CHAPTER 63

Vitamin C (Ascorbic Acid) Deficiency and

Excess
NELSON’s HOUR
Svendson P. Ordanza, MD
2nd year Pediatrics resident
Dr. Jose N, Rodriguez Memorial Hospital and Sanitarium
VITAMIN C
Vitamin C

 Ascorbic acd, anti-scorbutic vitamin

 Water soluble vitamin
 for synthesis of collagen at the level of hydroxylation of lysine and proline in precollagen
 involved in neurotransmitter metabolism (conversion of dopamine to norepinephrine and
tryptophan to serotonin), cholesterol metabolism (conversion of cholesterol to steroid
hormones and bile acids), and the biosynthesis of carnitine
 maintain the iron and copper atoms, cofactors of the metalloenzymes, in a reduced
(active) state
Vitamin C

 As an important antioxidant (electron donor) in the aqueous milieu of the body

 enhances nonheme iron absorption, the transfer of iron from transferrin to ferritin, and the
formation of tetrahydrofolic acid and thus can affect the cellular and immunologic
functions of the hematopoietic system
Dietary Needs and Sources of Vitamin C

 The best food sources of vitamin C are citrus fruits and fruit juices, peppers, berries,
melons, guava, kiwifruit, tomatoes, cauliflower, and green leafy vegetables
 Vitamin C is easily destroyed by prolonged storage, overcooking, and processing of foods
 An adequate intake is 40 mg for ages 0-6 mo and 50 mg for 6-12 mo. For older children
the recommended dietary allowance is 15 mg for ages 1-3 yr, 25 mg for 4-8 yr, 45 mg for
9-13 yr, and 65-75 mg for 14-18 yr. The recommended dietary allowances during
pregnancy and lactation are 85 mg/day and 120 mg/day, respectively. The requirement for
vitamin C is increased during infectious and diarrheal diseases.
 Children exposed to smoking or environmental tobacco smoke also require increased
amounts of foods rich in vitamin C
 Vitamin C Deficiency

 Scurvy
 At risk:
 Children fed predominantly heat-treated (ultrahigh-temperature or pasteurized) milk or unfortified formulas and
not receiving fruits and fruit juices are at significant risk for symptomatic disease.
 Infants and children on highly restrictive diets, devoid of most fruits and vegetables, are at risk of acquiring
severe vitamin C deficiency
 Vitamin C Deficiency
 In Scurvy, there is defective
formation of connective
tissues and collagen in skin,
cartilage, dentine, bone, and
blood vessels, leading to their
fragility. In the long bones,
osteoid is not deposited by
osteoblasts, cortex is thin,
and the trabeculae become
brittle and fracture easily
 Clinical Features of Vitamin C Deficiency
 early manifestations of vitamin C deficiency are irritability, loss of appetite, low-grade fever,
musculoskeletal pain, and tenderness in the legs.
 Pseudoparalysis: leg swelling—most marked at the knees and the ankles. infant might lie with
the hips and knees semiflexed and the feet rotated outward (frogleg position)
 Subperiosteal hemorrhages in the lower-limb bones sometimes acutely increase the swelling
and pain, and the condition might mimic acute osteomyelitis or arthritis
 Scorbutic rosary: A “rosary” at the costochondral junctions and depression of the sternum
 Gum changes
 Anemia
 Clinical Features of Vitamin C Deficiency
 Anemia: related to impaired iron absorption and coexistent hematopoietic nutrient
deficiencies, including iron, vitamin B12 , and folate
 Hemorrhagic manifestations of scurvy include petechiae, purpura, and ecchymoses at pressure
points; epistaxis; gum bleeding; and the characteristic perifollicular hemorrhages
Laboratory Findings and Diagnosis in Scurvy
 usually based on the characteristic clinical picture, the
radiographic appearance of the long bones, and a history of
poor vitamin C intake
 typical radiographic changes occur at the distal ends of the
long bones and are particularly common at the knees.
 The cortex is thin and dense, giving the appearance
of pencil outlining of the diaphysis and epiphysis
 The white line of Fränkel, an irregular but thickened white
line at the metaphysis, represents the zone of well-calcified
cartilage
 sclerotic rings (Wimberger sign): The epiphyseal centers
of ossification also have a ground-glass appearance and are
surrounded by a sclerotic ring
Laboratory Findings and Diagnosis in Scurvy
 The zone of rarefaction (Trümmerfeld zone), a linear
break in the bone that is proximal and parallel to the
white line, represents area of debris of broken-down
bone trabeculae and connective tissue, is a more
specific but late radiologic feature of scurvy
 A Pelkan spur is a lateral prolongation of the white
line and may be present at cortical ends
 Epiphyseal separation can occur along the line of
destruction, with either linear displacement or
compression of the epiphysis against the shaft
Laboratory Findings and Diagnosis in Scurvy

