Menorrhagia in Patients With Type I Glycogen Storage Disease

Article (PDF Available)inObstetrics and Gynecology 122(6) · November 2013with158 Reads
DOI: 10.1097/01.AOG.0000435451.86108.82 · Source: PubMed
Abstract
To evaluate menorrhagia in a cohort of women with glycogen storage disease type I because it appears to be an under-recognized problem in females of reproductive age. A retrospective chart review was performed on 13 menstruating patients with glycogen storage disease type I (age 23-48 years) for a diagnosis of menorrhagia. Nine (69%) (confidence interval 0.39-0.91) women had development of menorrhagia. Median hemoglobin values in these patients were generally low (range 9.5-12.85 g/dL) but not different from those of the nonmenorrhagia group (hemoglobin range 9.55-11.0 g/dL) with glycogen storage disease type I. Four patients with menorrhagia required hospitalization or emergency department visits for treatment of menorrhagia. Two of the four patients hospitalized required blood transfusion, with an additional patient requiring a transfusion during pregnancy. Eight patients (89%) either were recommended to have or required medical or surgical treatment of their menorrhagia. Glycogen storage disease type I is associated with menorrhagia. The evaluation should include assessment of coagulation functions and referral to a gynecologist, hematologist, or both, because bleeding diathesis and polycystic ovary syndrome are common in patients with glycogen storage disease type I.
Menorrhagia in Patients With Type I
Glycogen Storage Disease
Original Research
Stephanie L. Austin, MS, MA, Areeg H. El-Gharbawy, MD, Vellor e G. Kasturi, MD , Andra James, MD,
and Priya S. Kishnani,
MD
OBJECTIVE: To evaluate menorrhagia in a cohort of
women with glycogen storage disease type I because it
appears to be an under-recognized problem in females
of reproductive age.
METHODS: A retrospective chart review was performed
on 13 menstruating patients with glycogen storage
disease type I (age 23–48 years) for a diagnosis of men-
orrhagia.
RESULTS: Nine (69%) (confidence interval 0.39–0.91)
women had development of menorrhagia. Median hemo-
globin values in these patients were generally low (range
9.5–12.85 g/dL) but not different from those of the non-
menorrhagia group (hemoglobin range 9.55–11.0 g/dL)
with glycogen storage disease type I. Four patients with
menorrhagia required hospitalization or emergency
department visits for treatment of menorrhagia. Two of
the four patients hospitalized required blood transfusion,
with an additional patient requiring a transfusion during
pregnancy. Eight patients (89%) either were recommen-
ded to have or required medical or surgical treatment of
their menorrhagia.
CONCLUSION: Glycogen storage disease type I is asso-
ciated with menorrhagia. The evaluation should include
assessment of coagulation functions and referral to
a gynecologist, hematologist, or both, because bleeding
diathesis and polycystic ovary syndrome are common in
patients with glycogen storage disease type I.
(Obstet Gynecol 2013;122:1246–54)
DOI: 10.1097/01.AOG.0000435451.86108.82
T
ype I glycogen storage disease (glucose-6-phosphatase
or translocase deficiency, von Gierke disease; Online
Mendelian Inheritance in Man 232200) is caused by
a defect in the glucose-6-phosphatase system. The effect
is profound hypoglycemia with fasting attributable to
inability to make glucose by gluconeogenesis or glyco-
genolysis. Two subtypes of glycogen storage disease I
are type Ia, which accounts for 8090% of glycogen
storage disease I cases and is caused by defective
glucose-6-phosphatase enzyme, and type Ib (which
accounts for most of the remaining cases), in which
translocase, the enzyme that transports glucose-6-phos-
phate across the microsomal membrane, is defective.
The majority of patients with glycogen storage
disease type I present with hepatomegaly, symptoms
of hypoglycemia, seizures, or a combination of these
during infancy. Secondary metabolic abnormalities
include lactic acidemia, hyperuricemia, and hyperlip-
idemia. Individuals with type Ib additionally have
neutropenia and impaired neutrophil function, and
can have recurrent bacterial infections.
