eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease

Polyglandular Autoimmune Syndrome, Type III

Author: KoKo Aung, MD, MPH, FACP, Associate Professor, Department of Medicine, University of Texas Health Science Center; Adjunct Assistant Professor of Public Health, University of Texas School of Public Health
Contributor Information and Disclosures

Updated: Oct 22, 2009

Introduction

Background

The concept of polyglandular failure is not new, having achieved recognition as early as in the 19th century. In 1853, Thomas Addison first described the clinical and pathological features of adrenocortical failure in patients who also appeared to have pernicious anemia (PA). In 1908, Claude and Gougerot suggested a common pathogenesis for these conditions in an article titled "Insufficance pluriglandulaire endocrinnienne." In 1926, Schmidt documented the association between adrenocortical failure and thyroiditis. Carpenter, in 1964, expanded the syndrome described by Schmidt to include insulin-dependent diabetes mellitus.

In 1980, Neufeld and Blizzard developed the first classification of polyglandular failure.² Neufeld and Blizzard's classification distinguishes 2 broad categories, PAS type I and PAS type II (PAS I and PAS II). An additional group, PAS type III (PAS III), was subsequently described. PAS III, in contrast to PAS I and II, does not involve the adrenal cortex. In PAS III, autoimmune thyroiditis occurs with another organ-specific autoimmune disease, but the syndrome cannot be classified as PAS I or II.

PAS III can be further classified into the following 3 subcategories:

• PAS IIIA - Autoimmune thyroiditis with immune-mediated diabetes (IMD) mellitus (type 1 diabetes mellitus)
• PAS IIIB - Autoimmune thyroiditis with PA
• PAS IIIC - Autoimmune thyroiditis with vitiligo and/or alopecia and/or other organ-specific autoimmune disease

PAS III is associated with the following diseases:

• Organ-specific autoimmune diseases
  • Celiac disease
  • Hypogonadism
  • Myasthenia gravis
• Organ-nonspecific or systemic autoimmune diseases
  • Sarcoidosis
  • Sjögren syndrome
  • Rheumatoid arthritis
• Other diseases
  • Gastric carcinoid tumor
  • Malabsorption due to exocrine pancreatic deficiency

Cases of PAS III associated with a different immunological or genetic disorders have been sporadically reported. The association of PAS III with common variable immunodeficiency (CVID) in a 24-year-old patient was described by Bahceci and colleagues.³ This patient had PAS III due to the presence of autoimmune thyroiditis, hypergonadotropic hypogonadism, and growth hormone deficiency, without adrenal or parathyroid disease. Such coexistence of PAS III and CVID may be due to autoimmunity and the association of both conditions with human leukocyte antigen (HLA).

A rare case of PAS III in monozygotic twins, in which one of the twins also had autoimmune leukopenia, was also reported,⁴ as was a case of PAS III with autoimmune leukopenia.⁵

In addition, a case of PAS III complicated with autoimmune hepatitis was reported from Japan.⁶ Another report from Japan described a 61-year-old woman with slowly progressive type 1 diabetes mellitus associated with chronic thyroiditis, pernicious anemia, and idiopathic thrombocytopenic purpura.⁷ This patient had DQA1 0102, 0103 and DQB1 0602, 0601 that were considered as type 1 diabetes protective HLA alleles.

A case reported from Poland described acquired von Willebrand syndrome in a patient with severe primary hypothyroidism associated with myasthenia gravis in the course of PAS III.⁸

Pathophysiology

Autoimmunity

Autoimmune disease affecting a single endocrine gland is frequently followed by impairment of other glands, resulting in multiple endocrine failure. The autoimmune pathogenesis of these disorders began to emerge in the mid-20th century. In 1956, Roitt and colleagues discovered circulating precipitating autoantibodies to thyroglobulin in patients with Hashimoto thyroiditis.

The identification of circulating organ-specific autoantibodies provided the earliest and strongest evidence for the autoimmune pathogenesis of polyglandular failure syndromes. Endocrine autoimmunities are associated with autoantibodies that react to specific antigens, whereas patients with collagen diseases synthesize immunoglobulins that recognize nonorgan-specific cellular targets, such as nucleoproteins and nucleic acids.

Cellular autoimmunity is also important in the pathogenesis of polyglandular failure syndromes. Histologic examination of the affected glands (eg, thyroid, parathyroid, ovaries, pancreatic islets, gastric mucosa) has demonstrated similar results, that is, mononuclear infiltrate composed mainly of lymphocytes, macrophages, natural killer (NK) cells, and plasma cells. The striking feature is the sparing of adjacent nontarget tissue. As the disease progresses, atrophy and fibrosis predominate.

