The thyroid in acquired immunodeficiency syndrome

Clinical Research

The Thyroid in Acquired Immunodeficiency Syndrome

Marcus A. Lima, MD, PHD, Leandro L. L. Freitas, MD,

Cristiano Montandon, MD, Dalmo C. Filho, MD, and M~rio L. Silva-Vergara, MD, PHD

Presented in part at the XXI Brazilian Congress of Pathology, Brasflia, DF, April 30 to May 4, 1997, and at the 49th Annual Meeting of the Brazilian Society for the Advancement of Science, Belo Horizonte, July 13-18, 1997.

MA Lima is professor of Endocrinology, Faculty of Medicine of"Tri~ngulo Mineiro" (FMTM)-- Uberaba, MG; LLL Freitas and C Montandon are recipients of a Scientific Initiation Fellowship from CNPq and monitors of Special Pathology, FMTM; Dalmo C. Filho and ML Silva-Vergara is a professor of Infectious and Parasitic Diseases, FMTM.

Address correspondence to Dr. Marcus Aurelho de Lima, Endocrinologia-Hospital Escola da Faculdade de Medicina do Tri~mgulo Mineiro, rua Gettilio Guarit~i, 130, 38.025-440, Abadia, Uberaba, MG, Brasil. E-mail: [email protected].

Endocrine Pathology, vol. 9, no. 3, 217-223, Fall 1998 �9 Copyright 1998 by Humana Press Inc. All rights of any nature whatsoever reserved. 1046-3976/98/9:217-223/$9.75

Abstract Forty-seven thyroids obtained at autopsy from patients with acquired immunodeficiency syndrome (AIDS) with no clinical manifestations of thyroid disease were analyzed systematically in order to determine the frequency and the major pathological characteristics of thyroid involvement in these individuals. The glands were obtained from 38 men and 9 women aged (on average) 33.6 yr. The specimens were weighed, measured, and evaluated after fixation in formalin. Histological examination was performed on at least 10 macroscopically normal and altered areas. The anatomopathological lesions detected in 29 glands (61.7%) were chronic nonspecific focal inflammation (48.2%); mycobacteriosis and colloid goiter (17.2%); histoplasmosis, cryptococcosis, and lipomatosis (13.7%), and paracoccidioidomycosis and hyperplastic nodules (3.4%). Although thyroid disease had not been clinically diagnosed, thyroid involvement was elevated (61.7%) and in 14 cases (29.7%) it was related to the immunodeficiency, with mycobacteria being the most common opportunistic agents. There appears to be no report of the association of lipomatosis with AIDS, although this was a frequent finding in the present study (13.7%), exceeding by far the rates reported in the literature (1-2%). Thus, thyroid lesions are frequent in AIDS patients, occurring in two thirds of the patients studied, especially those with disseminated infection. Key Words: Thyroid; AIDS; autopsy; immunodeficiency.

Introduction The acquired immunodeflciency syn-

drome (AIDS) is characterized by the direct or indirect action of human immunodeficiency virus (HIV) on the cells of the immune system, especially those with CD4 § markers, causing affected individuals to be susceptible to opportunistic infections and malignancies [1-4]. Many studies have been published over the last few years to describe the organic alterations and the clinical repercussions provoked by these opportunistic agents and by malignancies associated with immunodeficiency [1,5].

The most clinically common opportunistic infection is oroesophageal candidi-

asis, and the infection most often identified at autopsy is that caused by cytomegalovirus (CMV) [4]. With respect to organ or system lesions, the lungs, skin, and mucosae are those most frequently involved from the early stages of the disease. With respect to the endocrine system, the adrenal gland is the first target [4,5]. Few studies are available about the thyroid gland, most of them representing case reports showing the presence of opportunistic agents such as Pneumocystis carinii [6-13], CMV [14], and malignancies [15,16] diagnosed by fine-needle aspirative biopsy or functional changes in the patient's gland in life [17-23].

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218 Endocrine Pathology Volume 9, Number 3 Fall 1998

The systematic study of autopsied patients with AIDS with no clinical manifestations of thyroid disease led to the pre- sentation of the results obtained in the present study, which was carried out with the objective of determining the frequency and major anatomopathological characteristics of thyroid involvement in these individuals.

