Two

types

of nutritional M.D.,

G. Makaronis,3

MB.,

C.

In

with

nutritional

ABSTRACT found

a close

phosphatase

and

correlation

100 infants

inverse

relationship

the

presence

between

hypophosphatemia

not

hypocalcemia

but

into

one with

groups. and

transport,

one

with

which

true

to

and

signs the

rickets

and

alone,

that

deficiency,

S. Do.viadis,’

responsive

rickets, of

of rickets.

deficiency

and

on

the

leads

other.

lesions.

It

Since

hypophosphatemia our

is

alkaline

There

was

no that

and

rickets

can be divided

and no or mild

perhaps

from

a defect

Am.

C/in.

.Vutr.

J.

we

serum concluded

infants

to hypocalcemia

hypophosphatemia.

D therapy,

and

bone

we suggest

resulting

M.D.

to vitamin

on the one hand,

of

severity

D deficiency

phosphate

i.e..

phosphorus.

is typical

vitamin

B.C/i.

rickets,

serum

by phosphate

primary

leads

Vreto.s,4

radiological

calcium

experimentally

two

of

serum

can be produced lesions,

between

in infants’

bone

in phosphate 29:

1222-

1226,

1976,

Hurwitz

et

al.

normal

calcium

caused

hypocalcemia

bone while

ash, a low

vitamin lar with

(Ca)

diet

rats

without a

that

evidence (P) diet

These

our clinical hypocalcemia

D

drop

in

of rickets, with added

lesions infants

and

findings

observation and tetany

a

vitamin

small

hypophosphatemia

lesions.

or no bone tion, while

in

and

caused

bone to

observed

with no phosphorus

D

severe

(I)

were

simi-

that infants had very mild

on radiological with severe

examinarachitic

bone

lesions had low P and normal Ca values in the serum. It is worth noting that according to Steendijk (2) the primary Haversian systems of

infant

bones

are

similar

to

those

of

rat

bones.

The gate

above the

considerations

relationship

led us to investi-

between

the

severity

of

The methods forthe estimation of Ca, P. and SAP have been described previously (3). Table I shows age and sex distribution of the 100 rachitic infants in relation to the mean values of serum Ca, P. and SAP. As may be seen, from Table I more boys (67) than girls (33) were affected. Bone radiograms were classified and graded as follows: I) no bone lesions, 2) doubtful rarefaction, with irregular fraying of the provisional zone of calcification of the ulna and/or radius, 3) definite rarefaction, with irregular fraying of the provisional zone of calcification of the ulna and/or radius, 4) define rarefaction as. in 3, plus cupping and widening of the distal end of ulna and/or radius, and 5) rarefaction plus cupping as in 4, plus diffuse osteoporosis of ulna and/or radius.

Results Figure 1 shows a statistically significant negative correlation between serum P and SAP (n -0.402, P < 0.01). In other words, the lower the serum P. the higher the SAP; this suggests a functional correlation between =

the rachitic

process,

of serum

alkaline

phosphatase

radiological

picture

hand,

serum

with

as expressed of the Ca

and

by the level (SAP)

bones

and

the

on the

one

P levels,

on

the

other.

high

bone

categories

Material

and methods

serum

Our material consists of 100 infants, who were considered as having vitamin D deficiency and who were treated with vitamin D from 1962 to 1974 in the Pediatric Unit of the Aghia Sophia Children’s Hospital. The diagnosis was based on raised SAP values (more than 20 King Armstrong (KA) units) jnd/or serum Ca levels below 8 mg/100 ml, and/or serum P levels below 4 mg/l00 ml. Venous

taken

1222

in the

blood

early

The

for

the

morning

Americati

biochemical

estimations

after

a fast

Journal

of

was

of at least

Clinical

8 hr.

Nutrition

turnover

and

tain plasma phosphate Table 2 shows the of

P values.

‘Financial Gate 2

bone

the

lesions

As may

assistance

and Elpen. Associate Professor

inability

to main-

near normal. distribution of the

was of

in

relation

be seen from supplied Pediatrics,

by the Director

five

to

the

Table firm

2

Cow, of

the

Institute of Child Health, Athens. Greece. Senior House Officer in the Pediatric Unit of the Aghia Sophia Children’s Hospital. Biochemist of the Aghia Sophia Children’s Hospital. President of the Institute of Child Health and Director of the Pediatric Unit of the Aghia

29: NOVEMBER

Sophia

Children’s

1976, pp. 1222

Hospital.

1226. Printed

in U.S.1.

