TSH-receptor autoantibodies in patients with chronic thyroiditis and hypothyroidism.

OBJECTIVES: The reported prevalence of TSH-receptor (TSHR) autoantibodies (TRAb) in patients with chronic thyroiditis (CT) range from 0 to 48%. The objective was to study the prevalence of TRAb in patients with CT and hypothyroidism and to correlate it with gender, age, thyroid dimensions, TSH levels, and autoimmune diseases. METHODS: The study comprised 245 patients with CT and hypothyroidism (median age 42 years, 193 females, 52 males) and 123 Italian healthy subjects matched for sex and age as controls. TRAb were tested with ELISA using a >2.5 IU/L cut off for positivity. TSHR blocking (TBAb) and TSHR stimulating autoantibodies (TSAb) were measured in 12 TRAb-positive patients using bioassays with Chinese hamster ovary (CHO) cells expressing wild-type or R255D-mutated TSHR. RESULTS: TRAb positivity was found in 32/245 (13.1%) patients and significantly correlated (p<0.05) with TSH levels. TRAb positivity was significantly higher in males vs. females (p=0.034), in females 16-45 years of age vs. >45 years of age (p<0.05) and in patients with reduced vs. normal/increased thyroid dimensions (p<0.05). Linear regression analysis showed a correlation between TRAb concentrations with age (p<0.05) and TRAb concentrations with TSH (p<0.01). In bioassay with TSHR-R255D all 12 patients tested were TBAb-positive while 33% were also TSAb-positive suggesting the presence of a mixture of TRAbs with different biological activities in some patients. CONCLUSIONS: TRAb have been found in patients with CT and hypothyroidism. A mixture of TBAb and TSAb was found in some patients and this may contribute to the pathogenesis of thyroid dysfunction during the course of the disease.

Cavernous Sinus Dural Arteriovenous Fistula in a Patient with Thyroid-Associated Ophthalmopathy: Complete Resolution after Medical Treatment.

Thyroid-associated ophthalmopathy (TAO) is a well-known and frequent epiphenomenon of a hyperthyroid autoimmune disease that can present with proptosis, strabismus, and diplopia. Ophthalmopathy can occur in the absence of overt Graves' disease, even in euthyroid patients. Cavernous sinus dural fistulas (CS-DAVF) are abnormal communications between the cavernous sinus (CS) and dural branches from internal carotid or external carotid arteries. They can often present with ocular symptoms that can mimic a thyroid-associated ophthalmopathy. CS-DAVF are usually successfully treated with an endovascular embolization that can be pursued both through a transvenous or transarterial approach. TAO and CS-DAVF can coexist especially when the ocular symptoms are unilateral. In those cases, an endovascular embolization is usually curative, but sometimes the procedure can fail. Our hypothesis is that some cases of CS-DAVF may be of secondary nature (i.e., caused by compression of the venous outlet by the hypertrophic ocular muscles); therefore, treating the ocular disease with medical therapy may solve the vascular problem as well. We present a case of a CS-DAVF in a patient with TAO successfully treated with sole medical therapy after the failure of a first-line endovascular treatment.

The natural history of autoimmune Addison's disease from the detection of autoantibodies to development of the disease: a long-term follow-up study on 143 patients.