 Biochemical tests are not very useful in the diagnosis of scurvy, because they do not reflect the
tissue status
Treatment

 Vitamin C supplements of 100-200 mg/day orally or parenterally ensure rapid and

complete cure. The clinical improvement is seen within 1 week in most cases, but the
treatment should be continued for up to 3 mo for complete recovery.
Prevention

 Breastfeeding protects against vitamin C deficiency throughout infancy. In

children consuming milk formula, fortification with vitamin C must be
ensured.
 Children consuming heat-treated milk or plant-based beverages (e.g., almond
milk, soy milk) should consume adequate vitamin C–rich foods in infancy.
 Dietary or medicinal supplements are required in children on restrictive diets
deficient in vitamin C, severely malnourished children, and those with chronic
debilitating conditions (e.g., malignancies, neurologic disorders). Providing
antenatal supplements of vitamin C to smoking mothers
Vitamin C Toxicity

 Larger doses can cause gastrointestinal problems, such as abdominal pain and
osmotic diarrhea
 Hemolysis has rarely been reported
 Megadoses of vitamin C should be avoided in patients with a history of urolithiasis
or conditions related to excessive iron accumulation, such as thalassemia and
hemochromatosis
 ages 1-3 yr, 400 mg; 4-8 yr, 650 mg; 9-13 yr, 1,200 mg; and 14-18 yr, 1,800 mg
tolerable upper intake levels
VITAMIN D
NAMES AND CHARACTERIST BIOCHEMICAL EFFECTS OF EFFECTS OF SOURCES
SYNONYMS ICS ACTION DEFICIENCY EXCESS

VITAMIN D
Vitamin D3 (3- Fat-soluble, stable Necessary for GI Rickets in Hypercalcemia, Exposure to
cholecalciferol), to heat, acid, absorption of growing children; which can cause sunlight (UV
which is alkali, and calcium; also osteomalacia; emesis, anorexia, light); fish oils,
synthesized in the oxidation; bile increases hypocalcemia can pancreatitis, fatty fish, egg
skin Vitamin necessary for absorption of cause tetany and hypertension, yolks, and
D2 (ergocalciferol absorption; phosphate; direct seizures arrhythmias, CNS vitamin D–
, from plants or hydroxylation in actions on bone, effects, polyuria, fortified formula,
yeast) are the liver and including nephrolithiasis, milk, cereals,
biologically kidney necessary mediating renal failure bread
equivalent; 1 µg = for biologic resorption
40 IU vitamin D. activity
RICKETS

