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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 2  |  Page : 295-307

Subclinical endocrine disorders: a brief overview of risks, diagnosis, and workup of these disorders


1 Department of Internal Medicine, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
2 Department of Internal Medicine, Al Shouhadaa Hospital, Menoufiya, Egypt

Date of Submission03-Jul-2014
Date of Acceptance16-Aug-2014
Date of Web Publication31-Aug-2015

Correspondence Address:
Ibrahim S Attiya
Al Shouhadaa Hospital, Menoufiya 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.163871

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  Abstract 

Introduction
Subclinical endocrine disorders are entities of mild degrees of endocrine dysfunction with no recognizable clinical findings.
Objectives
To shed light on up-to-date information on subclinical endocrine disorders and provide a brief overview of the risks, diagnosis, and workup of these disorders.
Materials and methods
We searched reference electronic databases, especially ScienceDirect, The Lancet, and Medscape, in the title of the article with the key words mentioned; extraction was carried out, including assessment of the quality and the validity of papers. Studies on subclinical disorders of each gland were collected; each study was reviewed independently. The data obtained were rebuilt in new language and divided into topics throughout the article.
Recent findings
There is strong evidence supporting the evolution of subclinical entities of various endocrine disorders. Some of these entities may behave as clinical ones, with possible adverse effects on body systems; thus, some symptoms may manifest soon, whereas others may be discovered accidently during routine laboratory and radiological investigations and they require careful periodic follow-up.
Conclusion
Subclinical hypothyroidism and subclinical Cushing's syndrome are well-known disorders. There have been advancements in early detection using screening programs and cases of these disorders. There is also evidence supporting their negative impact on cardiovascular morbidity and quality of life. Large-scale randomized-controlled trials are needed to inform how to best care for these and to gain more knowledge of these disorders.

Keywords: incidentalomas, normocalcemic primary hyperparathyroidism, prediabetes, progression, risks, subclinical central diabetes insipidus, subclinical Cushing′s syndrome, subclinical hypo/hyperthyroidism, subclinical phaeochromocytoma, subclinical primary aldosteronism


How to cite this article:
Gazareen SS, Shoeib SA, Dawoud AA, Attiya IS. Subclinical endocrine disorders: a brief overview of risks, diagnosis, and workup of these disorders. Menoufia Med J 2015;28:295-307

How to cite this URL:
Gazareen SS, Shoeib SA, Dawoud AA, Attiya IS. Subclinical endocrine disorders: a brief overview of risks, diagnosis, and workup of these disorders. Menoufia Med J [serial online] 2015 [cited 2020 Apr 6];28:295-307. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/295/163871


  Introduction Top


With advancements in the biochemical and imaging techniques in the endocrinological field, new entities have been emerging in the medical field. Subclinical disease is an illness that remains below the radar of clinical detection, and has no recognizable clinical findings [1] . These entities encompass mild degrees of endocrine gland dysfunction. Their clinical significance is uncertain, which leads to controversy over the appropriateness of diagnostic and treatment strategies. Many doctors may find it difficult to decipher and find the appropriate way to deal with such disorders. In this review, we attempted to present clinicians with updated knowledge of some of these disorders.


  Materials and methods Top


Objectives

To provide up-to-date information on subclinical endocrine disorders and provide a brief overview of the risks, diagnosis, and workup of these disorders.

Search strategy

A systematic search was performed of several bibliographical databases to identify relevant reports in any language. These included ScienceDirect, The Lancet, Medscape, and Cochrane electronic Databases. The search was performed in the recent electronic databases from 2002 to 2013. All the studies were assessed independently for inclusion of any updated information on subclinical disorders of the endocrine system. The article title and abstracts were screened initially and then second articles were read in full and further assessed for eligibility.

Data extraction/data synthesis

Data extraction was performed, including assessment of the quality and the validity of papers. Studies on subclinical disorders of each gland were collected; each study was reviewed independently. The obtained data were rebuilt in new language and divided into topics throughout the article.