Downloaded from https://academic.oup.com/ajcn/article-abstract/29/11/1222/4649714 by University of Rhode Island user on 09 December 2018

P. Lapatsani.c,2

rickets

NUTRITIONAL

TABLE The ml)

RICKETS

IN

INFANTS

1223

I

age and sex of rachitic infants and serum alkaline phosphatase

in relation to the mean (SAP) (KA units)

values

of serum

calcium

(Ca),

Age

in

No,

months

Ca

49 18 67

2-6 7-12 Total

8.4± 9.0

±

Mean

No. of patients

SAP

patients

(mg/

100

Girls

Mean values o f serum

of

(P)

P 1.5 1.0

5.1 4.2

± ±

values

of serum

1.3 1.0

33±11 41 ± 13

18 IS 33

85

8.4 ±0.7

5.3±

8.9

4.0

0.8

±

SAP=57.95-4,44 n100,

SAP

P

Ca

±

1.0

36±14

I

43

±

20

SP P(0,01

r-O,4O2

80

71

4

65 .

LU In 4 I-

55

4 I In

0 I

45 -J

4 -J

4 I

35 LU in

30

25

2(

2

1

3

4 5 P mg/lOOmi

SERUM I. The

FIG.

the

more

shows bone values.

with

As

may

bone

between

the

lower

seen

lesions

values

were typically P values. Table 3 the distribution of the five categories of lesions in relation to the serum Ca

associated

severe

relationship

serum

from

this

table,

there

was

6 (SP)

of serum

8

7

P and

no

significant

ity

of the bone

9

of SAP

(KA

relationship

between

words,

lesions hypocalcemic

exhibit

rickets-like

lesions.

illustrative

cases

Two

units).

and serum infants did are

the

sever-

Ca. In other not typically

reported

for

the

Downloaded from https://academic.oup.com/ajcn/article-abstract/29/11/1222/4649714 by University of Rhode Island user on 09 December 2018

Boys

phosphorus

LAPATSANIS

1224

two types 2-month-old

of

following

an was

episode

of

on a milk

TABLE 2 The relation between and serum phosphorus

rickets. admitted

convulsions.

formula

bone

Case to the

without

I: a Unit

The vitamin

lesions

(SP)

AL.

D and

the biochemical

were:

blood

findings

sugar

68

on admission

mg/l00

ml,

serum

Ca

6.8 mg/lOO ml, serum P 7.1 mg/lOO ml, and SAP 28 KA units. The x-ray film showed no rachitic bone lesions (Fig. 2) Case 2: a 10-month-old infant was admitted to the Unit because

of pallor

and

a milk

formula

without

biochemical mg/lOO ml, SAP

36

typical

fever.

findings serum

KA

infant D

was

were: serum P 3.1 mg/l00

units.

rachitic

The vitamin

The

bone

x-ray

lesions

the

Ca ml,

and

film

(Fig.

on

and

9.5

showed

3).

Discussion The

traditional

pathogenesis d.f. 28, Xo2 41.3, X2 Dependent X SP, mg/l00 ml Y C, D, F, as defined in the text). TABLE 3 The relation between bone and serum calcium (SCa)

82.7, bone

= =

X2 > Xo. lesions (A, B.

vitamin

lesions

45

0

0

I

0

0

CDE

56 67 78 89 lOll

0 0 3 6 3

I 6 4 9 4

0 0 3 7 1

0 1 4 5 0

0 0 2 7 4

mild

=

36.4, X = 35.7, Xo2 > X2. Indemg/lOO ml, Y = bone lesions (A, B.

FIG.

owing

Our

2. X-Ray

film

(case

the

reveal seen

chemical rickets etiology ing that

sign. in

this

would

latter

group

like

on

no

bone

in the al. (I)

lesions.

that or

only

radiography.

marked bone leas their main to suggest has

same infant. produced two

that

a different

and pathogenesis, without vitamin D deficiency and

cannot coexist Hurwitz et

I), no rachitic

We

causes

instead

have

as

or

diof Ca, which in with or withrachitic bone

absorption hypocalcemia ultimately

However, infants that have sions have hypophosphatemia

lack

intake

sunlight,

hypocalcemia

and

is that

inadequate

to

lesions

etiology

rickets

findings

with bone

of

to

exposure

lesions. infants

B

d.f’. 24, Xo pendent X SCa. C. D. E).

D,

insufficient

minished intestinal turn brings about out tetany and

A

X

of

view

of nutritional

implyrickets types

of

Downloaded from https://academic.oup.com/ajcn/article-abstract/29/11/1222/4649714 by University of Rhode Island user on 09 December 2018

infant

nutritional infant was

ET

NUTRITIONAL

3. X-Ray

film

(case

deficiency in rats. In the first group fed a diet with normal Ca and P without vitamin D, the animals had low serum Ca, but normal serum P and nearly normal amounts of Ca and P in their bones. The second, fed a diet high in Ca, low in P and adequate in vitamin D, developed hypophosphatem ia, hypercalcemia, and

a severe

P deficit

of

Ca

and

P in

their

bones with characteristic rickets-like signs. Our two groups of infants seem to conform to these two types of deficiency. The first group of

infants

min no

D and or

only

had

as primary

cause

presented

with

very

bone

mild

lack

of vita-

hypocalcemia lesions

and

(Table

3).

