Phosphorus2-3, diphosphoglycerate

Mineral Metabolism NUTR 626

Caraline Tompkins & Chantal Otelsberg

Learning Objectives Describe and explain homeostasis, digestion,

utilization/metabolic function, storage, and excretion of phosphorus

To understand likelihood, symptoms, and diseases related to phosphorus deficiency, along with the potential of toxicity

Describe and explain biochemical tests/assessment of status, DRI/RDA/AI of phosphorus

To understand acquired disorders of phosphorus metabolism To answer and describe Critical Thinking Question

Key Facts Integral role in mineralized tissues

Integral component of the body’s energy source -> ATP contains high-energy phosphate bonds, as do creatine phosphate

Impact of parathyroid hormone (PTH) and vitamin D on phosphorus metabolism and urinary phosphorus excretion

Phosphorus flux Hormonal regulation of phosphorus metabolism

Several inherited disorders of phosphorus metabolism Led to new therapies for individuals and dysregulated

mineral metabolism

Key Facts continued… Plays a vital role in the dissociation of oxygen

from hemoglobin Essential for pH regulation in human body P is part of phospholipids, is present in every cell

membrane in the body Intracellular signaling processes depend on

phosphorus-containing compounds i.e. cAMP, cGMP, and inositol triphosphate/IP3

Historical Anecdotes Phosphorus was discovered in 1669 by Hennig

Brand Brand called P “cold fire”

He isolated the mineral from urine. The name comes from the Greek words “phos”

and “phoros” meaning “light” and “bearer” because the glowing pigment when it is exposed to oxygen

Homeostasis Three key hormones regulate phosphorus

homeostasis 1,25-dihydroxyvitamin D (calcitriol), which is

produced in the kidney and increases active transport absorption.

Parathyroid Hormone (PTH). A secretion of PTH stimulates calcitroil production, which increases phosphorus absorption. PTH also lowers the renal phosphate threshold, which

is the determination of serum phosphate levels tested in urine.

PTH limits renal proximal tubule reabsorption and increases calcium renal proximal tubule reabsorption. Responsible for quick regulation.

Homeostasis cont. Fibroblast Growth Factor (FGF23) is produced

by specialized bone cells within the skeleton. It regulates the phosphorus available for mineralization in newly formed bone matrix. FGF23 also suppresses the reabsorption of

phosphorus in the renal proximal tubule and reduces the renal phosphate threshold. Responsible for long term regulation.

These all work together to ensure serum phosphate levels and whole body stores remain within a normal range.

Digestion Phosphorus in most food is in the form of readily

hydrolyzable organic phosphate esters. Once consumed, phosphorus reaches the intestine in

the form of organic phosphorus complexes which are made up of carbohydrates, lipids, and proteins.

Within the lumen, phosphatases help to digest and hydrolyze the organic forms into inorganic forms.

Organically bound phosphorus must be digested enzymatically to release inorganic phosphate for absorption.

Digestion cont. Phytic acid (found in legumes and grains) is non-

digestible due to the lack of phytase production in the human intestine

Diets high in phytate- containing foods can lead to iron, zinc, and calcium malabsorption due to absorption being blocked by ingested phytate.

The principal factor influencing phosphorus bioavailability is co-ingested calcium, which binds phosphorus and prevents its absorption.

Absorption Infants and children have the highest phosphorus

absorption ability at 65% to 90%. Adults absorb 50% to 70% of phosphorus consumed. The gastrointestinal tract absorbs 75 to 80% of the

ingested phosphate. The major site of absorption is the jejunum, but

phosphorus is absorbed throughout the entire intestine.

Peak phosphorus absorption occurs 1 hour after eating.

Absorption cont. Most absorbed phosphorus is in the form of

inorganic phosphate. Absorption is considered to be a combination of

active transport (regulated component) and passive diffusion.

Those who meet the requirements for protein and calcium will automatically meet the phosphorus requirements.

Low birth weight infants can be deficient in phosphorus .

Methods of Absorption Absorption occurs by two process

1. Saturable, carrier-mediated active transport 2. Passive diffusion

Since the majority of absorbed phosphorus is inorganic, passive diffusion is the primary absorption process and is load dependent

This is possible due to the acidic pH of the duodenum It is thought that the intercellular junction of the small

intestine exhibits low permeability to phosphate ions, which minimizes paracellular diffusion

Methods of Absorption cont. Active transport absorption method is used when phosphorus

intake is low. This method involves a sodium-phosphate co-transporter, which

carries two sodium's for each phosphate. Calcitriol and low-phosphorus diets are known to increase the

number of co-transporters in the intestinal brush border membrane.

