Gian Franco Bottazzo

EVIDENCE FOR A LONG PREDIABETIC PERIOD IN TYPE I (INSULIN-DEPENDENT) DIABETES MELLITUS

In a prospective investigation of the prediabetic period before onset of type 1 (insulin-dependent) diabetes, HLA genotypes were determined in 582 healthy parents and siblings of 160 affected children. Islet cell antibody was sought by both the conventional (ICA-IgG) and the complement fixation (CF-ICA) techniques during regular prospective observation over a mean period of 2.0 years. 4 siblings and 2 parents became diabetic; the interval before detection of any biochemical abnormality exceeded a year in 4 of these (range 3-30 months), and in all cases ICA-IgG was positive from the outset, CF-ICA being positive in 5. These observations suggest that the initiation of pathogenesis may precede the abrupt clinical onset of diabetes by several years, even in children. This has important implications, both for research and for possible future prophylaxis.

COMPLEMENT-FIXING ISLET-CELL ANTIBODIES IN TYPE-I DIABETES: POSSIBLE MONITORS OF ACTIVE BETA-CELL DAMAGE

Evidence is presented for the existence of a separate species of islet-cell antibodies which fix complement. Investigations in type I diabetics, non-diabetic polyendocrine patients, and unaffected first-degree relatives of type I diabetic probands show that the complement-fixing islet-cell antibodies are more closely related to the onset of clinical disease than the conventional islet-cell antibody, and they tend to disappear more rapidly. The complement-fixing antibodies may reflect damage of pancreatic beta cells more selectively and may be preferable to the conventional antibody as a serological marker for studying the natural history of type I diabetes.

EVIDENCE FOR THYROID-GROWTH-STIMULATING IMMUNOGLOBULINS IN SOME GOITROUS THYROID DISEASES

Abstract To investigate the possibility that goitrous enlargement in autoimmune thyroid disease could be induced by autoantibodies stimulating thyroid-cell growth, organ cultures of guineapig thyroid segments were exposed to immunoglobulins (Ig) from several groups of patients with goitrous and non-goitrous thyroid diseases. The growth-stimulating effects of the immunoglobulins were measured with nucleic-acid cytophotometry and confirmed with thymidine autoradiography. DNA synthesis was enhanced by immunoglobulins from patients with goitrous Graves disease, whereas normal immunoglobulins caused some inhibition. Immunoglobulin from non-goitrous thyrotoxic patients and from patients with primary myxœdema gave responses comparable to the normal Ig. Thyroid growth was also induced by Ig from patients with Hashimoto goitres, especially those with recurrences after partial thyroidectomy or those in whom the gland failed to shrink on full thyroxine replacement. Ig from 10 women with simple euthyroid colloid goitres, 3 of whom had had one or more recurrences after previous thyroidectomies, also gave rise to increased DNA synthesis in the thyroid cultures, whereas Ig from goitres of known aetiology, such as single autonomously functioning adenoma, or dyshormonogenesis failed to stimulate cell growth under the same conditions. In the thyrotoxic patients the trophic effects in vitro correlated well with the size of the glands in vivo rather than with the degree of toxicity. These results suggest the existence of distinct types of thyroid-stimulating antibodies, some of which increase hormone release, whereas others promote thyroid-cell growth. They also suggest that some forms of euthyroid goitres, histologically classified as colloid goitres, may be due to thyroid growth-stimulating antibodies and may be considered as a new form of thyroid autoimmunity.

Can Future Type I Diabetes Be Predicted? A Study in Families of Affected Children

This article examines the risk of type I (insulin-dependent) diabetes in siblings of affected children, in relation to HLA genotypes. The 288 available siblings of 160 diabetic probands were grouped according to the number of HLA haplotypes in common with their probands. HLA-identical siblings (both haplotypes in common) have an approximately 100 times greater risk of developing the disease than that in the general population, and this risk is significantly higher than that in haplo-identical siblings (one haplotype in common) P = 0.008). Thus, in Northern European populations, some 30% of HLA-identical siblings are expected to be diabetic by the age of 30 yr. The risk in nonidentical siblings (neither haplotype in common) is not significantly increased. These findings carry implications for genetic counseling and research.

AN ASSESSMENT OF GLUCOSE INTOLERANCE IN ACROMEGALY AND ITS RESPONSE TO MEDICAL TREATMENT

The prevalence of abnormal carbohydrate tolerance has been assessed in sixty‐nine acromegalic patients using six different criteria for the definition of diabetes mellitus. Family history, HLA status and the incidence of pancreatic islet cell antibodies have been documented and the effect of 3 months therapy with bromocriptine on oral glucose tolerance has been assessed in sixty‐one patients.