Recent findings

There is strong evidence supporting the evolution of subclinical entities of various endocrine disorders. Some of these entities may behave as clinical ones, with possible adverse effects on body systems; thus, some symptoms may manifest soon, whereas others may be discovered accidently during routine laboratory and radiological investigations and they only require careful follow-up. Some have definite diagnostic criteria, but others do not and are studies still ongoing.


  Discussion Top


Subclinical disease is an illness that remains below the radar of clinical detection, and has no recognizable clinical findings [2] .

Subclinical pituitary disorders

Subclinical central diabetes insipidus

Central diabetes insipidus (CDI) is a rare hypothalamus-pituitary disease because of deficiency in arginine-vasopressin/arginine vasopressin (AVP) synthesis from the hypothalamus and/or of release from the posterior hypophysis, characterized by polyuria and polydipsia. It may be complete or partial, permanent or transient [3] .

Pathophysiology

It can be the outcome of diseases that affect the hypothalamus-infundibulum-posthypophysis axis. If the damage is limited to the infundibulum and the posterior lobe of the pituitary, this leads to partial (subclinical) or transient CDI as newly synthesized hormone can still be released into circulation as long as the nuclei are intact. Destruction of over 80% of synthesizing neurons is required to determine CDI. About 30% of patients with CDI have no apparent cause and it is considered idiopathic. Among these, autoimmune diseases play an important role even if the actual prevalence is probably underestimated. In patients showing symptoms or signs related to idiopathic hypothalamic-pituitary damage, histopathological characteristics are the gold standard for the diagnosis of autoimmune clinical/subclinical CDI [4] .

Gestational CDI occurs more frequently in multiple pregnancies because of larger placenta secreting more vasopressinase and increase in the size of pre-existing cranioparingiomas and prolactinomas, compressing the post-pituitary glands; thus, pregnancy may expose a pre-existing subclinical CDI [5] .

Diagnosis

Diagnosis is made on the basis of a history of polyuria and polydipsia, physical examination, imaging studies of the brain and pituitary gland confirmed by measurement of serum electrolytes, urine-specific gravity, plasma AVP, and simultaneous plasma and urine osmolality after water deprivation plus desmopressin challenge tests. The diagnosis of subclinical/partial CDI is made according to the following criteria: subnormal response of plasma AVP after a prolonged water deprivation test and increase in urinary osmolality ranging from 9 to 50% after an injection of DDAVP. Urine osmolality less than 300 mOsm/kg and plasma osmolality more than 295 mOsm/kg after dehydration and increase in urine osmolality more than 750 mOsm/kg following the administration of desmopressin are the hallmarks of complete CDI. AVPcAb is useful when an autoimmune CDI is suspected and cranial MRI findings to investigate the persistence of a hyperintense signal and diseases involving the hypoyhalamic-neurohypophysis axis [4],[6] .

The proposed workup is shown in [Figure 1] on the basis of the diagrams of Di Iorgi et al. [6] and Bellastella et al. [4] .
Figure 1: Workup algorithm of subclinical central diabetes insipidus

Click here to view


Subclinical thyroid dysfunction

Subclinical thyroid dysfunction is an early condition of mild thyroid hormone excess or deficiency, characterized by abnormal serum thyroid stimulating hormone (TSH) and normal free thyroxine (FT4) and free tri-iodothyronine (FT3) [2] .

Subclinical hypothyroidism

Subclinical hypothyroidism is a common biochemical finding in the general population. It occurs in 4-20% of the adult population. This wide range is because of differences in age, sex, body mass index, race, dietary iodine intake, and cutoff concentrations of serum TSH [7] .

It can classified as follows:

  1. Mild disease with serum TSH 5-9 mU/l.
  2. Severe disease with serum TSH more than 10 mU/l [2] .
Etiopathology

It is more common in iodine-sufficient countries [1] .

Serum TSH may increase after subacute, postpartum, or painless thyroiditis and after infiltrative diseases (Riedel's thyroiditis, amyloidosis). Acquired thyroid hormone deficiency may develop after partial thyroidectomy, radioiodine treatment, and external radiotherapy of the head and neck. Physiological increases of TSH could occur as diurnal variations, during recovery from nonthyroidal illness, after withdrawal of thyroid hormone therapy in patients in a euthyroid state [1] .