1
During the past decades, improved dietary and
medical management have significantly improved
survival, resulting in an increased number of patients
reaching adulthood.
24
This has led to recognition of
the effect of glycogen storage disease type I on repro-
ductive health. Puberty often is delayed in males and
females.
5
Lee et al
6
reported that women with glyco-
gen storage disease type I commonly had a polycystic
appearance of their ovaries even before puberty.
Although adult women (n56) with glycogen storage
From the Departments of Pediatrics, Divisions of Medical Genetics, Duke
University Medical Center, Durham, North Carolina, and University of
Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and the Department of
Obstetrics and Gynecology, University of Virginia School of Medicine, Charlottes-
ville, Virginia.
Supported by the Childrens Fund for Glycogen Storage Disease Research and the
Association for Glycogen Storage Disease, United States.
The authors thank the glycogen storage disease type I patient population who
participated in this study.
Presented in part at the American Society of Human Genetics Annual Meeting,
Philadelphia, Pennsylvania, November 1115, 2008.
Corresponding author: Vellore Kasturi, Duke University Medical Center,
GSRB1, 905 La Salle Street, DUMC 103857, Durham, NC 27710; e-mail:
vellore.kasturi@duke.edu.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2013 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/13
1246 VOL. 122, NO. 6, DECEMBER 2013 OBSTETRICS & GYNECOLOGY
disease type I had polycystic ovaries that were associ-
ated with hyperinsulinism, manifestations of hyperan-
drogenism such as acne and hirsu tism did not occur.
There is not much information available regarding
anovulatory bleeding in these patients. It is not clear
how the features of polycystic ovary syndrome affect
fertility because successful pregnancies have been
reported.
7,8
Glycogen storage disease type I has been associ-
ated with a bleeding diathesis attributable to impaired
platelet function,
9
a von Willebrandlike defect,
10
or
both. Commo nly reported symptoms include epi -
staxis, easy bruising, bleeding gums, and excessive
bleeding after surgery. In a report by the European
Study on glycogen storage dise ase type I (age range
0.445.4 years), 19% of the patients had recurrent or
severe epistaxis, 3% had prolonged bleeding after sur-
gery, and 2% had urogenital tract bleeding, gastroin-
testinal bleeding, or both.
5
Although, heavy menstrual
bleeding, or menorrhagia, is the most common symp-
tom that women with bleeding disorders usually expe-
rience, there has been no specific reference to
menorrhagia as a bleeding manifestation of glycogen
storage disease type I in the literature we reviewed to
date.
Menorrhagia is defined as prolonged or excessive
bleeding (more than 80 mL of blood loss per
menstrual cycle).
11
Several circumstances correlate
with this amount of blo od loss, such as soaking
through one pad or more during 1 hour, soaking
through night clothes, clots larger than 1 inch in diam-
eter, and low ferritin.
12
Of note, ferritin is not a reliable
indicator of menorrhagia in women with glycogen
storage disease type I, because it could be normal or
elevated and does not correlate with anemia noted in
these patients.
13
Most data regarding the prevalence of
menorrhagia in women with bleeding disorders come
from reports of women with von Willebrand disease,
but menorrhagia has also been reported in hemophilia
carriers, women with factor XI deficiency, women
with rare factor deficiencies, and women with platelet
dysfunction.
14
Because glycogen storage disease type I
has been associated with a bleeding diathesis attribut-
able to impaired platelet function, a von Willebrand
like defect similar to that in women with bleedi ng
disorders, or both impaired platelet function and
a von Willebrandlike defect, the likelihood of men-
orrhagia in this population should be considered. In
this clinical report, we evaluate and characterize the
features of menorrhagia in menstruating females with
glycogen storage disease type I who attend the Duke
Metabolic Clinic to determine wheth er menorrhagia
was an under-reported symptom in these patients.
MATERIALS AND METHODS
After receiving Duke University Institutional Review
Board approval and patient consent through a natural
history study, a retrospective chart review was per-
formed on 13 patients between the ages of 23 and 48
years with glycogen storage disease type I for a diag-
nosis of menorrhagia.