BACKGROUND: Adrenal cortex autoantibodies (ACAs) and/or 21-hydroxylase (21OHAb) are markers of autoimmune Addison's disease (AAD) and progression to overt AAD. The reported cumulative risk of developing AAD varies from 0 to 90% in different studies. AIM: To assess the predictive value of different parameters in the progression toward AAD in patients with ACA and/or 21OHAb-positive patients with autoimmune polyendocrine syndromes (APS). MATERIALS AND METHODS: Twenty-nine patients with APS-1 and 114 patients with APS-2 or APS-4 were followed up for a median of 10 years (range 6 months to 33 years) and were assessed using ACTH test. The risk of AAD was estimated according to age, gender, stage of adrenal dysfunction, associated diseases and antibody titer. Univariate and multivariate Cox proportional hazard models were used for statistical analysis. RESULTS: The cumulative risk (CR) of developing AAD was higher in APS-1 patients (94.2%) than in patients with APS-2/APS-4 (38.7%). The CR was high in both male and female APS-1 patients, while in patients with APS-2/APS-4 it was high only in males. Stage 1 (increased plasma renin) for patients with APS-1 and Stage 2 (no response of cortisol to ACTH test) for patients with APS-2/APS-4 were established as the points of no return in the progression to AAD. Adjusted hazard ratio analyses by multivariate Cox model for AAD showed that gender, diseases and adrenal function were independent risk factors for developing clinical AAD. The risk of developing clinical AAD appears to subside after 19 years of follow-up. CONCLUSIONS: A model for estimating the probability to survive free of AAD has been developed and should be a useful tool in designing appropriate follow-up intervals and future therapeutic strategies.

From Appearance of Adrenal Autoantibodies to Clinical Symptoms of Addison's Disease: Natural History.

Recent progress in the immunopathology field has greatly improved our understanding of the natural history of autoimmune diseases, particularly of Addison's disease. Addison's disease is known to be a chronic illness characterized by adrenocortical gland insufficiency that develops following a long and mainly asymptomatic period, characterized by the presence of circulating autoantibodies directed to adrenal cortex antigens. In this chapter we describe the groups of subjects at risk of developing Addison's disease, together with the diagnostic tests considered the most appropriate for evaluating adrenal function: determination of basal plasma adrenocorticotropic hormone (ACTH) levels, plasma renin activity, plasma aldosterone and cortisol levels, and cortisol levels after intravenous stimulation with ACTH (ACTH test). The employment of specific clinical, immunological and functional criteria in the subjects with autoantibodies to the adrenal cortex allows identifying those at risk of developing overt disease. The independent risk factors for the progression to adrenal failure have also been identified and they contribute to different risks of developing clinical Addison's disease. Based on the risk level, the subjects should be monitored over time to observe early signs of adrenal dysfunction, and start substitutive treatment as soon as possible. For patients presenting with high risk, prevention strategies and trials might be available.

From the Veins to the Heart: A Rare Cause of Varicose Veins.

The presence of pulsating varicous veins is an uncommon finding, generically attributed to right heart failure. The precise causes of this phenomenon have been poorly defined in the literature. The finding of this infrequent condition is important because it may be a sign of major diseases, often not known. Here we described a 75-year-old woman presented to the Angiology Unit for the presence of bilateral pulsatile swelling in her groin and along both lower limbs. A bedside ultrasound examination showed an arterial like pulsating flow both in the superficial and in the deep veins of the lower limbs due to a severe tricuspid regurgitation not previously known.

Clinical and pathological findings of a fatal systemic capillary leak syndrome (Clarkson disease): a case report.

Systemic capillary leak syndrome (SCLS) is a rare disorder with episodes of hypotension, hypoalbuminemia, and hemoconcentration. During attacks endothelial hyperpermeability results in leakage of plasma proteins into the interstitial space. Attacks vary in severity and may be lethal.A 49-year-old previously healthy man was admitted to hospital for hypovolemic shock, anasarca with pleuropericardial effusion, muscle fatigue, and oliguria occurring after a flu-like syndrome. Laboratory data showed an increase in hematocrit (65%), leucocytes (24.590 µ/L), creatinine (2.5 mg/dL), creatine phosphokinase (10.000 U/L), and a decrease in serum albumin (17 g/L) without proteinuria. Immunoglobulins of class G/λ monoclonal gammopathy were detected (1.3 g/L). The initial suspicions addressed to a protein-loosing syndrome or to an effort-related rhabdomyolysis. Initial therapy was based on steroids, albumin, and high molecular weight plasma expanders (hydroxyethyl starch). Because of high hematocrit, phlebotomy was also performed. The patient had complete clinical remission and a diagnosis of SCLS was finally made. He received prophylactic therapy with verapamil and theophylline that was self-stopped for intolerance (hypotension and tachycardia). He had a new crisis 2 days after a physical effort, and was admitted in intensive care unit. The patient died for severe hypovolemic shock with multiorgan failure and sudden cardiac arrest 15 hours after hospital admission. Postmortem investigation revealed massive interstitial edema of main organs with myocardial hyperacute ischemia.Studies on SCLS are limited for the rarity of the disease and its unpredictable course. Both prophylactic and acute crisis treatments are empirical and optimal management of severe attacks is still lacking.

