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Original Studies |
Departments of Pediatrics (M.M., G.B., G.C., M.A.), Biometry-Scientific Direction (C.K.), and Radiology (E.G.), University, IRCCS Policlinico S. Matteo, Pavia, Italy
Address all correspondence and requests for reprints to: Mohamad Maghnie, M.D., Department of Pediatrics, IRCCS Policlinico S. Matteo, I-27100 Pavia, Italy. E-mail: maghnie{at}smatteo.pv.it
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Abstract |
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The six patients with GH deficiency at the time of evaluation had a significantly lower GH response to GHRH than the other patients [median peak, 7.3 vs. 21.5 µg/L (P = 0.03); median area under the curve, 4.7 vs. 13.5 µg/L (P = 0.03)]; levels in the latter group did not differ significantly from those in 20 age- and sex-matched controls with constitutional or familial short stature. Two patients who had GH responses to GHRH of 20.6 and 23 ng/mL at 2.8 and 9.5 yr of age developed GH deficiency at 6.5 and 11.2 yr of age, respectively. The TSH response to TRH was less than 10 mU/L in three patients, two of whom later developed central hypothyroidism. ACTH and cortisol responses to CRF, and PRL responses to TRH were normal in all cases, and LH and FSH responses to GnRH were compatible with pubertal stage. Abnormalities in arginine vasopressin responses to water deprivation or hypertonic saline infusion were seen only in four patients who had preexisting diabetes insipidus (DI); one patient who later developed DI had normal findings. On standard MRI, posterior pituitary hyperintensity was absent only in the patients with DI. Pituitary stalk thickening was seen in seven patients, including three who did not have DI and had normal arginine vasopressin responses. Delayed posterior and anterior enhancement on dynamic MRI was present in two patients, both of whom later developed central hypothyroidism. Patients with single system disease had a lower 5-yr probability of LCH reactivation (41% vs. 83% for those with multisystem disease; P = 0.21) and a significantly lower risk of endocrine dysfunction (P = 0.007).
In this series, dynamic evaluation of pituitary function was not a useful predictor of late endocrine sequelae, with the possible exception of the progressively decreasing TSH response to TRH. Similarly, a standard MRI was not predictive, although dynamic imaging may be informative regarding evolving pituitary hormone deficiency.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Anterior pituitary deficits, primarily GH deficiency, are also common complications of LCH (4, 8, 9, 14, 15, 16). Predictors of late GH deficiency and of other anterior pituitary deficits such as central hypothyroidism are also lacking. To provide additional information on long term endocrine sequelae, we evaluated anterior hypothalamic and posterior pituitary MRI morphology and function in patients followed for prolonged periods (median, 10 yr) after the diagnosis of biopsy-proven LCH. Specifically, we studied the frequency and temporal pattern of LCH-related endocrine deficits and assessed the predictive ability of dynamic endocrine tests and MRI to identify patients at risk for anterior or posterior pituitary hormone dysfunction.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Evaluation of anterior pituitary function
After GHRH administration (Test 1–29, Serono, Italy; 1 µg/kg, iv), blood samples for GH measurement were drawn at 0, 15, 30, 60, and 120 min. In patients with GH deficiency, testing was performed 1 month after withdrawal of recombinant human GH (rhGH) therapy. Serum GH levels were measured by RIA (Pharmacia, Uppsala, Sweden). The intra- and interassay coefficients of variation were 5.1% and 5.6%, respectively, at 1.1 µg/L, 2.9% and 4.3% at 4.2 µg/L, 2.5% and 3.5% at 10.9 µg/L, and 4.5% and 4.7% at 24.1 µg/L. Serum T3, T4, free T4, free T3, and TSH were tested basally; TSH and PRL were evaluated 5, 10, 20, 30, 40, 60, and 120 min after TRH treatment (Reflact, Hoechst, Frankfurt, Germany; 200 µg/m2, iv). ACTH and cortisol responses to ovine CRF (Clinalfa, Switzerland; 1 µg/kg, iv) were determined at baseline and 15, 30, 45, 60, 90, and 120 min postinjection. Twenty children with isolated GH deficiency served as controls for the TRH and CRF tests. The responses of FSH and LH to GnRH (Relisorm L, Serono, Italy; 100 µg/m2) were measured at baseline and 30, 60, and 120 min after injection. Standard RIAs were used to measure TSH, T3, T4, free T4, free T3, PRL, ACTH, cortisol, and FSH/LH.
