23b.1 Phos­phorus

Phos­phorus is the 11^th most abundant element yet phos­phorus is not present in nature as elemental phos­phorus, instead occurring mainly bound to oxygen as phos­phate (Ferro, 2018). Deposits of phos­phate-rich rock in the earth's crust slowly release phos­phate which builds up in soils over time, entering the food chain via soil microbes, and then crops, livestock, and other components of the human food supply. However, deposits of rocks rich in phos­phate are limited across the globe. When mined, these phos­phate deposits are largely used as fertilizers for crop growth (Ferro, 2018).

Phos­phorus is often the key growth-limiting factor for all living things. As an essential nutrient, phos­phorus functions in critical pathways and cellular components in all life forms on earth, ranging from subcellular viruses to complex plants and animals, all dependent on phos­phate for energy, growth, reproduction, structure, and homeo­stasis facilitated through signal transduction. Phos­phates participate in all biological processes providing energy stored in phos­phodiester bonds of ATP (the phos­phodiester backbone of RNA and DNA). Other functional roles include the structural integrity of cell membranes as phos­pholipids, regulation of acid base balance, mineral­ization of teeth and bones, lipid transport in blood, and signalling pathways essential to main­taining phos­phate homeo­stasis. As phos­phate has such a critical role in so many biological processes, phos­phate homeo­stasis must be tightly regulated. In conditions when sources of phos­phate are deficient, growth or reproduction is limited, whereas with excess, toxicity may occur, which in humans may manifest as disease (Hernando et al., 2021).

23b.2 Biological forms of phos­phate and their measurement

The three forms of phos­phorus bound to oxygen that occur in nature are shown in Figure23b.1:

an ionic anion, an inorganic salt, and as an organic compound, using phytate as the example. Inorganic or mineral phos­phate largely comprises the different salts of ortho­phos­phate that occur in greater abundance than pyrophos­phate. Within the pH range of the human body, the two main forms of ortho­phos­phates are H₂PO₄^-1 and HPO₄². The organic form of phos­phate occur when bound to a carbon atom of protein, lipids, nucleic acids, and other organic compounds, usually through phos­phate ester linkages. The total body phos­phate content in an adult human is about 900g of elemental phos­phorus, existing mainly in the skeleton and teeth, with less amounts in soft tissues.

The phos­phate in bone and teeth is present as calcium phos­phate hydroxy­apatite (Ca₁₀(PO₄)₆(OH)₂). Less than 1% of phos­phorus occurs in the extra­cellular space. Intra­cellular phos­phate consists largely of organic molecules such as creatine phos­phate, ATP, nucleic acids, phos­pholipids and phos­pho­proteins in concen­trations of phos­phate of about 1mmol/L.

When assayed in biological fluids and tissues, only inorganic phosphate is measured. Prior to analysis, the analytical samples other than serum must be ashed to remove the organic material, after which the residue is dissolved in dilute acid in preparation for analysis by AOAC, AAS or ICP-MS, which report total phosphorus as elemental P. In food composition databases and tables, the values are expressed as mg elemental P per serving or per 100g food item.

Clinically, the terms phos­phate and phos­phorus are used interchangeably. However, because elemental phos­phorus does not occur in the human body, phos­phorus is usually measured as mg phos­phate and can be converted to molar P concent­ration by dividing the measured weight in mg by the atomic weight of P (31).

23b.3 Interpretive criterion: serum phos­phate

Serum phos­phate is the most frequently used bio­marker of phos­phorus status in a clinical setting, and is usually measured in the fasting state. However, the measure­ment of a single fasting serum phos­phate concen­tration represents only a small portion of the total body phos­phate, and hence does not always reflect the body phos­phate stores. Measure­ment of serum or plasma phos­phate concen­tration requires the use of anti­coagulants such as heparin which do not interfere with the color reaction described for the AOAC spectro­photo­metric method described in 23b.2. Hemolyzed samples are not suitable for phos­phate measure­ment as erythro­cyte phos­phate confounds the measure­ment and hemo­globin contributes color inter­ference. Serum phos­phate concen­trations can also be affected tempor­arily by acute shifts of phos­phate between intra­cellular and extra­cellular compart­ments without affecting total body content (Uribarri & Oh, 2018).

