harrison based notes washington manual hypophosphatemia tumor calcinosis tumour induced osteomalacia hyperphosphatemia PHEX hypophospahtemic rickets

1. PHOSPHORUS

2. PHOSPHORUS
• CRITICAL FOR BONE FORMATION AND CELLULAR ENERGY METABOLISM
• TOTAL BODY PHOSPHOROUS IS 600 G
• 85 % IN BONES

3. PHOSPHOROUS EXIST IN SEVERAL FORMS

4. COMPONENTS OF TOTAL PLASMA PHOSPHATE

5. • IN CELLS AND IN THE ECF, PHOSPHORUS EXISTS IN SEVERAL FORMS
• PREDOMINANTLY AS H2PO4– OR NAHPO4– , WITH PERHAPS 10% AS HPO42– .

6. PHOSPHORUS
• MOST ABUNDANT INTRACELLULAR ANION
• PARTICIPATES IN GLYCOLYSIS AND HIGH ENERGY PHOSPHATE (ATP) PRODUCTION
• BOTH AS THE FREE ANION(S) AND AS A COMPONENT OF NUMEROUS ORGANOPHOSPHATE COMPOUNDS,
INCLUDING STRUCTURAL PROTEINS, ENZYMES, TRANSCRIPTION FACTORS, CARBOHYDRATE AND LIPID
INTERMEDIATES, HIGH-ENERGY STORES (ATP [ADENOSINE TRIPHOSPHATE], CREATINE PHOSPHATE), AND
NUCLEIC ACIDS

7. • APPROXIMATELY 85% OF TOTAL BODY PHOSPHORUS IS IN BONE, AND MOST OF THE REMAINDER
IS WITHIN CELLS. THUS, SERUM PHOSPHORUS LEVELS MAY NOT REFLECT TOTAL BODY
PHOSPHORUS STORES
• 1% OF TOTAL BODY PHOSPHATE IN ECF

8. • NORMAL SERUM PHOSPHATE IS 3.0-4.5 MG/DL
• BEST MEASURED IN FASTING
• DUE TO DIURNAL VARIATION
• LOWER VALUE IN MORNING
• HIGHER AT NIGHT
• HIGHER AT POST MEALS

9. PHOSPHORUS LEVEL

10. DIURNAL VARIATION IN PHOSPHOROUS LEVEL
• SERUM PHOSPHATE LEVELS VARY BY AS MUCH AS 50% ON A NORMAL DAY. THIS REFLECTS THE
EFFECT OF FOOD INTAKE BUT ALSO AN UNDERLYING CIRCADIAN RHYTHM THAT PRODUCES A
NADIR BETWEEN 7 AND 10 A.M

12. ABSORPTION OF PHOSPHATE

13. ABSORPTION OF PHOSPHATE
• PHOSPHATE IS WIDELY AVAILABLE IN FOODS AND IS ABSORBED EFFICIENTLY (65%) BY THE SMALL
INTESTINE EVEN IN THE ABSENCE OF VITAMIN D
• ACTIVE TYPE IIB SODIUM PHOSPHATE CO TRANSPORTERS(NPT2B) ON APICAL MEMBRANE
• PHOSPHATE ABSORPTIVE EFFICIENCY MAY BE ENHANCED (TO 85–90%) VIA ACTIVE TRANSPORT
MECHANISMS THAT ARE STIMULATED BY 1,25(OH)2D.

14. REGULATION OF PHOSPHOROUS ABSORPTION
• PTH REGULATES THE INCORPORATION AND RELEASE OF MINERALS FROM BONE STORES AND
DECREASES PROXIMAL TUBULAR REABSORPTION OF PHOSPHATE, CAUSING URINARY WASTING
• PHOSPHATE CONCENTRATION ITSELF REGULATES RENAL PROXIMAL REABSORPTION
• INSULIN LOWERS SERUM LEVELS BY SHIFTING PHOSPHATE INTO CELLS
• CALCITRIOL
• INCREASES SERUM PHOSPHATE BY ENHANCING INTESTINAL PHOSPHORUS ABSORPTION.