If information regarding the menstrual cycle was
not available, then the patients were asked to respond
to a set of questions (revi ewed by a gynecologist A.J.),
which included the following menstrual cycle infor-
mation details: frequency; duration; quantity of men-
strual flow; and age of onset. Examples of the
questions included the following: Do you soak
through one pad or more in an 1 hour?; Do you
soak through night clothes?; Do your periods last
more than 2 weeks?; and Do you have clots larger
than 1 inch in diameter? This occurred either during
an outpatient visit or through a telephone call or
e-mail. The study used a positive response to one of
these questions to define menorrhagia or a previous
documented diagnosis of menorrhagia.
Patients attending the Duke metabolic clinic are
evaluated and followed-up on a yearly or bi-yearly
basis. Routine evaluations include a comprehensive
history, physical examination, and dietary consulta-
tion by an experienced metabolic dietitian, during
which adherence to dietary intervention is encour-
aged but not formally assessed. Laboratory evalua-
tions include electrolytes, blood glucose, liver and
kidney functions, and complete blood count, in
addition to secondary markers of metabolic control
(lactic acid, uric acid, triglycerides, and cholesterol).
Based on glycogen storage disease type I guidelines,
alpha-fetoprotein and carcinoembryonic antigen also
are assessed in this age group.
15
An additional evaluation for menorrhagia assess-
ment included thyroid function, which was evaluated
to exclude abnormalities that may contribute to
menorrhagia. Coagulation studies were available for
some, but not all, patients. These included platelet
aggregation studies in response to collagen, adenosine
diphosphate, arachidonic acid, and risto cetin, and
a von Willebrand factor panel, which includes FVIII
and von Willebrand factor antigen (von Willebrand
factor:Ag) and activity (von Willebrand factor:RCo).
Blood type was obtained to guide interpretation of
von Willebrand factor studies. Patients usually have
regular liver imaging studies consisting of an ultra-
sound examination, magnetic resonance examination,
or computed tomography scan to evaluate liver size,
presence of liver adenomas, and liver architec ture. At
VOL. 122, NO. 6, DECEMBER 2013 Austin et al Menorrhagia and Glycogen Storage Disease I 1247
Table 1. Clinical Summary of Patients
Patient
Current
Age (y)
Age at
Diagnosis
of GSD 1
Age at
Diagnosis of
Menorrhagia
(y) Mutations Noted
Complications
of Disease
or Risk
Factor for
Anemia
Other Bleeding
Symptoms
1 23 6 mo 20 Homozygous for
c.247C.T
(p.Arg 83Cys)
None known Epistaxis
2 48 3 y 40 Homozygous for
c.1039C.T
(p.Gln347stop)
Hepatic adenomas, long-standing
hypothyroidism on synthroid, renal
transplantation at age 38 y
Epistaxis, easy
bruising, gum
bleeding
3 42 6 y 22 Homozygous for
c.1039C.T
(p. Gln347stop)
Hepatic adenomas, history of
nephrolithiasis, arthritis requiring
large doses of aspirin
Epistaxis, gum
bleeding,
bleeding during
pregnancy
4 36 2 y 11 Compound
heterozygous
for c.371C.A
(p. Ala124Glu)
and c.1039C.T
(p.Gln347stop)
Hepatic adenomas Easy bruising,
bleeding after
surgery
5 32 10 mo 16 Compound
heterozygous for
c.79delC
(p.Gln27ArgfsX9)
and c.1039C.T
(p.Gln347stop)
Hepatic adenomas Bleeding during
pregnancy
6 31 14 mo 22 Compound
heterozygous for
c.79delC
(p.Gln27ArgfsX9)
and c.1039C.T
(p.Gln347stop)
Hepatic adenomas None
7 28 18 mo 15 NA Hypothyroidism Epistaxis, easy
bruising, gum
bleeding
8 36 8 mo 11 or 12 NA Hepatic adenomas Epistaxis, easy
bruising, gum
bleeding
9
36 NA Mid 20s NA None Epistaxis, easy
bruising, gum
bleeding
GSD 1, glycogen storage disease type 1; p.o. t.i.d., orally, three times per day; ED, emergency department; IUD, intrauterine device; NA, not
available.