Table 23b.1 Normal Inorganic Serum phos­phate Values for Children and Adults. For more information on disorders of serum phos­phate see (Koumakis et al., 2021).

Sample	Reference Ranges
	mg/dL	mmol/L
Cord	3.7 ‑ 8.1	1.2 ‑ 2.8
Child	4.5 ‑ 5.5	1.45 ‑ 1.78
Adult	2.7 ‑ 4.5	0.87 ‑ 1.45
Older Adult > 60y	M: 2.3 ‑ 3.7 F: 2.8 ‑ 4.1	M: 0.74 ‑ 1.2 F: 0.90 ‑ 1.3

Serum phos­phate concen­trations are main­tained within a narrow range (see Section 23b.5 for details of the hormonal regulation of serum phos­phate). In adults, total serum inorganic phos­phate ranges between 0.87-1.45mmol/L (Table 23b.1): 56% is ionized, 20% bound to protein and 24% bound to other cations. However, there is a signif­icant amount of organic phos­phate in serum (7.5‑8.0mg/dL or 2.4‑2.6mmol/L) which is not included in the analytical method used by clinical laboratories. When serum phos­phate concen­trations fall below the normal range, a condition called hypo­phos­phat­emia occurs, whereas for concen­trations above the normal range, hyper­phos­phat­emia develops; serious clinical con­sequences can arise from both conditions.

Several factors affect serum phos­phate concen­trations. Diurnal variation in serum phos­phate occurs with concen­trations lowest at 9AM and highest at 7PM. There is also a seasonal variation, whereby levels are higher during the summer than during the winter; this may arise because phos­phorus absorption is stimulated by the greater synthesis of vitamin‑D with higher summer sunlight exposure. Serum phos­phate is also higher in women than in men (by about 0.31mg/dL, 0.1mmol/L), and higher in children (i.e., normal range 1.45‑1.78mmol/L) than adults (i.e., normal range 0.87‑1.45mmol/L); see Table 23b.1.

Normal serum phos­phate values for children and adults are shown in Table 23b.1. Hypo­phos­phatemia is usually defined as serum phos­phate < 0.87mmol/L and hyperphos­phatemia as a serum phos­phate > 1.45mmol/L; see Section 23b.8 for more discussion of abnormalities in serum phos­phate (Koumakis et al., 2021).

23b.4 Phos­phate balance

Phos­phate balance is the result of the inter­action of intes­tinal absorption of dietary phos­phate, renal phos­phate excretion, and exchange of phos­phate between extra­cellular and bone and intra­cellular phos­phate pools (Figure 23b-2.). At present, the only easily available parameter to study total body phos­phate in a clinical setting is to measure the serum phos­phate concen­tration, usually in the fasting state. This measure­ment represents only a small portion of the total body phos­phate, as noted above, and can also be affected by shifts of phos­phate between intra­cellular and extra­cellular compart­ments (Uribarri & Oh, 2018).

The kidneys play a major role in phos­phate balance (Figure 23b.2) by adjusting urinary excretion (output) to match net gastro­intes­tinal absorption (input) of phos­phate to maintain zero balance in an adult or, to retain phos­phate to main­tain positive balance in a child for growth, or for a pregnancy. In healthy subjects, the kidneys reabsorb about 89% of the filtered load of phos­phate, with the rest being excreted in the urine. Plasma phos­phate filtered in the glomerulus is mainly reabsorbed in the proximal renal tubules (75%), with only 10% reabsorbed in the distal tubules, leaving about 10‑15% in the urine.

Gastro­intestinal (GI) phos­phate absorption in humans has tradition­ally been measured as the difference between dietary and fecal phos­phate content; this net phos­phate absorption is a linear function of dietary phos­phate intake (IOM, 1997). For a dietary phos­phate intake within the range of 4‑30mg/kg/day (280‑2100mg per day for an adult), net absorption is about 60‑65%. Shown in Figure23b.3 are the two main transport systems for intestinal phos­phate absorption: one is an active, sodium-dependent, satur­able and trans­cellular tran­sporter, and the other is a passive, sodium-indepen­dent, non-saturable and para­cellular trans­porter (Marks, 2019). The intestinal sodium-dependent transporter is regulated by vitamin D and parathyroid hormone (PTH) and is often referred to as “active” transport. In contrast, the paracellular phos­phorus absorption pathway lacks a tight regulation and depends on the phos­phate concent­ration gradient across the epi­thelium, the electrical gradient (lumen negative), and tight junction permeability (Calvo & Uribarri, 2021).