16. • DAILY DIETARY CONTENT 500–1000 MG/DL

22. RENAL HANDLING OF PHOSPHATE
• MAJORITY OF PHOSPHATE (85%)
REBSORPTION BY 3 RENAL SODIUM
PHOSPHATE COTRANSPORTERS
• LOCATED IN APICAL BORDER OF PCT
• NPT2A
• NPT2C
• PIT-2

24. • SITE OF REGULATION OF PHOSPHATE REABSORPTION IS PROXIMAL RENAL TUBULE
• CONTROL OF SERUM PHOSPHATE IS DETERMINED MAINLY BY THE RATE OF RENAL
TUBULAR REABSORPTION OF THE FILTERED LOAD, WHICH IS ~4–6 G/D.
• PHOSPHATE CLEARANCE IS ENHANCED BY ECF VOLUME EXPANSION AND IMPAIRED BY
DEHYDRATION.
• URINARY EXCRETION IS NOT CONSTANT BUT VARIES DIRECTLY WITH DIETARY INTAKE

25. FGF23 EFFECT ON CALCITRIOL
FGF23 also leads to reduced synthesis of
1,25(OH)2D, which may worsen the resulting
hypophosphatemia by lowering intestinal phosphate
absorption

26. Levels of these transporters at the apical surface of
these cells are reduced rapidly by PTH and FGF 23

28. HYPOPHOSPHATEMIA

29. HYPOPHOSPHATEMIA
• FASTING SERUM PHOSPHATE CONCENTRATION <2.5 MG/DL

30. ETIOLOGY
• INADEQUATE INTESTINAL PHOSPHATE ABSORPTION,
• EXCESSIVE RENAL PHOSPHATE EXCRETION
• RAPID REDISTRIBUTION OF PHOSPHATE FROM THE ECF INTO BONE OR SOFT TISSUE

31. IMPAIRED INTESTINAL PHOSPHATE ABSORPTION
• ALUMINUM-CONTAINING ANTACIDS
• SEVALAMER

32. REDUCED RENAL TUBULAR PHOSPHATE
REABSORPTION
• PTH/PTHRP-DEPENDENT
• PTH/PTHRP-INDEPENDENT

33. PTH/PTHRP-DEPENDENT
• PRIMARY HYPERPARATHYROIDISM
• SECONDARY HYPERPARATHYROIDISM
• VITAMIN D DEFICIENCY/RESISTANCE
• CALCIUM STARVATION/MALABSORPTION
• BARTTER’S SYNDROME
• AUTOSOMAL RECESSIVE RENAL HYPERCALCIURIA WITH HYPOMAGNESEMIA

34. PTH/PTHRP-INDEPENDENT
TUBULAR PHOSPHATE WASTING
• WITH ASSOCIATED RICKETS AND OSTEOMALACIA.
• ALL THESE DISEASES MANIFEST SEVERE HYPOPHOSPHATEMIA; RENAL PHOSPHATE WASTING,
SOMETIMES ACCOMPANIED BY AMINOACIDURIA; INAPPROPRIATELY LOW BLOOD LEVELS OF
1,25(OH)2D; LOW-NORMAL SERUM LEVELS OF CALCIUM; AND EVIDENCE OF IMPAIRED
CARTILAGE OR BONE MINERALIZATION
• FGF23 IS SYNTHESIZED BY CELLS OF THE OSTEOBLAST LINEAGE, PRIMARILY OSTEOCYTES

35. FGF23
cells of the osteoblast lineage, primarily osteocytes
renal phosphate wasting
severe hypophosphatemia
low blood levels of 1,25(OH)2D
impaired cartilage or bone mineralization
low-normal serum
levels of calcium

36. AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC
RICKETS
(ADHR)
• AUTOSOMAL DOMINANT
• ACTIVATING FGF23 MUTATIONS
• THESE MUTATIONS ALTER A CLEAVAGE SITE THAT ORDINARILY ALLOWS FOR INACTIVATION OF
INTACT FGF23

37. X-LINKED HYPOPHOSPHATEMIC RICKETS (XLH)
• WHICH RESULTS FROM INACTIVATING MUTATIONS IN AN ENDOPEPTIDASE TERMED PHEX
(PHOSPHATE-REGULATING GENE WITH HOMOLOGIES TO ENDOPEPTIDASES ON THE X
CHROMOSOME) THAT IS EXPRESSED MOST ABUNDANTLY ON THE SURFACE OF OSTEOCYTES AND
MATURE OSTEOBLASTS
• HIGH FGF23 LEVELS

40. AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC
SYNDROMES
ectonucleotide
pyrophosphatase/
phosphodiesterase 1 (ENPP1)
dentin matrix protein-1
(DMP1)
both of which normally are highly expressed in bone and
presumably regulate FGF23 production

41. TUMOR-INDUCED OSTEOMALACIA (TIO)
• ACQUIRED DISORDER IN WHICH TUMORS, USUALLY OF MESENCHYMAL ORIGIN AND GENERALLY
HISTOLOGICALLY BENIGN, SECRETE FGF23 AND/OR OTHER MOLECULES THAT INDUCE RENAL
PHOSPHATE WASTING.
• SUCH TUMORS TYPICALLY EXPRESS LARGE AMOUNTS OF FGF23 MRNA, AND PATIENTS WITH
TIO USUALLY EXHIBIT ELEVATIONS OF FGF23 IN THEIR BLOOD.
• RESOLVES COMPLETELY WITHIN HOURS TO DAYS AFTER SUCCESSFUL RESECTION OF THE
RESPONSIBLE TUMOR.

43. DENT’S DISEASE

44. DENTS DISEASE
• X-LINKED RECESSIVE DISORDER
• CAUSED BY INACTIVATING MUTATIONS IN CLCN5, A CHLORIDE TRANSPORTER EXPRESSED
IN ENDOSOMES OF THE PROXIMAL TUBULE;
• FEATURES INCLUDE
• HYPERCALCIURIA,
• HYPOPHOSPHATEMIA,
• RECURRENT KIDNEY STONE

45. RENAL PHOSPHATE WASTING
• POORLY CONTROLLED DIABETIC PATIENTS
• ALCOHOLICS
• DIURETICS
• CERTAIN OTHER DRUGS AND TOXINS

46. CAUSES OF PTH/PTHRP-INDEPENDENT
TUBULAR PHOSPHATE WASTING
• EXCESS FGF23 OR OTHER “PHOSPHATONINS”
• INTRINSIC RENAL DISEASE
• OTHER SYSTEMIC DISORDERS
• DRUGS OR TOXINS

47. EXCESS FGF23 OR OTHER “PHOSPHATONINS”
• X-LINKED HYPOPHOSPHATEMIC RICKETS (XLH)
• AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIA (ARHP)
• AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS (ADHR) (DMP1, ENPP1 DEFICIENCY)
• TUMOR-INDUCED OSTEOMALACIA SYNDROME (TIO)
• MCCUNE-ALBRIGHT SYNDROME (FIBROUS DYSPLASIA)
• EPIDERMAL NEVUS SYNDROME

