J R Soc Med 2004;97:322-325
doi:10.1258/jrsm.97.7.322
© 2004 Royal Society of Medicine
Routine biochemistry in suspected vitamin D deficiency
Steven R Peacey MD FRCP
Department of Diabetes and Endocrinology, Bradford Teaching Hospitals NHS
Trust, Duckworth Lane, Bradford, West Yorkshire BD9 6RJ, UK
E-mail:
srpeacey{at}talk21.com
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SUMMARY
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Vitamin D deficiency, which continues to be widespread amongst
persons of
Asian descent in the UK, is often detected from abnormal
results on routine
biochemistry. The aim of this study was to
assess the frequency of abnormal
results from routine baseline
tests of serum calcium, phosphate, and alkaline
phosphatase
in patients who subsequently proved to have vitamin D deficiency
and
secondary hyperparathyroidism. A retrospective examination was
undertaken
to assess these baseline indices in a cohort of 84
such patients seen in
Bradford—5 male; 80 of Asian descent;
median age 46 years (range 16-82);
serum 25-hydroxyvitamin D<10
µg/L; parathyroid hormone >54 ng/L.
Calcium was normal in 55 patients (66%), phosphate in 68 (81%) and alkaline
phosphatase in 24 (29%). In only 5 patients were all three indices outside the
normal range. The median parathyroid hormone concentration was significantly
greater in patients with abnormal routine biochemistry (145 [range 55-1662]
ng/L) than in patients with normal routine biochemistry (88 [59-322] ng/L) but
the median 25-hydroxyvitamin D levels did not differ (3.1 [1.3-9.9] and 3.0
[1.5-7.3] µg/L). Routine biochemistry was normal in 20% of cases.
If routine biochemistry is relied upon to detect vitamin D deficiency and
osteomalacia, a substantial minority of cases will be missed.
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INTRODUCTION
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The high prevalence of vitamin D deficiency and osteomalacia
within the
Asian community in the UK has been amply documented
since the
1960s.
1-4
In 1976 Ford and co-workers, having studied
the vitamin D status of Bradford's
Asian children, wrote of
the urgent need for prophylactic
measures.
3
Nevertheless, local
awareness of this condition remains poor and sizeable
numbers
of patients with clinically severe vitamin D deficiency and
osteomalacia
continue to be seen in secondary care. To address this major
public
health issue the UK Department of Health opted for a strategy
that
relies on enhancement of professional awareness, health
education, and vitamin
D supplementation for particular groups
rather than widespread fortification
of
foods.
5,6
In practice,
reliance is often on case finding, with a low threshold for
considering
vitamin D deficiency and osteomalacia in patients of Asian descent
who
present with musculoskeletal symptoms. In addition, the ‘routine
biochemistry’
sought by primary care practitioners includes serum
adjusted
calcium (Ca), phosphate (PO) and total alkaline phosphatase
(ALP),
often in conjunction with 25-hydroxyvitamin D (25-OHD).
The last is
particularly expensive.
Whilst previous studies have examined biochemical indicators in patients
with histological osteomalacia, the aim of the present investigation was to
determine the frequency of normal and abnormal ‘routine
biochemistry’ in a well-defined group of patients who were shown to have
25-OHD deficiency and secondary hyperparathyroidism.
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PATIENTS AND METHODS
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In 1999 a computerized database (Access, Microsoft Corp, USA)
was
established within the Department of Diabetes and Endocrinology
to record data
prospectively on all patients with a definite
endocrine diagnosis. A
retrospective search of this database
was made to identify patients with a
diagnosis of vitamin D
deficiency or osteomalacia. Patients included in this
cohort
had been referred either because of a biochemical abnormality
detected
by their general practitioner or because in other secondary-care
settings
(endocrine, diabetes, general medicine) they had reported
musculoskeletal
symptoms. 116 patients were identified. 32 of
these were excluded from further
analysis because of inadequate
biochemical data (
n=10), concomitant
primary/tertiary hyperparathyroidism
(hypercalcaemia) (
n=7),
diagnostic label of hypoparathyroidism
incorrect (
n=4), renal
impairment (
n=6), liver disease (
n=1),
phenytoin therapy
(
n=2) and pretreatment with vitamin D (
n=2).
The remaining
84 patients all had their 25-OHD, parathyroid
hormone (PTH), Ca, PO and ALP
measured before treatment, and
subsequent analysis is restricted to this
group. All 84 had
both hypovitaminosis D (<10 µg/L) and a raised PTH
(>4
ng/L). The timing of the samples proved to be evenly distributed
throughout
the year.
