0021-972X/01/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2001 by The Endocrine Society
Vol. 86, No. 5
Printed in U.S.A.
LETTERS TO THE EDITOR
Graves’ Ophthalmopathya
To the editor:
The fact that Kahaly et al. (1) apparently ignore patients lost to follow-up may have lead them to draw false conclusions.
They report recovery in 12 of 18 patients with Graves’ ophthalmopathy treated with orbital radiotherapy in 20 divided fractions of 1 Gray
(Gy) over 20 weeks (group A). This success rate of 67% was, according
to the authors, significantly higher than the rates of 59% and 55% obtained with treatment regimens of 1 and 2 Gy in 10 fractions over 2 weeks
(groups B and C). The authors subsequently conclude that the 1 Gy/
week regimen was the most effective.
One thing is that it seems quite implausible that the difference between a success rate of 67% (12 of 18) compared with a success rate of
55% (12 of 22) could reach P equal to 0.007 as reported. In a ␹2 test the
finding is clearly insignificant (P ⬎ 0.5). But, we comment also on
another major problem in the data handling.
As reported by the authors, three patients were excluded before the
statistical analysis “because of insufficient follow-up and poor compliance” of whom all were originally randomized to group A. This is not
subject to further discussion in the paper, but it seems certainly not
unlikely that the drop-outs could have represented treatment failures
because compliance with the 20-week treatment protocol must have
been difficult to assertain if no progress was noted by the patient. In an
intention-to-treat perspective the recovery rate in group A should, therefore, have been calculated as 12 of 21 corresponding to 57%. This obviously wrecks any attempt to claim superiority of the 20-week protocol.
Erik Christiansen and Allan Kofoed-Enevoldsen
Department of Endocrinology and Internal Medicine
Herlev Hospital
DK 2730 Herlev, Denmark
Reference
1. Kahaly GJ, Rösler HP, Pitz S, Hommel G. 2000 Low versus high-dose radiotherapy for Graves’ ophthalmopathy: a randomized single blind trial. J Clin
Endocrinol Metab. 85:102–108.
Radiotherapy for Graves’ Ophthalmopathyb
To the editor:
We would like to express our thanks for giving us the opportunity to
respond to the letter of the Danish colleagues and to their constructive
points of criticism. We have tried to comply with their points where
possible and to answer facts that remained unclear. The therapeutic
outcome of the randomized, single-blind trial comparing low- vs. highdose orbital radiotherapy for patients with Graves’ ophthalmopathy
(GO) was assessed according to predefined objective criteria, e.g.
changes in lid fissure width, proptosis, diplopia, and changes in eye
muscle area (1–3). A detailed NO SPECS classification showing the
changes in these classes and their degrees both before and after radiotherapy among all groups has been documented. The clinical activity
score for GO (4) and a subjective evaluation by the patients (satisfaction
rate at the end of the trial) have been added. All patients were euthyroid
before and during therapy. With the exception of subjects with optic
neuropathy, this series included consecutive patients with previously
untreated and congestive GO. Because one group of patients was treated
with a protracted protocol during 20 weeks, subjects with optic neua
Received November 12, 2000. Address correspondence to: Dr. Erik
Christiansen, Department of Endocrinology and Internal Medicine, Herlev Hospital, DK-2730 Herlev, Denmark.
b
Received February 6, 2001. Address correspondence to: Prof. George
J. Kahaly, M.D., Department of Endocrinology and Metabolism, University Hospital, Building 303, Mainz 55101, Germany.
ropathy were excluded from the study and were treated either with high
doses of steroids iv or decompressed surgically. All investigations were
performed 24 weeks after starting radiotherapy, and neither the radiologist nor the ophthalmologist was informed with respect to the exact
study protocol.
In group A (protracted protocol with a single dose of 1 Gray (Gy) per
week for a therapy period of 20 weeks), 3 of 21 patients dropped out
within 4 weeks after starting treatment. They lived more than 100 km
from the university hospital and were no longer willing to drive so far
once weekly for retrobulbar irradiation. For these 3 subjects, baseline
values only were available. Because both ophthalmic data and valuable
information regarding further follow-up were missing, we did not include these patients in the definitive analysis. Even if the 3 excluded
patients were considered in the evaluation of the results, similar outcome would be registered between the short 20-Gy regimens and the
protracted protocol. Nevertheless, the objective ophthalmic parameters,
the findings of the imaging techniques [e.g. magnetic resonance imaging
(5, 6), the further follow-up after radiotherapy, the lower rate of subsequent orbital surgery, and especially both the markedly higher satisfaction rate and the minimal side effects] led to a differentiated evaluation of this new therapy regimen and to the conclusions that the
protracted protocol seemed to be at least as effective and far better
tolerated than the short-arm regimens. We are not drawing false conclusions, because even if the recovery rate in the protracted radiotherapy
group should have been calculated as 12 of 21 patients corresponding
to 57%, this would give us a similar success rate as in the other two
groups. The somehow misleading P value was based on the comparison
of basic data between the two groups. Statistical analysis was performed
with the help of all obtained values both within as well as between the
three different radiotherapy groups. Therefore, we do think that the A
protocol might be presented as one aim of the study, namely protracting
the treatment scheme and giving antiphlogistic low doses once a week
only in subjects with an orbital inflammatory disease, led to markedly
different results in comparison with the standard daily regimens. Nevertheless, to further underline the potential advantages of this protocol,
we definitely recommend to increase the number of GO patients treated
with this new regimen. With this purpose in mind, a European randomized, double-blind, multicenter trial comparing a low-dose shortarm radiotherapy regimen and a protracted protocol will start in the near
future.