 Rickets is a disease of growing bone caused by unmineralized

matrix at the growth plates in children only before fusion of the
epiphyses
 Risk factors: people with increased skin pigmentation, African
American descents who lives in the industrialized countries,
breatsfed infants with no sunlight exposure
 Etiology of Rickets
Vitamin D Disorders
 Nutritional vitamin D deficiency
 Congenital vitamin D deficiency
 Secondary vitamin D deficiency
 Malabsorption
 Increased degradation
 Decreased liver 25-hydroxylase
 Vitamin D–dependent rickets types 1A
and 1B
 Vitamin D–dependent rickets types 2A
and 2B
 Chronic kidney disease
Calcium Deficiency
 Low intake
 Diet
 Premature infants (rickets of  Overproduction of fibroblast growth
prematurity) factor-23
 Malabsorption  Tumor-induced rickets*
 Primary disease  McCune-Albright syndrome*
 Dietary inhibitors of calcium  Epidermal nevus syndrome*
absorption
 Neurofibromatosis*
Phosphorus Deficiency
 Fanconi syndrome
 Inadequate intake
 Dent disease
 Premature infants (rickets of
 Distal renal tubular acidosis
prematurity)
 Aluminum-containing antacids
Renal Losses
 X-linked hypophosphatemic rickets*
 Autosomal dominant
hypophosphatemic rickets*
 Autosomal recessive
Clinical Manifestations of Rickets
 Craniotabes is a softening of the cranial
bones and can be detected by applying
pressure at the occiput or over the parietal
bones
 Widening of the costochondral junctions
results in a rachitic “rosary ,” which feels
like the beads of a rosary as the examiner's
fingers move along the costochondral
junctions from rib to rib
Clinical Manifestations of Rickets
 Growth plate widening is also responsible for
the enlargement at the wrists and ankles
 The horizontal depression along the lower
anterior chest known as Harrison
groove occurs from pulling of the softened
ribs by the diaphragm during inspiration
 windswept deformity occurs when one leg is
in extreme valgus and the other is in extreme
varus
 Clinical Features of Rickets
General  No incisors by age 10 mo  Enlargement of wrists and ankles
 Failure to thrive (malnutrition)  No molars by age 18 mo  Valgus or varus deformities
 Listlessness  Caries  Windswept deformity (valgus
 Craniosynostosis deformity of one leg with varus
 Protruding abdomen
deformity of other leg)
 Muscle weakness (especially Chest
 Anterior bowing of tibia and femur
proximal)  Rachitic rosary
 Coxa vara
 Hypocalcemic dilated cardiomyopathy  Harrison groove
 Leg pain
 Fractures (pathologic, minimal  Respiratory infections and atelectasis
trauma) Hypocalcemic Symptoms
Back
 Increased intracranial pressure  Tetany
 Scoliosis
Head  Seizures
 Kyphosis
 Craniotabes  Stridor caused by laryngeal spasm
 Lordosis
 Frontal bossing
Extremities
 Delayed fontanel closure (usually
closed by 2 yr)
 Delayed dentition
Diagnosis of Rickets
 metaphyseal fraying and cupping of the
distal radius and ulna can be seen in xray
findings
 It is supported by physical examination
findings, history, and laboratory results
consistent with a specific etiology
 Rickets: Clinical Evaluation
 the initial evaluation should focus on a dietary history, emphasizing intake of both vitamin D and
calcium.
 rickets has occurred in children given products that are called “milk” (e.g., soy milk) but are
deficient in vitamin D and minerals
 Cutaneous synthesis mediated by sunlight exposure is an important source of vitamin D. Children
with increased skin pigmentation are at increased risk for vitamin D deficiency because of
decreased cutaneous synthesis
 The presence of maternal risk factors for nutritional vitamin D deficiency, including diet and sun
exposure, is an important consideration when a neonate or young infant has rachitic findings,
especially if the infant is breastfed
 Malabsorption of vitamin D is suggested by a history of liver or intestinal disease
Rickets: Clinical Evaluation

 anticonvulsants phenobarbital and phenytoin, increase degradation of vitamin D

 A history of renal disease (proteinuria, hematuria, urinary tract infections) is an additional
significant consideration, given the importance of chronic kidney disease as a cause of
rickets
 Rickets: Clinical Evaluation

 The initial laboratory tests in a child with rickets should include serum calcium,
phosphorus, alkaline phosphatase (ALP), parathyroid hormone (PTH), 25-hydroxyvitamin
D, 1,25-dihydroxyvitamin D (1,25-D), creatinine, and electrolytes

Disorder Ca Pi PTH 25-(OH)D 1,25- ALP URINE URINE

(OH)2 D Ca Pi
Vitamin N, ↓ ↓ ↑ ↓ ↓, N, ↑ ↑ ↓ ↑
D
deficiency
 Nutritional Vitamin D Deficiency
 remains the most common cause of rickets globally and is prevalent, even in industrialized countries
 Etiology: MC occurs in infancy, combination of poor intake and inadequate cutaneous synthesis
 Transplacental transport of vitamin D typically provides enough vitamin D for the 1st 2 mo of life
unless there is severe maternal vitamin D deficiency
 clinical features are typical of rickets commonly presenting with symptoms of hypocalcemia
 Stoss therapy , vitamin D (300,000-600,000 IU) is administered orally (preferred) or intramuscularly
as 2-4 doses over 1 day (vitamin D3 is preferred to D2 because of longer half-life of D3 
 Alternative strategy is daily vitamin D with a minimum dose of 2,000 IU/day for a minimum of 3 mo
 followed by daily vitamin D intake of 400 IU/day if <1 yr old or 600 IU/day if >1 yr old. It is
important to ensure that children receive adequate dietary calcium (minimum of 500 mg/day) and
phosphorus
 Nutritional Vitamin D Deficiency
 Prognosis:
Most children with nutritional vitamin D deficiency have an excellent response to treatment
 Prevention
universal administration of 400 IU of vitamin D to infants <1 yr old. Older children with risk factors for
inadequate intake should receive 600 IU/day
 Congenital Vitamin D Deficiency
 Congenital rickets 
 is quite rare in industrialized countries
 occurs when there is severe maternal vitamin D deficiency during pregnancy.
 Maternal risk factors include poor dietary intake of vitamin D, lack of adequate sun exposure, and closely
spaced pregnancies