Experimental animal models of PAS III have been described. In BioBreeding/Worcester (BB/W) rats, the frequency of chronic lymphocytic thyroiditis was remarkably increased in diabetic insulin-treated BB/W rats.⁹

Animal models have provided many of the insights into endocrine immunities. Polyglandular immunity, including gastritis, oophoritis, orchitis, and thyroiditis, could be induced in genetically susceptible mice by depleting T lymphocytes permanently or transiently. By using the model of neonatal thymectomy, it has been demonstrated that early interactions between the lymphoid system and target organs are important in the pathogenesis of autoimmunity. Furthermore, it also was demonstrated that CD4⁺ splenocytes from adult (but not neonatal mice) contain regulatory populations that can prevent the transfer of autoimmune endocrinopathies.

An autoimmune attack of a target organ often begins in individuals who have a genetic predisposition after an unknown precipitating event. The early process manifests by provoking autoantibody production, and it may arrest at this stage. Progressive disease is associated with secondary responses against antigens released by damaged tissue. Disease initially is detectable by observing minimal biochemical abnormalities such as elevation of trophic hormones. Organ function loss may plateau before the threshold of critical organ mass is reached, or it may progress to clinically overt disease. Early hormone replacement therapy may decelerate the destruction of surviving tissue; but, at the late stage, complete organ atrophy is inevitable.

Environmental factors

Some authorities postulate that environmental precipitators of autoimmunity might play a role in polyglandular autoimmunity. Viral infection may exaggerate the ongoing immune response and precipitate glandular failure, although no human epidemiological studies show infection triggering polyglandular autoimmunity.

The links between congenital rubella infection, type 1 diabetes mellitus, and hypothyroidism are well known. Reovirus type I infection in susceptible mice causes type 1 diabetes mellitus and growth failure.

International comparisons show a positive correlation between type 1 diabetes mellitus prevalence and ingestion of cow milk. Circulating autoantibodies against a peptide with homology to bovine serum albumin and human islet cell surface protein have been observed in patients with IMD.

Development of PAS III after interferon-alpha therapy for hepatitis C has been described, raising the possibility of interferon-enhanced major histocompatibility complex expression, which in turn initiated the onset of organo-specific autoantibodies and the clinical manifestations of autoimmune diseases.

Genetic factors

PAS III, as well as PAS II, is associated with HLA class II genes with apparently distinctive HLA alleles for each. The underlying non-HLA genes of PAS III remain to be further defined genetically. PAS III is often observed in individuals in the same family, suggesting that its inheritance could be an autosomal dominant trait with incomplete penetrance.^10,11

HLA-DRB1*04/DQA1*0301/DQB1*0302 is the predominant HLA haplotype associated with susceptibility in IMD. Interestingly, the HLA-DQB1*0602 allele protects against IMD, even if the HLA-DQB1*0301 or DQB1*0302 susceptibility gene is present. HLA-DQB1*0301 is the HLA haplotype frequently associated with autoimmune thyroiditis. HLA-DRB1*13 is associated with vitiligo. Alopecia areata is strongly associated with DQB1*03 and DRB1*1104, which appear to be markers of general susceptibility to alopecia areata. In addition, the frequency of HLA-DRB1*0401 and DQB1*0301 is remarkably increased among patients with alopecia totalis and those with alopecia universalis, the most extensive form of the condition.

Multigenetic involvement in the development of the individual components of PAS III has been proved. For example, IMD is linked to several loci in non-HLA genomic regions. Furthermore, autoimmune thyroiditis also is polygenic.

Frequency

United States

The exact prevalence of PAS III in the United States is unknown.

International

The exact international prevalence of PAS III is unknown.

Mortality/Morbidity

The morbidity and mortality of PAS III is determined by the individual components of the syndrome.

Race

No racial or ethnic difference in frequency of PAS III has been reported.

Sex

PAS III is more common in females than in males.

Age

PAS III typically is observed in middle-aged women but can occur in persons of any age.

