Laboratory investigations, both basal and dynamic, include assays of free catecholamines and their metabolites in plasma and 24-hour urine.

Basal Measurements

 Plasma and urinary catecholamines, metanephrines, and vanillyl mandelic acid

Catecholamines have a short half-life; therefore, their determination, both plasma, and urinary, makes it difficult to discriminate between a pathologic overproduction and a peak secretion during sampling. Furthermore, their secretion is intermittent and independent of tumor size.

Metanephrines (metanephrine and normetanephrine) within the tumor are consistently produced through a process independent of catecholamine release. Furthermore, they have a longer half-life in circulation than catecholamines. Therefore, the metanephrine assay has a higher sensitivity and specificity than the catecholamine assay. Plasma and urinary concentrations of metanephrines correlate with tumor size and activity. Since some tumors produce only one type of catecholamine, it is preferable to measure metanephrines and normetanephrine separately; in this case, we speak of fractionated metanephrines. Finally, increased adrenaline or metanephrine indicates the adrenal gland origin, being the exclusive site of adrenaline production and contributing 90% to circulating metanephrine and only 35% to circulating normetanephrine.

Since some drugs, psychological stress, intense exercise, high protein meals, and some foods rich in catecholamines (banana, coffee, citrus fruits, cocoa, nuts, vanilla, pineapple) may alter the levels of catecholamines and their metabolites, blood sampling should be performed in the morning, after overnight fasting (8–12 hours) and in clinostat, to minimize the effect of the sympathetic nervous system. Similarly, for the determination of catecholamines and their metabolites in 24-hour urine, certain foods (see above) and drugs that might interfere should be avoided in the 48 hours before and during sample collection; in addition, emotional and physical stresses and strenuous exercise should be minimized before and during collection. Urinary catecholamines are unstable; therefore, collected urine should be stored in acid and away from light. On the other hand, urinary metanephrines are stable at room temperature for up to 3 days or longer if stored at 4 °C, without the need to add acid. Creatinine should always be assessed for adequacy in the 24-hour urine collection. Both plasma and urinary assays of catecholamines and metanephrines are performed by high-pressure chromatography (HPLC).

Vanil mandelic acid, the end-product of catecholamine (adrenaline and noradrenaline) metabolism, similarly to cat echolamines, is measured on a 24-hour urine sample, after diet, abstention from strenuous exercise and stress in the 48 hours preceding collection; an acid, such as hydrochloric or muriatic acid, must be added to the container.

Chromogranin A

 Chromogranin A is a glycoprotein secreted by medullary cells of the adrenal medulla and sympathetic nervous system. The measurement is performed by the immunoradiometric method (IRMA). In the case of pheochromocytoma, although its levels correlate with the tumor mass, plasma chromogranin A has a modest sensitivity, and, therefore, its use in clinical practice is limited. High levels of chromogranin A are also found in medullary thyroid carcinoma, small cell lung carcinoma, and epithelial carcinomas with neuroendocrine differentiation (prostate, breast, ovary, pancreas, colon).

Dynamic Investigations

Refer to Table 1 for the clonidine suppression test.

Table1. Clonidine suppression test

Diagnosis and Therapy

Patients with clinical signs and symptoms or at high risk of developing a pheochromocytoma/paraganglioma (Table 2) should undergo laboratory investigations to demonstrate excessive catecholamine production (Fig. 1).

Table2. Patients to be screened for pheochromocytoma/ paraganglioma

Fig1. Diagnostic algorithm for pheochromocytoma/ paraganglioma. (Copyright EDISES 2021. Reproduced with permission)

Since catecholamines are metabolized within chromaffin cells to metanephrines (an intratumoral process that occurs independently of catecholamine release), the measurement of free plasma metanephrines is the test of choice to confirm the diagnosis of pheochromocytoma, with the highest sensitivity and specificity (99% and 89% respectively). Alternatively, fractionated urine metanephrines can be measured, but they have a slightly lower sensitivity and specificity (97% and 67%, respectively). The sensitivity and specificity of the plasma and urinary catecholamine assay are 84% and 81%, 86%, and 88%, respectively. The urinary vanyl mandelic acid assay has a very low sensitivity (68%), although the specificity is high (95%); the low sensitivity of this test makes it less useful in clinical practice.

Normal values of free plasma metanephrines exclude the presence of a pheochromocytoma. In contrast, a 4-fold increase in free plasma metanephrines above the reference limit indicates an almost 100% probability of tumor. In cases where plasma/urinary free metanephrines are only slightly increased (<3- 4 times the reference limit), the assay should be repeated after discontinuing interfering drugs; persistently elevated values suggest the presence of tumor, whereas normal values make it less likely. The clonidine suppression test that does not suppress elevated plasma levels of normetanephrine after 3 hours of administration has high sensitivity and specificity (100 and 96%, respectively) for tumor diagnosis in doubtful cases.