* Only one time point available.
Glycogen storage disease IB.
1248 Austin et al Menorrhagia and Glycogen Storage Disease I OBSTETRICS & GYNECOLOGY
Severity of Menorrhagia
and Duration
Need for
Hospitalization
Because of
Vaginal Bleeding
Hemoglobin
Level Median
(g/dL) and
Range (Normal,
12.0–15.5)
Need for
Transfusion
Past Treatments
for Menorrhagia
Current
Treatment for
Menorrhagia
and Outcome
Soaking 4 pads in an hour and
soaking through night clothes
beginning
at approximately age 20 y
Yes 9.5 (8.0–10.7) Yes Norethindrone acetate 5 mg
p.o. t.i.d.
Ethinyl estradiol
or
norethindrone
acetate
Heavy and irregular periods
beginning at age 23 y and
lasting for approximately 5
mo before initiation of
therapy
Yes 9.9 (2.6–13.0) Yes Transvaginal estrogen
treatment, cyclic
medroxyprogesterone
acetate (not responsive),
estradiol or norethindrone
acetate transdermal
system
Uses progesterone
as needed for
heavy bleeding,
endometrial
ablation is
recommended
Soaking through menstrual
pads and bed sheets,
occurring inconsistently
since kidney transplantation
Yes (bleeding
during
pregnancy)
10.7 (8.7–12.3) No No response to
medroxyprogesterone
acetate
Endometrial
ablation
(successful
procedure)
Passing clots larger than 1 inch
in diameter, soaking through
night clothing, soaking
through more than one pad
in an hour, lasting for
approximately last 14 y since
age 16 y
Yes (ED x 3 visits) 10.45 (6.3–14.9) No Ethinyl estradiol and
norgestrel,
medroxyprogesterone
acetate
None, no
menstrual
bleeding
abnormalities
after liver
transplantation
Passing clots larger than 1 inch
in diameter and requiring
iron supplementation, lasting
for approximately 7 y since
age 22 y
No 10.2 (9.5–11.1) Yes (during
pregnancy)
Medroxyprogesterone
acetate
None
Irregular menses with cramping
and sometimes heavy
menstrual bleeding, started
oral contraceptive pill at age
13 y because of menorrhagia
that often required
emergency department visits
Yes 12.85 (10.9–14.0) No None Patient plans
endometrial
ablation or
levonorgestrel
IUD
Menses often lasting 2 wk or
more with moderate
bleeding (3 tampons per day)
Yes 11.7 (11.0–12.5) No Medroxyprogesterone
acetate, did not respond
to progestin-only pill, for
8 mo beginning at age 23
y
Levonorgestrel
IUD,
breakthrough
bleeding
Irregular periods every 6 wk,
bleeds through night clothes
and tampons
No 11.6* No Did not respond to oral
norethindrone, responded
to combined pill but had to
discontinue with the
diagnosis of hepatic
adenomas, dilatation and
curettage
None, stopped
after
adenomas
were
diagnosed
Heavy period with clots lasting
7 d; soaks through night
clothes
No 9.8 (9–10.6) No Ethinyl estradiol and
norethindrone but
stopped soon after
starting because of fear of
risk of liver damage
None,
childbearing
age
VOL. 122, NO. 6, DECEMBER 2013 Austin et al Menorrhagia and Glycogen Storage Disease I 1249
our center, regular abdominal imaging studies are
usually extended into the pelvic area to evaluate for
leiomyomas, polyps, endometrial hyperplasia, and
cancer. The patients treated at our cente r were offered
care for their menorrhagia by a gynecologist with
experience in glycogen storage disease type I (A.J.);
other patients were referred to a local gynecologist
with advice from our center. Interventions included
noninvasive (hormonal therapy) procedures, invasive
surgical procedures, or both.
