Case Report
Ann Nutr Metab 2005;49:107–109
DOI: 10.1159/000084743
Adult Hypophosphatasia and a Low
Level of Red Blood Cell Thiamine
Pyrophosphate
Khanh Vinh Quoc Luong Lan Thi Hoang Nguyen
Vietnamese American Medical Research Foundation, Westminster, Calif., USA
Key Words
Hypophosphatasia
Thiamine pyrophosphate

Alkaline phosphatase
Abstract
Objective: To report the first adult case of hypophospha-
tasia and absence of intestinal alkaline phosphatase
(ALP) isoenzymes associated with a low level of red
blood cell thiamine pyrophosphate. Methods: We de-
scribe the clinical manifestation and laboratory findings
in our patient and discuss underlying factors that poten-
tially contribute to her condition. Results: A 33-year-old
Vietnamese-American female was referred for a long
history of low levels of serum ALP and absence of intes-
tinal ALP isoenzyme. She had a normal level of urinary
phosphoethanolamine and a high level of plasma pyri-
doxal-5p-phosphate. She was found to have a low level
of red blood cell thiamine pyrophosphate. Conclusion:
Our adult case of hypophosphatasia presented with an
absence of intestinal ALP isoenzyme that might result in
decreasing the absorption of thiamine in the intestinal
tract. Therefore, the thiamine level should be considered
in hypophosphatasia with absence of intestinal ALP iso-
enzyme.
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Published online: March 29, 2005
Introduction
In humans there are at least four distinct isoenzyme
forms of alkaline phosphatase (ALP): tissue-nonspecific
ALP (TNSALP), also known as ‘liver/bone/kidney ALP’,
and tissue-specific intestinal, placental, and germ-cell
ALP. A separate gene encodes each isoenzyme. Expres-
sion of placental, intestinal, and germ-cell ALPs is lim-
ited to a few specific tissues, whereas TNSALP is present
in many cell types and is especially rich in mineralizing
bone. Reduction of ALP activity has been known in hy-
pophosphatasia. It is a rare heritable type of rickets or
osteomalacia. A lack of ALP activity might result in ab-
normal extracellular metabolism of several phosphory-
lated compounds including phosphoethanolamine (PEA),
inorganic pyrophosphate (PPi) and pyridoxal-5-phos-
phate (PLP) [1]. In 1999, Iqbal et al. [2] reported that their
2 hypophosphatasia patients had high levels of red blood
cell (RBC) thiamine pyrophosphate (TPP). However, thi-
amine is necessary in the diet of most vertebrates and
some microorganisms. In mammalian cells, TPP-requir-
ing enzymes involved in decarboxylation of pyruvic and

