Hematology

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Vitamin B6 deficiency as a cause of

polyneuropathy in POEMS syndrome: rapid
recovery with supplementation in two cases

Hajime Yasuda, Yoshiki Furukawa, Kenya Nishioka, Makoto Sasaki, Yutaka

Tsukune, Shuichi Shirane, Nobutaka Hattori, Miki Ando & Norio Komatsu

To cite this article: Hajime Yasuda, Yoshiki Furukawa, Kenya Nishioka, Makoto Sasaki, Yutaka
Tsukune, Shuichi Shirane, Nobutaka Hattori, Miki Ando & Norio Komatsu (2022) Vitamin B6
deficiency as a cause of polyneuropathy in POEMS syndrome: rapid recovery with supplementation
in two cases, Hematology, 27:1, 463-468, DOI: 10.1080/16078454.2022.2060456

To link to this article: https://doi.org/10.1080/16078454.2022.2060456

© 2022 The Author(s). Published by Informa

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Group

Published online: 12 Apr 2022.

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HEMATOLOGY
2022, VOL. 27, NO. 1, 463–468
https://doi.org/10.1080/16078454.2022.2060456

CASE REPORT

Vitamin B6 deficiency as a cause of polyneuropathy in POEMS syndrome: rapid

recovery with supplementation in two cases
Hajime Yasuda a, Yoshiki Furukawaa, Kenya Nishiokab, Makoto Sasakia, Yutaka Tsukunea, Shuichi Shiranea,
Nobutaka Hattorib, Miki Andoa and Norio Komatsu a,c,d
a
Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan; bDepartment of Neurology, Juntendo University
School of Medicine, Tokyo, Japan; cLaboratory for the Development of Therapies Against MPN, Juntendo University School of Medicine,
Tokyo, Japan; dDepartment of Advanced Hematology, Juntendo University School of Medicine, Tokyo, Japan

ABSTRACT KEYWORDS
Background: The etiology of POEMS syndrome and its associated polyneuropathy have not Pyridoxine; vascular
been fully elucidated. The clinical picture of POEMS-associated polyneuropathy and endothelial growth factor;
nutritional polyneuropathy due to vitamin B6 (VB6) deficiency are strikingly similar, both VEGF; endocrinopathy;
being typically sensorimotor, symmetrical, stocking and glove distribution, and more severe peripheral neuropathy;
pyridoxal phosphate
in the lower extremities. hydrate; treatment;
Case presentation: We report two consecutive POEMS patients with VB6 deficiency who demyelination
showed unusual rapid and drastic recovery of polyneuropathies within 6–8 weeks after oral
VB6 supplementation. Case 1 was supplemented with VB6 from time of autologous stem
cell transplantation. Polyneuropathy began to improve within one week, and he became
walker-free and could walk unaided with a cane within 6 weeks. Case 2 was supplemented
with VB6 from time of stem cell harvest, and he became cane-free and his gait almost
normalized within two months. Nerve conduction studies were also confirmatory of
neurologic recovery in both cases.
Conclusions: Objective physical improvement of POEMS-associated polyneuropathy has been
reported to typically require approximately a year after autologous stem cell transplantation,
and together with our observations of VB6 deficiency and supplementations leading to
accelerated recoveries of polyneuropathy, VB6 deficiency most probably contributes to
POEMS-associated polyneuropathy. VB6 acts as a coenzyme in approximately 150
biochemical reactions. VB6 has been reported to inhibit the hypoxia-inducible factor/
vascular endothelial growth factor (VEGF) pathway, and VEGF levels are known to corollate
with disease activity of POEMS syndrome. Therefore, VB6 deficiency may contribute not only
to POEMS-associated polyneuropathy, but also to the etiology of POEMS syndrome itself.