Descriptive statistics were used to characterize the
patient population and laboratory results. Mann-
Whitney test was used to differentiate median values
between the menorrhagia and nonmenorrhagia
groups. Metabolic and coagulation parameters were
reported as mean6range values. P#.05 was co nsid-
ered significant. A 95% confidence interval was used.
RESULTS
In this study of patients with glycogen storage disease
type I, we evaluated 13 for menorrhagia. Their ages
ranged from 23 to 48 years. Nine women (69%;
confidence interval 0.390.91) had manifestations of
menorrhagia; results are summ arized in Table 1.
Menorrhagia or other menstrual abnormalitie s have
not been documented in the remaining four patients.
Most of the patients with menorrhagia experi-
enced abnormal bleeding in their late teens to early
20s (average age of onset was 18 years). Participants
described their periods as heavy, with significant
bleeding lasting from 1 to 3 days per period. Four
women described their cycles as lasting more than 28
days. Six patients were not using hormonal therapy
before the onset of their heavy periods; documenta-
tion regarding hormonal therapy before the onset of
menorrhagia was lacking for three patients. The
menorrhagia was severe and even life-threatening in
some instances, because four patients required hospi-
talization or emergency department visits and three
patients received blood transfusions. One patient has
been hospitalized and received trans fusions several
times over the past 8 years. Leiomyomas, polyps,
endometrial hyperplasia, and cancer were excluded.
Hemoglobin was documented to be as low as 2.6 g/dL
in the menorrhagia group, in which all patients were
anemic during at least one time point (data in Table 1).
Median hemoglobin in patients without menorrhagia
was as low as 9.55 g/dL (range 9.5511.0 g/dL; data
not included). There was no difference in median
hemoglobin levels between patients with and without
menorrhagia; however, there were three patients in
the group with menorrhagia requiring a blood trans-
fusion, including one patient during pregnancy, and
four patients required hospitalization for vaginal
bleeding or menorrhagia. Platelet counts were normal
for all patients.
Tables 2 and 3 show the results of metabolic pa-
rameters for women with and without menorrhagia,
respectively, expressed as median value and range,
obtained during the reported period of menorrhagia.
Both groups of patients with glycogen storage disease
type I had hyperlactatemia and hyperlipdemia. How-
ever, the group of patients with menorrhagia showed
a more adverse metabolic profile in the form of lower
blood glucose leve ls (the median was in the hypogly-
cemia range) and higher lactate levels and triglycer-
ides when compared with the nonmenorrhag ic group,
although the difference was insignificant (P#.05).
Tables 4 and 5 show the results of coagulation
parameters in patients with and without menorrhagia,
respectively, expressed as the median value and
range. Coagulation studies showed that median values
for adeno sine diphosphateinduced platelet aggrega-
tion, von Willebrand factor:Ag, and von Willebrand
factor:RCo were generally lower in the menorrhagia
group compared with the nonmenorrhagia group, but
the difference was not statistically significant (P#.05).
The lack of statistical significance is likely secondary
to the low statistical power given the small sample
sizes because of the limited number of patients who
had available study data during that time. Of note,
seven of nine patients with menorrhagia and four
of four patients without menorrhagia (data not
shown) also reported other symptoms indicative of
a bleeding diso rder, such as easy bruising, excessive
bleeding after surgery, or gum bleeding and nose
bleeding (Table 1).
Six of the nine patients with menorrhagia had
documented liver adenomas. Two of the four patients
without menorrhagia had liver adenomas. Eight
patients with menorrhagia (89%) in our study used
hormonal therap y. For seven of nine patients, hor-
monal therapy was prescribed for management of
menorrhagia. Patient 3 had an endometrial ablation
after medroxyprogesterone therapy was not sufficient
enough to correct her bleeding, and another woman
(patient 8) was treated with dilation and curettage in
addition to failed progesterone only therapy. This
patient (patient 8) had success with combined estrogen
and progesterone therapy but had to discontinue the
use of estrogen because of development of liver
adenomas. Patient 4 was initially treated with ethinyl
estradiol and norgestrel and medroxyprogesterone
acetate therapy, but she reported that her menorrha-
gia and metabolic parameters did not improve until
she received a liver transplant. Patients 8 and 9
1250 Austin et al Menorrhagia and Glycogen Storage Disease I OBSTETRICS & GYNECOLOGY
eventually discontinued hormonal therapy as a result
of hepatic adenomas and patient anxiety regarding
liver damag e.