48. DECREASED RENAL PHOSPHATE REABSORPTION
• HYPOCALCEMIA,
• HYPOMAGNESEMIA,
• SEVERE HYPOPHOSPHATEMIA.

50. DUE TO RAPID UPTAKE INTO AND UTILIZATION BY
CELLS
• INSULIN THERAPY FOR DIABETIC KETOACIDOSIS
• METABOLIC OR RESPIRATORY ALKALOSIS
• RECOVERY FROM METABOLIC ACIDOSIS
• IV DEXTROSE SOLUTIONS
• REFEEDING SYNDROME
• ANTECEDENT STARVATION OR MALNUTRITION,
• ADMINISTRATION OF IV GLUCOSE WITHOUT OTHER NUTRIENTS,
• ELEVATED BLOOD CATECHOLAMINES (ENDOGENOUS OR EXOGENOUS)

51. HYPOPHOSPHATEMIA
• DURING THE PHASE OF ACCELERATED NET BONE FORMATION
• PARATHYROIDECTOMYAFTER SEVERE PRIMARY HYPERPARATHYROIDISM
• DURING TREATMENT OF VITAMIN D DEFICIENCY
• LYTIC PAGET’S DISEASE
• OSTEOBLASTIC METASTASES

52. RESPIRATORY ALKALOSIS
Respiratory alkalosis
increase intracellular pH
accelerates glycolysis
increase in glucose utilization
increase in glucose and phosphorus movement into cells

53. PROLONGED HYPERGLYCEMIA
• GLUCOSE LOADING IS SEEN IN PATIENTS
WITH PROLONGED HYPERGLYCEMIA WHO
RECEIVE INSULIN

54. hyperglycemia
osmotic diuresis (from glycosuria)
insulin is given
(which drives PO4 into cells
hypophosphatemia

55. severe hypophosphatemia
ATP depletion
shift from oxidative phosphorylation toward glycolysis
associated tissue or organ dysfunction

57. OXYHEMOGLOBIN
DISSOCIATION CURVE
Phosphate depletion
depletion of 2,3-diphosphoglycerate
shifts the oxyhemoglobin dissociation curve to the left
less likely to release oxygen to the tissues

58. HEMOLYTIC ANEMIA IN HYPOPHOSPHATEMIA
Reduction of high energy phosphate production from glycolysis
reduce the deformability of red cells
hemolytic anemia

59. REVERSIBLE HEART FAILURE
Phosphate depletion
impair myocardial contractility
reduce cardiac output

61. CF

62. Acute, hypophosphatemia Chronic hypophosphatemia
Severe less severe
occurs mainly or exclusively in hospitalized
patients with underlying serious medical or
surgical illness and preexisting phosphate
depletion due to excessive
urinary losses, severe malabsorption, or
malnutrition
with a clinical presentation dominated by
musculoskeletal complaints such as bone
osteomalacia,
pseudofractures, and proximal muscle
weakness or, in children, rickets
and short stature

63. Acute Hypophosphatemia
Muscular abnormalities
• Proximal muscle
weakness,
• rhabdomyolysis,
• impaired diaphragmatic
function,
• respiratory failure
• congestive heart failure
Neurological abnormalities
• Parasthesia,
• dysarthria,
• confusion,
• seizures or coma
Haematological
Enhanced oxygen dissociation
causes tissue hypoxia, and
haemolysis.
Impaired phagocytosis and
opsonization leading to
increased susceptibility to
bacterial and fungal infections.
mineralization defect leading to
rickets in children ahd
osteomalacia in adults

64. CF
• FAILURE TO WEAN FROM MECHANICALVENTILATION IN PATIENTS WITH SEVERE
HYPOPHOSPHATEMIA

66. • THE NORMAL DAILY MAINTENANCE DOSE OF PHOSPHORUS IS 1,200 MG IF GIVEN ORALLY
• THE IV MAINTENANCE DOSE OF PO4 IS LOWER, AT 800 MG/DAY, BECAUSE ONLY 70%
OF ORALLY ADMINISTERED PHOSPHATE IS ABSORBED FROM THE GI TRACT

67. • SERIOUS SEQUELAE SUCH AS PARALYSIS, CONFUSION, AND SEIZURES ARE LIKELY ONLY AT
PHOSPHATE CONCENTRATIONS <0.25 MMOL/L (<0.8 MG/DL).
• RHABDOMYOLYSIS MAY DEVELOP DURING RAPIDLY PROGRESSIVE HYPOPHOSPHATEMIA

