University Departments of Medicine and Clinical Biochemistry (I.S.F., S.O.R.) and Neurology (J.R.H.), and Medical Research Council Cognition and Brain Sciences Unit (J.R.H.), Addenbrookes Hospital, Cambridge CB2 2QQ, United Kingdom; and Department of Medicine, Singleton Hospital (M.K.J., M.E.), Swansea SA2 8QA, United Kingdom
Address all correspondence and requests for reprints to: Prof. Stephen ORahilly, University Departments of Medicine and Clinical Biochemistry, Box 157, Addenbrookes Hospital, Cambridge CB2 2QQ, United Kingdom. E-mail: sorahill{at}hgmp.mrc.ac.uk
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Introduction |
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Other than the very rare encephalopathy associated with Hashimotos thyroiditis, there are few examples where the central nervous system is a target organ in the context of autoimmune endocrine disease. The highly specific nature of the central nervous system involvement in this novel syndrome suggests the involvement of a molecular target for autoimmunity shared among the hippocampus, the hair follicle, and the hypothalamus and/or corticotroph. We suggest that the term triple H syndrome may serve to alert clinicians to this previously undescribed triad.
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Case Reports |
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Subject A, a British Caucasian woman, presented to a dermatologist
in 1990 at the age of 41 yr with progressive alopecia, which, over the
subsequent 2 yr, resulted in total loss of body hair (Fig. 1A). She was also noted to have patchy,
symmetrical vitiligo (Fig. 1B
). In 1992 she was referred to a
psychiatrist because of complaints of fatigue and memory loss.
Endogenous depression was diagnosed, and antidepressant medication was
commenced. At that time the results of a tetracosactrin test were
reported as normal. Over the subsequent year her symptoms failed to
improve, and further laboratory investigations included a random plasma
cortisol of 50 nmol/L. She was referred to an endocrinologist
(M.K.J.).
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On examination, she was a mildly obese Caucasian female who was fully
alert and cooperative, but appeared vague and easily distracted. She
had alopecia universalis and widespread scattered vitiligo. Blood
pressure was 90/60 mm Hg with no postural fall. The results of relevant
endocrine studies are shown in Table 1.
During an insulin tolerance test she achieved an inadequate peak
cortisol of 159 nmol/L despite adequate hypoglycemia. Isolated ACTH
deficiency was confirmed by the demonstration of an absent ACTH
response during a CRF-41 test and a normal response to depot
tetracosactrin (1 mg); pituitary function was otherwise normal. A
computed tomographic scan of the brain was normal. Circulating
antibodies to thyroid microsomal antigen were detectable, and a test
for gastric parietal cell antibodies was weakly positive. Antiadrenal,
antigliadin, and antiendomysin antibodies were negative. Hydrocortisone
replacement therapy was commenced. Although hydrocortisone therapy led
to an improvement in her fatigue, the memory problems became more
severe, and she was referred to Cambridge for formal neuropsychological
testing. By this time she was severely functionally disabled, being
unable to recall the directions to nearby shops and forgetting to
undertake basic household tasks and personal hygiene measures.
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Subject B
A 39-yr-old British Caucasian female presented in 1991 with a 5-month history of progressive fatigue and lethargy, such that she was unable to perform routine household tasks. She also gave a history of forgetfulness, which had become so marked that she would forget to pick up her children from school. She subsequently developed alopecia areata of her scalp with typical clinical features, including exclamation mark hairs. She was menstruating normally and had no previous or family history of endocrine disease. The only past medical history was of atopic asthma, for which she had taken inhaled corticosteroids in the past. No inhaled steroids had been used in the 6 months before presentation. Clinical examination was unremarkable, with normal body habitus and body hair, no abnormality of skin pigmentation, and no postural fall in blood pressure.
Endocrine evaluation. To investigate the possibility of adrenocortical insufficiency a short tetracosactrin (0.25 mg) test was performed. The 30-min cortisol concentration was slightly subnormal at 500 nmol/L. Over the subsequent months two further short tetracosactrin tests were performed, which demonstrated a progressive reduction in 30 min cortisol response (420, then 310 nmol/L). In response to the injection of 1 mg depot tetracosactrin, her plasma cortisol was more than 1000 nmol/L, indicating that the adrenal insufficiency was central in origin. An insulin tolerance test was performed, which resulted in an inadequate peak cortisol of 340 nmol/L despite adequate hypoglycemia. There was no other endocrine abnormality. A MRI scan of the hypothalamus and pituitary was normal.
Neuropsychological evaluation. Neuropsychological evaluation
showed a mild, but definite, impairment in both verbal and nonverbal
anterograde episodic memory, with preservation of other cognitive
abilities (Table 2).
She was commenced on hydrocortisone replacement therapy, with
considerable improvement in fatigue. Over the subsequent 12 yr the
alopecia areata resolved, and there was subjective and objective
improvement in her memory. The patients body weight has remained
stable. Attempts to gradually withdraw hydrocortisone replacement have
not been tolerated due to the recurrence of fatigue. Repeat
neuropsychological evaluation 15 months after presentation showed
objective improvement on memory scores (Table 2).