Introduction
POEMS syndrome is a paraneoplastic syndrome attrib-
uted to an underlying plasma cell neoplasm. The
acronym POEMS stands for polyneuropathy, organo-
megaly, endocrinopathy, monoclonal plasma cell dis-
order, and skin changes. Other characteristic features
not included in the acronym are papilledema, extra-
vascular volume overload, sclerotic bone lesions, and
thrombocytosis/erythrocytosis. The etiology of
POEMS syndrome and its diverse manifestations have
not been fully elucidated, but many of the clinical
manifestations are thought to be the result of
increased vascular permeability and neovasculariza-
tion secondary to cytokine overproduction of which
vascular endothelial growth factor (VEGF) plays a
central role. POEMS-associated polyneuropathy is typi-
cally sensorimotor, symmetrical, stocking and glove
distribution, and more severe in the lower extremities
[1,2]. POEMS-associated polyneuropathy is usually
slowly progressive, but onset and progression may
be acute in certain patients with various contributing
factors [3,4]. Anti-plasma cell therapy including autolo-
gous stem cell transplantation (ASCT) is often effective
for POEMS syndrome, but recovery of polyneuropathy
is usually an extremely slow process [2]. We report
two consecutive POEMS patients presenting with
vitamin B6 (VB6) deficiency who experienced unusual
rapid recovery of polyneuropathy after VB6 sup-
plementation. The clinical picture of polyneuropathy
seen in POEMS syndrome and VB6 deficiency are strik-
ingly similar, and we speculate that VB6 deficiency
plays a major role in POEMS-associated polyneuropa-
thy. The coenzymatic function of VB6 has been
reported to inhibit the hypoxia-inducible factor (HIF)/
VEGF pathway, and VEGF levels are known to correlate
with disease activity of POEMS syndrome [5]. Thus, VB6
deficiency may contribute not only to polyneuropathy,
but also to the etiology of POEMS syndrome itself.

CONTACT Hajime Yasuda hyasuda@juntendo.ac.jp

© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrest-
ricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
464 H. YASUDA ET AL.
Case presentation
Case 1 is a 50-year-old man presenting with polyneuro-
pathy, hyperpigmentation, edema, hypertrichosis, IgA-
lambda type M-protein, and an elevated serum VEGF
of 9470 pg/mL (normal range: 62–707 pg/mL). CT
scans revealed an isolated thoracic spine sclerotic
bone lesion (T9) and splenomegaly. POEMS syndrome
was diagnosed, and because bone marrow evaluation
revealed no clonal plasma cell proliferation, radiation
therapy of 40Gy to the T9 bone lesion was carried
out. However, no improvements in serum VEGF levels
and clinical symptoms (polyneuropathy, hyperpigmen-
tation, edema, hypertrichosis) were observed, and thus
thalidomide-dexamethasone therapy was initiated in
August 2018. Nearly a year of thalidomide-dexametha-
sone therapy led to a significant decrease of serum
VEGF levels, but again the clinical symptoms did not
improve. ASCT with melphalan 200 mg/m2 condition-
ing was carried out in April 2019. Subsequently, we dis-
covered that serum VB6 levels were undetectably low
at <2.0 ng/mL (normal values: 6.0–40.0 ng/mL for
males, commercially analyzed by SRL Inc., Tokyo,
Japan, as reported previously [6]) (Figure 1). Sup-
plementation with 60 mg/day of pyridoxal phosphate
hydrate (PPH) was initiated, and polyneuropathy
began to rapidly improve after 1 week of adminis-
tration, and within 6 weeks, he became walker-free
and could walk unaided with a cane. During these 6
weeks, hyperpigmentation was also almost completely
resolved.
Case 2 is a 51-year-old man presenting with poly-
neuropathy involving all four limbs, edema, hyperpig-
mentation, IgG-lambda type M-protein, and an
elevated serum VEGF of 3350 pg/mL. CT scans
revealed a thoracic spine tumor (T2-4) that was com-