69. • SERUM LEVELS OF PHOSPHATE AND CALCIUM MUST BE MONITORED CLOSELY (EVERY 6–12 H)
THROUGHOUT TREATMENT

70. CHRONIC HYPOPHOSPHATEMIA

71. XLH,ADHR, TIO, AND RELATED RENAL TUBULAR
DISORDERS

72. TIO
• LOCALIZED BY RADIOGRAPHIC SKELETAL SURVEY OR BONE SCAN (MANY ARE LOCATED IN BONE)
OR BY RADIONUCLIDE SCANNING USING SESTAMIBI OR LABELED OCTREOTIDE
• EXTIRPATION OF THE RESPONSIBLE TUMOR

74. HYPERPHOSPHATEMIA

75. • FASTING SERUM PHOSPHATE CONCENTRATION >5.5 MG/DL
• HIGHER IN CHILDREN AND NEONATES <7 MG/DL

76. CAUSES
• IMPAIRED GLOMERULAR FILTRATION,
• HYPOPARATHYROIDISM,
• EXCESSIVE DELIVERY OF PHOSPHATE INTO THE ECF (FROM BONE, GUT, OR PARENTERAL
PHOSPHATE THERAPY)
• COMBINATION OF THESE FACTORS

77. Decreased renal excretion • Acute renal failure
• Chronic renal failure
Acute tissue destruction • Tumor-lysis syndrome,
• severe haemolysis,
• Rhabdomyolysis,
• crush injury
Increased renal phosphate reabsorption • Hypoparathyroidism
• Acromegaly
• Thyrotoxicosis
Miscellaneous • Excess phosphate administration
• Vitamin-D intoxication
• Metabolic or respiratory acidosis

79. REDUCED GFR
reduced GFR
chronic renal insufficiency
Hyperphosphatemia
phosphate retention.
impairs renal synthesis of 1,25(OH)2D
secondary hyperparathyroidism

80. HYPOPARATHYROIDISM
Hypoparathyroidism
increased expression of NaPi-2 co-transporters in the proximal tubule
hyperphosphatemia

81. CAUSES OF HYPOPARATHYROIDISM
• AUTOIMMUNE DISEASE;
• DEVELOPMENTAL,
• SURGICAL,
• RADIATION-INDUCED ABSENCE OF FUNCTIONAL PARATHYROID TISSUE;
• VITAMIN D INTOXICATION OR OTHER CAUSES OF PTH-INDEPENDENT HYPERCALCEMIA;
• CELLULAR PTH RESISTANCE (PSEUDOHYPOPARATHYROIDISM OR HYPOMAGNESEMIA)
• INFILTRATIVE DISORDERS SUCH AS WILSON’S DISEASE AND HEMOCHROMATOSIS
• IMPAIRED PTH SECRETION CAUSED BY HYPERMAGNESEMIA, SEVERE HYPOMAGNESEMIA,
• ACTIVATING MUTATIONS IN THE CASR.

82. TUMORAL CALCINOSIS
• RARE GROUP OF GENETIC DISORDERS IN WHICH FGF23 IS
PROCESSED IN A WAY THAT LEADS TO LOW LEVELS OF ACTIVE
FGF23 IN THE BLOODSTREAM.
• THIS MAY RESULT FROM MUTATIONS IN THE FGF23
SEQUENCE OR VIA INACTIVATING MUTATIONS IN THE
GALNT3 GENE, WHICH ENCODES A GALAC-TOSAMINYL
TRANSFERASE THAT NORMALLY ADDS SUGAR RESIDUES TO
FGF23 THAT SLOW ITS PROTEOLYSIS
• INACTIVATING MUTATIONS OF THE FGF23 CO-RECEPTOR
KLOTHO