Materials and Methods

Case Selection

The thyroid glands were obtained from 47 patients with AIDS with no clinical manifestations of thyroid disease admitted to the Infectious and Parasitic Diseases ward, Faculty of Medicine of "Tri~ngulo Mineiro" (Uberaba, Brazil). Patients were autopsied in the Surgical Pathology Service of the Teaching Hospital of the same insti- tution between July 1994 and December 1996. A total of 267 autopsies were performed during this period. The specimens were submitted to the systematic studies described in the following sections.

Thyroid Examination

The thyroids were removed from the cadaver by the technique of Letulle [24], carefully dissected from perithyroid tissue, fixed in 3.7% formalin, weighed, and measured. The lobes and isthmus were then cut longitudinally at 2-3 mm intervals and systematically examined macroscopically. All the changes visualized by ectoscopy were recorded and sampled for histology. At least 10 fragments/case of unchanged areas were also examined in order to study histologically lesions that might not have been observed macroscopically. Thus, four segments of each lobe and two of the isthmus were sampled; the four fragments of the lobes represent the three thirds and the

junction of the upper with the middle third, respectively. Slides were first stained with hematoxylin and eosin (H&E) and examined under the light microscope. When infections were suspected on the basis of HE staining, special stains such as Grocott, Fite-Faraco, and mucicarmine were applied.

The clinical information about the patients and their disease was obtained from the medical records and the anatomopathological findings were obtained from the autopsy report.

Results

The autopsies were performed on 38 men (80.8%) and 9 women (19.2%) ranging in age from 18-67 yr (mean: 33.6 yr), with the 26-35-yr age range being the most frequent (20 patients, 45.5%). With respect to exposure to AIDS, 18 patients (38.3%) were drug abusers, 13 (27.7%) had contracted HIV by sexual contact, and 8 (17.0%) were both drug abusers and sexu- ally promiscuous.

The body mass index (BMI) of the patients ranged from 12-33 kg/m 2 (mean: 18.6 kg/m 2) and the patients with the high- est BMI weighed 100 kg and had general- ized visceromegaly.

A general analysis of all the organs of the 47 autopsies studied showed changes owing to immunosuppression in all cases. The most frequently detected opportunistic agent was CMV (23 cases, 48.9%), followed by Candida sp. in 18 (38.3%) and by Toxoplasma gondii and mycobacteria in 12 (25.5%) (Table 1). As can be seen in Table 2, more than one opportunistic agent was detected in many of the autopsied individuals, with 14 cases (27.6%) presenting two agents, 7 (14.8%) presenting three, 6 (12.7%) presenting four, and 1 (2.1%) presenting seven. In 17 cases (36.1%), only

The Thyroid in AIDS 219

Table 1, Frequency of Infections in 47 Patients with Acquired Immunodeficiency Syndrome

Infectious agent Number of patients Frequency (%)

Cytomegalovirus 23 48.9 Candida sp 18 38.3 Mycobacteria 12 25.5 Toxoplasma gondii 12 25.5 Cryptococcus neoformans 11 23,4 Histoplasma capsulatum 6 12.7 Pneumocystis carinii 6 12.7 Human papilloma virus 5 10.6 Human herpes virus 2 4.2 Paracoccidioides brasiliensis 1 2.1 Nocardia 1 2.1

Table 2. Thyroid and Systemic Anatomopathological Findings in 17 of 47 Patients with AIDS Submitted to Autopsy a

Sex Age (yr) Thyroid findings Systemic findings

1. Male 18 Cn Cn, Mcb 2. Male 40 Mcb Mcb 3. Male 36 Mcb Mcb, Csp 4. Female 33 Mcb Mcb, Tg 5. Male 33 Hc Hc 6. Male 25 Hc Hc, Tg, Csp, CMV, HPV, HSV, Pc 7. Female 32 Cn Cn, CMV, Csp, HPV 8. Male 20 Cn Cn, Csp, CMV 9. Male 49 Pb Pb, CMV