DISCUSSION
As patients with glycogen storage disease type I live
longer, newer perspe ctives of the natural history of the
disease are emerging. Menorrhagia is an under-
reported problem that should be evaluated in these
patients and added to the list of causes of anemia in
females with glycogen storage disease type I.
Possible causes of menorrhagia in glycogen
storage disease type I are related to an acquired
bleeding diathesis attributable to von Willebrandlike
defect,
10
platelet dysfunction,
9
or both. Autoimm une
hypothyroidism, which may be particularly more
common in glycogen storage disease type Ib, could
be another contributing factor.
16
The platelet defect in
glycogen storage disease type I has been described as
an acquired qualitative platelet abnormality manifest-
ing by decreased prothrombin consumption, abnor-
mal aggregation reactions, prolonged bleeding time,
and low platelet adhesiveness.
9
In the patients with
menorrhagia, metabolic control seemed inadequate
compared with that in the group without menorrha-
gia; however, the sample numbers are small. These
findings combined suggest that patients with glycogen
storage disease type I and menorrhagia had a more
significant bleeding defect related to platelet dysfunc-
tion and von Willebrand factor abnormalities.
Patients with glycogen storage disease type I are
already at risk for chronic anemia. The anemia can
occur for several reasons, such as restricted diet,
bleeding within liver adenomas, and renal involve-
ment. Additionally, Roy et al
13
found that anemia,
often iron refract ory anemia, in glycogen storage dis-
ease type I was related to the production of hepcidin
from large hepatic adenomas. Six of the nine patients
with menorrhagia in this study had adenomas; unfor-
tunately, a measure of hepcidin is not clinically avail-
able. As a result of the anemi a, the episodes of
menorrhagia these patients experience add additional
burden to their already strained hematopoiesis.
In our study, eight pat ients were prescribed
medical or surgical intervention for management of
their menorrhagia at some point in time despite
attempts to optimize dietary control. In patients with
Table 2. Metabolic Parameters in Patients With Menorrhagia
Patient
Cholesterol
(mg/dL)
(Normal\200
mg/dL) (n 59)
Triglycerides (mg/dL)
(Normal\150 mg/dL)
(n59)
Lactic Acid
(mmol/L)
(Normal 0.5–2.2
mmol/L) (n5 8)
Uric Acid (mg/dL)
(Normal 2.5–8.0
mg/dL) (n 59)
Glucose (mg/dL)
(Normal[70
mg/dL) (n 59)
1 295 909 12 4.8 100
2 282 630 6.3 6.5 55
3 443 832 NA 2.6 62
4 261 1,194 10.2 6.5 56
5 217 507 5.1 5.1 50
6 232 549 6.4 6.2 36
7 284 589 7.7 7.3 82
8 230 647 8.7 3.4 99
9* 216 1,042 9.7 10.7 54
Median range
(minimum–
maximum)
261 (216–443) 647 (507–1,194) 8.2 (5.1–12) 6.2 (2.6–10.7)
* Glycogen storage disease Ib.
Table 3. Metabolic Parameters in Patients Without Menorrhagia
Patient
Cholesterol
(mg/dL) (n54)
Triglycerides
(mg/dL) (n5 4)
Lactic Acid
(mmol/L) (n54)
Uric Acid
(mg/dL) (n54)
Glucose
(mg/dL) (n54)
10 247 580 3.1 6.8 105
11 328 519 2.6 7.1 151
12 349 363 6.7 10.8 88
13* 164 550 6.9 7.4 61
Median range (minimum–maximum) 288 (164–349) 535 (363–580) 4.9 (2.6–6.9) 7.3 (6.8–10.8) 97 (61–151)
* Glycogen storage disease Ib.