 symptomatic hypocalcemia, intrauterine growth retardation, and decreased bone ossification, along
with classic rachitic changes
 Treatment of congenital rickets includes vitamin D supplementation and adequate intake of calcium
and phosphorus.
 Use of prenatal vitamins containing vitamin D (600 IU) prevents this entity
 Secondary Vitamin D Deficiency
 inadequate intake, absorption, decreased hydroxylation in the liver, and increased degradation
 Occurs in patients with variety of liver and GI diseases, including cholestatic liver disease, defects in
bile acid metabolism, because Vitamin D is fat soluble
 Severe liver disease, which usually is also associated with malabsorption, can cause a decrease in 25-
D formation as a result of insufficient enzyme activity.
 Rickets from vitamin D deficiency can develop in children receiving anticonvulsants (e.g.,
phenobarbital, phenytoin) or antituberculosis medications (e.g., isoniazid, rifampin) by increasing the
degradation of vitamin D thru inducing the cytochrome P450 (CYP) system
 Treatment: 25-D (25-50 µg/day or 5-7 µg/kg/day)
vitamin D–dependent rickets type 1A
autosomal recessive disorder
have mutations in the gene encoding renal 1α-
hydroxylase, preventing conversion of 25-D into 1,25-
D
They have normal levels of 25-D but low levels of
1,25-D
responds to long-term treatment with 1,25-D
(calcitriol). Initial doses are 0.25-2 µg/day
Vitamin D–dependent rickets type 1B
secondary to a mutation in the gene for a 25-
hydroxylase.
low levels of 25-D but normal levels of 1,25-D
espond to pharmacologic doses of vitamin D2 (3,000
U/day)

Disorder Ca Pi PTH 25-(OH)D 1,25- ALP URINE URINE Pi

(OH)2 D Ca
VDDR, N, ↓ ↓ ↑ N ↓ ↑ ↓ ↑
type 1A
VDDR, N, ↓ ↓ ↑ ↓ N ↑ ↓ ↑
type 1B
 Vitamin D–Dependent Rickets, Type 2 A Vitamin D–Dependent Rickets, Type 2B

mutations in the gene encoding the vitamin D
receptor, preventing a normal physiologic response to
1,25-D.
Approximately 50–70% of children have alopecia ,
which tends to be associated with a more severe form
of the disease and can range from alopecia areata to
alopecia totalis
extremely high doses of vitamin D2 (25-D or 1,25-
D). initial dose of 1,25-D should be 2 µg/day, but
some patients require doses as high as 50-60 µg/day.
Calcium doses are 1,000-3,000 mg/day
result from overexpression of a hormone response
element–binding protein that interferes with the
actions of 1,25-D
Alopecia may be present.
extremely high doses of vitamin D2 (25-D or 1,25-
D). initial dose of 1,25-D should be 2 µg/day, but
some patients require doses as high as 50-60 µg/day.
Calcium doses are 1,000-3,000 mg/day

Disorder Ca Pi PTH 25-(OH)D 1,25- ALP URINE Ca URINE Pi

(OH)2 D
VDDR, N, ↓ ↓ ↑ N ↑↑ ↑ ↓ ↑
type 2A
VDDR, N, ↓ ↓ ↑ N ↑↑ ↑ ↓ ↑
type 2B
 Chronic Kidney Disease
 there is decreased activity of 1α-hydroxylase in the kidney, leading to diminished production of 1,25-D.
 Unlike the other causes of vitamin D deficiency, patients have hyperphosphatemia as a result of decreased renal
excretion
 Therapy requires the use of a form of vitamin D that can act without 1-hydroxylation by the kidney (calcitriol),
which both permits adequate absorption of calcium and directly suppresses the parathyroid gland
 ecause hyperphosphatemia is a stimulus for PTH secretion, normalization of the serum phosphorus level through a
combination of dietary phosphorus restriction and use of oral phosphate binders is important 

Disorder Ca Pi PTH 25-(OH)D 1,25- ALP URINE Ca URINE Pi

(OH)2 D
Chronic N, ↓ ↑ ↑ N ↓ ↑ N, ↓ ↓
kidney
disease
 Calcium Deficiency
 Rickets secondary to inadequate dietary calcium is a significant problem seen in some countries in Africa
 Diet that has low calcium content, typically <200 mg/day if <12 mo old or <300 mg/day if >12 mo old
 Diets is Africa usually has reliance on grains and green leafy vegetables, the diet may be high in phytate, oxalate, and
phosphate, which decrease absorption of dietary calcium
 Children with calcium deficiency have the classic signs and symptoms of rickets
 Laboratory findings include increased levels of ALP, PTH, and 1,25-D
 dietary supplement (doses of 700 [age 1-3 yr], 1,000 [4-8 yr], and 1,300 [9-18 yr] mg/day of elemental calcium