Most organic and inorganic phos­phate is absorbed in the small intestine after liberation by gut and intes­tinal enzymes. However, the dominant plant source of phos­phate, phytate (Figure 23b-1), is poorly absorbed in humans because of lack of the enzyme phytase. Many colonic bacteria produce phytases (myo-inositol hexa­kis­phos­phate phos­pho­hydro­lases) capable of sequent­ially hydro­lyzing phytate, releasing phos­phate. Liberated inorganic phos­phate then has the potential to be absorbed in the colon via para­cellular transport, although the overall importance of this remains uncertain. Increasing solidity of distal colon fecal contents could potentially make soluble phos­phate less access­ible for para­cellular absorption. Never­the­less, a recent review concluded that at least 50% of phos­phate present in phytate is recovered as phos­phate in 24‑hour urine collections based on results of a series of earlier human studies (Calvo & Uribarri, 2021).

23b.5. Hormonal regulation of serum phos­phate

Serum phos­phate concent­ration must be main­tained within a very narrow range to avoid adverse health con­sequences and risk of disease such as soft tissue calci­fication or cardio­vascular disease. Regulation of serum phos­phate involves the inter­play of four organs, phos­phate membrane trans­porters bound in these organs, and the actions of three endocrine hormones that influence the activity of the phos­phate trans­porters (Uribarri & Calvo, 2023). The four major organs involved in regulating serum phos­phate are the kidneys, bone, intestine, and para­thyroid glands. There are two families of sodium-phos­phate membrane trans­porters specific to these organs. They include the SLC34 group of NaPi‑2a, b, c, chiefly located in the kidney and intestine, and the SLC20 family (PiT‑1 and 2) largely found in bone, intestine, soft tissue, muscle, with some in the kidney (Forster et al., 2013). The activity of these two families of sodium-phos­phate membrane trans­porters is control­led by three endo­crine hormones: para­thyroid hormone (PTH), calcit­riol (1‑25,dihydroxy­chole­calciferol; (1‑25(OH)₂D), the active meta­bolite of vitamin D), and fibro­blast growth factor 23 (FGF‑23). The three phos­phate regu­lating hormones are endo­crine hormones meaning that they are secreted into the circu­lation by a specific organ, but act upon a distal organ.

As illustrated in Figure 23b.4, PTH is secreted by the para­thyroid glands when the rise in serum phos­phate triggers a decrease in serum ionized calcium or is sufficiently elevated to directly stimulate PTH secretion. Circu­lating PTH rapidly acts to decrease NaPi‑2a and NaPi‑2c co‑trans­porters in the renal proximal and distal tubules. A decrease in membrane co‑trans­porters acutely decreases phos­phate reabsorp­tion and increases phos­phate excretion in the urine. When normal serum phos­phate concent­ration is filtered in the glomerulus, about 75% of phos­phate is reabsorbed in the proximal tubule and 10% from the distal tubule with 10‑15% lost in urine, as noted earlier.

The action of PTH rapidly lowers serum phos­phate by increas­ing urinary loss, and rapidly increases serum calcium and to a lesser degree phos­phate by stimulating bone resorption. PTH action more slowly restores serum calcium through up‑regu­lation of the renal cyto­chrome enzyme Cyp27b1 that catalyzes the activ­ation of 25‑hydroxy vitamin D to the active meta­bolite, calcitriol (1,25(OH)₂D) secreted by the kidney into the circu­lation. In turn, the circu­lating hormonal form of vitamin D, calcitriol, acts on the small intestine to increase active calcium transport, thus PTH rapidly corrects serum phos­phate and calcium concent­rations that stray from the normal range (Uribarri & Calvo, 2023).