TSH secretion is sensitive to both minor increases and decreases in serum free T4; thus, abnormal TSH levels occur during development of hypothyroidism and hyperthyroidism before free T4 abnormalities are detectable [8] .

Transient expression of TSH-receptor blocking antibodies may explain the recovery of thyroid function in some cases [9] .

Inadequate thyroid hormone therapy and poor compliance may be responsible for exogenous causes [2] .

Diagnosis: a detailed assessment of personal and familial history, pharmacological evaluation, and an accurate clinical assessment are required [2] .

Serum TSH measurement is the primary screening test for the diagnosis and evaluation of therapy. The presence of elevated thyroperoxidase (TPO) antibody titer helps to predict progression to overt hypothyroidism [7] .

In 50% of cases, TSH will normalize on repeat testing. Annual TSH monitoring is reasonable for individuals with positive (TPO) antibodies, but for those with negative antibodies, 2-3-yearly monitoring is sufficient [10] .

Possible risks

A high risk of disease progression has been observed in pregnant women with asymptomatic autoimmune thyroiditis. It depends on the cause, basal TSH value, and the patient's age. The annual rate of progression was about 4% in women with elevated serum TSH and positive antithyroid antibodies, 2-4% in those with only elevated serum TSH concentrations, and 1-3% in those with only antithyroid antibodies present [8] .

The lipid pattern is particularly altered in those with serum TSH more than 10 mU/l, smokers, and insulin resistance. Long-term untreated SHypo may be associated with vascular/endothelial dysfunction and dyslipidemia, which increase the risk of atherosclerosis and CHD.

Cardiac function (systolic and diastolic) is altered in young patients with mild SHypo because of reduced expression of sarcoplasmic reticulum calcium ATPase. Vascular dysfunction may be caused by impaired nitric oxide availability, leading to an increase in systemic vascular resistance and central arterial stiffness and increasing the risk of diastolic hypertension [2] .

Subclinical hyperthyroidism

Subclinical hyperthyroidism (SHyper) is a low-undetectable serum TSH with thyroid hormone (FT4 and FT3) concentrations in the upper limit, but within their respective reference range [1] .

It can classified as follows:

  1. Mild disease (serum TSH 0.1-0.4 mU/l).
  2. Severe disease (serum TSH level<0.1 mU/l) [2] .
Etiopathology

Its prevalence is 1-2% in the general population, but higher in those older than 60 years of age, women, and African-Americans [11] .

It can be divided into two categories:

  1. Exogenous: caused by thyroid hormone therapy.
  2. Endogenous: commonly associated with autonomous thyroid function such as Graves' disease, toxic multinodular goiter, and toxic adenoma. It may be reversible or persistent [2] .
Possible risks

Exogenous SHyper is evaluated by a symptom-rating score; patients were found to have specific manifestations of overt hyperthyroidism, with higher prevalence of palpitations, tremor, sweating, nervousness, and anxiety (adrenergic overactivity) compared with normal individuals. Patients with endogenous SHyper evaluated by The Wayne score (a clinical index of hyperthyroidism) showed significantly higher values than the controls, especially young and middle-aged patients [8] .

The risk of progression to overt hyperthyroidism is higher in patients with Graves' disease than in toxic multinodular goiter [2] .

Patients with SHyper had higher BMIs and increased frequency of hyperlipidemia, diabetes, and hypertension compared with euthyroid individuals. It is associated independently with an increased risk for all-cause and CVD mortality [12] .

Shyper has been reported to increase heart rate, left ventricular mass, cardiac contractility, diastolic dysfunction, and atrial arrhythmias in relatively young patients [13] .

SHyper carries a clear risk for atrial fibrillation, especially in elderly patients, because of a positive chronotropic effect of thyroxine on the heart. Small increases of FT4 within the normal range may increase the dose-dependent risk of venous thrombosis and increase bone turnover and loss, predisposing to fragility, fractures, and muscle weakness, and consequently falls and fractures. TSH has been proposed to inhibit bone turnover directly by binding to TSH receptors on osteoclast and osteoblast precursors [14] .