Clinical

History

• The clinical symptoms of PAS III are a constellation of manifestations of endocrine gland failures that comprise the syndrome.
• Autoimmune thyroiditis
  • Autoimmune thyroiditis is the characteristic of all subcategories of PAS III.
  • The presenting symptoms are goiter, those due to hypothyroidism, or both. Occasionally, destruction of the gland early in the process gives rise to the release of thyroid hormones, creating a transient hyperthyroid state (ie, Hashitoxicosis). When this process is complete, hypothyroidism becomes apparent.
  • Fatigue and depression are leading symptoms in many patients with autoimmune thyroiditis. Weight gain, cold intolerance, constipation, dry hair, sluggishness, somnolence, hoarseness, and menorrhagia also are major clinical symptoms.
  • Although some patients report a sensation of tightness in the neck, pain is usually not a prominent symptom. Patients may have a history of other autoimmune conditions such as inflammatory bowel disease, celiac disease, gonadal dysgenesis (Turner syndrome), and hepatitis C.
• Immune-mediated diabetes
  • Classic symptoms of IMD are polyuria, polydipsia, and polyphagia. Polyuria is secondary to osmotic diuresis caused by hyperglycemia. Polydipsia is secondary to hyperosmolality. Polyphagia is probably secondary to deficient glucose utilization in the cells of the hypothalamic ventromedial nuclei.
  • Weight loss despite polyphagia is characteristic.
  • Blurred vision is common and also is secondary to hyperosmolality.
  • Paresthesia in the extremities may be present at presentation, although it is usually reversible with better glycemic control. Paresthesia is thought to be secondary to transient impairment of peripheral sensory nerve function caused by hyperglycemia.
  • Rapid development of insulin deficiency, usually precipitated by infection or other forms of stress, could result in diabetic ketoacidosis (DKA) as the initial presentation of type 1 diabetes mellitus. Abdominal pain, nausea, and vomiting are common in DKA, along with above symptoms. Altered mental status and rapid breathing are symptoms associated with severe DKA.
• Pernicious anemia
  • Usual presenting features include insidious onset of fatigue, weakness, lightheadedness, headache, vertigo, tinnitus, and palpitations secondary to anemia.
  • Vague gastrointestinal symptoms, such as anorexia or diarrhea, may be present. Sore tongue, numbness and tingling in the extremities, and difficulty with balancing may be present at onset or may develop later in the course.
  • Neuropsychiatric manifestations may not parallel symptoms of anemia. In addition to the above neurological symptoms, irritability, memory loss, depression, hallucinations, agitation, suicidal ideation, and sphincter disturbances are recognized manifestations.
• Vitiligo
  • Vitiligo is associated with many autoimmune endocrinopathies. Patients with an early age of onset are less likely to have PAS II or other endocrinopathies.
  • Loss of skin pigmentation in vitiligo has been linked to autoimmune destruction of melanocytes by antityrosinase and antimelanocyte antibodies. The leading symptom is loss of skin pigmentation, which is more noticeable around the mouth, eyes, nose, nipples, umbilicus, or anus. Trauma to the skin results in further loss of pigmentation (Koebner phenomenon).
• Alopecia
  • Autoimmune alopecia (alopecia areata) ranges in severity from (1) small round patches of hair loss that regrow spontaneously to (2) persistent extensive patchy involvement to (3) the loss of all scalp hair (alopecia totalis) or all scalp and body hair including eyelashes, eyebrows, underarm hair, and pubic hair (alopecia universalis).
  • In the latter, absence of eyebrows results in perspiration trickling into the eyes; absence of eyelashes results in little protection from dust and glare. Absence of nasal hairs results in lack of protection in the nostrils or sinuses from foreign particles in the air. Spontaneous remission and recurrence are common.

Physical

• Autoimmune thyroiditis
  • Physical findings in autoimmune thyroiditis are goiter, hypothyroidism, or both. The thyroid gland is palpably enlarged in classic goitrous autoimmune thyroiditis (Hashimoto disease). The entire thyroid gland is diffusely enlarged and is firm. The surface of the thyroid gland often is bosselated, that is, characterized by numerous bosses or rounded protuberances.
  • Extrathyroidal signs of autoimmune thyroiditis and hypothyroidism include facial pallor; bradycardia; hypertension; delayed relaxation of deep-tendon reflexes; and nonpitting edema (myxedema) of the skin of the hands, feet, and eyelids.
• Immune-mediated diabetes
  • Dry skin and mucous membranes may be observed secondary to fluid loss associated with osmotic diuresis.
  • Severe dehydration or severe DKA may lead to hypotension.
• Pernicious anemia
  • The most striking physical sign of PA is pallor.
  • Mild scleral icterus may be present secondary to indirect hyperbilirubinemia caused by intramedullary hemolysis.
  • The tongue usually is smooth, raw, and beefy.
  • Systolic flow murmur and tachycardia may be present secondary to anemia.
  • Neurological signs may vary from diminished vibration and joint position sense to gross motor, sensory, and cognitive deficits.
  • A marked discordance may be present between the severity of neurological signs and the degree of anemia (see History).
• Vitiligo
  • Vitiligo is characterized by symmetric areas of complete pigment loss, particularly affecting the periorificial areas and bony prominences.
  • The hairs within the patches of vitiligo often remain pigmented. However, in older lesions, the hairs also become white. Wood-lamp examination reveals more apparent chalky-white areas.
• Alopecia
  • Alopecia areata causes different patterns of hair loss.
  • These include a localized patch of hair loss, a netlike pattern of hair loss, a serpentine pattern of hair loss that covers the periphery of the scalp similar to a serpent forming a turban over the edges of the scalp, and a diffuse form that affects the whole scalp without distinct patches.

Causes

See Pathophysiology.

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