Download A patient with severe, recurrent hypoglycemia and glycemic

CASE STUDY
www.nature.com/clinicalpractice/endmet
A patient with severe, recurrent hypoglycemia
and glycemic lability who underwent
islet transplantation
Edmond A Ryan* and AM James Shapiro
S U M M A RY
Background A 48-year-old woman who was diagnosed with type 1
diabetes at 5 years of age presented to our Clinical Islet Transplant
Program with severe, recurrent hypoglycemia and glycemic lability.
She was diligent with her diet, used a continuous subcutaneous insulin
infusion pump (32 U per day), and monitored her glucose levels typically
eight times a day. The patient usually had one hypoglycemic reaction a day,
experienced a severe reaction once a month, and had marked variability
of her glucose values. On presentation, her HYPO score was 584 and her
lability index was 868 mmol/l2/h per week.
Investigations HYPO score, lability index score, screening for diabetes
complications, and routine pretransplant evaluation.
Diagnosis Severe, recurrent hypoglycemia and glycemic lability associated
with type 1 diabetes.
Management The patient underwent islet transplantation. Posttransplant, the problems with hypoglycemia abated and excellent stable
glycemic control was attained, although some side effects from the
immunosuppressive drug, sirolimus, were evident. Insulin was reinstituted
2.5 years after surgery, at lower doses than before the transplant because of
deterioration in graft function. Occasional episodes of hypoglycemia have
occurred and some glycemic lability has recurred, although endogenous
insulin secretion is still preserved.
KEYWORDS glycemic lability, hypoglycemia, immunosuppression,
islet transplantation, type 1 diabetes
CME
EA Ryan is the Medical Director and AMJ Shapiro is the Director of the
Clinical Islet Transplant Program, AB, Canada.
Correspondence
*Clinical Islet Transplant Program, 2000 College Plaza, 8215 112th Street, Edmonton, AB,
T6G 2C8, Canada
[email protected]
Received 10 January 2006 Accepted 7 April 2006
www.nature.com/clinicalpractice
doi:10.1038/ncpendmet0201
JUNE 2006 VOL 2 NO 6
This article offers the opportunity to earn one
Category 1 credit toward the AMA Physician’s
Recognition Award.
THE CASE
A 48-year-old woman who was diagnosed with
type 1 diabetes 43 years previously, presented early
in 2001 to our Clinical Islet Transplant Program
with recurrent hypoglycemia and glycemic
lability that had been present for several years.
She was diligent with her diet, used a continuous
subcutaneous insulin infusion pump, and monitored her glucose levels typically eight times a
day. Total insulin requirements were 32 U per
day (0.6 U/kg). Despite these efforts, she usually
had one hypoglycemic reaction a day. The patient
felt she needed outside help to recognize the hypoglycemia about twice a month, and third-party
assistance to treat the hypoglycemia reaction once
a month. In the year before presentation, she had
required glucagon therapy twice for her hypoglycemia. On presentation, the patient’s HYPO
SCORE was 584 (median in a typical patient with
type 1 diabetes 143; interquartile range 46–423)
and her LABILITY INDEX (LI) was 868 mmol/l2/h
per week (median in a typical patient with
type 1 diabetes 223 mmol/l2/h per week; interquartile range 130–329 mmol/l2/h per week).1
The glycated hemoglobin A1c (HbA1c) was 6.6%
(normal range 4.3–6.1%). Given that her problems with hypoglycemia and glycemic lability
were serious, and that both her HYPO score and
LI exceeded the 75th percentile, she was offered
an islet transplant.
The patient’s past history was noncontributory.