Bone resorption induced by the thyroid hormones is mainly observed in the cortical bone (wrist), to a significantly low extent in the trabecular bone (spine), and to an intermediate extent in the mixed cortical-trabecular bone (hip) [15] .

A proposed workup of subclinical thyroid dysfunction is shown in [Figure 2] on the basis of flowcharts of Cooper and Biondi [1] and Wiersinga [14] .
Figure 2: Workup of subclinical thyroid dysfunction

Click here to view


Subclinical parathyroid disorders

Normocalcemic primary hyperparathyroidism

It is defined as persistently normal serum calcium levels in the presence of high levels of parathyroid hormone (PTH). Both ionized and serum calcium within the normal levels are required for diagnosis [16] .

Pathophysiology

The first concept postulated that there was resistance to target tissues. An oral calcium load causes inadequate suppression of PTH and lower serum calcium more in normocalcemic than classic hypercalcemic patients [17] .

It could be a first stage of the disease or a specific condition characterized by renal and bone resistance to the action of PTH. The potential contribution of high sodium intake, low phosphate levels, high estrogen levels, or lack of CaSR expression changes has been reported [18] .

Another concept was based on the evolution of the hypercalcemic form as there was an initial increase in the serum PTH level. This first phase was postulated to be subclinical because PTH levels were almost never obtained in normocalcemic patients. Their hypothesis went on to state that the second phase would be the clinical stage when hypercalcemia became overt [19] .

Diagnosis

Searching for causes of secondary hyperparathyroidism syndrome is the first step that should be taken. In particular, vitamin D deficiency needs to be ruled out. In addition, it is also important to rule out other causes of secondary hyperparathyroidism, such as urinary calcium leak and reduced creatinine clearance. It is identified during the evaluation of patients with low bone density in specialized metabolic bone units; however, some patients are diagnosed because of fragility fracture, nephrolitiasis, hypercalciuria, high serum PTH values, or incidental discovery of an enlarged parathyroid on cervical ultrasonography [15] .

The diagnosis is made on the basis of elevated PTH levels, confirmed at least two times in the absence of hypercalcemia (normal total and ionic serum calcium levels). Another significant aspect is the cut-off point for PTH elevation because this depends on the measurement method used [17] .

Possible risks

The absence of hypercalcemia does not imply that patients are asymptomatic. Few data are available on its course, although the logical evolution to hypercalcemia does not appear to always occur [17] .

Skeletal risks

Histomorphometric studies have shown an increased risk of fracture in cortical bone and reduced risk in cancellous bone. There are no specific data on hip and other non-vertebral fractures in these patients [20] .

Renal risk

Renal stones are present in ~7% of these patients, which is higher than that for the controls (1.6%). However, shortly after parathyroidectomy, the risk of recurrent nephrolithiasis is reduced compared with those with idiopathic renal stones [21] .

Metabolic changes

Common metabolic changes have been found in normocalcemic PHP. Compared with controls, these patients had greater body mass, glucose, VLDL cholesterol, LDL/HDL cholesterol, triglyceride and uric acid levels, and lower HDL cholesterol levels [22] .

Cardiovascular risk

The prevalence of cardiovascular risk factors (high blood pressure, hyperlipidemia, glucose metabolism changes) was similar, but lower than that in hypercalcemic PHPT [23] . A proposed workup is shown in [Figure 3].
Figure 3: Workup scheme of normocalcemic primary hyperparathyroidism

Click here to view


Subclinical diabetes mellitus (prediabetes)

Before patients develop type 2 diabetes mellitus (T2DM), they almost always have 'prediabetes,' defined by blood glucose levels that are higher than normal, but not yet high enough to be diagnosed as diabetes. Doctors sometimes refer to prediabetes as impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) [24] .

The International Diabetes Federation estimate for the global prevalence of IGT was 7.9% among adults (aged 20-79 years) in 2010 and will increase to 8.4% by 2030 [25] .