VOL. 122, NO. 6, DECEMBER 2013 Austin et al Menorrhagia and Glycogen Storage Disease I 1251
glycogen storage disease type I, the role of dietary
management is well-known, and its effect on meta-
bolic control is maintained through patie nt co mpli-
ance. Metabolic compliance can be a challenge,
especially in children and young adults with chronic
illness. Adherence to a trea tment regimen is compli-
cated and dependent on many factors.
17
Improved
metabolic control may improve the hemostatic abnor-
malities.
5,10
For patients with glycogen storage disease
type I who hav e not shown improvement with dietary
management alone, referral to a hematologist with
experience in coagulation abnorm alities is indicated
for further management because they may benefit from
other forms of hemostatic therapy such as 1-desamino-
8-
D-arginine vasopressin
18,19
and antifibrinolytics.
These agents have side effects that need to be moni-
tored carefully.
Our recommendation is that a gynecologist
should perform a full gynecologic evaluation and
use usual gynecologic therapies to manage menorrha-
gia. Given the risk for adenomas in glycogen storage
disease type I,
20,21
special considerations have to be
taken into account when prescribing hormonal treat-
ment for menorrhagia. Estrogen is known to contribute
to both benign and malignant hepatocellular tumors.
22
As a result of the increased risk of adenomas in patients
with glycogen storage disease type I, estrogen should
be avoided whenever possible.
23
Progestin-only contra-
ceptives do not pose the same risk and may be used;
however, with long-term use of medroxyprogesterone
acetate, there is risk for reduced bone mineral density,
which needs to be monitored in this population.
24
Because of neutropenia, there is increased risk of infec-
tion in patients with glycogen storage disease type Ib,
and whether this infection risk extends to intrauterine
devices is unknown.
Experience with treating menorrhagia in other
bleeding diathesis has suggested endometrial ablation
as a promising option since the early 1990s.
25
Endome-
trial ablations are less invasive and quicker than hys-
terectomies. A review of the Cochrane database by
Lethaby concluded that the newer second-generation
Table 4. Coagulation Parameters in Patients With Menorrhagia
Patient
von Willebrand Factor
Antigen (Normal for O Blood
Type Group 40–150; Not O
55–190) (n55)
von Willebrand Factor
Antigen Ristocetin Cofactor
Activity (Normal for O Type
Blood Group 45–130; Not O
65–150) (n55)
ADP Aggregation
(Normal[60) (n54)
Blood
Group
Type
1463533A+
2798188O+
4847148A2
53425NAO2
6384343A+
Median range
(minimum–
maximum)
46 (34–84) 43 (25–81) 45.5 (33–88)
ADP, adenosine diphosphate; NA, not available.
Table 5. Coagulation Parameters in Patients Without Menorrhagia
Patient
von Willebrand Factor
Antigen (Normal for O Blood
Type Group 40–150; Not O
55–190) (n54)
von Willebrand Factor
Antigen Ristocetin Cofactor
Activity (Normal for O Blood
Type Group 45–130; Not O
65–150) (n54)
ADP Aggregation
(Normal[60) (n54)
Blood
Group
Type
10 58 67 45 A+
11 41 22 74 O+
12 75 53 95 NA
13* 101 109 62 A+
Median range
(minimum–
maximum)
66.5 (41–101) 60.0 (22–109) 62.0 (45–95)
ADP, adenosine diphosphate; NA, not available.
* Glycogen storage disease Ib.
1252 Austin et al Menorrhagia and Glycogen Storage Disease I OBSTETRICS & GYNECOLOGY
techniques of ablation, which treat the whole cavity at
once, are easier to perform and safer.
26
In 2005, au-
thors from the Mayo Clinic concluded that endome-
trial ablation appears to be a safe procedure that
improves the quality of life in patients with von Wille-
brand diseaserelated menorrhagia.