In terms of diabetes complications, she had been
treated for proliferative retinopathy, her microalbumin excretion rate was 9 μg/min (she had
been taking 10 mg enalapril per day for 3 years)
and she experienced no neuropathy or vascular
disease. The patient underwent an islet transplant in late 2001. Briefly, percutaneous access to
the portal vein was established in the radiology
suite and the islet preparation was allowed to
infuse slowly with regular monitoring of the
NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 349
©2006 Nature Publishing Group
CASE STUDY
www.nature.com/clinicalpractice/endmet
Capillary fasting
glucose (mmol/l)
11 –
10 –
9–
8–
7–
6–
5–
Insulin units/kg
per day
Capillary postmeal
glucose (mmol/l)
16 –
14 –
12 –
10 –
8–
6–
4–
Capillary premeal
glucose (mmol/l)
HbA1c (%)
7.0 –
6.8 –
6.6 –
6.4 –
6.2 –
6.0 –
5.8 –
10 –
9–
8–
7–
6–
5–
0.6 –
0.5 –
0.4 –
0.3 –
0.2 –
0.1 –
0–
Lability score
1000 –
800 –
600 –
400 –
200 –
Hypoglycemia score
0–
700 –
600 –
500 –
400 –
300 –
200 –
100 –
0–
Pre-TX
6 months 12 months 24 months 36 months 48 months
Time
Figure 1 Changes in hemoglobin A1c, capillary fasting, premeal and postmeal
glucose levels, insulin use, lability index, and hypoglycemia score pretransplant
and over 4 years of follow-up post-transplant in the patient described.
HbA1c, hemoglobin A1c; pre-TX, pretransplant.
350 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM
©2006 Nature Publishing Group
portal pressure to help detect any possible
thrombosis. Once the infusion was complete,
the catheter was removed and the tract plugged
to lessen the risk of bleeding. After the transplant, she was given the immunosuppressant
drugs sirolimus, starting dose of 0.1 mg/kg per
day (target trough levels 12–15 ng/ml), and
tacrolimus, starting dose of 2 mg twice daily
(target trough levels 3–6 ng/ml). The problems
with hypoglycemia resolved, and the patient’s
glucose levels stabilized, but she still required
10 U of insulin per day. The patient had a second
transplant 4 months later because of her need
for continuing exogenous insulin; she received
a total of 593,270 islet equivalents or 10,594 islet
equivalents per kg over the two procedures.
After the second transplant, the patient
became insulin independent and remained off
insulin for 2.5 years (Figure 1). Her HbA1c fell
to 6%, and 77% of her premeal capillary glucose
values were in the target range of 3.5–7.8 mmol/l.
Over a 1-month period, no glucose values
were under 3.5 mmol/l and only three values were
over 10.0 mmol/l. The patient continued to
receive immunosuppressive therapy: sirolimus
(target trough levels 8–10 ng/ml) and tacrolimus
(target trough levels 3–6 ng/ml).
In 2003, 2 years after the transplants, she had
no problems with hypoglycemia, her HYPO score
was 0, and the LI was 90 mmol/l2/h per week. The
patient’s mean premeal capillary glucose levels
were 6.5 mmol/l (target levels 5.0–7.2 mmol/l),
but her fasting glucose levels were elevated to
7.2 mmol/l (normal <5.6 mmol/l). Renal function remained normal, with serum creatinine
levels of 63 μmol/l, an albumin excretion rate
of 11 μg/min, and the creatinine clearance
was 1.79 ml/sec/1.73m2. Hypercholesterolemia
developed and she was given 40 mg simvastatin
per day and enalapril was continued at a higher
dose of 10 mg twice daily because her blood pressure had risen. The patient experienced problems with mouth ulcers, gastrointestinal upset,
and peripheral edema that were thought to be
side effects of sirolimus therapy. Sirolimus was,
therefore, stopped and 1,000 mg mycophenolate
mofetil was given twice daily to the patient.
The side effects improved within 3 months of
discontinuing sirolimus, but she continued
on statin therapy for hypercholesterolemia and
antihypertensive medications.