Pathophysiology

Several studies have shown that both isolated IFG and isolated IGT are characterized by insulin resistance and impaired insulin secretion. There are some differences in the nature of the defects between them. Individuals with isolated IFG manifest hepatic insulin resistance, but have relatively normal skeletal muscle insulin sensitivity in contrast to those with isolated IGT [26],[27] .

The pathogenesis of T2DM may involve gene-environment interactions, which increase susceptibility to development of three metabolic defects: insulin resistance, insulin secretory defects, and increased gluconeogenesis by the liver. The primary defects are believed to be insulin resistance and early pancreatic b-cell susceptibility, which are worsened by obesity and physical inactivity. As the disease progresses, more global pancreatic defects result in increased hepatic gluconeogenesis, leading to an increase in fasting plasma glucose, a stage termed IFG. Continuous increase in hyperglycemia will lead to insulin resistance because of exhaustion of pancreatic b-cells. If insulin resistance is severe enough, IGT may occur.

Identifiable dysglycemic phase

Both IFG and IGT are asymptomatic, intermediate states of abnormal glucose regulation that precede overt T2DM.

Identifiable latent phase

The early stages of T2DM after biologic onset are frequently asymptomatic. Some studies have reported that diabetes may be present for as long as 9-12 years before a clinical diagnosis. However, these estimates represent mean values only, and the asymptomatic period may vary widely.

Tissue damage during the preclinical stage

Studies of patients with newly diagnosed T2DM provide evidence of early diabetes-related tissue damage during the preclinical phase. In the United Kingdom Prospective Diabetes Study, 50% of newly diagnosed diabetes cases had evidence of diabetes-related complications [25] .

Diagnosis/diagnostic criteria: any of the following three approaches is acceptable.

Impaired fasting glucose/impaired glucose tolerance criteria

Prediabetes is identified by IFG (glucose levels 100-125 mg/dl) and/or IGT (glucose levels 140-199 mg/dl) following a 2-h 75-g oral glucose tolerance test performed in the morning.

Hemoglobin A1C criteria

Values between 5.5 and 6.4% should be a sign to perform more specific glucose testing [Table 1] [26],[27],[28] .
Table 1 Comparison of 2006 World Heal th Organization and 2003/2011 and 2012 American diabetes association diagnostic criteria [28]

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Metabolic syndrome criteria

The presence of metabolic syndrome, on the basis of National Cholesterol Education Program IV Adult Treatment Panel III criteria and also known as insulin resistance syndrome, is a prediabetes equivalent [26],[27] .

Testing to detect T2DM and prediabetes should be considered in children and adolescents who are overweight and who have two or more additional risk factors for diabetes, although the disease remains rare in the general pediatric population [23] .

Possible risks

Patients with impaired glucose homeostasis are generally asymptomatic. Characteristics of related risk factors for cardiovascular disease may be present, even with a mild degree of hyperglycemia. They include a history of hypertension, obesity, dyslipidemia, and macrovascular disease, such as stroke, coronary disease, or peripheral vascular disease [29] .

Progression of prediabetes to diabetes may take many years, but may also be rapid. The incidence is the highest in individuals with combined IFG and IGT and similar in those with isolated IFG or IGT. The average risk of progression is about 5-10%/year in individuals with IFG or IGT compared with ~0.7%/year in normoglycemic individuals [30] .

Both IFG and IGT are associated with a 20% increase in cardiovascular risks compared with normoglycemia [31] .

Patients with IGT had significantly more microvascular and macrovascular complications than patients with normoglycemia. The prevalence of complications also increased among patients with Isolated-IFG relative to patients with normoglycemia, although not to the same degree [32] .

Retinopathy

The Blue Mountains Eye Study found a 10% retinopathy incidence among individuals with fasting plasma glucose (FPG) (99-112 mg/dl) and 20% among individuals with FPG (113-126 mg/dl) [33] .

Neurological

Data from studies suggest that intraepidermal nerve fiber loss is an early feature of metabolic syndrome, prediabetes, and established diabetes, and correlated positively with neuropathic severity [27] .

Prevention recommendations

According to the American Diabetes Association guidelines 2013 (see [Figure 4].
Figure 4: Prediabetes prevention recommendations [24].