Calcitriol stimulates carrier-mediated absorption in the duodenum and jejunum.

As calcium absorption rises in response to vitamin D, less calcium is left behind to bind with unabsorbed phosphorus, so phosphorus absorption would rise under high vitamin D status.

Factors Influencing Absorption

Factors influencing phosphorus absorption: Vitamin D enhances absorption by increasing carrier-

mediated absorption (calcitriol) Phytic acid inhibits absorption (found in legumes and

grains) due to the lack of phytase in the intestine. Excessive intake of magnesium, aluminum, and calcium

also inhibit absorption. Magnesium and phosphorus complex together and render

each other unavailable for absorption. Aluminum hydroxide, calcium acetate and calcium

carbonate block absorption of phosphorus when given with a meal. Especially helpful in people with high blood phosphorus concentrations.

Transport Phosphorus is quickly absorbed from the intestine and into the

blood. Appears in the blood about an hour after ingestion. Transport happens across the enterocytes basolateral membrane

by facilitated diffusion. Phosphorus is found in both organic (70%) and inorganic (30%)

forms in the bloodstream. A small amount of inorganic phosphate is found complexed with

calcium, magnesium, or sodium as salts in blood. Uptake of phosphorus into the cell occurs passively, driven by the

chemical gradient. 3 mg/kg/day of phosphorus is secreted into the intestine as a

component of digestive pancreatic and intestinal enzymes.

Digestion/Absorption/Transfer of PO4

Metabolism Phosphorus is a trace element (micronutrient) in the

biosphere.

The regulatory apparatus is optimized to deal with environmental scarcity.

As the generation and growth of new organisms and tissues increases, so does the requirement of phosphorus.

Phosphorus is easily metabolized and only becomes an issue when Renal disease is present.

Mutations of the FGF23 gene affects phosphorus absorption and metabolism.

As renal function declines, the kidneys can no longer handle large phosphorus loads which leads to hyperphosphatemia, which eventually impairs intestinal calcium absorption.

Utilization Phosphorus is found in all cells in the body. Forms the backbone of DNA and RNA. Is an essential component of phospholipids

that form all membrane bilayers. Is a key component of ATP and creatine

production . Plays a role in bone mineralization and

resorption during bone remodeling.

Utilization cont. Plays a vital role in the dissociation of oxygen

from hemoglobin and oxygen delivery. Many intracellular signaling process depend on

phosphorus containing compounds. Also part of cAMP and cGMP, which are second

messengers that activate certain protein kinases. Inorganic phosphate helps buffer pH changes in

the extracellular fluid, and is involved in the storage of intracellular energy (glycogen synthesis).

Excretion The major route of excretion is by the kidneys. The

kidneys filter phosphorus, which is then reabsorbed by the renal proximal tubules (about 95%).

What is not reabsorbed by the tubules, is excreted in the urine.

20-25% of consumed phosphorus is excreted in the feces

Phosphate excretion in urine is inhibited by phosphorus deficiency, calcitriol, alkalosis, estrogen, and thyroid and growth hormones.

Excretion cont. The kidney plays the predominant role in the

regulation of systemic phosphorus economy. When the body is in phosphorus homeostasis, the

amount excreted in the urine is roughly equal to the amount absorbed in the GI tract.

When phosphorus status is compromised, renal reclamation of phosphorus increases dramatically to maximize phosphorus retention.

Dietary SourcesMeat Poultry FishEggs Milk Milk Products 60%Nuts LegumesCereal Grains 20%

Food Additives - inorganic PO4 salts(sodium phosphate, sodium aluminum phosphate, monocalcium phosphate, etc. 10% of intake) not required to be listed on nutritional label due to nonnutritive functions

P bound to AA serine, threonine, tyrosine Research suggests typical diet ingestion (1ooo- 1500 mg/d) Phosphorus Intake:

• ~8% increase between 1977-1985 in food supply and disappearance data

• ~13% between 1980-1994• ~10% to 15% estimated increase in last decade

Phosphorus: RDA/RDI/UL

Upper Limit Infants (1 yr+)

not established due to inefficient data available after 1997 for non-exclusively breastfed babies in U.S.

