mobilferrin, an intracellular protein that ferries the Fe2+ to the basolateral membrane. The enterocyte then translocates the Fe2+ across the basolateral membrane, possibly via ferroportin transporter 1 (FPN1, SLC40A1). The mRNA encoding FPN1 has an iron response element (see p. 99) in its 5′ untranslated region; thus, an increase in intracellular iron levels would be expected to decrease FPN1 synthesis. Following the exit of Fe2+ from the enterocyte via FPN1, the ferroxidase hephaestin—a homolog of the plasma protein ceruloplasmin, which carries copper (see p. 970)—apparently oxidizes the Fe2+ to Fe3+, which then binds to plasma transferrin (see p. 42) for carriage in the blood.

Once in the circulation, nonheme iron bound to transferrin is ultimately deposited in all the tissues of the body, but it has a particular predilection for the liver and reticuloendothelial system. Inside these cells, it binds to the protein apoferritin to form ferritin (see p. 971), the major storage form of iron. Smaller amounts of storage iron exist in an insoluble form called hemosiderin.

Heme Iron

Derived from myoglobin and hemoglobin, heme iron is also absorbed by duodenal epithelial cells. Heme iron enters the cells either by binding to a brush-border protein or through an endocytotic mechanism. Inside the cell, heme oxygenase enzymatically splits the heme iron, thus releasing free Fe2+, CO, and biliverdin (see Fig. 46-6A). The cell reduces the biliverdin to bilirubin, which the liver eventually excretes in bile (see Box 46-1). The enterocyte then handles the Fe2+ in the same manner as nonheme iron.

Iron absorption is tightly regulated by the size of existing body iron stores. In physiologically normal subjects, iron absorption is limited but is markedly increased in states of iron deficiency, caused most often by gastrointestinal bleeding or excessive menstrual flow. For example, the expression of DMT1 and FPN1 increases in iron deficiency. Conversely, an increase in iron stores modestly reduces iron absorption.

The molecular mechanisms by which iron stores regulate iron absorption play a role in the pathophysiology of hemochromatosis (see Box 45-6). Hepcidin, a 25–amino-acid peptide secreted by hepatocytes, reduces duodenal iron absorption by downregulating the iron exporter ferroportin (FPN1). Hepcidin is a negative regulator of iron absorption. Indeed, mice that fail to express hepcidin have elevated body iron stores, whereas mice with enhanced hepcidin expression have profound iron deficiency.




Length (m)



Area of apical plasma membrane (m2)









Crypts or glands






Nutrient absorption



Active Na+ absorption



Active K+ secretion