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Subclinical adrenal disorders

Subclinical phaeochromocytoma

Phaeochromocytoma (Phaeo) is a neuroendocrine catecholamine-releasing tumor arising from chromaffin cells in the adrenal medulla. When arising outside the adrenal gland, it is referred to as a secreting paraganglioma (sPGL), which should be distinguished from other para-gangliomas, located in the head and neck region (HNPGL). Both Phaeo and sPGL are sympathetic in origin, producing catecholamines whereas HNPGLs are parasympathetic in origin and do not produce significant amounts of catecholamines [34] .

Pathophysiology

The amount of catecholamines released by the tumor are correlated positively with tumor size; thus, small tumors in their early stages of development are generally associated with few or mild symptoms [35] .

Patients may present more often with paroxysmal signs and symptoms, but beyond the secretory crisis, leading to normotension and clinical silence. The continuously higher plasma noradrenaline may cause downregulation of adrenoceptors, contributing toward a milder clinical picture. Some of the cosecreted peptides such as adrenomedullin and pituitary adenylate-cyclase activating peptide may have vasodilating effects that may counteract some of the effects exerted by the catecholamines [34] .

Dopamine-producing tumors are rare, but reasonably common among patients with familial syndromes. Dopamine is a peripheral vasodilator and decreases noradrenaline release from sympathetic nerve endings, counteracting the effects of noradrenaline and attenuating the clinical picture [36] .

Diagnosis

Laboratory diagnosis

The recommended screening test for initial assessment is the measurement of plasma free-metanephrines or urine-deconjugated differential metanephrines that have a longer half-life and are produced continuously by the tumor [37] .

Increased levels of plasma dopamine and plasma chromogranin A may suggest malignancy [38] .

Imaging: anatomical imaging

Computed tomography or MRI is the first radiological approach in patients with PGLs. MRI is better than computed tomography for the detection of extra-adrenal disease.

Functional imaging (scintigraphy)

131I or 123I-metaiodobenzylguanidine (MIBG) scintigraphy is a first-line nuclear medicine technique in the evaluation of patients with PGLs. MIBG has chemical similarities to norepinephrine and is concentrated in chromaffin tissue [37] .

Positron emission tomography imaging

Somatostatin analogs labeled with gallium-68 had a better sensitivity in the detection of small tumors or metastases located in the lung or skeleton. PET with 6-[ 18 F]-fluoro-DA can detect metastatic lesions with better sensitivity than 131 I-MIBG, whereas PET with 6-[ 18 F]-fluoroDOPA is superior in imaging sPGLs and HNPGLs [39] .

Genetic screening

It is indicated to rule out familial syndromes. Testing for every possible gene would be inappropriate and expensive; however, genetic tests can be selected according to family history, catecholamine secretion profile, patient age, and primary tumor site [38] .

To date, 10 susceptibility genes have been discovered, with familial cases of around 40%. Carriers should be enrolled in a follow-up program for early diagnosis [34] .

Possible risks

Phaeo/sPGL are generally benign tumors, but may be 'malignant' on clinical grounds because of the metabolic and cardiovascular effects exerted by the high levels of circulating catecholamines. The most deleterious consequences are caused by the abrupt release of catecholamines, which may occur spontaneously or may be caused by several different factors [Figure 5] [40] .
Figure 5: Factors reported to induce hypertensive crises in patients with pheochromocytoma [34]

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The subclinical picture does not exclude the potential occurrence of hypertensive crises causing serious cardiovascular events and even death because of the abrupt release of catecholamines. A very high level of medical alertness is recommended when even mild signs or symptoms suggest the possible presence of these tumors. It may also be associated with pulmonary, cardiovascular, abdominal, neurological, renal, and metabolic complications [Table 2], for prevention and precautions, see [Figure 6] [39],[41],[42] .
Figure 6: DOS and DONTS in pheochromocytoma [42]

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Table 2 Emergency situations related to catecholamine excess released from pheochromocytoma [41]

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Subclinical Cushing's syndrome

This term is used to refer to autonomous cortisol secretion in patients who do not have the typical signs and symptoms of hypercortisolism [43] .