The Mann-Whitney U test was used for unpaired non-parametric data and
Spearman's rank correlation test to look for associations. A P value
of <0.05 was taken as statistically significant. Local laboratory normal
ranges were used as indicated. PTH was measured by whole-molecule
double-antibody immunoassay (Nichols Advantage), 25-OHD by manual extraction
single-antibody radioimmunoassay (DiaSorin, Stillwater, Minnesota), Ca by
colorimetric-cresolphthalein complexone (Roche Hitachi 747), ALP by IFCC
method, DEA buffer (Roche Hitachi 747), and PO by a
colorimetric-phosphomolybdate method (Roche Hitachi 747). All assays were
performed according to the manufacturers' instructions. Laboratory reference
ranges for these indices were: 25-OHD 10-45 µg/L, PTH 10-54 ng/L, Ca
2.15-2.55 mmol/L, PO 0.8-1.3 mmol/L, ALP 50-240 IU/L.
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RESULTS
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79 of the 84 patients were female; 80 were of Asian descent
and 4 European.
The median age at diagnosis was 46 years (range
16-82). Median (range) serum
25-OHD was 3.1 (1.3-9.9) µg/L,
PTH 117 (55-1662) ng/L, Ca 2.20
(1.14—2.44) mmol/L, PO
1.01 (0.45-1.56) mmol/L, ALP 286 (91-2863)
IU/L.
Ca was normal in 55 (66%), PO normal in 68 (81%) and ALP normal in 24 (29%)
patients (Figure 1
a-c). In 17 (20%) patients, Ca, PO and ALP were
all within the normal range. Only 5 (6%) patients had all three biochemical
indices outside the normal range. The most frequent combined abnormality was
low calcium and raised ALP (with or without abnormal PO), present in 24 (29%)
patients, and the most frequent isolated abnormality was a raised ALP, present
in 27 (32%) patients. Only 2% of patients had a low PO in isolation.
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Figure 1. Serum adjusted calcium (a), phosphate (b) and total
alkaline phosphatase (c) in patients with 25-OHD deficiency and
secondary hyperparathyroidism (n=84) [Horizontal lines indicate
lower limits of normal ranges]
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Patients with normal biochemistry (Ca, PO and ALP), termed group N
(n=17), were compared with patients in whom there was at least one
abnormality (low Ca, low PO or raised ALP), termed group ABN (n=67).
The PTH concentration was significantly greater in group ABN (145 [range
55-1662] ng/L) than in group N (88 [59-322] ng/L; P<0.002)
(Figure 2a). 25-OHD
did not differ between group ABN (3.1 [1.3-9.9] µg/L) and group N (3.0
[1.5-7.3] µg/L); P=0.96 (Figure
2b). A negative correlation was found between PTH and
calcium (r=-0.57, -0.7 to -0.4; P<0.0001) and a positive
correlation between PTH and ALP (r=0.6, 0.45 to 0.72;
P<0.0001). Overall, a weak negative correlation was found between
PTH and 25-OHD (r=-0.39, -0.56 to -0.18; P=0.002). A
border-line positive correlation was found between 25-OHD and calcium
(r=0.22, 0 to 0.42; P=0.05). 5 patients (6%) proved to have
coeliac disease—3 out of the 4 with European origins and 2 of the 80
with Asian origins.
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Figure 2. Serum PTH (a) and 25-OHD (b) in patients with normal
biochemistry (group N) and patients with at least one biochemical abnormality
(group ABN). Limit of detection for 25-OHD=1.5 µg/L
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DISCUSSION
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In the context of 25-OHD deficiency, a raised PTH usually indicates
secondary
hyperparathyroidism (unless there is concomitant primary or
tertiary
hyperparathyroidism). PTH is the best biochemical marker
of underlying
histological
osteomalacia;
7 and,
at very least,
secondary hyperparathyroidism leads to bone resorption and
osteoporosis.
8 This
study of patients with 25-OHD deficiency and secondary
hyperparathyroidism
shows that 20% have normal routine biochemistry
(Ca, PO and ALP) and that, if
laboratory testing is confined
to routine biochemistry, a substantial minority
(20%) of these
high-risk cases will be missed. It may be argued that, since
patients
were commonly referred to our department
because of abnormal
biochemistry,
this may reflect selection bias. However, in primary care the
modes
of presentation mean that an even higher proportion with
‘biochemical
osteomalacia’ are likely to escape detection by
routine
biochemistry.
9
In Asians, a raised PTH is a better determinant of histological
osteomalacia than
25-OHD7,10
and the extent of the increase is likely to reflect the severity of bone
disease.4 In the
present study, patients with abnormal routine biochemistry had a greater
increase in PTH than those with normal biochemistry—in other words,
abnormal routine biochemistry may point to more advanced bone disease. In
previous work, only 10% of patients with histological osteomalacia
were found to have normal routine
biochemistry,7,11
probably because they had more advanced bone disease than our cohort.
