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Case Report

Ann Nutr Metab 2005;49:107–109 Published online: March 29, 2005


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 Introduction


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

© 2005 S. Karger AG, Basel Khanh V.Q. Luong, MD, PhD


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port the first adult case of hypophosphatasia with absence mal concentration of urinary PEA [6, 9], which was also
of intestinal ALP isoenzyme associated with a low level seen in our patient.
of RBC TPP. 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
Case Presentation
[11], and there is a positive correlation between the mag-
A 33-year-old Vietnamese-American female was referred for a nitude of the increase and the severity of the clinical
long history of low levels of serum ALP. Her past medical histories symptoms [12]. In Canadian Mennonites, carriers of se-
were remarkable for dental problems as a child, hyperthyroidism vere forms of hypophosphatasia have also been detected
and urinary tract infection. Her older sister also had a low level of
by measurement of the plasma PLP concentration [13].
serum ALP and a history of multiple caries of the teeth. Family
members declined further investigation of hypophosphatasia that The usefulness of assaying the plasma PLP concentration,
ran in their family. At the time of examination, she was in a euthy- before and after oral pyridoxine loading, in the assign-
roid state and did not take any medications. She had a normal ment of carriers has recently been assessed in this popula-
physical examination except for multiple caries of the teeth. Labo- tion and this approach was found to be relatively sensitive
ratory data were as follows: glucose 93 mg/dl (normal 70–105);
and specific. Therefore, our patient had a high level of
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 PLP and a low activity of ALP that suggested an adult
0.8 mg/dl (normal 0.6–1.1); blood urea nitrogen 11 mg/dl (normal form of hypophosphatasia.
6–24); total protein 7 g/dl (normal 6.3–8.3); albumin 4.6 g/dl (nor- In 1999, Iqbal et al. [2] reported that their 2 hypophos-
mal 3.9–5.1); globulin 2.4 g/dl (normal 1.5–3.8); total bilirubin phatasia patients had high levels of RBC TPP. However,
0.8 mg/dl (normal 0.1–1.2); aspartate transaminase 19 U/l (normal
they could not conclude in 1 case with renal failure and
!31); alanine transaminase 16 U/l (normal !31); triiodothyronine
uptake 29% (normal 23–36); thyroxine (by radioimmunoassay) the other patient had a severe childhood form of hypo-
7.4 g/dl (normal 5–12); triiodothyronine (by radioimmunoassay) phosphatasia. This inborn error of metabolism is charac-
104 ng/dl (normal 50–160); sensitive thyroid-stimulating hormone terized biochemically by subnormal activity of the tissue-
1.4 mIU/ml (normal 0.5–4.6), and ALP 22 U/l (normal 40–135). nonspecific (bone/liver/kidney) isoenzyme of alkaline
The electrophoresis fractions of serum ALP were: 0% intestinal
phosphatase (TNSALP). Activity of tissue-specific intes-
(normal 3–11), 67% bone (normal 23–60), and 33% liver (normal
38–70). The other special blood tests were as follows: leukocyte tinal, placental, and germ-cell ALP isoenzymes (TSALP)
ALP score 56 (normal 11–95); PLP (by radioenzymatic assay) is not usually diminished [14] in hypophosphatasia.
66 ng/ml (normal 5–24); TPP (by high-performance liquid chroma- Bone-derived ALP in the serum of infantile hypophos-
tography) 61 nmol/l (normal 79–178); vitamin B1 assessment (ac- phatasia was reported to migrate abnormally slow on elec-
tivation by TPP) 0.1% (normal !23%); 24-hour urine for PEA (by
column chromatography) 41 mol/g creatinine (normal 38–155),
trophoresis [15]. These abnormal enzymes partially re-
and 24-hour urine for hydroxyproline 24 mg/g creatinine (normal semble intestinal ALP, and it has been suggested that in-
25–77). Roentgenograms revealed diffuse osteopenia throughout testinal ALP is induced in certain tissues to compensate
the skeleton. Her bone mineral density of the lumbar spine, mea- for the lack of TNSALP [16–18]. However, Fallon et al.
sured by dual-energy X-ray absorptiometry, revealed a T-score of [19], based upon a polyclonal antibody to the human liv-
–1.19 and a Z-score of –1.13. A T-score of the left hip was –0.78.
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
Discussion al. [18] used isoelectric focusing and enzyme inhibition
studies and suggested that a low level of ALP activity de-
Accumulation of PEA, PPi and PLP is usually seen in tected in organs of 1 patient was intestinal ALP. In addi-
hypophosphatasia. The urinary PEA concentration is in- tion, there were some reports [20–22] about a reduction
creased in subjects with all clinical forms of the disease or no activity of intestinal ALP in hypophosphatasia pa-
[4–6], but it is not specific for hypophosphatasia. These tients. Of interest, our patient had a low level of TPP and
levels correlate inversely with the liver ALP, but there is absence of intestinal ALP isoenzyme activity. Intestinal
no correlation between urinary PEA and circulating bone ALP occurs in a high concentration in the brush borders
ALP isoenzymes [7] in hypophosphatasia. In addition, of intestinal cells. Schaller and Holler [23] reported that
urinary PEA levels can be increased in a variety of other intestinal ALP is involved in the process of active thia-
disorders [6, 8]. However, some subjects with hypophos- mine absorption in the intestinal tract. They have dem-
phatasia and their kindred members might exhibit a nor- onstrated that L-phenylalanine, an inhibitor of intestinal

108 Ann Nutr Metab 2005;49:107–109 Luong/Nguyen


ALP, decreased the transport of thiamine in vivo as well monophosphate during the intestinal transport in the rat.
as in vitro. Ethanol is well known to impair the intestinal However, a lack of intestinal ALP activity is not neces-
absorption of thiamine in humans [24, 25] and animals sarily attributable to hypophosphatasia. Intestinal ALP is
[26]. Zucoloto et al. [27] studied the effect of chronic eth- found in the serum of 20–25% of normal adult popula-
anol consumption on the activities of residual small bow- tions [30, 31], and when present, it contributes approxi-
el brush border enzymes and found that ALP activity is mately 13–29% of the total activity of ALP [32].
decreased in the mucosa and in the enterocyte brush bor- In conclusion, our adult case of hypophosphatasia pre-
der. Matsuda et al. [28] also reported that ALP activity sented with a high level of plasma PLP but a normal uri-
was significantly decreased 1 h after oral administration nary PEA level. She had a low ALP activity with absence
of ethanol at 0.5 and 2.5 g/kg and suggested that intestinal of intestinal ALP isoenzyme that might result in decreas-
ALP plays a functional role in the active transport of thi- ing the absorption of thiamine in the intestinal tract. There-
amine. Furthermore, Rindi et al. [29] found that intesti- fore, the thiamine level should be considered in hypophos-
nal ALP can transphosphorylate thiamine to thiamine 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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