27
However, its
long-term efficacy appears to be lower in patients with
von Willebrand disease when compared with women
with menorrhagia without von Willebrand disease.
Subsequently, a 2012 study by Huq et al
28
showed that
endometrial ablation appears to be a safe and effective
long-term treatment for heavy menstrual bleeding in
women with inherited disorders of bleeding. They
found that it significantly decreased menstrual blood
loss and improved quality of life.
28
The limitation of this study includes lack of
knowledge of the exact pathophysiology of menor-
rhagia. Further analysis of ovarian function and
endometrial pathology is required to determine
whether the menorrhagia in these patients is attribut-
able to bleeding diathesis, poor metabolic control,
endocrine dysfunction, or other factors. These pa-
tients are also at risk for development of other
gynecologic pathologies prevalent in the general
population. Given the increased incidence of poly-
cystic ovarian syndrome and insulin resistance as
described in the study from 1995 by Lee et al, they
are more likely to have anovulatory bleeding.
7,29
When anovulatory, these patients are at risk for devel-
opment of endometrial hyperplasia and endometrial
carcinoma because of unopposed estrogen.
30
Endo-
metrial ablation in the setting of hyperp lasia can mask
the detection of superimposi ng cancer, and therefore
is not a good therapeutic option in this situation.
Treatment with an int rauterine levonorgestrel device
or oral progesterone and close monitoring is a safe
option in these patients because they address the issue
and can prevent progression to endometrial carci-
noma.
31
However, if the bleeding is attributable to
a bleeding diathesis, these patients are good candi-
dates for endometrial ablation or for strategies to treat
the underlying coagul ation defect.
18,32
Careful risk
benefit evaluation is necessary because of the risk
for infection in patients with glycogen storage disease
type Ib. There is no available literature to guide in this
decision-making. Thus, we recommend further stud-
ies addressing pathophysiology of menstrual bleeding
in glycogen storage disease type 1b and safety of lev-
onorgetrel intrauterine devices.
Menorrhagia is a clinical manifestatio n of bleed-
ing in a subset of females with glycogen storage
disease type I that warrants further systematic study
in the future, perhaps as a co llaborative effort with
a larger group of patients. The lack of statistical
significance in this study is likely attributable to the
low statistical power given the small sample sizes. In
a given patient, it is necessary to evaluate whether the
cause of the bleeding is attributable to an endocrine
issue, hematologic factors, metabolic control, or other
factors. Specialists treating females with glycogen
storage disease type I need to be aware of this
condition. The multidisciplinary management team
approach for females with the disease should include
the expertise of a gynecologist and hematologist
familiar with the condition.
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1254 Austin et al Menorrhagia and Glycogen Storage Disease I OBSTETRICS & GYNECOLOGY
  • [Show abstract] [Hide abstract] ABSTRACT: Purpose: Glycogen storage disease type I (GSD I) is a rare disease of variable clinical severity that primarily affects the liver and kidney. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib), resulting in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa. Patients with GSD I have a wide spectrum of clinical manifestations, including hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Individuals with GSD type Ia typically have symptoms related to hypoglycemia in infancy when the interval between feedings is extended to 3–4 hours. Other manifestations of the disease vary in age of onset, rate of disease progression, and severity. In addition, patients with type Ib have neutropenia, impaired neutrophil function, and inflammatory bowel disease. This guideline for the management of GSD I was developed as an educational resource for health-care providers to facilitate prompt, accurate diagnosis and appropriate management of patients. Methods: A national group of experts in various aspects of GSD I met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Results: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (hepatic, kidney, gastrointestinal/nutrition, hematologic, cardiovascular, reproductive) involved in GSD I. Conditions to consider in the differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are also addressed. Conclusion: A guideline that facilitates accurate diagnosis and optimal management of patients with GSD I was developed. This guideline helps health-care providers recognize patients with all forms of GSD I, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It also helps to identify gaps in scientific knowledge that exist today and suggests future studies.
    Full-text · Article · Nov 2014

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