Clinical scoring systems have been used to detect osteomalacia and have
been suggested as a screening
procedure.7,12
However, two of the four discriminative criteria used in such a scoring system
do not apply to the majority of Asians in Bradford. Whilst health education,
professional awareness and appropriate use of supplements should remain the
mainstay for prevention of this condition, a biochemical strategy is required
where patients present with musculoskeletal symptoms. Although ALP is commonly
abnormal in osteomalacia and may predict histological
osteomalacia,11
total ALP is commonly raised in Asian patients because of obesity or
type 2 diabetes mellitus, leading to a high false-positive rate for
osteomalacia if used
alone.7 Routine
measurement of PO seems of negligible benefit. Although some workers advocate
measurement of 25-OHD wherever deficiency is
suspected,13 this
is probably a waste of resources in populations with a high prevalence of
vitamin D deficiency, since this expensive test may still not indicate whether
musculoskeletal symptoms are attributable to vitamin D deficiency. Although
the same might be argued for measurement of PTH, it is less costly (about
£9 rather than £25), is more predictive of
osteomalacia7,10
and is therefore a better initial test for Asian patients with musculoskeletal
symptoms. A reasonable policy is to measure Ca and
PTH7,9,14
in the first instance and to presume a diagnosis of vitamin D
deficiency/osteomalacia if PTH is raised in association with a low or
low-normal calcium (to avoid inclusion of patients with primary
hyperparathyroidism). Measurement of creatinine, endomysial antibodies and
mean corpuscular volume (MCV) will detect patients with renal disease and
identify patients who should be investigated for possible coeliac disease.
Coeliac disease accounted for 2.5% of Asian cases in this study and should not
be forgotten as a cause of osteomalacia in this
group.15,16
In summary, for populations with a high prevalence of vitamin D deficiency
or osteomalacia, biochemical assessment of suspected cases should include
measurement of PTH, Ca, creatinine, FBC and endomysial antibodies. If only
routine biochemistry is used, a substantial minority of these high-risk cases
will be missed.
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Acknowledgments
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I thank Linda Wood for continuing maintenance of the departmental
endocrine
database and Doug Hirst for the laboratory assay details.
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REFERENCES
|
|---|
- Dunnigan MG, Paton JPJ, Hasse S, McNichol GW, Gardner MD, Smith CM.
Late rickets and osteomalacia in the Pakistani community in Glasgow.
Scott Med J1962; 7:159
-67[Medline]
- Ford JA, Colhoun EM, McIntosh WB, Dunnigan MG. Rickets and
osteomalacia in the Glasgow Pakistani community, 1961-71.
BMJ1972; ii:677
-80
- Ford JA, McIntosh WV, Butterfield R, et al. Clinical and
subclinical vitamin D deficiency in Bradford children. Arch Dis
Child 1976;51:939
-43[Abstract/Free Full Text]
- Finch PJ, Ang L, Eastwood JB, Maxwell JD. Clinical and histological
spectrum of osteomalacia among Asians in south London. Quart J
Med 1992;83:439
-48[Medline]
- Committee on Medical Aspects of Food Policy. Working
Party on the Fortification of Food with Vitamin D. London: HM
Stationery Office, 1980
- Panel on Dietary Reference Values of the Committee on Medical
Aspects of Food Policy. Dietary Reference Values for Food Energy
and Nutrients for the United Kingdom. London: HM Stationery
Office, 1991
- Nisbet JA, Eastwood JB, Colston KW, et al. Detection of
osteomalacia in British Asians: a comparison of clinical score with
biochemical measurements. Clin Sci1990; 78:383
-9[Medline]
- Lips P. Vitamin D deficiency and secondary hyperparathyroidism in
the elderly: consequences for bone loss and fractures and therapeutic
implications. Endocr Rev2001; 22:477
-501[Abstract/Free Full Text]
- Solanki T, Hyatt RH, Kemm JR, Hughes EA, Cowan RA. Are elderly
Asians in Britain at a high risk of vitamin D deficiency and osteomalacia?
Age Ageing1995; 24:103
-7[Abstract/Free Full Text]
- Mawer EB, Backhouse J, Hill LF, et al. Vitamin D
metabolism and parathyroid function in man. Clin Sci Molec
Med 1975;48:349
-65
- Peach H, Compston JE, Vedi S, Horton LWL. Value of plasma calcium,
phosphate and alkaline phosphatase measurements in the diagnosis of
histological osteomalacia. J Clin Pathol1982; 35:625
-30[Abstract/Free Full Text]
- Peach H, Compston JE, Vedi S. Value of the history in diagnosis of
histological osteomalacia among Asians presenting to the NHS.
Lancet1983; ii:1347
-9
- Plehwe WE. Vitamin D deficiency in the 21st century: an unnecessary
pandemic? Clin Endocrinol2003; 59:22
-4[Medline]
- Parfitt AM. Screening for vitamin D depletion.
Lancet1984; i:227
-8
- Thalayasingham B. Coeliac disease as a cause of osteomalacia and
rickets in the Asian immigrant population. BMJ1985; 290:1146
-7[Free Full Text]
- Sheikh S, Williamson K, Kearley K, Bassindale S, Lancaster T.
Danger of stereotyping in suspected osteomalacia. BMJ2001; 323:149
-51[Free Full Text]
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