Evaluation of posterior pituitary function
Patients with DI discontinued treatment (intranasal 1-desamino-8-D-arginine-vasopressin) 24 h before the start of the study. A 24-h urinary volume was collected. Free access to fluids and food was allowed before a 7-h water deprivation test, carried out between 0830–1530 h. Serum sodium, plasma osmolality, and arginine vasopressin (AVP) at 0, 2, 4, 6, and 7 h were measured. Urinary osmolality was recorded at 0 and 7 h.
Hypertonic saline testing was performed at 0900 h after an overnight fast. Fluid intake was stopped 3 h before testing. After patients urinated, 3% NaCl was administered iv at a rate of 0.1 mL/kg·min for 120 min. Plasma Na, AVP, and plasma and urinary osmolalities were measured at 0, 30, 60, 90, and 120 min, as described previously (11). The results were interpreted by plotting on a nomogram according to the method of Robertson (17).
MRI
To evaluate pituitary morphology and hypothalamic-pituitary vascular supply, standard (16 patients) and dynamic (12 patients) MRI studies were performed using a spin-echo technique on a 1.5 T superconductive system (Magnetom, Siemens, Germany). Sagittal and coronal T1-weighted images (TR, 400 ms; TE, 15 ms; three excitations) were obtained using 3-mm sections (matrix size of 256 x 256, 20-cm field of view). Dynamic sagittal images were acquired using a flip angle of 80°, a section thickness of 6 mm, a 128 x 128 matrix, and a 25-cm field of view. Twenty rapid images were obtained every 4 s for 90 s after injection of gadopentetate dimeglumine (0.1 mmol/kg BW). Times of enhancement of the anterior and posterior pituitaries were calculated as previously described (18).
Statistical analysis
Descriptive statistics were computed for all variables. For plasma hormone assays, the area under the curve (AUC) was calculated according to Matthews et al. (19). The Mann-Whitney U test was used to compare median values of measures for study patients vs. controls and for patients with and without endocrine deficits. The time to disease reactivation was estimated using the method of Kaplan and Meier (20). Risk group comparisons were performed using the log-rank test. For all analyses, a two-tailed P-value of 0.05 was considered statistically significant. Statistica 5.1 (Statsoft, Tulsa, OK) was used for statistical computations.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. The 5 male and 12
female patients had a median age of 2.1 yr at diagnosis, 8.6 yr at
study evaluation, and 14 yr at the most recent follow-up. Six patients
had single system disease (bone or skin) at diagnosis, and 11 had
multisystem disease that included organ dysfunction in 5 cases. Initial
treatment was with chemotherapy in all but 2 cases; 1 child had surgery
only, and 1 had a spontaneous remission. Eight patients had disease
reactivation, at a median time of 0.6 yr after the start of treatment
(range, 0.1–7.5 yr). Patient 12 developed promyelocytic leukemia and
underwent successful bone marrow transplantation 1 yr before endocrine
evaluation (21). All patients are currently alive and free of active
disease, with the exception of 1 child who died during liver
transplant.
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Patterns of growth are illustrated in Table 2. GH deficiency was identified after a
median interval of 4.9 yr (range, 1–9.1 yr) in eight patients. Low
serum insulin-like growth factor I levels and growth arrest were
documented along with DI at disease reactivation in one additional case
(patient 4). GH treatment (rhGH, 15 mIU/m2·week in six or
seven s.c. daily doses) was effective in all seven patients treated,
with no adverse effects; median height velocities during the first and
second years were 9.1 and 6.6 cm/yr, respectively; three patients
(cases 13, 14, and 15) had completed GH treatment.
