Robert Volpé

Essential cryoglobulinaemia; review of the literature and report of a case treated with ACTH and cortisone.

Abstract A case of cryoglobulinaemia is presented in which extensive investigation and postmortem examination failed to reveal an underlying cause. The clinical manifestations included an unusually long history of cold sensitivity and purpura, rigors, fever, atypical Raynauds phenomenon, deafness, epistaxis, stomatitis, postnasal bleeding, dyspnoea, cyanosis, pulmonary emboli, melaena, blotchy pigmentation of lower extremities, thrombophlebitis and gangrene of toes. This patient did not exhibit retinal haemorrhages. Cryoglobulin may be said to be the generic term for a group of serum proteins which have the common physical property of precipitating on exposure to the cold. This precipitation is due to a state of decreased solubility of the protein in the blood, and has been demonstrated to occur in vitro at temperatures occurring within the body. The possible mechanisms of production of this relative insolubility and the possible role of complement and lipoprotein are discussed. Cryoglobulinaemia is most often a secondary phenomenon. This protein may be found in small quantities in many disease states but large concentrations are rare. When large amounts are found multiple myeloma is frequently the cause. Occasionally, as in our case, no definite aetiology is demonstrated. It is suggested that tissue reaction is a factor in the pathogenesis of the lesions; and the possibility exists that the patients own precipitating cryoglobulin might have acted as a foreign protein, stimulating a tissue response with associated rigors and fever, and resulting in subsequent purpura. The theory that this type of reaction is of great importance is further supported by the favourable results of treatment with ACTH, without significant decrease in the concentration of cryoglobulin. The pathologic condition of this disorder appears to depend upon the initial deposition of cryoglobulin in blood vessels of varying size, with subsequent local reaction, secondary thrombosis, ischemia of the tissue supplied by the vessels and resultant necrosis. An increasing concentration of cryoglobulin may lead to the appearance of lesions at higher and higher temperatures, and may explain the appearance of lesions in areas of the body where the temperature could not be materially affected by the external environment.

EVIDENCE THAT ANTITHYROID DRUGS INDUCE REMISSIONS IN GRAVEs' DISEASE BY MODULATING THYROID CELLULAR ACTIVITY

The nature of the remission induced by antithyroid drugs (ATD) in Graves’ disease (GD) has been the subject of several recent reviews (Weetman & McGregor, 1984; Weetman et al., 1984a; Burman & Baker, 1985; Ratanachaiyavong & McGregor, 1985; Volpt, 1985). Weetman and colleagues (1 984a) have summarized the evidence for an ATD effect on the natural history, suggesting that this is due to direct immunosuppression. We here present a different view, namely that ATD exert an indirect immunoregulatory action through their direct effect on thyroid cells. First, a review of the arguments put forward in favour of a direct immunosuppressive effect of ATD is presented. These arguments are derived from several observations. In patients with G D treated with thionamide drugs, thyroid stimulating antibody (TSAb), and indeed other thyroid autoantibodies, tend to decline in most (but not all) patients over time (Pinchera et al., 1969,1979; McGregor etal., 1980a, 1980c, 1982; Karlsson & Dahlberg, 1981). Inpatients treated surgically after long-term drug therapy, intrathyroidal lymphocytes are found to be reduced (Beck et al., 1975), and the thymus also regresses (Simpson et al., 1975). In patients with G D treated with thionamides, the subset of suppressor T lymphocytes (which is low in the untreated state) tends to normalize when patients are taking antithyroid drug therapy (Ludgate et al., 1984). A reduction of thyroid autoantibody production on thionamide therapy has been found in experimental autoimmune thyroiditis {Rennie et al., 1983). And finally, the increased rate of remission which occurs in patients treated with ATD when compared to propranolol-induced remissions or spontaneous remission would seem to indicate an immunosuppressive effect of the former agents (Weetman & McGregor, 1984; Weetman et al., 1984a). Further support for the theory has come from in-vitro studies in which an immunosuppressive effect can be shown by these drugs on peripheral blood mononuclear cells (McGregor et al., 1980a). This is now thought to be due to a direct effect on the antigen presenting cell (Weetman et al., 1983) by interference with oxidative reactions within the cell (Weetman et al., 1984b). Moreover, McGregor et al. { 1982) and How et al. ( I 982) have shown that ATD act only on thyroid autoantibodies in Graves’ disease since gastric parietal cell antibodies and antinuclear factor levels do not change with such treatment. Such data imply that ATD act locally on immune cells within the thyroid.