When excessive intake of phos­phate is sustained over time, or kidney function fails resulting in hyperphos­phatemia, hormonal control of serum phos­phate is reliant on regu­lating intestinal phos­phate absorp­tion and renal tubular phos­phate reabsorp­tion and may require the action of the bone secreted hormone FGF‑23 (Raush & Foeller, 2022). In response to hyper­phos­phatemia, FGF‑23 is secreted by osteo­cytes in bone and similar to PTH, FGF‑23 acts to suppress co-trans­porter action (proximal tubule NaPi‑2a and NaPi‑2c), decreasing renal reabsorp­tion and increasing urinary phos­phate excre­tion but acts to supress PTH secre­tion (not shown) . In contrast to the action of PTH, FGF‑23 inhibits 1,25‑dihydroxy vitamin D renal synthesis and intestinal phos­phate absorption by down­regu­lating renal cytochrome P450 (Cyp27b1) expression (the key enzyme for calcitriol produc­tion), and enhanc­ing renal Cyp24a1 produc­tion, thus catalyzing the inactivation of 1,25‑dihydroxy vitamin D.

FGF-23 action may be depend­ent or independ­ent of Klotho, a beta‑glu­curoni­dase enzyme that occurs as both a trans­membrane protein and a sec­reted renal protein, and which can function as a co‑receptor to FGF‑23 (not shown in Figure 23b.4). Although many of Klotho's functions remain unclear, it has a proven role in phos­phate regulation (Kuro-O, 2019). FGF‑23 clearly suppresses cal­citriol synthesis and, with time, PTH secretion; however, initially in response to high serum phos­phate, PTH is believed to stimulate FGF‑23 secretion from osteocytes (Raush & Foeller, 2022). Not shown in the simplified diagram of hormonal control of serum phos­phate (Figure 23b.4), calcitriol upregulates Na-Pi co-trans­porters (an action opposite to that of FGF‑23) in both the intes­tine and proximal renal tubules which leads to both increased intes­tinal absorption of phos­phate and increased renal phos­phate reabsorp­tion. Calcitriol suppresses PTH secretion and has a negative feedback action on renal 1‑alpha hydroxy­lase (Cyp27b1), thereby reducing its own produc­tion. With lower calcitriol concent­rations, 24‑hydrolxy­lase is upreg­ulated, increasing the production of 24,25‑dihy­droxy vitamin D effectively inactiv­ating calcitriol hormonal action.

23b.6 Nutrient reference values

In 1997, the Institute of Medicine (U.S. and Canada) determined adult age specific Estimated Average Requirement (EAR) values for phos­phorus derived from studies using serum phos­phorus as a biomarker (IOM, 1997). For adults 19‑50 years, the EAR was based on the relation­ship between serum phos­phate and absorbed intake determined from earlier published data. This relation­ship was then used to translate absorbed intake to the amount of ingested phos­phorus based on an assumed efficiency of absorption of 62.5% from a mixed diet not high in phytate (Calvo & Whiting, 2018). An intake of phos­phorus of 580mg/d meets the needs of 50% of the adult population (≥ 19y) and therefore was set as the EAR and served as the basis for determining the Recommended Daily Allowance (RDA) for phos­phate that covers the phos­phorus needs of 97% of the adult population. For children, the biomarker used to set the EAR for dietary phos­phorus intake was based on published factorial estimates of accretion of phos­phate into bone; see IOM (1997) for more details. For infants, the AI was set to reflect the observed mean intakes of infants fed principally with human milk (IOM, 1997).

The EAR and RDA values for phos­phorus for infants, children and adults by age and sex, and for the physiologic states of pregnancy and lactation recommended in 1997, are shown in Table 23b.2.

Table 23b.2 US and Canadian phos­phorus Dietary Reference Intakes (mg P/day). Estimated Average Requirement (EAR), Recommended Dietary Allowance (RDA, or Adequate Intake equivalent) and Upper Level (UL) for phos­phorus * Applies to pregnant and lactating women. Source: (IOM, 1997).

Age/sex groups	EAR	RDA	UL
0‑6 mo	--	100 (AI)	-
6‑12 mo	--	275 (AI)	-
1‑3y F & M	380	460	3000
4‑8y F & M	405	500	3000
9‑18y F & M	1055	1250	4000
19‑50y F* & M	580	700	4000
51‑70y F & M	580	700	4000
71+ F & M	580	700	3000

A tolerable upper intake level (UL) for phos­phate was also set in 1997 as part of the Dietary Reference Intakes (DRIs). The UL is considered to be a safe intake level, but as intake increases above the UL, risk for adverse events increases (IOM, 1997). The UL for adults is set at 4000mg/d. Research­ers now question the method used by the IOM panel that set a value nearly six times higher than the RDA for phos­phorus, suggesting a need to revisit the UL (Whiting & Calvo, 2018). The increased use of phos­phate-contain­ing food additives in processing led the European Food Safety Authority (EFSA) to reassess the safety of phos­phate additives and cumu­lative phos­phate intakes. The 2019 EFSA review resulted in a revision of the “group acceptable daily intake” (ADI) of 4.2g phos­phate per day to the lower value of 2.8g phos­phate per day for an average 70kg adult (EFSA, 2019).