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Anterior pituitary function
Pituitary GH reserve was reduced in the 6 patients with GH
deficiency diagnosed before dynamic testing (Table 3). The median peak GH response to GHRH
was significantly lower in this group than in the 11 patients without
previously diagnosed GH deficiency (7.3 vs. 21.5 µg/L;
P = 0.03). These 6 patients also had a significantly
lower GH median AUC (4.7 vs. 13.5 µg/L for patients
without GH deficiency; P = 0.03). The control group’s
median GH peak response to GHRH (23.4 µg/L; range, 14.2–40.4) and
median AUC (14.7 µg/L; range, 8.7–27.4) did not differ from
responses in the LCH patients not previously diagnosed with GH
deficiency.
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The TSH response to TRH was normal (median peak, 15.5 mU/L; range,
10.5–20) in all but three patients, whose peak values were below 10
mU/L (patients 12, 13, and 16; Table 3
). AUCs in these three patients
(6.8, 3.9, and 4.5 mU/L) were also lower than those in subjects with
normal peak TSH responses (median, 7.4 mU/L; range, 7.3–12.6). We then
compared peak values and AUCs for the six patients with at least one
previously diagnosed hormone defect to those of patients with no
identified deficits and found no significant differences
(P = 0.4). These six patients had a median peak TSH
value of 15.8 mU/L (range, 12.8–19) and a median AUC of 7.6 mU/L
(range, 7.8–12.6). Controls (patients with isolated GH deficiency) had
a median peak TSH response of 14.7 mU/L (range, 12.5–19.2) and a
median AUC of 7.7 mU/L (range, 7.1–11.9).
During posttesting follow-up, two of the three patients with TSH
responses to TRH below 10 mU/L (cases 12 and 13) developed central
hypothyroidism. These patients showed a pattern of continued decrease
in the TSH response over time, as illustrated in Fig. 1. In case 12, evaluation of the
nocturnal TSH surge (2%) before treatment start was compatible with
that reported in central hypothyroidism (22).
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Posterior pituitary function
Responses to the short dehydration and hypertonic saline infusion
tests (Table 4) were normal in all
patients except those with previously diagnosed DI. The AUCs of the AVP
response to water deprivation and to hypertonic saline infusion were
lower in the 4 evaluated patients with DI than in the 10 remaining
patients (medians, 0.4 vs. 4.8 and 0.4 vs. 4.0,
respectively; P = NS). We then compared AVP responses
of 3 patients who had pituitary stalk thickening on MRI (described
below) but lacked clinical symptoms of DI to those of patients without
DI who lacked this imaging finding, and found no differences (median
AUCs, 4.4 vs. 5.7 during dehydration and 3.7 vs.
4.1 during hypertonic saline infusion, respectively; P
> 0.05). The absolute value and percentage of AVP increase observed
after water deprivation or 3% NaCl administration did not differ
significantly, regardless of pituitary stalk size, in the absence of
DI.
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MRI findings
On standard MRI studies, posterior pituitary hyperintensity was absent in all patients with DI who were included in this evaluation. Pituitary stalk thickening, indicating local histiocytic infiltration, was found in seven patients, including three who did not have DI at the time of testing (cases 1, 3, and 5). Findings on dynamic MRI were normal in all but two patients (cases 12 and 13), in whom delayed posterior and anterior pituitary enhancement suggested abnormal local vascularization. Both of these patients developed central hypothyroidism during subsequent follow-up.
Prognostic factors
The observation time was not independently associated with an increased risk of endocrine dysfunction (by Mann-Whitney test, P = 0.61). Patients with localized disease (bone or the skin only) at diagnosis had a 41% estimated 5-yr probability of LCH reactivation, compared with 83% for patients with multisystem disease (P = 0.21). The risk of endocrine dysfunction was significantly greater in patients with multisystem disease (11 patients, 9 events) than in those with single system disease (6 patients, 0 events; P = 0.007).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Treatment of growth delay appeared both safe and effective. The median height velocity during the first and second years of rhGH treatment was similar to that obtained in idiopathic GH deficiency. Outcomes to date, although for limited numbers, suggest that the effect of rhGH treatment on final height in these patients with LCH may equal or exceed that reported for idiopathic GH deficits by our group (25). We observed no adverse treatment effects, and there was no association between rhGH administration and reactivation of LCH. One patient with etoposide-related acute promyelocytic leukemia, which appears to be cured after bone marrow transplantation, had no adverse events during 3 yr of follow-up after initiation of rhGH therapy.