Children (1-8 y) 3 g/dayMales (9-70 y) 4 g/day

Females (9-70 y) 4 g/dayMales ( >70 y) 3 g/dayFemales ( >70 y) 3 g/dayPregnancy (14-50 y) 3.5 g/dayLactating (14-50 y) 4 g/day

Biochemical tests/assessment of status

Testing & Assessment Serum phosphate level

(determined by renal phosphate threshold – controlled by PTH & FGF23) Concentration slightly

higher than UL signifies biomarker of CVD

HPO4 and H2PO4- in a 4:1 ratio at 7.4 pH = measured in blood tests

Phosphorus balance

Whole body accretion New tissue growth

Less critical than assessment of other minerals/nutrients

High protein diets are high in organic phosphorus *phosphotase and phytic acid Urinary Phosphate Plasma Phosphorus

concentrations Phosphate content in

RBC

Deficiency (hypophosphatemia) Serum phosphate concentrations

lower than 0.5mmol/L Rarely occurs in typical diets

Due to likely starvation and chronic undernutrition

Clinical deficiency due to long-tern administered glucose and TPN

Deficiency due to non-dietary metabolic disorders

When deficient, cellular dysfuction occurs in all tissues Resulting in decreased synthesis

of ATP

Effects of deficiency Anorexia

Anemia Muscle: Muscle weakness or

muscle-fiber degeneration Skeleton: Rickets, Osteomalacia,

or Bone Pain Susceptibility to infection Renal loss of phosphate Ataxia (lack of muscle coordination) Confusion, Neural abnormalities Death

Hypophosphatemia

Potential Toxicity/Hyperphosphatemia

Humans fall at the low end of spectrum of phosphorus intake

• Plasma concentration at and above 2.2 mmol/L Mostly due to renal failure

(urinary phosphate excretion rises in proportion to dietary intake)

Related to vitamin D intoxication

Increase in intake in recent years due to cola beverages and food

Can cause adverse effects on skeleton, soft tissue calcification

Increased PTH release

Need more research on effective means of controlling hyperphosphatemia in patients with end-stage renal failure

Severe Hyperphosphatemia: metastastic calcification (kidneys and

coronary arteries) increased porosity of skeleton

[Cardiomyopathy & skeletal myopathy]

Severe leads to hypocalcemia, in itself, then leads to tetany and death

Chronic Hyperphosphatemia: Rickets in children Osteomalacia in adults

Genetic Disorder Tumoral Calcinosis

High levels of serum phosphate, elevated vit. D levels, and normal serum Ca concentrations

Calcification in joints results from high serum phosphate and normal calcium concentration (not inverse realtionship)

Increased renal tubular phosphate reabsortion and high vit. D levels

Circulating FGF23 levels are low

Groups at Risk of Deficiency

Infants Fed unfortified human

milk Fed long-term formula

diet

Vegetarians P in form of phytate

from greens Phytase enzyme missing

Alcoholics Decompensated liver

disease Malnutrition

Elderly Treated for diabetic

acidosis Excessive use of P-

binding antacids

Disorders of Phosphorus Metabolism

Starvation & Refeeding Syndrome P depletion occurs Glucose metabolism increases use of intracellular phosphate Rapid fall in P concentrations

Metabolic Bone Disease of Prematurity (preterm infants) Deficiency of P due to delayed or inadequate enternal feedings, parenternal

nutrition unfortified human milk, malabsorption, and medicine intake, etc. Causes impaired bone growth

Diabetic ketoacidosis treatment Insulin drives glucose and P into cells and cause rapid fall in extracellular

plasma phosphate X-Linked Hypophosphatemic Rickets

Loss of function of phosphate-regulating gene on X-chromosome Autosomal Dominant/Recessive Hypophosphatemic Rickets

Mutation causes loss-of-function of FGF23

Causes Hypophosphatemia

Interactions with other nutrients Absorption of phosphorus can be affected by magnesium,

aluminum, and calcium intake. Example: overuse of antacids that contain aluminum

hydroxide can cause phosphorus depletion particularly if the diet is limiting in phosphorus. The same can be said for calcium salts.