AUTOIMMUNE CRANIAL DIABETES INSIPIDUS: ITS ASSOCIATION WITH OTHER ENDOCRINE DISEASES AND WITH HISTIOCYTOSIS X

Thirty‐nine patients with idiopathic cranial diabetes insipidus (DI) and 81 secondary to hypothalamic lesions were investigated for the presence both of associated autoimmune diseases and autoantibodies. Eleven (28%) of the idiopathic but none of the secondary DI cases had an overt autoimmune disease. A further two patients with idiopathic DI had associated organ‐specific autoantibodies. Autoantibodies to vasopressin (AVP)‐secreting hypothalamic cells were detected in 12 patients with idiopathic DI (31 %). Seven out of 13 cases of DI secondary to histiocytosis X (HX) were also positive (54%), whereas only two (3%) of the other 68 sera from patients with secondary DI reacted with AVP cells. Of the 13 patients with DI associated with frank organ‐specific autoimmune diseases or autoantibodies alone, eight (62%) were positive for AVP‐cell antibodies. The finding of associated autoimmune diseases in a patient with idiopathic DI is therefore suggestive of an autoimmune origin of DI, and this can be supported by the detection in the serum of AVP cell antibodies. In cases of HX, the new finding of the presence of AVP‐cell antibodies reflects hypothalamic infiltration by HX cells, and suggests that these DR+‘Langer‐hans‐like’ cells play more than a passive role in the hypothalamic lesion.

EVIDENCE FOR RAISED K-CELL LEVELS IN TYPE-I DIABETES

The proportion of blood mononuclear cells forming low-affinity rosettes with sheep erythrocytes (K cells) was abnormally high in 13 (57%) of 23 children with classical type-1 diabetes at diagnosis but normal in children who had had diabetes for more than a year. A raised proportion of K cells was also found in 5 out of 10 unaffected siblings with islet-cell antibodies and at least one HLA haplotype in common with the diabetic proband; and in 10 (45%) of 22 subjects with type-1 diabetes and co-existent autoimmune thyroid disease irrespective of the duration of diabetes or the presence of islet-cell antibodies. These findings may be new evidence for lymphocyte-mediated beta-cell destruction and support the idea of immunogenetic heterogeneity within type-1 diabetes.

ORGAN-SPECIFIC CARDIAC ANTIBODIES : SEROLOGICAL MARKERS FOR SYSTEMIC HYPERTENSION IN AUTOIMMUNE POLYENDOCRINOPATHY

Circulating organ-specific autoantibodies are serological markers of destruction or impairment of the relevant endocrine tissue cells and may be associated with abnormal hormone levels with or without clinical evidence of overt disease. We sought organ-specific cardiac antibodies in patients with autoimmune polyendocrinopathy because of increasing evidence that the heart has endocrine characteristics (secretion of atrial natriuretic peptide [ANP] and other peptide hormones). Serum samples from 166 patients with polyendocrinopathy, 80 with autoimmunity confined to one gland, and 200 healthy blood donors were tested for these antibodies by means of immunofluorescence on human heart. Skeletal muscle was used to identify cross-reacting antibodies. Organ-specific cardiac antibodies were detected in significantly more of the patients with autoimmune polyendocrinopathy (28 [17%]) than of those with autoimmunity confined to one gland (1 [1%]) or of normal subjects (7 [3.5%]; p = 0.0001). Among the patients with autoimmune polyendocrinopathy, the prevalence of systemic hypertension was higher in those with cardiac autoantibodies than in those without (5/28 [18%] vs 2/80 [3%]; p = 0.01); the same was true for a family history of hypertension (11 [42%] vs 5 [7%]; p = 0.0001). There were no significant differences in mean basal or stimulated ANP concentrations between patients with or without antibodies or between patients and controls. 5 of the 22 antibody-positive patients had ANP concentrations outside the normal range, but these disturbances were not associated with systemic hypertension or a family history of the disorder. Patients with autoimmune polyendocrinopathy can have organ-specific cardiac antibodies, which may represent novel serological markers for an autoimmune form of systemic hypertension in the absence of overt cardiac disease.

Thyroid Growth Stimulating and Blocking Immunoglobulins

Publisher Summary The main circuit of regulation by thyroid-stimulating hormone (TSH) involves the stimulation of plasma membrane adenylate cyclase, resulting in increased cytoplasmic levels of cyclic AMP, which will enhance the synthesis and secretion of thyroid hormones. Antibodies to the TSH-receptor might likewise be dissociated, and some of them might trigger metabolic pathways separate from those which result in hormone synthesis and secretion, but will stimulate thyroid growth. Apart from antibodies that bind to the receptor and stimulate the metabolism of cell, another variety of receptor antibodies has been identified that block TSH-induced activities of the cell. The chapter also discusses two quantitative cytochemical techniques for the detection of thyroid growth-stimulating or thyroid growth-blocking immunoglobulins—one is based on nucleic acid cytophotometry and the other on the measurement of glucose-6-phosphate dehydrogenase activity.

Early Detection of Autoimmune Endocrine Disorders

Organ specific autoimmunity (AI) has been demonstrated in all the defined endocrine organs except the pineal gland and is now being studied in the paracrine systems of the gastrointestinal tract and the hypothalamus. The ‘autoimmune’ endocrine disorders are characterized by the presence of antibodies in the patients’ serum which may be detected years before the onset of clinical symptoms and are useful monitors of the lesions well before hormonal deficiencies can be measured by metabolic tests. In the case of ‘stimulating’ antibodies that produce hormone excess, and hormone receptor antibodies generally, the situation is far more complex.