pressing the spinal cord parenchyma, and multiple
osteosclerotic and osteolytic lesions in the thoracic
spine. The thoracic spine tumor was resected to
relieve spinal cord compression, and pathology
revealed a plasmacytoma. Thus, multiple myeloma
complicated by POEMS syndrome was diagnosed.
Postoperative radiation therapy of 24Gy was adminis-
tered to the original site of plasmacytoma, and three
courses of VRD (bortezomib, lenalidomide, dexa-
methasone) therapy were administered. Although the
patient’s gait disturbance improved and was able to
walk with a cane after resection of the plasmacytoma,
thereafter, his symptoms became fixed for approxi-
mately six months and numbness and loss of sensation
especially in the lower extremities persisted. In
October 2020, VB6 levels were found to be low at
3.8 ng/mL, and supplementation with 60 mg/day of
PPH was initiated (Figure 1). Subsequently, the
patient’s lingering symptoms of polyneuropathy sud-
denly started to improve, and he became cane-free
and his gait almost normalized within two months
after initiation of VB6 supplementation. The patient
underwent two more courses of VRD therapy and pro-
ceeded to ASCT with melphalan 200 mg/m2 condition-
ing in December 2020. The clinical course of case 2 has
been previously reported elsewhere [7].
Nerve conduction studies (NCS) also confirmed
improvements in polyneuropathy before and after
VB6 supplementation in both cases 1 and 2 (Table 1),
although one limitation is that the pre-evaluation of
NCS was not timed exactly before initiation of VB6
administration. Although VB6 supplementations were
ceased after ASCT in both cases, no relapses of poly-
neuropathy have occurred and both cases have main-
tained normal serum VB6 levels thereafter, and thus
VB6 deficiency may be a sign of worse disease status
in POEMS syndrome. In line with previous reports,
aspartate aminotransferase (AST) and alanine amino-
transferase (ALT) levels were low in both cases due
to VB6 deficiency, but elevations to normal levels
were observed with VB6 supplementations (Figure 1).
Discussion
Improvement of polyneuropathy in POEMS patients is
a slow process, and in a study of 17 patients, it was
reported that more than 12 months after ASCT was
necessary for an objective physical improvement to
be seen [2]. Compared to this, drastic improvements
in polyneuropathy were seen within 6–8 weeks in
our two POEMS patients after VB6 supplementation.
The clinical picture of POEMS-associated polyneuropa-
thy and nutritional polyneuropathy due to VB6
deficiency are strikingly similar, being typically sensor-
imotor, symmetrical, stocking and glove distribution,
and more severe in the lower extremities. Also
common to both polyneuropathies is that a proportion
of patients experience painful dysesthesias [1,8].
Together with our observations, it is tempting to
speculate that VB6 deficiency is the underlying cause
of POEMS-associated polyneuropathy. One argument
may be that within the limited data in humans, VB6-
deficient polyneuropathy has been reported to be pre-
dominantly due to axonopathy, whereas POEMS-
associated polyneuropathy involves both demyelina-
tion and axonopathy [1,9,10]. However, VB6 is necess-
ary as a coenzyme in sphingolipid synthesis and
therefore crucial for myelin formation, and in theory,
VB6 deficiency can well contribute to demyelination
[11]. Furthermore, in a study of rats fed a VB6-
deficient diet, overt polyneuropathy developed, and
nerve pathology revealed abnormal thinning of
myelin [12]. Therefore, VB6-deficient polyneuropathy
may also involve both demyelination and axonopathy
as is seen in POEMS-associated polyneuropathy.
VB6 deficiency in POEMS patients has not been pre-
viously studied. Besides the two cases presented here,
in actual, there was one more POEMS patient recently
 HEMATOLOGY 465