Synthetic polymers are used as binders of dietary phosphate.

These absorption inhibitors can be used for those who need a low phosphorus diet, like patients with kidney disease, to help prevent hyperphosphatemia.

Primary Research Article The relation between serum phosphorus levels and clinical outcomes after acute

myocardial infarction (2013) . Authors: Doron Aronson, Michael Kapeliovich, Haim Hammerman, Robert Dragu Funding: No funding or support reported.

Background: Elevated serum phosphorus levels have been linked with cardiovascular disease and mortality, especially in the presence of normal renal function.

Methods: Association between serum phosphorus levels and clinical outcomes in 1663 patients with acute myocardial infarction. Patients were categorized into 4 groups based on serum phosphorus levels.

Results: Mean patient follow up was 45 months. Lowest mortality was found in patents with serum phosphorus between 2.5-3.5 mg/dL. Higher phosphorus level were associated with increased risk of heart failure, but not the risk of myocardial infarction or stroke. The effect of elevated phosphorus levels was more pronounced in those with chronic kidney disease.

Conclusion: A graded, independent association between serum phosphorus and all-cause mortality and hear failure in patients after acute myocardial infarction was found. The risk for mortality appears to increase with serum phosphorus levels within the normal range and is more prominent in the presence of CKD.

Primary Research Article Title: Low calcium:phosphorus ratio in habitual diets affects serum parathyroid hormone

concentration and calcium metabolism in healthy women with adequate calcium intake Authors: Virpi E. Kemi, Merja U.M. Karkkainen, Hannu J. Rita, Marika M.L. Laaksonen, Terhi A. Outila and

Christel J.E. Lamberg-Allardt Funding: The Academy of Finland, the Ministry of Education, the Finnish Graduate School of Applied

Bioscience and the Juho Vainio Foundation Authors has no financial or personal interests in organizations that sponsored study

Background: Excessive dietary P intake alone can be damaging to bone by means of increased PTH secretion, but adverse effects on bone increase when Ca intake is low. In most countries, P dietary intake is abundant, whereas Ca intake fails meeting RDAs. Therefore, optimal Ca: P ratio is hard to achieve.

Methods & Objectives: To investigate how habitual dietary Ca:P ration affects serum PTH (S-PTH) concentration and other Ca metabolism markers in a population with generally adequate Ca intake. Cross-sectional analysis of 147 healthy females aged 31-43 years, fasting blood samples and three separate 24-h urinary samples were collected. Participants kept a 4-d food diary and were divided into quartiles according to dietary Ca:P ratios.

Results: A total of 44% of participants had a dietary Ca intake below RDA values. Mean intake was 647 mg/d. The average habitual dietary Ca:P ratio of the participants corresponded with the ratio in Finnish females in 2007 study (similar to NHANES). Ca intake was adequate or high in participants, reflecting a high dairy intake. None of the participants achieved the suggested dietary Ca:P ratio of 1, which contributes to severe adverse affects on mineral metabolism and bone health. This was due to excessive P content in their habitual diets, rather than low dietary Ca intake, as mean P intake exceeded 2:4-fold and mean dietary Ca intake 1:3-fold the Nordic Nutritional recommendations for P and Ca (600 mg/d and 800 mg/d).

Conclusions: In habitual diets, low Ca:P ratio may interfere with homeostasis of Ca metabolism and increase bone resorption, as indicated in higher S-PTH and U-Ca levels. Habitually low dietary Ca:P rations are common in Western diets, more attention should be focused on decreasing excessively high dietary P intake and increasing Ca intake to the recommended level.

Critical Thinking QuestionWhile a primary deficiency of phosphorus is not known to occur in man, hypophosphatemia is associated with certain clinical disorders/conditions. Discuss some of the conditions associated with hypophosphatemia and the effects of depleted phosphorus.

Some of the conditions associated with hypophosphatemia are renal disease, refeeding syndrome, and Dent’s syndrome. A deficiency usually results in anorexia, leukocyte dysfunction, reduced cardiac output, decreased diaphragmatic contractility, arrhythmias, skeletal muscle and cardiac myopathy, weakness, and neurological problems (Ataxia and paresthesia), and possible death.

Conclusion: Food for thought Phosphorus is…

Necessary for all cell function

Energy source for ATP production

Abundant in foods Critical for renal

functioning

Any questions?

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