10. Male 54 Mcb Mcb, Tg, Csp, CMV 11. Male 57 Hc Hc, Csp, CMV 12. Female 49 Mcb Mcb 13. Male 25 Cn Cn, Csp 14. Male 38 Hc, lipomatosis Hc 15. Female 29 Lipomatosis, hypotrophy Tg, CMV, Cn, HPV 16. Male 61 Lipomatosis, hyperplastic Csp, Noc, KS

nodule 17. Male, 31 Lipomatosis CMV

aAbbreviations: Cn, Cryptococcus neoformans; Mcb, mycobacteriosis; Hc, Hystoplasma capsulatum; CMV, cytomegalovirus; Csp, Candida sp; Pb, Paracoccidioides brasiliensis; Pc, Pneumocystis carinii; Tg, Toxoplasmagondii; HPV, human papilloma virus; HSV, herpes simplex virus; Noc, Nocardia; KS, Kaposi's sarcoma.

one infectious agent was detected at autopsy. The lungs were involved in 28 cases (59.5%), the central nervous system (CNS) in 24 (51%), and lymph nodes in 23 (48.9%). The endocrine organ most often involved was the adrenal gland, with alterations in 19 cases (40.4%), followed by the thyroid (14 patients, 29.7%). With respect

to AIDS-associated malignancies, there was only one case (2.2%) of Kaposi's sarcoma involving the esophagus, stomach, and duodenum.

Thyroid weight ranged from 8-55 g (mean weight: 17.5 g), with the largest thyroid measuring 7.0 • 6.5 x 3.0 cm and the smallest 4.3 x 3.3 x 1.5 cm. Eight (17%) glands presented macroscopic nodules, five of which had a colloid aspect (62.5%).

Microscopic analysis showed that 31 thyroids (65.9%) had large follicles containing flocculent colloid with calcium oxalate crystals and with slight or virtually absent cell activity. Connective tissue in general was scarce in 23 glands (48.9%). The opportunistic infections detected were mycobacteriosis in five cases (17.2%), histoplasmosis (Fig. 1) and cryptococcosis (Fig. 2) in four cases (13.7%), and paracoccidioidomycosis (Fig. 3) in one case (3.4%). The most important pathological findings in addition to opportunistic infections in 29 thyroids (61.7%) were nonspeciflc focal chronic inflammation (14 cases, 48.2%), colloid goiter (5 cases, 17.2%), and lipomatosis (4 cases, 13.7% - Fig. 4).

In the 14 cases (29.7%) with thyroid involvement by an opportunistic infection, systemic candidiasis was present in seven cases (50%), CMV and mycobacterioses in six (42.8%), and histoplasmosis and cryptococcosis in four (28.5%). In these cases, the organs most often involved were the lungs and lymph nodes in 13 cases (92.8%), and the adrenal glands in 9 cases (64.2%). In six patients (42.8%), the same agent simultaneously infected all of these four organs.

Discussion

HIV infection and AIDS may directly or indirectly involve virtually the entire


Fig. 1. Histoplasmosis. Nuclei and an artifactual clear zone are well-demonstrated histologically by hematoxylin and eosin staining within macrophages (arrows, •

Fig. 2. Cryptococcic thyroiditis in which encapsulated and nonencapsulated forms are well demonstrated by mucicarmine stain (•

endocrine system, including the thyroid [25]. The involvement of any organ in AIDS is due to the direct action of the virus or to the viral action on the immunologic system leading to opportunistic infections and malignancies, or they may be due to the side effects of the drugs used to treat the various complications of this syndrome

[1-3], although the clinical characteristics of this involvement are not so evident [20]. The present study demonstrates that, in AIDS, the thyroid may be involved by multiple processes in addition to those pre- viously reported, such as P. carinii [6-13] and CMV infection [14] and malignancies [15,16]. This involvement is frequent, and was observed in two thirds of the cases in the present study.