Current mean dietary phos­phate intakes of Americans are 2‑3-fold higher than the RDA for all age groups > 1y (with the single exception of rapidly growing adolescents), but do not exceed the current UL. None­the­less, excess phos­phate intake is assoc­iated with growing evidence of poten­tial non­com­munic­able disease risk. This is of concern especially when consid­ering the high intakes of bio­avail­able phos­phate that may occur from the consumption of ultra-pro­cessed foods. Con­sequently, con­sider­ation should be given to revising the 1997 DRI’s (notably the UL) (Uribarri & Calvo, 2023).

23b.7 Dietary sources

Dietary sources of phos­phate include both organic and inor­ganic phos­phate. Phos­phate is present in most food sources and is usually highest in animal protein compared to plant protein sources. Import­antly, the bio­avail­ability of phos­phorus differs between protein derived from animal sources compared to plant derived protein. In addition to con­tain­ing protein, plants store phos­phate as phytate (Figure 23b.1). Phos­phate is stored as phytate in unrefined cereals, oil seeds, and legumes that requires enzym­atic or physical action to release phos­phate bound to phytate. Bioavailability of phytate-phos­phorus is low unless foods are processed using home-based methods such as soaking, germin­ation, or ferment­ation, or com­mercial methods such as canning and extrusion (Tefarra, 2021), all of which having the potential to improve phos­phate avail­ability from phytate. While these methods of proces­sing improve phos­phate avail­ability from phytate, commercial processing leading to proces­sed and ultra-processed foods may involve the addition of phos­phate-containing additives that provide highly available sources of phos­phate, such as sodium phos­phate salts shown in Figure 23b-1 (Calvo & Uribarri, 2021).

Examples of animal, plant, and additive sources of phos­phate are shown in Table 23b.3, with the foods clas­sified according to the NOVA system (Monteiro et al., 2017), which reflects their degree of processing. The NOVA system classifies foods into four groups, with the fourth group called “ultra-processed”. A recent cross-sect­ional study of the United States food supply found that 71% of packaged foods and beverages were ultra-proces­sed and 60% of energy intake came from ultra-proces­sed foods, an increase over past decades (Baldridge et al., 2019).

High ultra-processed food consumption patterns are associated with increased risk of cardio­vascular disease and mortality (Juul et al., 2021), chronic kidney disease (Cai et al., 2022), and various other serious chronic diseases. Specifically, ultra-proces­sed foods such as cured meats containing added inorganic phos­phates are associated with carotid intimal thick­ening (Itkonen et al., 2014), decreased renal function (Duong et al., 2022), and low HDL cholesterol (Fulgoni et al., 2022). Causality between phos­phate additive use in ultra-proces­sed foods and increased risk of chronic disease or mortality remains to be established. However, there is growing aware­ness that the use of phos­phate additives in food processing increases the total phos­phate availability and content of foods.

Table 23b.3 Characteristics and sources of phos­phate (organic (OPi), inorganic (IPi) or phytate) in foods classified according to degree of commercial processing. * Indicates presence of > 1 IPi additive by many top selling packaged foods. ** Indicates frequent use > 1 IPi additive + processed protein isolates or concentrate. No determination (ND) made for Group 2. Source: Modified from (Uribarri & Calvo, 2023), using the NOVA system of Monteiro et al. (2017).