Myasthenia Gravis following Low-Osmolality Iodinated Contrast Media.

We describe the case of 79-year-old man admitted to our general hospital for a 6-week history of progressive dysphagia to solids and liquids associated with weight loss. To reach a diagnosis a total body CT scan with low-osmolality iodinate contrast agent was performed. Two hours later the patient developed an acute respiratory failure requiring orotracheal intubation and mechanical ventilation. The laboratory and neurological tests allow formulating the diagnosis of myasthenia gravis. In literature, other three case reports have associated myasthenic crisis with exposure to low-osmolality contrast media. This suggests being careful in administering low-osmolality contrast media in myasthenic patients.

Diagnosis and classification of autoimmune parathyroid disease.

Hypoparathyroidism (HP) is clinically characterized by the presence of hypocalcemia, usually associated with specific signs and symptoms that depend on how severe and chronic the disease becomes. HP is usually caused by surgical removal of all four parathyroids, while other forms are rarer. Autoimmune HP can occur as an isolated disease or as part of an autoimmune polyendocrine syndrome. Here we review what is known about parathyroid gland autoimmunity, focusing on recently-proposed parathyroid autoantibody markers, and particularly those directed against NACHT leucine-rich-repeat protein 5 and calcium-sensing receptor. We also describe the clinical characteristics of HP and design a diagnostic algorithm for autoimmune HP.

Addison's disease: a survey on 633 patients in Padova.

OBJECTIVE: Addison's disease (AD) is a rare endocrine condition. DESIGN: We aimed to evaluate clinical, immunologic, adrenal imaging, and genetic features in 633 Italian patients with AD followed up since 1967. METHODS: Adrenal cortex autoantibodies, presence of other autoimmune and nonautoimmune diseases, nonadrenal autoantibodies, adrenal imaging, and genetic profile for HLA-DRB1 and AIRE were analyzed. RESULTS: A total of 492 (77.7%) patients were found to be affected by autoimmune AD (A-AD), 57 (9%) tuberculous AD, 29 (4.6%) genetic-associated AD, 10 (1.6%) adrenal cancer, six (0.94%) post-surgical AD, four (0.6%) vascular disorder-related AD, three (0.5%) post-infectious AD, and 32 (5.1%) were defined as idiopathic. Adrenal cortex antibodies were detected in the vast majority (88100%) of patients with recent onset A-AD, but in none of those with nonautoimmune AD. Adrenal imaging revealed normal/atrophic glands in all A-AD patients: 88% of patients with A-AD had other clinical or subclinical autoimmune diseases or were positive for nonadrenal autoantibodies. Based on the coexistence of other autoimmune disorders, 65.6% of patients with A-AD were found to have type 2 autoimmune polyendocrine syndrome (APS2), 14.4% have APS1, and 8.5% have APS4. Class II HLA alleles DRB1*03 and DRB1*04 were increased, and DRB1*01, DRB1*07, DRB1*013 were reduced in APS2 patients when compared with controls. Of the patients with APS1, 96% were revealed to have AIRE gene mutations. CONCLUSIONS: A-AD is the most prevalent form of adrenal insufficiency in Italy, and ∼90% of the patients are adrenal autoantibody-positive at the onset. Assessment of patients with A-AD for the presence of other autoimmune diseases should be helpful in monitoring and diagnosing APS types 1, 2, or 4 and improving patients' care.