The conclusion of the primary study aim is the absence of statistical
differences, with respect to clinical ophthalmic signs, between low and
high doses of orbital radiotherapy. Recent data from our institution have
failed to show any beneficial differences for the high-dose treatment (7).
To evaluate the long-term efficacy and tolerability of radiotherapy for
GO patients, as well as to determine the risk of radiation-induced retinopathy, data of 125 GO subjects irradiated between 1982 and 1998 have
been examined retrospectively. Total doses of 20 or 10 Gy (2 or 1 Gy/
day) were administered. Median follow-up was 5 yr (0.5–17 yr). No
significant differences were registered between the two treatment
groups. After irradiation, median decrease of the objective parameters
at the latest ophthalmic investigation prior to orbital decompression or
squint surgery were as follows: for proptosis ⫺2 mm in both groups; lid
fissure width ⫺2.5 vs. ⫺2 mm (10 vs. 20 Gy), and intraocular pressure
in up gaze ⫺3 vs. ⫺4.5 mm Hg. Constant diplopia was present in 43 vs.
37% (10 vs. 20 Gy) of the GO subjects before and in 26 vs. 24% after
radiotherapy. Decompression and squint surgery were necessary in 28
(10 Gy) vs. 33% (20 Gy) and in 36 vs. 44%, respectively. No retinopathy
occurred up to 17 yr after 10 Gy, whereas nonproliferate vascular
changes (focal capillary occlusions with microaneurysms) were noted in
4 diabetics and in 1 hypertensive subject (4%) 7–11 yr after 20 Gy. Thus,
in the long run, efficacy of 10 and 20 Gy seems similar, whereas side
effects may occur after high-dose radiotherapy.
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JCE & M • 2001
Vol. 86 • No. 5
LETTERS TO THE EDITOR
G. J. Kahaly, H. P. Rösler, S. Pitz, F. Krummenauer,
and G. Hommel
Departments of Endocrinology/Metabolism (G.J.K.), Radiology
(H.P.R.), Ophthalmology (S.P.), and Medical Statistics
(F.K., G.H.)
Gutenberg–University Hospital
Mainz 55101, Germany
References
1. Kahaly GJ, Rösler HP, Pitz S, Hommel G. 2000 Low- vs. high-dose radiotherapy
for Graves’ ophthalmopathy–a randomized, single-blind trial. J Clin Endocrinol
Metab. 85:102–108.
2. Kahaly GJ, Gorman CA, Kal KB, et al. 2000 Radiotherapy for Graves’ ophthalmopathy. In: Prummel MF, ed. Recent developments in Graves’ ophthalmopathy. Boston: Kluwer Publishers; 115–131.
3. Gorman CA. 1998 The measurement of change in Graves’ ophthalmopathy.
Thyroid. 8:539 –543.
4. Anonymous. 1992 Classification of eye changes of Graves’ disease. Thyroid.
2:235–236.
5. Just M, Kahaly GJ, Higer HP, et al. 1991 Graves’ ophthalmopathy: role of MR
imaging in radiation therapy. Radiology. 179:187–190.
6. Müller-Forell W, Pitz S, Mann W, Kahaly GJ. 1999 Neuroradiological diagnosis of thyroid-associated orbitopathy. Exp Clin Endocrinol Diabetes.
107:177–183.
7. Kahaly GJ, Rösler HP, Pitz S, Krummenauer F. 1999 Longterm follow-up of
low- and high-dose radiotherapy for Graves’ ophthalmopathy. Thyroid suppl.
72nd Annual Meeting of the American Thyroid Association, Palm Beach, FL,
1999, p 29 (Abstract).
Vitamin D Receptor Status in Parathyroid
Adenomas c
To the editor:
We are pleased to learn that our initial finding of loss of vitamin D
receptor in parathyroid adenomas by immunohistochemistry (1, 2) has
now been confirmed by independent investigators looking at vitamin D
receptor messenger RNA (3).