Autoimmune thyroiditis, adrenalitis and oophoritis

Abstract Described here is a young woman suffering from autoimmune thyroiditis, adrenalitis and oophoritis. This patient was carefully investigated by endocrine studies, with humoral antibodies to thyroid and adrenal, and the release of migration inhibition factor by her lymphocytes when cultured with thyroid, adrenal and ovarian antigens. Cell-mediated immunity appears to be the most important factor in the pathogenesis of these closely related disorders. A discussion of the interrelationship of these organ-specific autoimmune endocrine gland disorders is presented.

Thyroiditis: current views of pathogenesis.

From indirect and circumstantial evidence it would appear that subacute thyroiditis is probably a viral infection of the thyroid gland. The thyroid may respond in the stereotyped manner to any one of a number of viruses. Despite the available evidence, however, the viral theory has yet to be finally proven. Autoimmunity does not appear to be a primary factor in the initiation of subacute thyroiditis, although transient immunologic responses occur as a secondary phenomenon. Autoimmune thyroiditis, on the other hand, is almost certainly a primary immunologic disease, and likely is due to a specific inherited defect in immunologic control. It would appear that both cell-mediated immunity and humoral immunity (i.e., T and B lymphocytes) are necessary for the full expression of this disorder.

Riedel’s thyroiditis associated with Hashimoto’s thyroiditis, hypoparathyroidism, and retroperitoneal fibrosis

A patient with Riedel’s struma (invasive fibrous thyroiditis) with hypothyroidism, hypoparathyroidism, and retroperitoneal fibrosis is reported. This disorder appeared to emanate from Hashimoto’s thyroiditis in this case. The possible relationship of the two entities is discussed.

Diabetes insipidus associated with dysplastic pancytopenia

This case report describes a 60-year-old man who presented with a three-year history of generalized malaise, decreased libido, polyuria, and polydipsia. He had been previously investigated for pancytopenia, and found to have a hypoplastic bone marrow. A diagnosis of central diabetes insipidus was established; the patient was also found to have a number of other defects in his hypothalamic-pituitary function. Hematologic studies again revealed peripheral pancytopenia associated with a hypoplastic megaloblastic bone marrow. Computed axial and nuclear magnetic resonance tomography failed to establish the nature of the morphologic lesion in the hypothalamus. A possible relationship between the hematologic and endocrine disturbance is discussed.

Hashimoto's thyroiditis manifesting monoclonal lymphocytic infiltration

Hashimotos thyroiditis (HT) and lymphoma arc sometimes difficult to distinguish between. Moreover, lymphoma sometimes develops in a thyroid gland from pre‐existing HT. Open‐ or large‐needle biopsy usually distinguishes between them; the specimen may be examined histologically and subjected to immunohistochemistry. Another possible method of examination is fine‐needle aspiration biopsy (FNAB). The cells obtained may be evaluated cytologically, and subjected to flow cytometry, using various antibodies. In this study, anti‐kappa and anti‐lambda antibodies are especially important, as a gross predominance of kappa or lambda B lymphocytes infiltrating the thyroid is evidence for a B cell monoclone. In this study, 15 patients were selected because of their rapidly growing goitres. They all underwent FNAB. Five had cytology typical of HT, and no evidence of monoclonality on flow cytometry. They were diagnosed as HT without further histopathology. The remaining 10 patients had cytology suspected of lymphoma, or evidence of monoclonality on flow cytometry, or both. These patients underwent open‐ or large‐needle biopsy. Only three of them were diagnosed histopathologically as lymphoma; the other seven were diagnosed histopathologically as HT, making 12 cases of HT in all. Five of these 12 cases, and one of the three cases of lymphoma showed flow cytometrical evidence of monoclonality; thus evidence of monoclonality from FNAB, while interesting, does not necessarily serve to differentiate between HT and lymphoma. Furthermore, the immunohistochemical assessment of monoclonalily did not correlate with the flow cytometrical assessment. Follow‐up evidence will be required to discover whether those patients with a B cell monoclone in their HT are the ones who develop a lymphoma.