-ketoglutaric acids are part of high molecular weight
complexes associated with the mitochondrial membranes.
Since all cells possess a requirement for TPP, thiamine
deficiency affects all organ systems, but the effects on the
neuromuscular are especially severe. Myopathy was re-
ported in some patients with hypophosphatasia [3]. With-
out proper diagnosis and effective treatment, patients
might suffer from vitamin deficiency. Therefore, we re-
Khanh V.Q. Luong, MD, PhD
14971 Brookhurst Street
Westminster, CA 92683 (USA)
Tel. +1 714 839 5898, Fax +1 714 839 5989
E-Mail Lng2687765@aol.com
port the first adult case of hypophosphatasia with absence
of intestinal ALP isoenzyme associated with a low level
of RBC TPP.
Case Presentation
A 33-year-old Vietnamese-American female was referred for a
long history of low levels of serum ALP. Her past medical histories
were remarkable for dental problems as a child, hyperthyroidism
and urinary tract infection. Her older sister also had a low level of
serum ALP and a history of multiple caries of the teeth. Family
members declined further investigation of hypophosphatasia that
ran in their family. At the time of examination, she was in a euthy-
roid state and did not take any medications. She had a normal
physical examination except for multiple caries of the teeth. Labo-
ratory data were as follows: glucose 93 mg/dl (normal 70–105);
calcium 9.1 mg/dl (normal 8.5–10.2); phosphorus 4.3 mg/dl (nor-
mal 2.5–4.5); magnesium 2 mg/dl (normal 1.6–2.6); creatinine
0.8 mg/dl (normal 0.6–1.1); blood urea nitrogen 11 mg/dl (normal
6–24); total protein 7 g/dl (normal 6.3–8.3); albumin 4.6 g/dl (nor-
mal 3.9–5.1); globulin 2.4 g/dl (normal 1.5–3.8); total bilirubin
0.8 mg/dl (normal 0.1–1.2); aspartate transaminase 19 U/l (normal
!31); alanine transaminase 16 U/l (normal !31); triiodothyronine
uptake 29% (normal 23–36); thyroxine (by radioimmunoassay)
7.4 g/dl (normal 5–12); triiodothyronine (by radioimmunoassay)
104 ng/dl (normal 50–160); sensitive thyroid-stimulating hormone
1.4 mIU/ml (normal 0.5–4.6), and ALP 22 U/l (normal 40–135).
The electrophoresis fractions of serum ALP were: 0% intestinal
(normal 3–11), 67% bone (normal 23–60), and 33% liver (normal
38–70). The other special blood tests were as follows: leukocyte
ALP score 56 (normal 11–95); PLP (by radioenzymatic assay)
66 ng/ml (normal 5–24); TPP (by high-performance liquid chroma-
tography) 61 nmol/l (normal 79–178); vitamin B1 assessment (ac-
tivation by TPP) 0.1% (normal !23%); 24-hour urine for PEA (by
column chromatography) 41 mol/g creatinine (normal 38–155),
and 24-hour urine for hydroxyproline 24 mg/g creatinine (normal
25–77). Roentgenograms revealed diffuse osteopenia throughout
the skeleton. Her bone mineral density of the lumbar spine, mea-
sured by dual-energy X-ray absorptiometry, revealed a T-score of
–1.19 and a Z-score of –1.13. A T-score of the left hip was –0.78.
Discussion
Accumulation of PEA, PPi and PLP is usually seen in
hypophosphatasia. The urinary PEA concentration is in-
creased in subjects with all clinical forms of the disease
[4–6], but it is not specific for hypophosphatasia. These
levels correlate inversely with the liver ALP, but there is
no correlation between urinary PEA and circulating bone
ALP isoenzymes [7] in hypophosphatasia. In addition,
urinary PEA levels can be increased in a variety of other
disorders [6, 8]. However, some subjects with hypophos-
phatasia and their kindred members might exhibit a nor-
108 Ann Nutr Metab 2005;49:107–109
mal concentration of urinary PEA [6, 9], which was also
seen in our patient.
Decreased catabolism of PLP is the most identified
metabolic abnormality in hypophosphatasia. Increased
plasma concentrations have been detected in all clinical
forms of the disease [10] and in pseudohypophosphatasia
[11], and there is a positive correlation between the mag-
nitude of the increase and the severity of the clinical
symptoms [12]. In Canadian Mennonites, carriers of se-
vere forms of hypophosphatasia have also been detected
by measurement of the plasma PLP concentration [13].
The usefulness of assaying the plasma PLP concentration,
before and after oral pyridoxine loading, in the assign-
ment of carriers has recently been assessed in this popula-
tion and this approach was found to be relatively sensitive
and specific. Therefore, our patient had a high level of
PLP and a low activity of ALP that suggested an adult
form of hypophosphatasia.
In 1999, Iqbal et al. [2] reported that their 2 hypophos-
phatasia patients had high levels of RBC TPP. However,
they could not conclude in 1 case with renal failure and
the other patient had a severe childhood form of hypo-
phosphatasia. This inborn error of metabolism is charac-
terized biochemically by subnormal activity of the tissue-
nonspecific (bone/liver/kidney) isoenzyme of alkaline
phosphatase (TNSALP). Activity of tissue-specific intes-
tinal, placental, and germ-cell ALP isoenzymes (TSALP)
is not usually diminished [14] in hypophosphatasia.
Bone-derived ALP in the serum of infantile hypophos-
phatasia was reported to migrate abnormally slow on elec-
trophoresis [15]. These abnormal enzymes partially re-
semble intestinal ALP, and it has been suggested that in-
testinal ALP is induced in certain tissues to compensate
for the lack of TNSALP [16–18]. However, Fallon et al.
[19], based upon a polyclonal antibody to the human liv-
er form of TNSALP, revealed normal amounts of immu-
noreactive TNSALP in the bone, liver, and kidney in 5
severely affected hypophosphatasia patients. Mueller et
al. [18] used isoelectric focusing and enzyme inhibition
studies and suggested that a low level of ALP activity de-
tected in organs of 1 patient was intestinal ALP. In addi-
tion, there were some reports [20–22] about a reduction
or no activity of intestinal ALP in hypophosphatasia pa-
tients. Of interest, our patient had a low level of TPP and
absence of intestinal ALP isoenzyme activity. Intestinal
ALP occurs in a high concentration in the brush borders
of intestinal cells. Schaller and Holler [23] reported that
intestinal ALP is involved in the process of active thia-
mine absorption in the intestinal tract. They have dem-
onstrated that L-phenylalanine, an inhibitor of intestinal
Luong/Nguyen
ALP, decreased the transport of thiamine in vivo as well
as in vitro. Ethanol is well known to impair the intestinal
absorption of thiamine in humans [24, 25] and animals
[26]. Zucoloto et al. [27] studied the effect of chronic eth-
anol consumption on the activities of residual small bow-
el brush border enzymes and found that ALP activity is
decreased in the mucosa and in the enterocyte brush bor-
der. Matsuda et al. [28] also reported that ALP activity
was significantly decreased 1 h after oral administration
of ethanol at 0.5 and 2.5 g/kg and suggested that intestinal
ALP plays a functional role in the active transport of thi-
amine. Furthermore, Rindi et al. [29] found that intesti-
nal ALP can transphosphorylate thiamine to thiamine
monophosphate during the intestinal transport in the rat.
However, a lack of intestinal ALP activity is not neces-
sarily attributable to hypophosphatasia. Intestinal ALP is
found in the serum of 20–25% of normal adult popula-
tions [30, 31], and when present, it contributes approxi-
mately 13–29% of the total activity of ALP [32].
In conclusion, our adult case of hypophosphatasia pre-
sented with a high level of plasma PLP but a normal uri-
nary PEA level. She had a low ALP activity with absence
of intestinal ALP isoenzyme that might result in decreas-
ing the absorption of thiamine in the intestinal tract. There-
fore, the thiamine level should be considered in hypophos-
phatasia with an absence of intestinal ALP isoenzyme.

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Adult Hypophosphatasia and a Low Level Ann Nutr Metab 2005;49:107–109 109
of RBC Thiamine Pyrophosphate
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