SCS should be assessed on the basis of three criteria:

  1. The patient has an adrenal adenoma that was detected serendipitously without any previous suspicion of adrenal disease.
  2. The patient does not present a clear Cushingoid phenotype.
  3. The endocrine workup shows autonomous/ACTH-independent cortisol secretion [44] .
Diagnosis

A variety of different approaches to diagnose SCS can be found, but there is no consensus on the best strategy. The concomitant use of multiple tests to study the hypothalamic-pituitary-adrenal axis may result in a higher probability of finding an altered test result by chance [45] .

The dexamethasone suppression test (DST) has been used extensively to assess the status of the hypothalamic-pituitary-adrenal axis in adrenal incidentalomas. It is considered the most valuable test to screen for SCS [46] .

Midnight serum cortisol is a reliable method to detect a disturbance in the cortisol rhythm, which may be an early marker of the disorder, but it requires hospitalization.

The late-night salivary cortisol is an easier alternative to midnight serum cortisol for screening. Recently, it has been suggested that it may be more specific than the 1-mg DST in identifying these patients [47] .

Serum ACTH level and DHEAS level are usually low. Serum cortisol levels more than 5 mg/dl after 1-mg overnight DST have been approved. The DST-UFC-ACTH (1 mg DST>3 mcg/dl, increased UFC, and ACTH<10 pg/dl) combination criteria are used as confirmatory tests [47] .

Possible risks

Few data are available on the long-term outcome of patients with subclinical hypercortisolism. These patients should be considered to be at an increased risk of cardiovascular events, but the difficulties in carrying out powerful prospective studies were an obstacle because of the limited sample size, insufficient duration of follow-up, and the retrospective design, and are inconclusive on whether mortality is higher than that in the general population [48] .

In a recent study, an increased prevalence of vertebral fractures in women with SCS was found, corroborating the notion that even subtle increase in glucocorticoid can exert an effect on bone quality, particularly with estrogen deficiency [49] .

The risk of progression from subclinical to overt Cushing's syndrome is minimal. Masses of 3 cm or greater are more likely to develop silent hyperfunction than smaller tumors, and the risk seems to plateau after 3-4 years, even if it does not subside completely. The critical issue is that SCS may predispose to diseases such as hypertension, obesity, or diabetes, which are clusters in the metabolic syndrome [47] .

Normotensive primary aldosteronism

Patients with mild hypertension and normotensive patients were excluded from screening of primary aldosteronism in patients with moderate to severe and/or resistant hypertension. A considerable number of normotensive individuals without hypokalemia have been discovered who may have subclinical forms of primary aldosteronism. Primary aldosteronism confirmed by suppression testing without hypertension might be termed normotensive and/or subclinical primary aldosteronism [50] .

Etiopathology



(1) Early state (preclinical) of the disease.

(2) Mild form (subclinical) of the disease.

(3) Low spontaneous baseline blood pressure:

(a) Conditions that cause vasodilation or sodium wasting:

(i) Estrogen, atrial/brain natriuretic peptide, Endothelial nitric oxide, poor response to angiotensin II or norepinephrine.

(b) Mineralocorticoid resistance because of environmental factors or genetic defects:

(i) Progesterone, urinary tract obstruction/infection, small bowel resection.

(4) Low sodium intake and/or high green tea consumption.

(5) Low BMI [50] .

The plasma aldosterone/plasma renin activity ratio (ARR) is an effective screening test for primary aldosteronism. Confirmative suppression tests, including the captopril suppression test, sodium loading test, or intravenous saline infusion test, should be recommended for all patients with increased ARR if plasma aldosterone concentrations are not consistently below the normal range (for proposed workup, see [Figure 7] [51] .
Figure 7: Workup scheme of subclinical (normotensive) primary aldosteronism

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Possible risks

Several studies have shown that these patients are at a high risk for target-organ damage, including atrial fibrillation, myocardial infarction, cardiomegaly, cerebral hemorrhage and stroke, pulmonary edema, and renal insufficiency because of excessive aldosterone. Normotensive patients with FH-I may complain of an increased left ventricular wall thickness and diastolic dysfunction [50] .


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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