NOVA Food Classification Definitions	Representative Foods (Prepared phos­phate Content:mg P/100 g)	Main Forms of phos­phate
Group 1. Minimally Processed,       Unprocessed Foods: Natural plant and animal foods and water processed by drying, crushing, grinding, fracturing, filtering, roasting, boiling non- alcoholic fermentation, past- eurizing, refrigeration, chilling, freezing, placing in container and vacuum packaged for storage	Cooked oatmeal (99) Boiled lentils (180) Boiled black beans (140) Soy flour (674) Corn flakes breakfast- cereal (58)	OPi from Plant-derived protein and phytate
	Baked chicken breasts (228) Baked tuna fillet (326) 2% Milk (92) Broiled beef steak (189) Boiled egg (126)	OPi from Animal- derived protein
Group 2. Processed Culinary       Ingredients Includes oils, butter, sugar, and salt that allows for preparing unprocessed foods at home	Soy oil (0) Butter (24) Sugar (0) Salt (0)	ND
Group 3. Processed Foods: Foods processed by various preservation or cooking methods or fermentation such as bread that usually contains 2 to 3 ingredients.	Grilled Chicken Patty,      from frozen (208) Cheddar Cheese (473) Canned Tuna* (311) Canned Green Beans* (19)	OPi from animal protein, plant protein, and phytate with use* of Pi additives
Group 4. Ultra-processed      Foods: Foods industrially formulated from substances derived from foods, additives, and ultra- processed products not usually used in home cooking such as hydrogenated oils, hydrolyzed proteins, added sugars and salt	Fried chicken nuggets*(213) Fried Sausages** (174) Battered fish sticks*(171) Baked frozen pizza* (215) Processed Cheese* (982) Cheerios breakfast- cereal** (448) Pancakes from Mix* (334) Shop white bread** (109)	OPi from Animal Protein with added **IPi and OPi from additives and isolates OPi from processed Plant protein having lower phytate but higher **IPi and OPi from additives and isolates

As can be seen in Table 23b.3, it is difficult to describe dietary sources of phos­phate as high or low without information on the source and form of phos­phate, and their relative bio­avail­ability. In general, both plant and animal protein sources are good sources as noted earlier. In addition, the phytate-phos­phorus present mainly in unre­fined cereals, oil seeds, and legumes may become bio­avail­able, if during proces­sing phytate has been hydro­lyzed, and phos­phate bound to phytate released prior to absorp­tion. Under the Nova classification, raw and minimally processed phytate rich plant foods have lower phos­phorus bioavailability than compar­ably proces­sed animal protein sources (Calvo & Uribarri, 2021).

In minimally processed and unprocessed foods (Group 1, figure 23b.3), the estimated percent phosphate absorption varies from less than 40% to 70% being generally lower in plant foods and higher in animal foods. There is very little data on the estimated phosphate absorption from processed culinary ingredients, but processed foods (Group 3, figure 23b.3) consumed as part of a mixed diet, can have an estimated percent phosphate absorption of greater than 60%. The absorptionn in ultra-processed (Group 4, figure 23b.3), animal foods may range from 90-100% but is lower in ultra-processed plant foods.

The presence of phos­phate additives in minimally and ultra­proces­sed foods (shown in Table 23b.3 by *) may or may not show differences in total phos­phate content compared to unpro­cessed foods if the content estimates are based on national nutrient content database inform­ation (Calvo, et al., 2014). There is a lack of accounting for the phos­phorus contrib­ution by phos­phate additives in most foods in the nutrient content data­bases resulting in a widely recog­nized under­estim­ation of phos­phorus intake (Calvo, et al., 2019). Regret­tably, many inves­tigators have only recently discovered the need to directly analyze the phos­phate content of the foods fed in studies to accurately design clinical trials examining dietary phos­phate meta­bolism (Stremke et al., 2018).

The phos­phorus content of packaged foods in the US and Canada does not require phos­phorus content to be listed on the label; however, if phos­phate additives were added, then their use must be identified but not quant­ified in the label ingred­ients list (Calvo et al., 2019). The US Food and Drug Administration (FDA) requires that all ingred­ients (additives) added to food during processing must have prior approval for use in one of the 32 specific technical functions recognized by the FDA. Phos­phate-con­tain­ing addit­ives and processed protein ingred­ients (isolates and hydroly­sates) are approved for at least 26 of these technical func­tions. Processed foods often contain one or more phos­phate additives (Sullivan et al., 2007), because the more frequ­ently used additives are approved for more than one tech­nical function. For example, of the more than 60 frequ­ently used phos­phate addi­tives more than 30 are approved for use as a nutrient supplement, 24 for use as a stabil­izer or thick­ener, 20 as emuls­ifiers and emuls­ifier salts and 18 as pH control agents. Under­standing the role of dietary phos­phate intake in chronic disease risk requires better under­standing of the role of phos­phate additives in food proces­sing as phos­phate additives can be added to foods for multiple functions, each contributing to higher phos­phate content which is not always captured by the basic tools used by nutrit­ional scien­tists to determine total phos­phate intake. A simple solution to this inaccuracy in the nutrient content data­bases is to require phos­phorus content on the Nutrient Facts Label (Calvo et al., 2019).