In 2004, the patient resumed insulin therapy of
12 U per day because of a deterioration in graft
function and because her postmeal capillary
RYAN AND SHAPIRO JUNE 2006 VOL 2 NO 6
CASE STUDY
www.nature.com/clinicalpractice/endmet
glucose values had risen to 9.1 mmol/l. After the
patient resumed insulin therapy, she experienced
occasional hypoglycemic episodes that gave
some warning symptoms and did not require
third-party assistance. Some glycemic lability
had also recurred. The patient felt that the islet
transplant had improved her major concerns
relating to severe hypoglycemia and glycemic
lability. In 2006, at the last patient followup, she was taking 23 U of insulin therapy
per day.
DISCUSSION OF DIAGNOSIS
Hypoglycemia is, by far, the most common acute
complication of patients with type 1 diabetes; for
a minority of patients the problem progresses to
episodes of severe hypoglycemia, such that the
patients become a risk to themselves and their
surroundings. Severe hypoglycemia is defined as
an episode of hypoglycemia in which third-party
assistance is required, and up to one third of
patients with type 1 diabetes might have episodes
of severe hypoglycemia in a year.2 Typically,
severe hypoglycemia is associated with hypoglycemic unawareness—the occurrence of
hypoglycemia without symptoms that permit
recognition of the condition. Hypoglycemia
elicits the classic defense mechanism, causing
the release of catecholamines, glucagon, cortisol,
and growth hormone; the former two hormones
act within minutes of the occurrence of hypoglycemia. In patients without diabetes, a decrease
in the levels of endogenous insulin and increase in
levels of glucagon are the pre-eminent defenses.
Neither of these mechanisms is operative in
patients with type 1 diabetes. Characteristically,
patients with type 1 diabetes lose their glucagon
response to hypoglycemia.3 The presence of
hyperinsulinemia and the lack of a fall in levels
of intraislet insulin are responsible for the loss
of the glucagon response to hypoglycemia.4
A patient with type 1 diabetes, therefore, is
completely dependent on the catecholamine
response to correct falling glucose levels, and
the associated sympathoadrenal response for
warning of the glucose decrement.5
The loss of autonomic warning symptoms
with a foundation of a blunted glucagon and
catecholamine response sets the stage for recurrent, severe hypoglycemia. Typically, this loss of
sympathoadrenal response is inducible by recurrent episodes of hypoglycemia6 and is potentially correctable by the scrupulous avoidance
of hypoglycemia.7 Even though hypoglycemia
JUNE 2006 VOL 2 NO 6 RYAN AND SHAPIRO
is more common in the presence of severe
autonomic neuropathy, it is not thought to be
caused by a structural defect in the autonomic
nervous system. Some have proposed that
the defect is cause by hypoglycemia-induced
autonomic failure, but the exact mechanism
remains unclear.5
If a patient has severe hypoglycemia it is mandatory to review dietary practices, insulin injection
techniques and timing, and insulin regimen.
Exclusion of associated diseases, such as celiac
disease, Addison’s disease, thyroid disease, and
gastroparesis, that might have a role is essential.
All of these associated diseases were examined
in the patient described and, as often occurs,
no obvious cause was found. Some patients
seem to have ongoing low glucose levels and
resist all attempts to raise the ambient glucose
values, as they feel unwell with glucose values
that are any higher. Other patients have very
labile diabetes—a condition characterized by
extremely variable glucose control associated
with unpredictable responses to insulin. Patients
with labile diabetes and hypoglycemia are the
most challenging to treat, given the unpredictability of their response to insulin. Insulininfusion pumps, carbohydrate counting, and
frequent glucose monitoring might all help,
as might the new continuous glucose monitors, which use a subcutaneous glucose sensor.8
Problems persist in a subset of these patients,
despite intensive diabetes therapy, as is evident
from the case presented.
