|
Mills and colleagues from the NIH, FDA, and CDC presented
long-term mortality data on patients who received pituitary-derived growth
hormone (pGH) from the National Hormone and Pituitary Program (NHPP) during the
years 1963–1985. Data through December 1996 were obtained for 6107 of the 6272
children who received pGH. Information regarding the reason for pGH treatment
and the specific cause of death was obtained. Death certificates were reviewed
in all but 3 instances. Causes of GH deficiency were categorized as idiopathic,
organic (including tumor-related or non-tumor related—eg septo-optic dysplasia,
histiocytosis, trauma, etc.), or other (including unknown causes, neurosecretory
defect, Turner syndrome, etc.). Subjects were classified as having isolated GH
deficiency, multiple hormone deficiencies, unspecified deficiency (insufficient
information to classify), or not applicable (non-GH deficient). Subjects with
adrenal insufficiency and/or a history of hypoglycemia were identified.
Observed mortality was compared to that expected in a similar US cohort.
Relative risks were calculated and a proportional hazards model constructed.
There were 433 deaths
from 1963–1996 compared to an expected number of 114. Thus the overall risk of
death was nearly 4 times that of the general population (RR, 3.8; 95% CI,
3.4–4.2;p<.0001). Only subjects with idiopathic isolated GH deficiency had a
death rate similar to that expected for the population at large. The highest
risk categories included patients with either benign or malignant tumors,
adrenal insufficiency, and hypoglycemia. Tumors, hypoglycemia, adrenal
insufficiency, and multiple hormone deficiencies were demonstrated to be
significant, independent risk factors by proportional hazards analysis. There
were 26 deaths from Creutzfeldt-Jakob disease (CJD). Two deaths were from
colorectal cancer; one of whom had familial polyposis and the other had
received radiation for a CNS tumor. One subject died from Hodgkin’s disease.
Thus, the reported associations between GH therapy and colorectal cancer or
Hodgkin’s disease were not observed.
Of interest is that 24.5% of the deaths were sudden and
unexpected. Of those, multiple hormone deficiencies were present in at least
74%, a history of hypoglycemia was present in 31% and seizures had occurred in
52%. Deaths followed a clinical course suggestive of adrenal insufficiency in
56% of deaths. Sudden unexpected death was also associated with the presence of
a medical problem other than isolated GH deficiency—craniopharyngioma (24%) or
other intracranial tumors (14%). Hypoglycemia in children was associated with a
9 fold increase in risk. The death rate in those with adrenal insufficiency
remained stable as children aged.
The authors emphasized 3 findings. First, hypoglycemia was
an important risk factor for death, which decreased as the children aged and
presumably could identify and treat their own symptoms. Second, tumors were an
important cause of death, even though the risk of colorectal cancer, Hodgkin’s
disease and overall cancer deaths were not increased. Third, adrenal
insufficiency was an unexpected high-risk factor leading to death even in
adulthood. They stated that increased steroid doses for even supposedly trivial
infections was important as 30 of these 35 subjects were found dead or comatose
and most likely died of unrecognized or inadequately treated adrenal
insufficiency.
Mills JL, Schonberger LB, Wysowski DK, Brown P, Durako SJ, Cox C, Kong F, Fradkin JE. Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients. J Pediatr 2004;144:430-436.
First Editor’s Comment: This report presents
some alarming and some re-assuring information. That patients who had received
pGH have a markedly increased relative risk of dying is alarming. That the
cause of their deaths, in many instances could be prevented by appropriate
glucocorticoid administration for rather trivial infections suggests that
endocrinologists are not teaching or reminding patients of the importance of
increasing their medications or seeking medical assistance at the first sign of
infection. The reassuring news is that there does not appear to be an increased
risk of colorectal cancer, Hodgkin’s disease or other cancers in this cohort.
Furthermore, there have been no new cases of CJD in subjects who began pGH
treatment after 1977.
These data are interesting and compelling and
deserve to be read by those who care for these children. At quick glance, it
might appear that pGH administration was a dangerous treatment. On closer
inspection, the facts are much friendlier. One can anticipate discussing these
findings with parents of these patients.
William L. Clarke, MD
Second Editor’s Comment: This is an important
paper which clearly documents higher mortality risks of hypopituitary patients
and the surprisingly high number of unexpected sudden deaths. The concern with
CJD is justified and requires continuous surveillance, but there isn’t much we
can do to prevent it in those who harbor the prion. However there is a lot we
must do when treating hypopituitary patients to prevent unexpected fatalities.
Adrenal insufficiency must be aggressively treated particularly in patients who
vomit when ill. It is not clear why the patients in this report failed to do
so, but it is clear that more emphasis is needed so patients receive
appropriate steroid replacement during periods of stress. Familiarity breads
complacency—or so it seems. However, there were 20 sudden deaths in patients
without adrenal insufficiency. The possibility that uncontrolled diabetes
insipidus played a role should also be kept in mind, particularly when oral
DDAVP therapy may not be effective, such as when a patient vomits.
Fima Lifshitz, MD
|
Current GGH - Vol. 24 No. 1
print version (pdf)
Printer Friendly
Email Paper