23b.8 Abnormalities in serum phos­phate

Phos­phate balance, a proxy for assessing phos­phate nutritional status, is best assessed by measur­ing fasting serum phos­phate concent­rations. Nevertheless, single fasting serum phos­phate measures do not always reflect the body phos­phate stores because acute shifts of phos­phate between body compart­ments may tempor­arily affect serum phos­phate without affecting total body phos­phorus content.

Table 23b.4 Mechanisms Causing Hypophos­phatemia Data source: Koumakis et al., (2021).

Paths to Acute Acquired Hypo- phos­phatemia	Causative Mechanism
Acute Shift in Extra- cellular to Intra- cellular Distribution	Refeeding syndrome Metabolic acidosis Glucose infusion and other carbohydrates Acute respiratory alkalosis Alcohol withdrawal Serious burns, surgical trauma Hyperthermia Hormonal or other agents : (insulin, glucagon,     cortisol, catecholamines, fructose) Rapid cell proliferation or uptake     (hungry bone syndrome, cancer)
Decreased Dietary Intake	Severe dietary restriction and     malnutrition (renal failure) Anorexia Kwashiorkor (severe protein /     calorie malnutrition)
Decreased Intestinal Absorption	Vitamin D deficiency Antacid overuse Phos­phate binder use Gastrointestinal malabsorption
Increased Renal Excretion	Primary hyperparathyroidism Secondary hyperparathyroidism (dietary     phos­phate excess and low calcium     intake or vitamin D deficiency) Metabolic acidosis (volume expansion, Fanconi     syndrome, tumor production of PTH-related     peptide, neurofibromatosis; acute falciparum     malaria, and various medications including     bisphos­phonates such as etidronate,     pamidronate, zoledronic acid for post-     menopausal osteoporosis)

Clinically, patients may present with either hypo­phos­phat­emia (serum phos­phate < 0.87mmol/L), or hyperphos­phatemia (serum phos­phate > 1.45mmol/L), with each one of these two condit­ions char­acter­ized by dif­ferent manifest­ations and causes that cannot always be attributed to issues with intakes of dietary phos­phate. The differ­ences in clinical manifest­ations and causes for hypo­phos­phatemia and hyper­phos­phatemia are summarized in Tables 23b.4 and 23b.5 (Koumakis et al., 2021).

Clinical manifestations of hypo­phos­phat­emia include muscle weakness, cardio­my­opathy, respir­atory insuf­ficiency, osteo­malacia, rickets, blood disorders, nervous system dysfunc­tion, hyper­cal­ciuria and impaired insulin secretion. Acute hyper­phos­phatemia is associated with hypo­calcemia, meta­static cal­cific­ation, the gradual progres­sion of renal failure, and secondary hyper­para­thyroid­ism (Uribarri & Calvo, 2023).

Trans­cellular phos­phate shifts such as those occurring with acute alkalosis can produce significant hypophos­phatemia by the intra­cellular shift of phos­phate, even though the total body phos­phate content is unaffected. These shifts are usually transient in nature; however, when hyper­phos­phatemia or hypo­phos­phatemia are chronic, there is usually a correlation between serum phos­phate levels and total body phos­phate. Moreover, there is a signif­icant circadian variation in serum phos­phate con­cent­ration, as well as gender and age differences in serum phos­phate unrelated to phos­phate intake effect on balance. Given these problems with signif­icant variation in serum concent­ration, the European Food Safety Authority (EFSA, 2015). as well as other countries did not consider serum phos­phate concent­ration to be an appro­priate biomarker for establishing dietary phos­phate require­ments or nutritional status.