Estimation of serum TSH receptor autoantibody concentration and affinity.

We have used the human monoclonal TSH receptor (TSHR) autoantibody (M22) as a labeled ligand in competition with individual patient TSHR autoantibodies (TRAb) to estimate their serum concentrations and affinities. TSHR coated tubes, (125)I-labeled M22 IgG and Fab, and patient sera IgG and Fab were used in these studies. In 15 patients with Graves' disease, TRAb concentrations ranged from 50 to 500 ng/mL of serum (5- 60 parts per million of total serum IgG) and TRAb IgG affinities from 3.0 +/- 1.0-6.7 +/- 1.54-10(10) L/mol (mean +/- SD; n=3). Fab fragment affinities were similar to those of intact IgG. Serum TRAb with blocking (TSH antagonist; 4 patients) activity had similar affinities (3.0 +/- 0.25-7.2 +/- 2.2-10(10) L/mol) to TRAb IgG from patients with Graves' disease, but blocking TRAb concentrations were higher (1.7 - 27 mg/mL of serum). The concentrations of TRAb that we observed in the sera of the 15 Graves' patient (0.33 - 3.3 nmol/L) can be compared with that of circulating TSH. In particular, a serum TSH concentration of 100mU/L (0.7 nmol/L) is in the same range as the concentrations of TRAb we observed. Such a TSH concentration (similar to that observed after injection of 0.9 mg of recombinant human TSH) would be expected to cause a similar degree of thyrotoxicosis as seen in Graves' disease. Consequently, the thyroid-stimulating potencies (i.e., activity per mol) of patient serum TRAb and human TSH appear to be of a similar magnitude in vivo as well as in vitro. Overall, our results indicate that serum TRAb affinities are high and show only limited variations between different sera whereas concentrations of the autoantibodies vary widely.

Estimated risk for developing autoimmune Addison's disease in patients with adrenal cortex autoantibodies.

CONTEXT: Patients with adrenal cortex autoantibodies (ACA) without overt autoimmune Addison's disease (AAD) are at risk of adrenal failure. DESIGN: To assess the contribution of different clinical, immunological, genetic, and functional factors in the progression to AAD, we followed up 100 ACA-positive and 63 ACA-negative patients without AAD for a maximum of 21 yr (mean 6.0 yr, median 4.8). ACA were measured by immunofluorescence and 21-OH autoantibodies (Abs) by RIA. Adrenal function was assessed by measuring basal levels of cortisol, aldosterone, ACTH, renin activity, and cortisol response to ACTH. The risk of developing AAD was calculated using survival and multivariate analyses. RESULTS: AAD developed in 31 ACA-positive patients and one ACA-negative patient. The cumulative risk of disease in ACA-positive patients was 48.5% [95% confidence interval (CI) 40.8-56.1]. The cumulative risk was higher in children than adults (100 vs. 31.9%; P < 0.0001), males than females (68.6 vs. 42.7%; P = 0.006), patients with subclinical rather than normal adrenal function at entry (87.4 vs. 30.1%; P < 0.0001), patients with hypoparathyroidism and/or candidiasis than patients with other autoimmune or nonautoimmune diseases (100 vs. 29.7%; P < 0.0001), and patients with high rather than low-medium ACA titers (62.8 vs. 41.2%; P = 0.12). The presence of human leukocyte antigen (HLA)-DRB1 did not appear to contribute to the prediction of AAD. Adjusted hazard ratios by Cox model for the development of AAD were 3.37 for males (CI 1.38-8.24), 5.23 for hypoparathyroidism and/or candidiasis (CI 1.53-17.92), 3.33 for high antibody titers (CI 1.43-7.78), and 6.15 for impaired adrenal function at entry (CI 2.79-13.57). CONCLUSIONS: These results were used to construct a risk algorithm for estimating the probability of developing AAD from the combination of gender, age, adrenal function, antibody titer, and associated autoimmune disorders at entry. The values of estimated risk could be used to decide appropriate follow-up intervals and future immunointervention strategies.