DI was also frequent in this series, occurring in 8 of the 17 patients and most often as an early complication (median time from LCH diagnosis, 0.5 yr). There was a clear concordance between the occurrence of DI and the diagnosis of GH deficits, in that all but 1 case of GH deficiency occurred in patients with previously diagnosed DI, although with a median interval of over 4 yr.
We assessed the ability of dynamic endocrine tests to predict the risk of later hormone deficits. The pituitary GH reserve, as reflected by the GH response to GHRH, was reduced in the patients with previously diagnosed GH deficiency, suggesting involvement of the anterior pituitary. However, whether GH deficits result from primary involvement of the anterior pituitary or from chronic hypothalamic damage remains unclear. The former interpretation conflicts with the widely accepted concept that the anterior pituitary is spared by LCH granulomatosis (26). Also, the reversal of low GH response after chronic GHRH administration in adults with Hand-Schuller-Christian disease (27) suggests that alterations may be confined to the hypothalamus. The concept of primary hypothalamic damage with secondary hypotropic pituitary degeneration remains to be evaluated in children with LCH, perhaps after repeated GHRH administration. Overall, in view of the extreme variability of "normal" GH responses to GHRH and the absence of abnormalities in GH response to GHRH in our patients who subsequently developed GH deficits, this test cannot be considered a useful predictive tool for GH failure in LCH patients.
Of interest, the parallel evaluation of thyroid function proved more informative. Two of the three patients with TSH responses less than 10 mU/mL at the time of testing showed progressive decreases and eventually developed the complete form of central hypothyroidism. Although patient numbers are small, these findings suggest that in the presence of a low TSH response to TRH, nocturnal evaluation of the TSH surge may be useful during the silent phase of central hypothyroidism, when serum thyroid hormone and TSH levels may remain in the low normal range for prolonged periods.
We attempted to identify indicators of partial posterior pituitary dysfunction that would also be predictive of subsequent central DI. Unfortunately, none of the measures studied proved sufficiently sensitive for this purpose. Plasma AVP increases, peak AVP levels, and percent change in AVP increase after 7-h water deprivation or administration of hypertonic saline did not differ between patients who maintained normal water homeostasis during follow-up and the patient who developed clinical and laboratory features of DI over 2 yr after testing. This finding is apparently not in keeping with the reported usefulness of measurement of urinary AVP in identifying partial posterior pituitary deficiency (28). In view of the wide range of urinary AVP values (10–70 pmol/L) in patients diagnosed with partial DI (28), reflecting the variability of renal sensitivity, we had addressed plasma AVP measurement as a possibly more sensitive tool. Thus, evaluation of posterior pituitary functional reserve using these measures unfortunately does not appear helpful in identifying preclinical DI.
A standard MRI was not useful in predicting subsequent DI. We found evidence of partial granulomatosis, indicated by pituitary stalk thickening in three patients who had normal AVP responses to water deprivation and hypertonic saline administration and who showed no clinical or laboratory features of DI during subsequent follow-up. Thus, this imaging finding does not appear to be associated with progression to posterior pituitary dysfunction, at least over the time period of this study. Potential imaging criteria for partial posterior pituitary deficiency has been reported in animal studies after chronic dehydration (administration of hypertonic saline for 2 weeks) (29), but the risk/benefit ratio of such an approach in humans is obviously unacceptable. However, dynamic MRI showed more promise, in that the identification of local vascular damage after hypothalamic-pituitary histiocytic infiltration in 2 of our patients was associated with subsequent central hypothyroidism. Further evaluation of this technique in the setting of long term follow-up is needed to determine its true prognostic value.
This study confirms the high risk of endocrine sequelae in childhood Langerhans cell histiocytosis, mainly in the patients with disseminated disease, with central DI and GH deficiency as the predominant deficits. In general, dynamic evaluation of posterior and anterior pituitary function did not prove to be a useful predictor of endocrine deficits, although low and progressively decreasing TSH responses to TRH may presage later thyroid failure. The standard MRI also lacked prognostic utility, whereas findings with dynamic MRI may be informative in regard to evolving pituitary hormone deficiency.
Received April 15, 1998.
Revised May 28, 1998.
Accepted June 2, 1998.
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