The present study demonstrates that the lungs are the organs most often involved (28 cases, 59.5%). With respect to the endocrine organs, the adrenal was the gland most often involved (40.4% of cases), with CMV being the most common opportunistic agent attacking the adrenals (48.9%), in agreement with the literature [2,4,5]. In the present series, there was only one case of AIDS-associated malignancy, a Kaposi's sarcoma involving the esophagus, stomach, and duodenum. The thyroid, as in the case of the adrenal gland [5], does not seem to be a target organ for opportunistic malignancies, i.e., Kaposi's sarcoma and non- Hodgkin's malignant lymphoma, even in cases where these malignancies dissemi- nate. In an autopsy study, involvement of the thyroid gland was detected in only 1 of 18 patients with Kaposi's sarcoma [4].

The infectious agents that most frequently involve the thyroid are P. carinii, CMV, and Mycobacterium tuberculosis, and this involvement seems to occur during more advanced phases of the disease when the patient presents systemic infections mainly involving the lungs and adrenals [2-4]. In the present study, we found no case of thyroid pneumocystosis (Table 2), although six patients presented with this type of infection (Table 1), which involved the lungs exclusively in all cases. In the only systematic Brazilian study of thyroids (data not published), the opportunistic agents most often detected were M. tuberculosis,


Fig. 3. Paracoccidioidornycosls. multiple budding (arrow, x200).

The Grocott stain demonstrates very effectively

Fig. 4. Isolated nontumoral deposition of mature adipose tissue (lipomatosis) between thyroidian follicles (x200).

CMV, Mycobacterium avium, and Crypto- coccus neoformans. In this series the most prevalent opportunistic agents were mycobacteria, found in five (10.6%) of the 47 patients. The thyroid was involved when infections were already present in other organs, especially when they were caused by two or more infectious agents.

Lungs and lymph nodes were involved in 13 (92.8%) of the 14 patients with thyroid involvement, whereas the adrenals were involved in 9 (64.2%) of these patients. Simultaneous involvement of four organs occurred in six patients (42.8%) and was caused by the following opportunistic agents: C. neoformans in three (50%), His- toplasrna capsulatum in two (33.4%), and Paracoccidioides brasiliensis in one (16.7%).

In contrast to what is observed in the adrenals [5], CMV infection appears to be infrequent in the thyroid. In this study, even though we identified disseminated CMV infection in 23 patients (48.9%)-- 14 of them (60.8%) presenting infection in the adrenals thyroids were not involved with this virus. Thus, it would appear that CMV tropism for the adrenal medulla occurs parallel to the tropism of HIV for neural tissues [5].

According to Heufelder and Hofbauer [3], as is the case for other acute and chronic diseases, abnormalities in thyroid function tests are frequently detected in patients with AIDS, although hypothyroidism is uncommon. The presence of clinical signs and symptoms of primary hypothyroidism in HIV-infected individuals generally represents extensive destruction of the gland, as demonstrated at autopsy [16]. The thyroids analyzed presented about 5-20% destruction of the parenchyma. The lesion was more extensive in only one case of paracoccidioidomycosis, reaching about 70%, although without clinical evidence of hypothyroidism, probably masked by the AIDS picture itself.

Another interesting finding was the presence of fatty infiltration or lipomatosis. The literature reports that the frequency of this finding in the thyroid is 1-2% and is associated with malignancies, amyloid goiter, hyperplastic nodule, chronic thyroiditis, dyshormonogenetic goiter, and atrophy


[26]. In the present study, the lesion occurred in 13.7% of cases and was associated with atrophy (one case), a hyperplastic nodule (one case) and acute thyroiditis caused by H. capsulatum (one case). The remaining cases did not present any other changes. The explanation for the high frequency of fatty deposits in these glands may possibly be the follicular inac- tivity caused by the debilitating condition of the patient, with consequent atrophy, similar to the mechanism observed in cases of pancreatic and salivary gland lipomatosis [27].

Finally, it can be seen that thyroid lesions are frequent, occurring in almost two thirds of the patients studied; these are mostly owing to opportunistic agents mainly affecting patients with disseminated infection.

It is useful to emphasize the importance of performing autopsies as a useful proce- dure for the detection of the different anatomopathological changes induced by AIDS.

Acknowledgment

This article was supported by CNPq (N~ 800.908/92-9 and 110.267/95-8).

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The thyroid in acquired immunodeficiency syndrome

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