Disorder Ca Pi PTH 25-(OH)D 1,25- ALP URINE Ca URINE Pi

(OH)2 D
Dietary Ca N, ↓ ↓ ↑ N ↑ ↑ ↓ ↑
deficiency
 Phosphorus Deficiency
 it is almost impossible to have a diet that is deficient in phosphorus, because phosphorus is present in most
food, however decreased phosphorus absorption can occur in diseases associated with malabsorption (celiac
disease, cystic fibrosis, cholestatic liver disease)
 Isolated malabsorption of phosphorus occurs in patients with long-term use of aluminum-containing antacids,
which chelates phosphate in the GI tract, leading to decreased absorption
 Treatment: combination of oral phosphorus and 1,25-D (calcitriol)
 phosphorus supplementation is 1-3 g of elemental phosphorus divided into 4 or 5 doses. Calcitriol is
administered at 30-70 ng/kg/day in 2 doses

Disorder Ca Pi PTH 25-(OH)D 1,25- ALP URINE Ca URINE Pi

(OH)2 D
Dietary Pi N ↓ N, ↓ N ↑ ↑ ↑ ↓
deficiency
 Rickets of Prematurity
 transfer of calcium and phosphorus from mother to fetus occurs throughout pregnancy, but 80% occurs during
the 3rd trimester
 Premature birth interrupts this process, with rickets developing when the premature infant does not have an
adequate supply of calcium and phosphorus to support mineralization of the growing skeleton
 Most cases of rickets of prematurity occur in infants with a birthweight <1,000
 Rickets of prematurity occurs 1-4 mo after birth. Infants can have nontraumatic fractures, especially of the legs,
arms, and ribs. Most fractures are not suspected clinically
 There may be classic rachitic findings, such as frontal bossing, rachitic rosary, craniotabes, and widened wrists
and ankles
 Serum phosphorus level is low or low-normal in patients with rickets of prematurity. Serum levels of calcium are
low normal, or high, and patients often have hypercalciuria. Elevated serum calcium levels and hypercalciuria
are secondary to increased intestinal absorption and bone dissolution caused by elevated 1,25-D levels and
inability to deposit calcium in bone because of an inadequate phosphorus supply
 Treatment: ensuring adequate delivery of calcium, phosphorus, and vitamin D
Hypervitaminosis D

 The signs and symptoms of vitamin D intoxication are secondary to hypercalcemia.

 GI manifestations include nausea, vomiting, poor feeding, constipation, abdominal pain,
and pancreatitis.
 Possible cardiac findings are hypertension, decreased QT interval, and arrhythmias.
 The central nervous system effects of hypercalcemia include lethargy, hypotonia,
confusion, disorientation, depression, psychosis, hallucinations, and coma.
 Hypercalcemia impairs renal concentrating mechanisms, which can lead to polyuria,
dehydration, and hypernatremia. Hypercalcemia can also lead to acute renal failure,
nephrolithiasis, and nephrocalcinosis, which can result in chronic renal insufficiency
Hypervitaminosis D: Lab findings

 classic findings in vitamin D intoxication are hypercalcemia, elevated levels of 25-D (>100
ng/mL), hypercalciuria, and suppressed PTH.
 Hyperphosphatemia is also common
 Surprisingly, levels of 1,25-D are usually normal.
Hypervitaminosis D: Treatment

 Rehydration lowers the serum calcium level by dilution and corrects prerenal azotemia.
The resultant increased urine output increases urinary calcium excretion

 The mainstay of the initial treatment is aggressive therapy with normal saline, often in
conjunction with a loop diuretic to further increase calcium excretion
 Glucocorticoids decrease intestinal absorption of calcium by blocking the action of 1,25-D.
There is also a decrease in the levels of 25-D and 1,25-D. The usual dosage of prednisone
is 1-2 mg/kg/24 hr
Hypervitaminosis D: Treatment

 Bisphosphonates inhibit bone resorption through their effects on osteoclasts.

 Hemodialysis using a low or 0 dialysate calcium can rapidly lower serum calcium in
patients with severe hypercalcemia that is refractory to other measures
 it is imperative to eliminate the source of excess vitamin D. Additional sources of vitamin
D such as multivitamins and fortified foods should be eliminated or reduced. Avoidance of
sun exposure, including the use of sunscreen, is prudent. The patient should also restrict
calcium intake