THE EFFECT OF BLOOD LEUCOCYTES FROM PATIENTS WITH HASHIMOTO'S DISEASE ON HUMAN THYROID CELLS IN MONOLAYER CULTURE

Peripheral blood leucocytes from healthy subjects (control leucocytes) and from patients with Hashimotos thyroiditis or idiopathic myxoedema, were incubated with 2‐3‐day‐old human thyroid cells in monolayer cultures. After 5‐6 days the Hashimoto leucocytes appeared to induce more thyroid cell destruction than control leucocytes. Thyroid cell function (measured by cell to medium (C/M) ratios of 131I) was reduced in cultures incubated with Hashimoto leucocytes, compared to those incubated with control leucocytes. This effect was not mediated by liberation of thyroid antibodies into the medium, but rather from a direct leucocyte/thyroid cell interaction with a resultant liberation of lysozymes. Preliminary observations indicated that the effect of the Hashimoto leucocytes on thyroid cells could be prevented by prior incubation of the former with anti‐thymocyte globulin; this suggested that sensitized lymphocytes may be directly responsible for the thyroid tissue injury of Hashimotos disease, perhaps with the adjunctive cooperation of the non‐specific macrophages. Leucocytes from patients with idiopathic myxoedema (with low or absent circulating thyroid antibodies) did not have any effect on the thyroid cells, perhaps because the concentration of peripheral sensitized lymphocytes may possibly have declined in these patients.

T LYMPHOCYTE SENSITIZATION AND SUPPRESSOR T LYMPHOCYTE DEFECT IN PATIENTS LONG AFTER TREATMENT FOR GRAVES’DISEASE

Circulating thyroid autoantibodies, T lymphocyte sensitization and suppressor T lymphocyte function were examined in thirty‐nine patients who had been treated for a mean of 10±2 years previously for hyperthyroid Graves’disease. Nineteen had been treated with radioactive iodine (131I), two with subtotal thyroidectomy, and eighteen were in long‐term remission after previous propylthiouracil (PTU) therapy. Sensitization of T lymphocytes to human thyroid antigen was studied by means of a modified migration inhibition factor test, using T lymphocyte enriched preparations, and antigen‐specific suppressor T lymphocyte function was assessed by the ability of T lymphocytes to suppress the production of migration inhibition factor by sensitized T lymphocytes of patients with active Graves’disease in response to human thyroid antigen. Despite effective correction of the hyperthyroid state in all patients, T lymphocyte sensitization to human thyroid antigen was still demonstrable in twelve of nineteen patients treated with 131I (63%), in nine of eighteen patients in remission after PTU treatment (50%) and in one of two patients after thyroidectomy. All those showing such sensitization also manifested a suppressor T lymphocyte defect. In three of the patients (all after 131I therapy) showing no such sensitization, there was nevertheless evidence of a suppressor T lymphocyte defect. On the other hand, thirteen patients (nine in the post‐PTU group, four in the post‐131I group) showed evidence of complete immunological remission. There was no correlation between the abnormal immunological findings and the number of years after treatment of the hyperthyroidism.

Long-term treatment of alcoholic liver disease with propylthiouracil. Part 2: Influence of drop-out rates and of continued alcohol consumption in a clinical trial

Although propylthiouracil has previously been shown to reduce the risk of mortality in alcoholic liver disease by 60%, generalized use of propylthiouracil for this condition has not occurred. Additional data are therefore presented on four aspects to provide a better assessment of its therapeutic effectiveness. First, the characteristics and the prognosis of dropouts were virtually identical in both the drug and placebo groups. Also the methodology and analysis employed, were designed to control for dropouts, thus providing an accurate interpretation of the outcome. Secondly, since 97% of the patients continued to drink, abstinence was not a precondition for the beneficial effect of propylthiouracil. However, the beneficial effect was observed most clearly in those patients who continued to drink at lower levels, whereas lower level drinking per se did not afford protection in placebo patients. Thirdly, serious side effects or clinical hypothyroidism occurred extremely rarely in these patients, many of whom have now received propylthiouracil for over 4 years. Fourthly, we discuss why the outcome in long-term clinical trials in alcoholic liver disease cannot be compared with effects observed in clinical trials lasting only a few weeks. Journal of Hepatology.