Endocrine and metabolic diseases can be categorized into clinical and subclinical types. Clinical diseases often present with typical symptoms and signs and can be easily diagnosed when combined with laboratory tests. Subclinical diseases lack typical clinical manifestations and are characterized only by mild abnormalities in laboratory tests. The diagnosis of endocrine and metabolic diseases typically includes three components: functional diagnosis, anatomical (localization) diagnosis, and etiological diagnosis. Classification and staging may also be necessary in certain cases.
Clinical Manifestations
Medical History
Information about the onset, duration, and severity of the disease provides valuable diagnostic clues. For example, type 1 diabetes usually presents with an acute onset and distinct symptoms such as polydipsia, polyuria, polyphagia, and weight loss, whereas type 2 diabetes typically has a more insidious onset, often without the classic "three polys and weight loss." A history of paroxysmal hypertension is often reported in patients with pheochromocytoma. Accompanying symptoms help assess the severity of the disease. For instance, inquiries about cardiovascular, renal, ocular, peripheral, and nervous system symptoms in diabetic patients can help determine whether chronic complications are present.
Past medical history is also important for etiological diagnosis. For example, women with postpartum hypopituitarism often have a history of postpartum hemorrhage, and patients with Nelson’s syndrome usually report a history of bilateral adrenalectomy. Personal history and medication history help identify exogenous or iatrogenic causes of the disease. For example, diuretics may lead to hypokalemia, and glucocorticoids may cause iatrogenic Cushing’s syndrome. Menstrual history and reproductive history are particularly relevant for diagnosing gonadal disorders. Family history is useful for diagnosing hereditary endocrine and metabolic diseases and for screening asymptomatic family members. For instance, diabetes related to mitochondrial gene mutations follows a maternal inheritance pattern, and medullary thyroid carcinoma should prompt attention to familial transmission.
Symptoms and Signs
Different endocrine and metabolic diseases have characteristic symptoms and signs. Features such as body build, distinctive facial appearances, or changes in lifestyle habits often provide important diagnostic clues. Hyperthyroidism, for example, manifests with symptoms of hypermetabolism, including weight loss and excessive sweating, along with exophthalmos in Graves' disease. Cushing's syndrome presents with centripetal obesity, a round moon face, and purple striae on the skin. Addison’s disease is associated with hyperpigmentation. Acromegaly is characterized by distinctive facial features and enlargement of the hands and feet. Diabetes is marked by polyuria, polydipsia, polyphagia, and weight loss.
Functional Diagnosis
Biochemical Testing Related to Hormones
Abnormalities in electrolytes or other biochemical markers in blood or urine provide indirect evidence of abnormal hormone levels and can aid in differential diagnosis. For example, primary aldosteronism presents with hypokalemia and metabolic alkalosis, along with inappropriate potassium excretion, due to increased aldosterone secretion. Renal tubular acidosis is associated with hypokalemia and metabolic acidosis. Cushing’s syndrome, caused by excess glucocorticoids, leads to hyperglycemia, hypernatremia, and hypokalemia. Adrenal insufficiency results in hyponatremia, hyperkalemia, and fasting hypoglycemia. Primary hyperparathyroidism, due to elevated parathyroid hormone levels, causes hypercalcemia, hypophosphatemia, and increased urinary calcium excretion, whereas hypoparathyroidism presents with hypocalcemia.
Measurement of Hormones and Their Metabolites
Measuring hormone levels in blood and urine reflects the functional status of endocrine glands and serves as a key basis for diagnosing endocrine and metabolic diseases. Thyroid function, for instance, can be assessed based on thyroid-stimulating hormone (TSH) and thyroid hormone levels, while 24-hour urinary free cortisol is a primary laboratory marker for diagnosing Cushing’s syndrome. The measurement of hormone metabolites can also indicate hormone levels. For example, blood levels of metanephrine (MN) and normetanephrine (NMN) reflect catecholamine status in the body, while urinary 17-hydroxycorticosteroids and 17-ketosteroids reflect cortisol levels.
Advances in detection technologies, from the first-generation radioimmunoassay (RIA) to the second-generation immunoradiometric assay (IRMA) and third-generation immunochemiluminescence assay (ICMA) and chemiluminescence immunoassay (CLIA), have progressively enhanced testing sensitivity and significantly improved the diagnostic and therapeutic capabilities for endocrine and metabolic diseases.
When analyzing hormone and metabolite test results, several factors should be considered:
- Normal reference ranges for hormones and their metabolites vary by age and sex.
- Hormone secretion follows specific rhythms. This requires specific blood sampling times and corresponding reference ranges. For example, plasma cortisol levels are typically measured at 8:00 AM, 4:00 PM, and midnight to account for circadian rhythms. Similarly, sex hormone levels vary throughout the menstrual cycle and are generally tested on days 2–3 of menstruation.
- Hormone secretion can be pulsatile. To minimize errors, at least two measurements of hormone levels are often required.
- Testing methods differ in specificity and sensitivity, leading to potential variations in results.
- Results should be analyzed in conjunction with upstream and downstream regulatory hormones or metabolites within the endocrine axis.