Quantifying the problems associated with
hypoglycemia has been challenging. The
CLARKE SCORE helps predict future problems
with hypoglycemia, but is less quantitative
than the HYPO score.9 The mean amplitude
of glycemic excursion (MAGE) has been used
to quantify glycemic lability, but only uses the
glucose values over a 2-day period. The MAGE
correlated with the LI (coefficient of correlation,
r = 0.291; P = 0.004), but the LI was much more
closely correlated with a clinical assessment
of lability than with the MAGE (r = 0.868 and
0.328, respectively).1 A HYPO score of more
than 1,047 (90th percentile) or a LI of more than
433 mmol/l2/h per week (90th percentile) indicates serious problems with hypoglycemia
or glycemic lability, respectively. The patient
described here presented to us with problems
caused by both hypoglycemia and glycemic
lability and she was, therefore, considered for
an islet transplant.
GLOSSARY
HYPO SCORE
A 4-week period of intensive
glucose monitoring coupled
with a year-long history
of episodes of severe
hypoglycemia that provides
a score of the severity of
hypoglycemia; also known
as hypoglycemia score
LABILITY INDEX (LI)
This index provides a
measure of glycemic lability
and is based on the square
of change in levels of
glucose from one reading
to the next, divided by the
time interval and summed
for a week
CLARKE SCORE
Predicts future problems
with hypoglycemia
NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 351
©2006 Nature Publishing Group
CASE STUDY
www.nature.com/clinicalpractice/endmet
TREATMENT AND MANAGEMENT
Islet transplantation provides endogenous
insulin that corrects glycemic lability and is
accompanied by a decrease in the number of
episodes of hypoglycemia, although, typically,
two transplants are required.10 Patients suitable for transplantation include those with
problems with hypoglycemia or lability, despite
optimization of diabetes therapy and no elevation of serum creatinine levels. Quantification
of hypoglycemia is facilitated by the HYPO score
and the glycemic instability by the LI. Either a
HYPO score or LI over the 90th percentile or both
over the 75th percentile warrants consideration
of an islet transplant.
The success of islet transplantation in terms
of stabilizing problematic hypoglycemia is
testimony to the dominance of regulated
insulin secretion in glucoregulation. Glucose
control was stable in the patient described after
transplantation. The fasting glucose levels were
disproportionately high, a common feature
after islet transplantation, which might reflect
some impairment in the regulation of endogenous glucose output by the intrahepatic islet
source of insulin. The price for these benefits,
however, is life-long immunosuppression and its
attendant side effects—most commonly mouth
ulcers, increased cholesterol levels, hypertension,
gastrointestinal upset, and proteinuria,11 plus
ovarian cysts and menorrhagia in premenopausal
women.12 In addition, long-term insulin independence is rarely maintained, as was the case in
the patient described, the probable explanation
being the limited islet mass that engrafts.10,13,14
The patient described experienced many of the
complications encountered after islet transplantation, including gastrointestinal upset, hypercholesterolemia, hypertension, and mouth
ulcers. Interestingly, many of these abated when
sirolimus was stopped. Of more importance
was the patient’s need to restart insulin after
30 months and the recurrence of some problems
with the sensing of hypoglycemia and lability.
As reported, 90% of patients who undergo
islet transplantation need to restart insulin
therapy, although 80% have persistence of
endogenous C-peptide.10
It is becoming apparent that the glucagon
response to hypoglycemia is not normalized15,16
after intrahepatic islet transplantation. The
role of the hepatic site in this lack of recovery
might be important, because intraperitoneal
islet transplants in dogs are associated with a
352 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM
©2006 Nature Publishing Group
normal glucagon response to hypoglycemia. It
is possible that the autoregulation of glucose
within the liver protects the transplanted islets
from hypoglycemia and, hence, causes the
blunted glucagon response. Also of note was
the recurrence of occasional episodes of hypoglycemia once insulin was resumed, despite the
use of lower doses of insulin compared with
the pretransplantation dose and the continuing endogenous insulin release. This suggests
that, in some patients, the impaired sympathoadrenal response is not fully restored to normal
despite the patient being off insulin for years
and presumably having avoided hypoglycemia
during this interval.