They cite our study showing the inverse relationship between serum
25-hydroxyvitamin D level and parathyroid gland weight (4). However,
they misquoted our findings. We found no correlation between serum
1,25-dihydroxyvitamin D levels and parathyroid gland weight.
D. Sudhaker Rao
Bone and Mineral Metabolism
Henry Ford Health System
Detroit, Michigan 48202-2689
and
A. Michael Parfitt
Division of Endocrinology
University of Arkansas
Little Rock, Arkansas 72205-7199
References
1. Rao D, Han Z-H, Phillips E, Palnitkar S, Parfitt A. 1997 Loss of calcitriol
receptor expression in parathyroid adenomas: implications for pathogenesis
(Abstract). J Bone Miner Res. 12:S107.
2. Rao D, Han Z-H, Phillips E, Palnitkar S, Parfitt A. 2000 Reduced vitamin D
receptor expression in parathyroid adenomas: implications for pathogenesis.
Clin Endocrinol 53:373–381.
3. Carling T, Rastad J, Szabo E, Westin G, Akerstrom G. 2000 Reduced parathyroid vitamin D receptor messenger ribonucleic acid levels in primary and
secondary hyperparathyroidism. J Clin Endocrinol Metab. 85:2000 –2003.
4. Rao D, Honasoge M, Divine G, et al. 2000 Effect of vitamin D nutrition on
parathyroid adenoma weight: pathogenetic and clinical implications. J Clin
Endocrinol Metab, 85:1054 –1058.
c
Received June 28, 2000. Address correspondence to: D. Sudhaker
Rao, M.D., Bone and Mineral Metabolism, Department of Internal Medicine, Henry Ford Health System, 2799 West Grand Boulevard, Room
E-1607, Detroit, Michigan 48202-2689.
Vitamin D Levels and Primary
Hyperparathyroidismd
To the editor:
I am grateful to Drs. Rao and Parfitt for pointing out the misquotation
in the article previously published in JCEM (1). In an elegant study they
show that serum 25-hydroxyvitamin D levels are related to parathyroid
gland weight (2). To my knowledge, serum 1,25-dihydroxyvitamin D3
levels have not been associated with parathyroid gland weight.
With regard to the reduced expression of vitamin D receptors in
parathyroid lesions of primary hyperparathyroidism, it is of interest that
the reduction in the protein level seems to be more substantial than in
the messenger RNA level (1, 3). This suggests that the reduced expression of vitamin D receptors in parathyroid adenomatous cells could be
due to both transcriptional and posttranscriptional mechanisms.
Tobias Carling
The Burnham Institute
La Jolla, California 92037; and
Department of Surgical Sciences
Endocrine Unit
Uppsala University Hospital
SE-75185 Uppsala, Sweden
References
1. Carling T, Rastad J, Szabo E, Westin G, Akerstrom G. 2000 Reduced parathyroid vitamin D receptor messenger ribonucleic acid levels in primary and
secondary hyperparathyroidism. J Clin Endocrinol Metab. 85:2000 –2003.
2. Rao DS, Honasoge M, Divine GW, et al. 2000 Effect of vitamin D nutrition on
parathyroid adenoma weight: pathogenetic and clinical implications. J Clin
Endocrinol Metab. 85:1054 –1058.
3. Sudhaker Rao D, Han ZH, Phillips ER, Palnitkar S, Parfitt AM. 2000 Reduced
vitamin D receptor expression in parathyroid adenomas: implications for pathogenesis. Clin Endocrinol (Oxf). 53:373–381.
Noninsulinoma Pancreatogenous Hypoglycemia in
Adults: Presentations of Two Cases e
To the editor:
We read with great interest the paper by Hirshberg et al. (1), who in
their 30-yr experience have not convincingly seen islet hyperplasia that
could be etiologically related to the patient’s hypoglycemia. In contrast,
recently Service et al. (2) have described five patients with severe postprandial hypoglycemia in whom partial pancreatic resection guided by
calcium stimulation was carried out. These patients did not have insulinoma. We have recognized two patients with this syndrome and would
like to confirm the existence of this unique nonneoplastic hyperinsulinemic hypoglycemic syndrome. Patient 1 was a 41-yr-old female who
presented with a 4-yr history of postprandial hypoglycemic episodes.
Recently she developed spontaneous hypoglycemic episodes, particularly during the nighttime. Three years before admission she had a 72-h
fast test, which was negative. Due to frequent hypoglycemic episodes
she entered our Institute for a repeat 72-h fast test, which was positive.