Figure 1. Clinical course of two POEMS patients with vitamin B6 deficiency. The dotted lines represent the lower limit of normal
for serum vitamin B6. ALT: alanine aminotransferase; ASCT: autologous stem cell transplantation; AST: aspartate aminotransferase;
NCS1: nerve conduction study (before VB6 administration); NCS2: nerve conduction study (after VB6 administration); OP: operation;
PPH: pyridoxal phosphate hydrate; RT: radiation therapy; THAL + DEX: thalidomide + dexamethasone; VB6: vitamin B6; VEGF: vas-
cular endothelial growth factor; VRD: bortezomib + lenalidomide + dexamethasone
466 H. YASUDA ET AL.

Table 1. Nerve conduction studies before and after vitamin B6 supplementation.

Case 1 Case 2
Limit of Before VB6 After VB6 Before VB6 After VB6
Nerve Site normal values supplementation supplementation supplementation supplementation
Left Left Right Right
Median Wrist-elbow MCV >48 m/s 23.9 30.2 44.3 52.6
nerve
Amp >5 mV 2.07 4.61 9.42 3.73
DL <4.5 ms 14.52 11.76 8.88 7.89
FWL <31.4 ms 48.7 47.3 24.4 20.0
FWO 6%, 1/16 94%, 15/16 100%, 16/16 100%, 16/16
Ulnar nerve Wrist-elbow MCV >46 m/s 29.2 37.9 45.1 59.8
groove
Amp >4.7 mV 2.68 4.29 6.41 5.79
DL <3.6 ms 18.06 12.72 8.79 7.62
FWL <31.7 ms N/A 46.8 30.9 28.9
FWO 0%, 0/16 69%, 11/16 100%, 16/16 100%, 16/16
Tibial nerve Ankle- MCV >36 m/s N/A N/A 31.8 39.9
popliteal
Amp >5.6 mV N/A N/A 5.43 7.67
DL <5.9 ms N/A N/A 15.8 13.1
FWL <56.8 ms N/A N/A 67.9 54.4
FWO N/A N/A 100%, 16/16 100%, 16/16
Peroneal Ankle-head MCV >37.1 m/s N/A N/A 30.1 41.6
nerve of fibula
Amp >0.7 mV N/A N/A 1.57 1.21
DL <6.2 ms N/A N/A 14.35 11.1
FWL <55.3 ms N/A N/A 62.9 52.8
FWO N/A N/A 94%, 15/16 100%, 16/16
Notes: Case1: Nerve conductions studies (NCS) showed improvements in motor conduction velocity, amplitude, distal latency, F-wave latency, and F-wave
occurrence in the Median and Ulnar nerves before and after VB6 supplementation. NCS was not performed in the lower extremities. Case 2: NCS showed
improvements in motor conduction velocity, distal latency, and F-wave latency in the Median, Ulnar, Tibial, and Peroneal nerves before and after vitamin
B6 supplementation. Amp: amplitude; DL: distal latency; FWL: F-wave latency; FWO: F-wave occurrence; MCV: motor conduction velocity; VB6: vitamin
B6.

found to have undetectably low VB6 levels of <2.0 ng/
mL at our institution. VB6 supplementation did not
have a clinical impact on this patient, but the degree
of polyneuropathy was much milder compared to
the two presented cases, making it difficult to assess
any neurologic improvements. Thus, in total, three
consecutive POEMS patients presented with VB6
deficiency at our institution, and VB6 deficiency may
be a universal finding among patients with POEMS
syndrome. VB6 is abundant in a wide range of food
sources, and the synthesis of VB6 by the gut flora
also contributes to VB6 intake. Therefore, VB6
deficiency is rare in the general population unless
special situations accompany such as malabsorption
due to bowel disease and resection, alcoholism,
eating disorders, hemodialysis, pregnancy, and
certain drugs (e.g. isoniazid, cycloserine, and penicilla-
mine) [6,11,13]. All three patients harbored none of
these traits.
VEGF levels have been reported to correlate with
POEMS disease activity, and VB6 is known to suppress
VEGF mRNA induction through inhibiting the VEGF
upstream regulator, HIF [5]. Thus, VB6 deficiency can
potentially contribute to the elevation of VEGF levels
and therefore may even play a role in the etiology of
POEMS syndrome. The main source of VEGF overpro-
duction in patients with POEMS syndrome remains
unclear due to reports with conflicting results. Nagao
et al reported that VEGF mRNA was not significantly
higher in plasma cells of POEMS syndrome compared
with other plasma cell dyscrasias, while Wang et al
reported that VEGF mRNA levels were significantly
higher in plasma cells of POEMS syndrome compared
to other plasma cell dyscrasias and are the source of
VEGF production. Wang et al also demonstrated that
bone marrow plasma cells exhibit higher levels of
VEGF mRNA expression compared to CD138-negative
cells in patients with POEMS syndrome, and also that
both monoclonal and polyclonal plasma cells of
patients with POEMS syndrome express equally high
levels of intracellular VEGF, which has been one of
the unsolved mysteries of POEMS syndrome [14,15].
However, a systemic dysregulation of HIF through
VB6 deficiency that equally affects both monoclonal
and polyclonal plasma cells would be a rational expla-
nation for this phenomenon [1].
VB6 acts as a coenzyme in approximately 150 bio-
chemical reactions that regulate metabolism of
amino acids, lipids, neurotransmitters, DNA, and
glucose [16]. Therefore, deficiency can lead to a wide
range of clinical manifestations that include, but are
not limited to, polyneuropathy, seizures, anemia, dia-
betes mellitus, dermatitis, stomatitis, and glossitis
[11]. Not only polyneuropathy, but also hyperpigmen-
tation rapidly regressed in case 1 after VB6 adminis-
tration, and we suspect that some of the skin
changes found in POEMS syndrome may be due to der-
matitis caused by VB6 deficiency. POEMS patients also
frequently present with endocrinopathies of which the
pathogenesis is unknown [1,17]. Surprisingly, both
 HEMATOLOGY 467