Acute adrenal failure as the heralding symptom of primary antiphospholipid syndrome: report of a case and review of the literature.

Acute adrenal failure is a potentially fatal condition if overlooked. Occasionally, acute adrenal insufficiency may ensue from bilateral adrenal haemorrhage in patients with known antiphospholipid syndrome (APS). APS is characterized by recurrent arterial and venous thrombosis, pregnancy complications and detection of autoantibodies to phospholipids. This syndrome may be associated with non-organ specific diseases (e.g. connective tissue disorders) or with malignancies, but it may also appear in isolated form (primary APS). In a very few cases the heralding manifestation is given by adrenal failure. We report here a 63-year-old man presenting with acute adrenal insufficiency as the opening clinical manifestation of an APS. We also carried out a computer-aided search of the literature to identify all cases of primary adrenal failure as the first-recognized expression of a primary APS, a condition that not so infrequently may be tackled by endocrinologists. 20 patients fulfilled the inclusion criteria. The great majority of them were males (75%) with a mean age of 42 years. Abdominal pain was present in 14 patients, followed by fever (13 patients) and hypotension (12 patients). The main morphological findings by computed tomography or magnetic resonance were consistent with bilateral adrenal haemorrhage in 11 patients. Lupus anticoagulant was present in all of the 19 tested patients. Our observations emphasize the importance in the assessment of clotting times, and possibly of antiphospholipid antibodies, in all patients with diagnosis of rapidly progressive adrenal failure and concurrent abdominal pain.

Helicobacter pylori infection and gastric autoimmune diseases: is there a link?

BACKGROUND: Helicobacter pylori is thought to be involved in atrophic body gastritis. We explored the prevalence of H. pylori infection in asymptomatic subjects with gastric parietal cell antibodies, as well as in patients with pernicious anemia, to evaluate a possible role of H. pylori gastric infection in gastric autoimmunity. PATIENTS AND METHODS: We studied 79 consecutive asymptomatic subjects with parietal cell antibodies, 24 patients with pernicious anemia, and 66 parietal cell antibody-negative controls. All patients underwent gastric biopsies for histology and detection of H. pylori. Red blood cell count and volume, serum levels of gastrin, pepsinogen I, iron, folic acid, vitamin B12, and circulating antibodies to H. pylori and to intrinsic factor were also determined. RESULTS: We found an atrophic body gastritis in 14 of the 79 asymptomatic subjects with parietal cell antibodies (18%) and in 2 of the 66 controls (3%) (p =.01). Mean levels of gastrin were increased (p <.0001), while those of pepsinogen were reduced (p <.001) compared with controls. H. pylori was identified at the gastric level and/or circulating anti-H. pylori antibodies were detected in 46 parietal cell antibody-positive subjects (58%) compared with 26 controls (39%) (p =.03). In patients with pernicious anemia we found an atrophic body gastritis in 18 of 24 cases (75%) (p <.001 vs. controls). Mean levels of gastrin were markedly increased (p <.0001) and those of pepsinogen I decreased (p <.0001) relative to controls. Only five of these patients (21%) had evidence of H. pylori infection compared with 46 of the parietal cell antibody-positive subjects (58%) (p =.003) and 26 of the controls (39%). Considering all patients with gastric autoimmunity (i.e. with parietal cell antibodies and/or with pernicious anemia), H. pylori was found in 44 of 72 of those without atrophy (61%) but in 6 of 31 with gastric body atrophy (19%) (p <.001), indicating that H. pylori infection is greatly reduced when gastric acid secretion decreases. CONCLUSIONS: The frequent detection of H. pylori infection in subjects with early gastric autoimmunity, indicated by the presence of parietal cell antibodies, suggests that H. pylori could have a crucial role in the induction and/or the maintenance of autoimmunity at the gastric level.