434

and its absence in women may reflect a diminished ability tomount a local immune response. The low sIgA levelbetween attacks may be a marker for this defect or an

aetiological factor in itself for recurrent UTIs.Other evidence to support a general mucosal defect comes

from studies in women with recurrent UTIs and low

urinary sIgA levels who also have low mucosal sIgA.12 Suchpatients are not only more prone to symptomatic influenzavirus infection but also have an attenuated rise in sIgA levelsduring the infection. Although hereditary factors have notbeen fully assessed, preliminary data show that parents ofchildren with recurrent UTIs have low urinary sIgA levels"and recurrent bacteriuria is often seen in successive

generations.ls However, there was some overlap in the levelsof sIgA of the study and reference groups." Healthymembers of the latter with low sIgA may be better able toincrease sIgA production when challenged or may

compensate for their low sIgA with other means of defence.Pi blood groups may contribute to UTI susceptibility;16 thisphenotype provides glycolipid receptors for the binding ofEscherichia coli strains, so other factors may need to beconsidered in conjunction with sIgA deficiency.The child with recurrent UTIs usually undergoes

detailed and expensive investigations and can experienceconsiderable illness despite the small risk of long-term renaldamage. Identification of a cause should help treatment,particularly the use of antibiotics and hygienic measures toprevent infection; treatments to improve local immunedefences are not yet practical. It might be tempting to usehigh sIgA excretion to select children for investigation byurinary tract imaging. Unfortunately, the test is

insufficiently discriminating but further refinement maymake it clinically useful.

NODULAR HYPERPLASIA AND CUSHING’SSYNDROME

"LET me have men about me that are fat"I might well bethe plea of radiologists using computerised tomographicscans to examine the adrenal glands-in patients withCushing’s syndrome the characteristically abundant

perinephric and adrenal fat allows excellent delineation ofthe glandular morphology. Such technical advances alsocreate diagnostic and therapeutic difficulties-for example,in the management of patients with adrenocortical

hyperactivity whose adrenal glands contain nodules.The pathophysiology of nodular adrenocortical

hyperplasia remains uncertain but two distinct disorders canbe identified. In macroscopic nodular hyperplasia, thecommoner condition, one or more nodules (of various sizes,but often up to several centimetres in diameter) coexist witha hyperplastic adrenal cortex.2,3 The degree of hyperplasia isvariable and in longstanding cases there may be atrophicfeatures. The crucial question is whether these adrenals are

16 Lomberg H, Hanson LA, Jacobsson B, et al. Correlation of Pi blood group,vesicoureteral reflux, and bactenal attachment in patients with recurrent

pyelonephritis. N Engl J Med 1983; 308: 1189-921 Shakespeare. Julius Caesar, act I, scene ii.2. Neville AM, MacKay AM. The structure of the human adrenal cortex in health and

disease. Clin Endocrinol Metab 1972; 1: 361-95.3 Smals AGH, Pieters GFFM, van Haelst UJG, Kloppenborg PWC. Macronodular

adrenocortical hyperplasia in longstanding Cushing’s disease. J Clin EndocrinolMetab 1984; 58: 25-31.

pituitary driven or autonomous in function. It has been

suggested that this condition, which occurs in 20-40% ofpatients with Cushing’s disease, represents a process oftransition from pituitary dependence to adrenal autonomy.Untreated Cushing’s syndrome carries a 50% five-yearmortality,4 so it is not feasible to observe patients withoutintervention. Support for the hypothesis is therefore patchyand often serendipitous. Patients with macronodular

hyperplasia give a longer history, and are older and morehypertensive than those with classic Cushing’s disease fromdiffuse hyperplasia. They are more resistant to

dexamethasone suppression, have lower corticotropinlevels, and the nodules and the hyperplastic adrenal tissueboth respond to corticotropin in vitro. 5 Adrenal

scintigraphy characteristically shows asymmetry of adrenalsize but with uptake on both sides.6 Pituitary surgery maycorrect the adrenal disorder, and simultaneous histologicalpresence of a corticotropin-immunostaining pituitaryadenoma and macronodular hyperplasia have beendocumented in a case which came to necropsy after a

myocardial infarction six days postoperatively.7Hermus and colleagues lately reported a patient who first

underwent pituitary surgery but whose hypercortisolismwas not controlled despite removal of adenomatous tissue.Three months later a large left adrenal gland containing asingle 33 g nodule was removed and cortisol secretion

improved but was still excessive; after six weeks a rightadrenalectomy was carried out and showed micronodularhyperplasia.8 Corticotropin levels were barely measurableinitially although they rose paradoxically, as did cortisol,after administration of gonadotropin releasing hormone.Cortisol also showed an excessively brisk response to

exogenous corticotropin which was much blunted after leftadrenalectomy. Plasma corticotropin concentration

gradually increased after removal of the left adrenal andbecame supranormal after the right adrenalectomy. Thesefindings strongly suggest the emergence of a macronodulehyperresponsive to corticotrcpin-ie, hypercortisolism issustained in the face of relatively suppressed corticotropinsecretion. Nevertheless, corticotropin appears necessary inthis condition, in contrast to fully autonomous adrenaladenomas or carcinomas, and a vigorous attack on thepituitary is warranted in the first place.

Pigmented multinodular adrenocortical dysplasia, whichis less common that the macroscopic form, is often familialand occurs in children and young adults. This condition isnot dependent on corticotropin but is possibly an

autoimmune disorder.9,10 Treatment must be directed at the

adrenal-usually adrenalectomy but possibly blockade ofadrenal steroidogenesis, by analogy with thyrotoxicosis.

4. Plotz CM, Knowlton AI, Ragan C. The natural history of Cushing’s syndrome. Am JMed 1952; 13: 597-614.

5. Lamberts SWJ, Bons EG, Bruining HA. Different senstitivity to adrenocorticotropinof dispersed adrenocortical cells from patients with Cushing’s disease withmacronodular and diffuse adrenal hyperplasia. J Clin Endocrinol Metab 1984; 58:1106-10.

6. Schteingart DE, Tsao HS. Coexistence of pituitary adrenocorticotropin-dependentCushing’s syndrome with a solitary adrenal adenoma. J Clin Endocrinol Metab1980; 50: 961-66.

7. Aron DC, Findling JW, Fitzgerald PA, et al. Pituitary ACTH dependency of nodularhyperplasia in Cushing’s syndrome. Am J Med 1981; 71: 302-06.

8. Hermus AR, Pieters GF, Smals AG, et al. Transition from pituitary-dependent toadrenal-dependent Cushing’s syndrome. N Engl J Med 1988; 318: 966-70.

9. van Berkhout FT, Croughs RJM, Kater L, et al. Familial Cushing’s syndrome due tonodular adrenocortical dysplasia: a putative receptor-antibody disease? ClinEndocrinol 1986; 24: 299-310.

10. Wulfratt NM, Drexhage HA, Wiersmga WM, van der Gaag RD, Jencken P, Mol JAImmunoglobulins of patients with Cushing’s syndrome due to pigmentedadrenocortical micronodular dysplasia stimulate in vitro steroidogenesis. J ClinEndocrinol Metab 1988; 66: 301-07.