Table 23b.5 Causes of Hyperphos­phatemia. Data source: Koumakis et al. (2021)

Duration of Hyperphos­phatemia	Mechanism Associated with Hyperphos­phatemia
Acute Hyperphos­phatemia	Acute kidney injury Increased intestinal absorption     of excess dietary load phos­phate-containing enemas Transcellular shifts from intra‑ to     extracellular (hemolysis, rhab-     domyolysis, acidosis, tumorlysis) Hyperthermia Heat stroke
Chronic Hyperphos­phatemia	Chronic kidney disease Hypoparathyroidism Pseudohypoparathyroidism Vitamin D intoxication Disorders of magnesium     regulation (PTH regulation) Acromegaly

In contrast, the Institute of Medicine of North America adopted the measurement of serum inorganic phos­phate as an acceptable and easy to monitor indictor for determining phos­phate requirements for adults in the U.S. and Canada (IOM, 1997).

23b.9. Disease risk linked to excess dietary phos­phate

High intakes of phos­phate that exceed the dietary requirements or upper tolerable level, often in the absence of hyper­phos­phat­emia, have been associated with risk of diseases such as cardio­vas­cular disease, and higher mortality in the general population (Uribarri & Calvo, 2013; Chang et al., 2014). An imbalance in the ratio of dietary calcium to phos­phate intake arising from a low calcium intake in the presence of diets containing phos­phate-con­tain­ing additives in ultra-proces­sed foods, has been assoc­iated with elevated concent­rations of para­thy­roid hormone (secondary hyper­para­thyroid­ism) (Kemi et al., 2009). Sustained secondary hyper­para­thyroid­ism can adversely impact bone formation, increasing the risk of bone fragility in advanced age. High phos­phate diets also impair kidney function over time and have been shown to increase the progression to end-stage renal disease (i.e., complete kidney failure) (Zoccali et al., 2011). More recently, risk of cancer, notably pros­tate cancer in men, was found to be assoc­iated with high dietary phos­phate (Lv et al., 2022), while studies in rodent models have reported strong evidence for risk of other types of cancer (Arnst & Beck, 2021).

A less studied disease risk of excess phos­phate intakes in the general population that has been associated with hyper­phos­phatemia (serum phos­phate ≥ 1.0, 42mmol/L) is anemia, as defined by low hemo­globin con­cent­rations. This finding was first revealed in U.S NHANES 2005‑2010 surveys, and later linked to inflam­mation (Wojcicki, 2013; Czaya et al., 2022). Other disease or health risks linked to high phos­phate diets include acceler­ated aging (Kuro-O, 2021) and kidney stones (Khan et al., 2018). All these adverse health risks assoc­iated with excessive phos­phate intakes high­light the urgent need for further research exploring how current dietary phos­phate intakes may impact health and longevity.

23b.10 Inherited and tumor-induced disorders of phos­phate metabolism

Genetic-related disorders of phos­phate meta­bolism , notably chronic hypo­phos­phatemia, are very rare in most populations, Moreover, they are unrelated to dietary phos­phate intakes, unlike the disorders associated with excessive phos­phate intakes. These genetic phos­phate disorders include X‑Linked Hypo­phos­phatemic Rickets (XLH); Auto­somal-dom­inant Hypo­phos­phatemic Rickets (ADHR); Auto­somal Reces­sive Hypo­phos­phatemic Rickets (ARHR), and Hereditary Hypo­phos­phatemic Rickets with Hyper­calciuria (HHRH). They are inherited diseases or result from missense muta­tions which all impact FGF‑23 metabolism, by either increasing circu­lating levels of the hormone or its activity, which ultimately lead to hypo­phos­phatemia arising from phos­phate wasting (i.e., excessive urinary phos­phate excretion in relation to serum phos­phate level). Sustained hypo­phos­phatemia can mani­fest as rickets in children and osteo­malacia in adults but can be treated with oral phos­phate sup­plement­ation, and more recently with biologics that block FGF‑23 renal hormone action (Athonvarangkul & Insogna, 2021).

Tumor-induced osteo­malacia (also known as oncogenic osteo­malacia) is also a disorder of phos­phate wasting, but it is not inherited, instead stemming from excessive levels of FGF‑23 secreted by tumors. Such excessive levels of FGF‑23 again promote renal phos­phate wasting resulting in under-mineral­ized bone (osteo­malacia), bone pain, fractures, and muscle weakness in adults (Brandi et al., 2021).

Acknowledgments

RSG is grateful to Michael Jory for the HTML design and his tireless work in directing the translation to this HTML version.