CONCLUSION
Patients with recurrent, severe hypoglycemia and
glycemic lability who are not responsive to intensive diabetes therapy (e.g. multiple daily insulin
injections or use of continuous subcutaneous
insulin infusion, frequent glucose monitoring,
and careful dietary adherence) are eligible for an
islet transplant, which can offer freedom from
hypoglycemia as well as stable glucose values.
The patient described exemplifies the advantages
and disadvantages of an islet transplant. Posttransplantation, the patient experienced a marked
relief from the problems of hypoglycemia, stable
glucose values, and better glycemic control;
however, she also experienced side effects from
the immunosuppressive drugs, slight fasting
hyperglycemia, and resumed taking small doses
of insulin. The islets survive for many years,
but the need for less toxic immunosuppression
and enhanced function of the remaining islets
is apparent.
References
1 Ryan EA et al. (2004) Assessment of the severity of
hypoglycemia and glycemic lability in type 1 diabetic
subjects undergoing islet transplantation. Diabetes 53:
955–962
2 Pedersen-Bjergaard U et al. (2004) Severe
hypoglycaemia in 1076 adult patients with type 1
diabetes: influence of risk markers and selection.
Diabetes Metab Res Rev 20: 479–486
3 Cryer PE et al. (2003) Hypoglycemia in diabetes.
Diabetes Care 26: 1902–1912
4 Gosmanov NR et al. (2005) Role of the decrement
in intraislet insulin for the glucagon response to
hypoglycemia in humans. Diabetes Care 28:
1124–1131
5 Cryer PE (2004) Diverse causes of hypoglycemiaassociated autonomic failure in diabetes. N Engl J Med
350: 2272–2279
6 Cryer PE (1992) Iatrogenic hypoglycemia as a cause of
hypoglycemia-associated autonomic failure in IDDM. A
vicious cycle. Diabetes 41: 255–260
RYAN AND SHAPIRO JUNE 2006 VOL 2 NO 6
CASE STUDY
www.nature.com/clinicalpractice/endmet
7
Fanelli C et al. (1994) Long-term recovery from
unawareness, deficient counterregulation and lack of
cognitive dysfunction during hypoglycaemia, following
institution of rational, intensive insulin therapy in IDDM.
Diabetologia 37: 1265–1276
8 Bode B et al. (2004) Alarms based on real-time
sensor glucose values alert patients to hypo- and
hyperglycemia: the guardian continuous monitoring
system. Diab Technol Therap 6: 105–113
9 Clarke WL et al. (1995) Reduced awareness of
hypoglycemia in adults with IDDM. A prospective
study of hypoglycemic frequency and associated
symptoms. Diabetes Care 18: 517–522
10 Ryan EA et al. (2005) Five-year follow-up after clinical
islet transplantation. Diabetes 54: 2060–2069
11 Senior PA et al. (2005) Proteinuria developing after
clinical islet transplantation resolves with sirolimus
withdrawal and increased tacrolimus dosing. Am J
Transplant 5: 2318–2323
JUNE 2006 VOL 2 NO 6 RYAN AND SHAPIRO
12 Cure P et al. (2004) Alterations of the female
reproductive system in recipients of islet grafts.
Transplantation 78: 1576–1581
13 Hering BJ et al. (2005) Single-donor, marginal-dose
islet transplantation in patients with type 1 diabetes.
JAMA 293: 830–835
14 Froud T et al. (2005) Islet transplantation in type 1
diabetes mellitus using cultured islets and steroidfree immunosuppression: Miami experience. Am J
Transplant 5: 2037–2046
15 Rickels MR et al. (2005) Islet cell hormonal
responses to hypoglycemia after human islet cell
transplantation for type 1 diabetes. Diabetes 54:
3205–3211
16 Paty BW et al. (2002) Intrahepatic islet transplantation
in type 1 diabetic patients does not restore
hypoglycemic hormonal counterregulation or symptom
recognition after insulin independence. Diabetes 51:
3428–3434
Competing interests
The authors declared
they have no competing
interests.
NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 353
©2006 Nature Publishing Group