83. TUMORAL CALCINOSIS

84. • ELEVATED SERUM 1,25(OH)2D,
• PARATHYROID SUPPRESSION,
• INCREASED INTESTINAL CALCIUM ABSORPTION, AND FOCAL HYPEROSTOSIS WITH LARGE,
LOBULATED PERIARTICULAR HETEROTOPIC OSSIFICATIONS (ESPECIALLY AT SHOULDERS OR HIPS)
AND ARE ACCOMPANIED BY HYPERPHOSPHATEMIA

85. elevated serum 1,25(OH)2D
increased intestinal calcium absorption hyperphosphatemia
focal hyperostosis with large, lobulated periarticular
heterotopic ossifications (especially at shoulders or hips)
parathyroid
suppression
inactivating
mutations in the
GALNT3 gene
inactivating
mutations of the
FGF23 co-receptor
Klotho
mutations in the
FGF23 sequence
low levels of active FGF23

86. • FGF23 RESISTANCE DUE TO INACTIVATING MUTATIONS OF THE FGF23 CO-RECEPTOR KLOTHO

87. INCREASED ECF
• OVERZEALOUS IV PHOSPHATE THERAPY,
• ORAL OR RECTAL ADMINISTRATION OF LARGE AMOUNTS OF PHOSPHATE-CONTAINING
LAXATIVES OR ENEMAS (ESPECIALLY IN CHILDREN),
• EXTENSIVE SOFT TISSUE INJURY OR NECROSIS (CRUSH INJURIES, RHABDOMYOLYSIS,
HYPERTHERMIA, FULMINANT HEPATITIS, CYTOTOXIC CHEMOTHERAPY),
• EXTENSIVE HEMOLYTIC ANEMIA,
• TRANSCELLULAR PHOSPHATE SHIFTS INDUCED BY SEVERE METABOLIC OR RESPIRATORY ACIDOSIS

88. CLINICAL MANIFESTATIONS
• THE FORMATION OF INSOLUBLE CALCIUM–PHOSPHATE COMPLEXES (WITH DEPOSITION INTO
SOFT TISSUES)
• ACUTE HYPOCALCEMIA (WITH TETANY)
• PULMONARY OR CARDIAC CALCIFICATIONS (INCLUDING DEVELOPMENT OF ACUTE HEART BLOCK)

89. TREATMENT
• VOLUME EXPANSION
• ENHANCE RENAL PHOSPHATE CLEARANCE.
• SALINE DIURESIS
• ACETAZOLAMIDE
• ALUMINUM HYDROXIDE ANTACIDS OR SEVALAMER
• CHELATING AND LIMITING ABSORPTION OF OFFENDING PHOSPHATE SALTS PRESENT IN THE INTESTINE.
• HEMODIALYSIS
• IN THE COURSE OF SEVERE HYPERPHOSPHATEMIA, ESPECIALLY IN THE SETTING OF RENAL FAILURE AND
SYMPTOMATIC HYPOCALCEMIA

90. • CALCIUM ACETATE AND CALCIUM CARBONATE
• PREFERRED AGENTS AND ARE ADMINISTERED WITH MEALS
• ALUMINIUM HYDROXIDE
• MAY BE USED FOR THE SHORT TERM
• CHRONIC USE IN PATIENTS WITH RENAL FAILURE SHOULD BE AVOIDED BECAUSE IT MAY CAUSE
ALUMINIUM TOXICITY CAUSING ADYNAMIC BONE DISEASE, PROXIMAL MYOPATHY AND ANEMIA.

91. PREVENTION
• RESTRICTION OF DIETARY PHOSPHATE TO 600-900 MG/DAY. AVOID PHOSPHORUS RICH
PRODUCTS LIKE MILK AND DAIRY PRODUCTS AND CARBONATED BEVERAGES CONTAINING
PHOSPHORIC ACID.