Tumors secreting only dopamine are rare, and, therefore, plasma dopamine and its metabolite 3-methoxytyramine are not routinely evaluated in most laboratories when pheochromocytoma/paraganglioma is suspected. However, these tests may be helpful in some cases, especially in metastatic disease where the metastatic tissue lacks the enzymes necessary for catecholamine synthesis. High levels of 3- methoxytyramine are a very sensitive marker of malignancy.

Once the diagnosis is made, radiologic evaluation allows localization of the tumor by anatomic imaging followed by functional imaging of the tumor tissue to distinguish between pheochromocytomas, paragangliomas, and other lesions. CT and MRI are recommended for initial anatomic tumor localization; both have high sensitivity (90–100%) but limited specificity (70–80%) due to the high prevalence of adrenal masses not associated with pheochromocytoma in the general population. MRI cannot expose the patient to radiation and, therefore, can be performed in children and pregnant women. Adrenal scintigraphy with iodine 123-labeled metaiodiobenzyl-guanidine (123I-MIBG) allows differential diagnosis between pheochromocytoma and paraganglioma because 123I-MIBG is concentrated in the chromaffin tumor tissue. Furthermore, scintigraphy can reveal the possible presence of multiple tumors and metastases. Scintigraphy has a high specificity (95–100%), especially in the case of malignant tumors and familial forms, but a limited sensitivity (85%), especially in the detection of metastases. Therefore, other investigations are recommended in cases where metastases are suspected, such as octreoscan with 111in- octreotide, since some tumors express somatostatin receptors, or positron emission tomography with 18F-dihydroxyphenylalanine (18F-DOPA), which appears to be superior to scintigraphy in detecting metastatic lesions.

Finally, genetic investigations aimed at identifying the mutated gene are indispensable for diagnosing hereditary forms of pheochromocytoma/paraganglioma and should be performed in all patients with the disease. At least one-third of patients have germline mutations responsible for the disease.

Since 1990, 14 different susceptibility genes have been identified. Among these, the primary are NF1 gene associated with neurofibromatosis type 1 (NF-1), RET gene associated with multiple endocrine neoplasia type 2 (MEN2), VHL gene responsible for von Hippel-Lindau syndrome (VHL), and the genes encoding the B, C, and D subunits of mitochondrial succinodehydrogenase (SDH), associated with pheochromocytoma/paraganglioma syndromes named PGL4, PGL3 and PGL1, respectively; SHDB mutations lead to the development of metastases in more than 40% of individuals with pheochromocytoma/ paraganglioma.

In addition to family history, features suggestive of a hereditary form of the disease are young age, bilateral or recurrent pheochromocytomas, bilateral or multiple head/ neck paragangliomas, or association between pheochromocytomas/paragangliomas and other malignancies. Since patients with pheochromocytoma or paraganglioma have a high prevalence of hereditary syndromes (MEN2, NF-1, and VHL), it is helpful to search for germline mutations even in patients without a known family history. Once an inherited syndrome is identified, genetic screening can be extended to family members.

The therapy of the first choice for pheochromocytomas is surgical excision.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الفكرية يصدر كتاب (دروس تمهيدية في الفقه – العبادات)

قسم الشؤون الطبية يشرع بتقديم لقاح الانفلونزا للمنتسبين

المجمع العلمي يختتم مسابقة العميد لحفظ القرآن الكريم في بغداد

لجنة البرامج المركزية تختتم فعاليات البرنامج المركزي الأسبوعي لمنتسبي العتبة العباسية المقدسة

المزيد

الآخبار الصحية

عناصر منزلية قد تؤثر على الخصوبة وفرص الحمل

شكل الدماغ قد يتنبأ بخطر الخرف قبل سنوات

طريقة صينية بسيطة للوقاية من السكري

هل تساعد المانغو في الوقاية من السكري؟

المزيد

الآخبار التكنلوجية

رقم غامض ولا إنترنت.. متوجون بنوبل للطب لم يعلموا بفوزهم

"سيري" تحت المجهر.. تحقيق فرنسي جديد ضد شركة "آبل"

أميركيان وياباني يفوزون بجائزة نوبل للطب

تحول غير مسبوق.. إنستغرام تمنح مفاتيحها للمستخدمين

المزيد

مواضيع ذات صلة

white blood cell scan (WBC scan, Inflammatory scan)

white blood cell count and differential count (WBC and differential, Leukocyte count)

vitamin D (25-hydroxy vitamin D2 and D3 ; 1,25-dihydroxyvitamin D [1,25(OH)2 D])

Basal Hormone Measurements of Testis

vitamin B12 (Cyanocobalamin and methylmalonic acid [MMA])

virus testing

viral cultures

varicella virus testing (Antibody testing for Varicella zoster virus, Varicella zoster virus [VZV], Herpes virus-3)

uroporphyrinogen-1-synthase

urine culture and sensitivity (C&S)

uric acid, blood, and urine

urea breath test (UBT, Helicobacter pylori breath test)