POEMS syndrome and VB6-deficient states have been Conclusions

associated with identical endocrinopathies or data in
Polyneuropathy is one of the most devastating manifes-
parallel including hypogonadism (low testosterone),
tations for patients with POEMS syndrome, and is irre-
hyperprolactinemia, hypothyroidism, diabetes melli-
versible in many cases because symptoms linger for
tus, and adrenal insufficiency. There is substantial evi-
long periods of time and damage accumulates even
dence for endocrinopathy developing under VB6-
after treatment initiation. Through our observations,
deficient states. Rats fed a VB6-free diet have been
VB6 deficiency may well be a universal finding
reported to show significantly decreased testosterone
amongst patients with POEMS syndrome, and early
plasma concentrations compared to controls [18].
rescue of polyneuropathy with VB6 supplementation as
VB6 deficiency can potentially cause hyperprolactine-
was observed in the presented cases would be most
mia because the conversion of dopa to dopamine is
ideal. The types and patterns of polyneuropathy and
VB6-dependent, and dopamine formation in hypo-
endocrinopathy in POEMS syndrome and VB6 deficiency
thalamic neurons has an inhibitory effect on prolactin.
are strikingly similar, and VB6 deficiency may be a cause
In line with this, two trials including a total of 349 par-
of multiple manifestations of POEMS syndrome. One
ticipants demonstrated that VB6 supplementation
limitation of this report is that the two patients presented
was effective in inhibiting post-partum lactation
were simultaneously being treated with drugs other than
[19]. Dakshinamurti et al reported in VB6-deficient
VB6, but the rapid neurological recoveries were only seen
rats low TSH, T3, and T4, and an intact TRH response,
directly after VB6 supplementation and therefore were
and thus demonstrated a hypothalamic type of
most likely attributed to VB6. Our observations need to
hypothyroidism [20]. As for diabetes mellitus, VB6
be validated in a larger number of patients, and the
deficiency has been reported to impair insulin
underlying mechanisms of VB6 deficiency occurring in
secretion in rats, and in vitro experiments of pancreas
POEMS patients need to be clarified.
perfusion have demonstrated equivalent results. Fur-
thermore, Drosophila with genetic mutations invol-
ving VB6 metabolism are known to develop Author contributions
diabetes mellitus [16]. In humans, VB6 deficiency
increases gestational glucose intolerance, and VB6 HY, YF, and KN wrote the manuscript, MS, YT, and SS
supplementation has been reported to improve collected and interpreted the data and did the litera-
glucose tolerance during pregnancy [21]. The catabo- ture research, NH, MA, and NK revised and approved
lism of tryptophan to serotonin is VB6-dependent, the manuscript.
and decreased serotonin in pancreatic islets has
been demonstrated to reduce β-cell proliferation in Data availability statement
a serotonin receptor 2B (HTR2B)-dependent manner,
Data from this study are available from the corresponding
and has been implicated as the underlying mechan-
author, Hajime Yasuda.
ism. Although VB6 deficiency has not been directly
linked to adrenal insufficiency, patients with depri-
vation of the VB6-dependent enzyme sphingosine Disclosure statement
phosphate lyase have been shown to develop
No potential conflict of interest was reported by the author(s).
adrenal insufficiency [22]. Autopsy cases of POEMS
patients have found structurally normal and non-
characteristic endocrine glands suggestive of a func- Funding
tional rather than a structural gland dysfunction, The author(s) reported there is no funding associated with
and this is supportive of the theory that VB6 the work featured in this article.
deficiency contributes to endocrinopathy in POEMS
syndrome [17].
Because the clinical manifestations of VB6 ORCID
deficiency are extremely diverse and none are Hajime Yasuda http://orcid.org/0000-0002-2896-7737
specific to VB6 deficiency, suspecting deficiency in Norio Komatsu http://orcid.org/0000-0003-1880-9126
the right patient can be difficult. However, patients
with VB6 deficiency are known to present with abnor-
mally low levels of AST and ALT [23], which is a useful
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