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Discussion |
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The occurrence of isolated ACTH deficiency in association with Hashimotos thyroiditis (7), insulin-dependent diabetes (8), or as part of a generalized autoimmune polyglandular syndrome (9), and the presence of circulating autoantibodies to endocrine cells strongly suggest that the majority of cases are autoimmune in etiology (10). Subject A had vitiligo and alopecia universalis, and subject B had alopecia areata, diseases of the integument that are often associated with polyglandular autoimmunity. In addition, subject A had circulating antibodies to thyroid microsomal antigen and gastric parietal cells. In surveys of patients with isolated ACTH deficiency, primary autoimmune hypothyroidism is the most common reported autoimmune condition (5, 11), but neither alopecia nor vitiligo has specifically been reported.
The most striking aspect of these cases is the presence of a marked disturbance of memory. The nature of the defect in central nervous system function was highly specific, affecting anterograde, but not retrograde, memory. In neither subject was there any evidence of a general decline in cognitive function. The pattern of cognitive deficit seen in the two patients is very unusual and suggests a pathological process limited to the hippocampal-fornix system (12, 13). A remarkable feature of the amnesia in subject A was the dissociation between severely impaired anterograde and preserved retrograde memory. In subject A the amnesia was permanent and extremely disabling, whereas in subject B, like her alopecia, it was a transient phenomenon. SPECT scanning in subject A revealed severe bilateral hypoperfusion in the hippocampal areas, and MRI scanning showed loss of volume in the medial areas of the hippocampus known to be involved in anterograde episodic memory. This pattern is identical to that seen in patients with other causes of circumscribed medial temporal lobe damage of the type described in autoimmune limbic encephalitis associated with remote neoplasm (14), in some patients with herpes simplex virus encephalitis (although most of these patients have more extensive cognitive deficits) and after anoxic brain damage (15, 16).
What possible mechanism could lead to this selective hippocampal damage? Its occurrence in subjects with other known or presumed disorders of immune dysregulation (alopecia areata, vitiligo, and isolated ACTH deficiency) is highly suggestive of an autoimmune etiology. This is further supported by the finding of oligoclonal bands in the CSF of subject A. The coexistence of several uncommon autoimmune disorders in the same subjects suggests the possible coexistence of shared autoimmune targets in hair follicle, hippocampus, and hypothalamus. POMC, the precursor of ACTH, is expressed in the hair follicle, the corticotroph, and the hypothalamic neurons, but there are no reports of POMC-expressing cell bodies in the hippocampus (17, 18). In this regard, POMC concentrations in the CSF, which are thought to be derived from hypothalamic neurons of subject A, were within the normal range (White, A., personal communication), suggesting the preserved integrity of that neuronal population. Receptors for CRH are expressed in pituitary corticotrophs, hair follicle, and hippocampus (19). Additionally, CRH has been reported to have profound effects on memory retention in rodents (20). We attempted to examine whether any circulating autoantibodies to CRH receptors are present in subject A, but her serum did not inhibit signaling through cloned CRH-1 or CRH-2 receptors (Brennand, J., personal communication). Similar studies with cloned melanocortin receptors were also negative (Mountjoy, K., personal communication). The absence of circulating antibodies to these components does not exclude them as potential autoimmune targets, as cell-mediated, rather than humoral, autoimmunity may be involved.
The development of severe hyperphagia and severe obesity in subject A is also of interest. This is unlikely to be due to high dose corticosteroid treatment alone, as this problem has persisted after the discontinuation of immunosuppressive doses of steroids. Although the patient has no conscious memory of eating her last meal, such "food amnesia" appears to be an unlikely explanation for her weight gain, as this is not seen in other cases of amnesia due to hippocampal damage despite more profound amnesia than that of subject A. We hypothesize that hypothalamic neurons expressing a shared autoimmune target may also have been subject to immune destruction. Given the known roles of both POMC-derived peptides and corticotropin-releasing factors and their receptors in the hypothalamic regulation of appetite (21), these would be attractive candidates for such a molecular target.
Autoimmune dysfunction of the central nervous system occurring as part of a syndrome of endocrine autoimmunity is a rare phenomenon. To our knowledge, only the occasional association of thyroid autoimmunity with Hashimotos encephalopathy or chorea represent well established examples (22, 23). The coexistence of this unusual form of amnesia with isolated ACTH deficiency in two patients is highly unlikely to be a chance finding. It is perhaps surprising that there are no previous reports of this association. Although it is unlikely that an amnesic state as severe as that seen in subject A would not be detected, the more subtle memory disturbances exhibited by subject B could readily be overlooked in a subject with a range of other nonspecific symptoms secondary to hypocortisolemia.
We suggest that memory be assessed more thoroughly in patients presenting with isolated ACTH deficiency, particularly if accompanied by autoimmune conditions such as alopecia areata or vitiligo. To aid the recognition of this unusual triad of features, we suggest that the term triple H syndrome accurately reflects the simultaneous dysfunction of hippocampus, hair follicle, and hypothalamic-pituitary-adrenal axis.
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Acknowledgments |
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Footnotes |
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2 Supported by the WellcomeTrust.
Received December 6, 1999.
Revised March 24, 2000.
Accepted April 1, 2000.
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References |
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