The existence of the second group becomes apparent from our having found a close relationship between the values of serum P and the

severity

of the

bone

lesions

(Table

2) and

2). typical

IN

INFANTS

rachitic

hone

1225

lesions,

an inverse relationship between SAP and serum P (Fig. I). Since SAP levels are thought to reflect bone cell function (4) it seems that hypophosphatemia rather than hypocalcemia is associated with the development of rickets-like bone lesions. This suggests that in these infants the primary rachitogenic factor is a lack of phosphorus and not of vitamin D and recalls the comment of Harrison et al. (5) that “the failure of bone salt deposition in growing bones which is the characteristic picture of rickets is correlated with the reduction of the concentration of serum phosphorus rather than with the decrease of serum calcium levels.” Since the plasma phosphate level reflects phosphate intake (7), hypophosphatemia in the second type of nutritional rickets is either

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FIG.

RICKETS

LAPATSANIS

1226

ET AL. foetus and young infant. In: Mineral Metabolism in Paediatrics, edited by D. Barltop and W. L. Burland. Oxford and Edinburgh: Blackwell Scientific Publications, 1969, p. 51. 3. LAPATSANIS, P., B. DEIiIANNI AND 5. D0xIADIS. Vitamin D deficiency rickets in Greece. J.

rickets

Pediat. 73: 195, 1968. DULRSMA, S., R. VAN KESTEREN, W. VISSER, J. ROELOFS AND J. RAYMAKERS. Serum alkaline phosphatase: Its relation to bone cells and its significance as indicator for vitamin D treatment in patients with renal insufficiency. In: Vitamin D and Problems of Uremic Bone Disease, edited by A. Norman, K. Schaefer, H. Grigoleit, D. Herrath, and E. Ritz. Berlin: Walter de Gruyter Co., 1975, p. 167. 5. HARRISON, E. C., H. E. HARRISON AND E. A. PARK. Vitamin D and citrate metabolism. Effect of vitamin D in rats fed diets adequate in both calcium and phosphorus. Am. J. Physiol. 192: 432, 1958.

(6),

points

to another

possible

cause

of

hypophosphatemia, i.e., a genetic defect in renal (8) or intestinal (9) P transport. This genetic defect acquires clinical significance only during the period of rapid growth during infancy. At other times the body can adequately cope with this minimal defect. Since vitamin D has been shown to act on both calcium and phosphate transport (10), it is not surprising that both groups, i.e., those with

true

phosphate treatment.

vitamin

D deficiency

deficiency, Moreover

phatemic

infants

and

responded in with

those

with

to vitamin

three

D

thank

Professor

Felix

rickets-like

Bronner

6.

bone

for

his

valuable

advice.

References I. HL’RWITZ, S., R. E. STA’i\ SNE) F. BRONNER. Role of vitamin D in plasma calcium regulation. Am. J. Physiol. 216: 254, 1969. 2. STEENDIJK, R. Bone and calcium homeostasis in the

DOxIADIS, TOS

hypophos-

lesions we have recently achieved healing by increased intake of P alone, without additional vitamin D. El We

4.

tional

7.

AXE)

rickets.

WATKINS, AND

S., C. ANGELIS, P. LAPATSANIS.

F.

Arch.

G. W., BRONNER.

Disease

T.

D.

Regulation

in the rat. International 1975. In press. 8. GLORIEUX,

P. KARANTZAS, Genetic

C. VRE-

aspects

Childhood JOHNSON, of

Workshop

of

51: 83,

E. E. plasma

on

nutri-

1976.

G0LLUB

phosphate

Phosphate,

F. H., C. R. SCRIVER, T. M. READE, M. A. ROSEBOROUGII. Use of phosphate and vitamin D to prevent dwarfism and rickets in X-linked hypophosphatemia. New EngI. J. Med. 287: 481, 1972. 9. SHORT, F. M., H. J. BINDER AXE) L. E. ROSENBERG. Familial hypophosphatemic rickets: defective transport of inorganic phosphate by intestinal mucosa. Science 179: 700, 1973. 10. BRONNER, F. Vitamin D deficiency’ and rickets. Am. J. Clin. Nutr. 29: 1307. 1976. GOLDMAN

ANt)

Downloaded from https://academic.oup.com/ajcn/article-abstract/29/11/1222/4649714 by University of Rhode Island user on 09 December 2018

the result of low P intake or, as seems more likely, of a discrepancy between P intake and the increased P needs of the growing infant. Our work, showing that there might be a genetic element in infants with nutritional