- Hormone secretion and testing can be affected by factors such as sleep, diet, medication, specific or nonspecific antibodies in the body, and overall health. Comprehensive clinical evaluation should incorporate these variables. For example, stress increases adrenocorticotropic hormone (ACTH), cortisol, and catecholamine concentrations. Excessive biotin intake (commonly found in supplements and treatments for multiple sclerosis) may interfere with the binding of hormones and antibodies, potentially affecting the measurement of thyroid hormones, TSH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and other hormones.
Dynamic Tests of Hormone Secretion
Dynamic tests of hormone secretion, based on feedback regulation mechanisms, help evaluate the functional state of endocrine glands and determine the location of abnormalities. These tests include stimulation tests and suppression tests.
Stimulation Tests
Stimulation tests are employed to assess the hormone reserve of endocrine glands and are often used in cases of suspected endocrine hypofunction. For instance, the ACTH stimulation test evaluates the adrenal cortex's reserve function to produce cortisol, while the insulin-induced hypoglycemia test assesses the anterior pituitary's ability to produce growth hormone (GH).
Suppression Tests
Suppression tests assess whether hormone synthesis and release are deregulated and unaffected by feedback mechanisms and are typically applied in suspected cases of endocrine hyperfunction. For example, the low-dose dexamethasone suppression test evaluates whether cortisol secretion is excessive, and the oral glucose tolerance test determines the autonomy of GH secretion by the pituitary.
Localization Diagnosis
Once hormone secretion abnormalities are identified, localization diagnosis is necessary to determine the site of pathology and distinguish between gland dysfunction and hormone-secreting tumors.
Imaging Examinations
Imaging techniques such as ultrasound, X-rays, CT, MRI, and endoscopic ultrasonography are valuable for locating endocrine system abnormalities. Different imaging modalities are selected based on the specific glands or lesion type. MRI is advantageous in diagnosing pituitary disorders, while ultrasound is more effective for thyroid and parathyroid diseases. For small lesions, thin-slice imaging (less than 3mm) using MRI or CT dynamic contrast enhancement improves lesion detection rates.
Radionuclide Imaging
Radionuclide imaging, such as thyroid scans using 123I, 131I, or 99mTc, evaluates the functional status of thyroid nodules. Parathyroid scans using 99mTc-MIBI identify lesions in primary hyperparathyroidism. PET-CT helps locate primary and metastatic endocrine tumors, especially when specific radioactive tracers are absorbed by endocrine tumor cells. For example:
- 18F-DOPA PET-CT detects pheochromocytomas and paragangliomas.
- 68Ga-Exendin-4 PET-CT identifies insulinomas.
- 68Ga-DOTATATE PET-CT localizes neuroendocrine tumors expressing somatostatin receptors.
- 68Ga-Pentixafor PET-CT aids in the localization diagnosis of primary aldosteronism.
- 18F-Fluorocholine PET-CT is utilized for diagnosing parathyroid hyperplasia or adenomas.
Venous Sampling
Venous catheterization enables blood sampling from the effluent veins of endocrine glands to determine hormone concentrations at specific sites. For instance, adrenal vein sampling (AVS) differentiates unilateral from bilateral lesions in primary aldosteronism, while inferior petrosal sinus sampling (IPSS) identifies whether elevated ACTH levels originate from the pituitary or extrapituitary sources, aiding in the differentiation of Cushing’s disease from ectopic ACTH syndrome.
Etiological Diagnosis
Immunological Testing
The presence of specific autoantibodies in plasma can confirm autoimmune involvement in disease etiology. Examples include glutamic acid decarboxylase antibodies (GADA) for diagnosing type 1 diabetes, TSH receptor antibodies (TRAb) in Graves’ disease, and thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb) in Hashimoto's thyroiditis.
Pathological Examination
Pathological diagnosis often relies on tissue obtained through biopsy. Fine-needle aspiration (FNA) of thyroid nodules, for instance, is commonly used to determine nodule characteristics due to its simplicity and minimal invasiveness. Examination of surgically removed tissues can establish the underlying cause of disease. However, determining whether an endocrine tumor is benign or malignant often requires an evaluation of the tumor’s biological behavior, such as capsular or vascular invasion. Immunohistochemical staining assists in identifying hormone components and determining the cellular origin of tumors.
Chromosomal Analysis
Certain endocrine and metabolic diseases stem from chromosomal abnormalities. For example, Turner syndrome involves the loss of one X chromosome (or mosaicism or structural anomalies of the X chromosome), while Klinefelter syndrome involves an extra X chromosome or mosaic karyotypes.
Molecular Biological Testing
Molecular biological techniques help clarify the causes of specific endocrine tumors, metabolic enzyme deficiencies, and various hormone resistance or hypersensitivity syndromes. For example, maturity-onset diabetes of the young (MODY) often results from mutations in the GCK gene, while CYP21A2 mutations are a common cause of congenital adrenal hyperplasia. Thyroid hormone resistance syndrome is linked to mutations in the thyroid hormone receptor-beta (TRβ) gene, and multiple endocrine neoplasia type 1 (MEN1) is frequently associated with mutations in the MEN1 gene. Whole-exome sequencing effectively identifies pathogenic variants in most hereditary endocrine diseases, while targeted single-gene or susceptibility gene testing is suitable for endocrine diseases with well-defined clinical phenotypes.