Within the first 24 h of fasting the test was disrupted due to neuroglycopenic symptoms, a glucose level of 1.8 mmol/L, and an insulin to
glucose ratio of 0.52 (insulin, 16.9 mU/L). Patient 2 was a 53-yr-old
female with a history of hypoglycemic episodes occurring both postprandial and during the nighttime. She had these symptoms 1.5 yr before
admission. A 72-h fast test was negative; the second test was positive.
After entering our Institute a third 72-h fast was interrupted within the
first 24 h with a glucose level of 2.3 mmol/L, an insulin to glucose ratio
of 0.47 (insulin, 19.6 mIU/L), and a C-peptide level of 0.29 nmol/L.
Computed tomography imaging, magnetic resonance imaging, and celiac angiography were negative for a pancreatic insulinoma. Intraoperd
Received January 25, 2001. Address correspondence to: Tobias
Carling, M.D., Ph.D., Department of Surgical Sciences, Endocrine Unit,
Uppsala University Hospital, SE-75185 Uppsala, Sweden.
e
Received December 4, 2000. Address correspondence to: Mirjana
S̆umarac-Dumanović, Institute of Endocrinology, Diabetes, and Diseases of Metabolism, University Clinical Center, Dr Subotica 13, 11000
Belgrade, Yugoslavia. E-mail: [email protected].
LETTERS TO THE EDITOR
ative ultrasound of the pancreas was negative. Both patients underwent
partial pancreatectomy (70 –75%). The pathological finding was islet cell
hyperplasia and nesidioblastosis. No insulinoma was found. Immunohistochemistry was as follows: chromogranin A-positive, insulin-positive cells. Patient 1 was free of hypoglycemic episodes for 7 months
postoperatively, after which hypoglycemic episodes reoccurred. A repeat 72-h fast was interrupted after 10 h of fasting with a glucose level
of 2.0 mmol/L and an insulin level of 9.7 IU/L. Diazoxide (800 mg/day)
in divided doses was ineffective. An ␣-glucosidase inhibitor prior to
meals was introduced, but this treatment after a while was ineffective
as well. Thus, this patient underwent total pancreatectomy, and no
insulinoma was detected. She is now diabetic. Patient 2 did not suffer
any hypoglycemic episodes during the 13-month follow up and with a
repeat 48-h fast. In conclusion, we confirm the possibility of the existence
of noninsulinoma pancretogenous hypoglycemia, which was proposed
by Service et al. (2).
Mirjana S̆umarac-Dumanović, Dragan Micić, and Vera Popović f
Institute of Endocrinology, Diabetes, and Diseases of Metabolism
University Clinical Center
11000 Belgrade, Yugoslavia
References
1. Hirshberg B, Livi A, Bartlett DL, et al. 2000 Forty-eight-hour fast: the diagnostic test for insulinoma. J Clin Endocrinol Metab. 85:3222–3226.
2. Service FJ, Natt N, Thompson GB, et al. 1999 Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in
f
We thank the two surgeons Prof. Dr. Jankovic and Prof. Dr. Milicevic
(Surgical Clinic, Belgrade University Clinical Center, Belgrade, Yugoslavia) for performing the operations and Dr. Cerovic (Pathology Department of VMA, Belgrade, Yugoslavia) for performing immunohistochemical analysis.
2329
adults independent of mutations in Kir6.2 and SUR1 genes. J Clin Endocrinol
Metab. 84:1582–1589.
Nesidioblastosis in Adults: A Clinical Enigma g
To the editor:
We appreciate the comments of Drs. Sumarac-Dumamovic, Micić,
and Popović. We believe they refer to two separate issues. First, the
report of Service et al. points out that the five patients they describe had
“exclusively postprandial hypoglycemia and negative fasts.” Thus, the
two patients described in the above comment did not have this syndrome. Our comment “that we have not seen islet hyperplasia or nesidioblastosis that could be etiologically related to the patients’ hypoglycemia” refers to sporadic case reports in adults that are
acknowledged to be very controversial in the discussion of the paper by
Service et al. For example, we have seen a patient who had a distal
pancreatectomy 10 yr ago with the pathologic findings of hyperplasia
and nesidioblastosis. Although the patient had transit relief of symptoms, hypoglycemia continued and recently on reoperation an insulinoma was enucleated from the remnant pancreas with complete relief of
hypoglycemia.
Thus, unfortunately neither our paper nor our experience clarifies the
clinical significance of the histologic finding of hyperplasia and/or nesidioblastosis in adult pancreatic specimens.
Boaz Hirshberg, H. R. Alexander, D. L. Bartlett, M. C. Skarulis,
S. K. Libutti, and P. Gorden
National Institutes of Health
Bethesda, Maryland 20892
g
Received January 24, 2001. Address correspondence to: Phillip Gorden, M.D., NIDDK Director, National Institutes of Health, Building 10,
Room 8S235, Bethesda, Maryland 20892.