After neuronal uptake, cytosolic catecholamines can be either retransported into storage vesicles or deaminated and metabolized through O -methylation by catechol O -methyltransferase or oxidation by the monoamine oxidases. The liver, with the enzyme alcohol dehydrogenase, is required for the complete degradation of catecholamines to vanillylmandelic acid VMA. In the blood stream, catecholamines have a very short half-life of only 1—2 min. The most common tumour, called phaeochromocytoma when located in the adrenal medulla, originates from chromaffin cells and excretes catecholamines.
Those tumours found in extra-adrenal chromaffin cells are sometimes referred to as secreting paragangliomas. Neoplasms may also be of neuronal lineage, such as neuroblastomas and ganglioneuromas. There have also been reports of neoplastic proliferation of sustentacular cells Lau et al. Phaeochromocytoma is a chromaffin cell neoplasm that typically causes symptoms and signs from episodic catecholamine release, including paroxysmal hypertension.
The tumour is an unusual cause of hypertension and accounts for approx. In population-based cancer studies, its frequency is approximately two cases per million of the population. The diagnosis of phaeochromocytoma is typically made in the fourth or fifth decade of life without gender differences, although, in the approx.
The tumours are vascular, although large ones may contain internal hemorrhagic or cystic areas. Other sites include the paravertebral sympathetic ganglia, the urinary bladder, other autonomic ganglia celiac, superior or inferior mesenteric , the thorax including the posterior mediastinum, the heart and paracardiac regions and the neck in sympathetic ganglia, the carotid body, cranial nerves or the glomus jugulare.
Bilateral and extra-adrenal tumours are more common in children. Familial phaeochromocytomas, typically part of syndromes, are more frequently bilateral, although less commonly malignant. A careful family history is essential, and relatives of patients with the familial syndromes, including Von Hippel—Lindau syndrome VHLS , multiple endocrine neoplasms MEN types 2A and 2B and hereditary neurofibromatosis should be screened for phaeochromocytoma Table 1.
Von Hippel—Lindau syndrome is an autosomal-dominant disorder resulting from germline mutations at the VHL tumour suppressor locus on chromosome 3p25—p The features of MEN type 2B include phaeochromocytoma, medullary thyroid carcinoma, multiple mucosal neuromas of the lips, tongue, buccal mucosa, eyelids, conjunctivae, corneas and gastrointestinal tract and a marfanoid body habitus.
RET mutations in MEN type 2A affect one of five Cys residues in the juxtamembrane extracellular domain, probably resulting in intermolecular disulfide formation and consequent constitutive activation of the kinase.
Germline mutations within the genes for the three subunits of the mitochondrial complex III, succinate dehydrogenase SDH , a heterotetrameric complex involved in the Krebs cycle, have been linked to familial phaeochromocytoma and paraganglioma syndrome. Inactivating germline mutations of subunit B SDHB locus on chromosome 1p35—p36 and of subunit D SDHD on chromosome 11q23 are inherited as auto-somal-dominant traits, although with variable penetrance and maternal imprinting Benn et al.
The genetic defect at the succinate dehydrogenase subunit C SDHC has not been linked to adrenal pheochromocytomas, but rather head and neck paraganglioma Schiavi et al. Patients with SDHD mutation are most likely to have head and neck paraganglioma and multifocal tumours, whereas those with the SDHB are most likely to have extra-adrenal abdominal paraganglioma with higher risks of malignancy Havekes et al.
Inter-individual phenotype variation has been observed in that the same germline mutation, for example SDHD Asp92Tyr, has yielded variable clinical phenotypes ranging from subclinical disease to malignant recurrence.
When evaluating subjects presenting with non-syndromic phaeochromocytoma without a family history of disease, Neumann et al.
Despite the occurrence of five germline mutations that lead to phaeochromocytoma, the decision for genetic testing should be based on several factors, including those seen in Figure 1 , such as family history, age, extra-adrenal sites or bilateral phaeochromocytoma. Algorithm for genetic testing in phaeochromocytoma and paraganglioma. Reproduced from Giminez-Roquelo et al. Phaeochromocytoma, new genes and screening strategies.
Clin Endocrinol 65, — For definitions of abbreviations and acronyms, see Table 1. The classical sign of phaeochromocytoma is hypertension, often labile or refractory to treatment. As phaeochromocytoma is a potentially curable form of hypertension, which can be life threatening, a high index of suspicion for the diagnosis is imperative, given a suitable clinical presentation.
Paroxysmal signs and symptoms may vary from many times daily to every week or month. The classical triad of symptoms includes headache, diaphoresis and palpitations or tachycardia. Less common symptoms include anxiety, tremulousness, pain in the chest or abdomen, weakness or weight loss.
Severe constipation or pseudo-obstruction may occur because catecholamines may inhibit peristalsis. Paroxysmal symptoms on micturition or bladder distention, or painless gross haematuria may suggest phaeochromocytoma of the bladder, which requires cystoscopy for diagnosis. Patients older than 60 years with phaeochromocytoma are most likely to report minor or no symptoms.
Presentation may be highly variable and can mimic other diseases. Phaeochromocytomas may occasionally secrete other hormones, such as calcitonin, ACTH, parathyroid hormone or somatostatin, and patients may have symptoms related to their excess. Certain reactions to medications may suggest phaeochromocytoma, such that patients may report an increase in blood pressure after receiving particular antihypertensive drugs, such as beta-adrenergic antagonists, or they may experience a remarkable fall in blood pressure after receiving alphaadrenergic antagonists such as prazosin.
Results of routine screening tests obtained for other purposes may suggest the diagnosis. Hypertriglyceridaemia and hyperglycaemia are common, and although half of the patients manifest glucose intolerance, frank diabetes is unusual. Lactic acidosis occurs rarely, even without shock. Typically, phaeochromocytoma is diagnosed by biochemical evidence of overproduction of catecholamines or their metabolites in plasma or urine samples.
Lenders et al. Creatinine is measured in the same sample as an index of adequacy and completeness of collection. Metanephrines, the metabolites of catecholamines from the enzyme catechol O -methyl-transferase, are released continuously by the tumour as catecholamines are metabolized, which may account for their more favourable diagnostic profile when compared with unmetabolized catecholamines that are released sporadically or at lower rates Figure 2. Metanephrines in phaeochromocytoma.
The detection of free metanephrines in plasma and conjugated metanephrines in urine has the highest sensitivity and specificity for diagnosis of phaeochromocytoma. COMT, catechol O -methyltransferase. Reprinted from Singh with permission from Elsevier. From Lenders et al. Artefactual false-positive assay results have been greatly minimized in recent years with the use of more specific assay methods based on the separation of catecholamines and metabolites by high-pressure liquid chromatography or specific enzymatic incorporation of radiolabels.
Potential sources of false-positive tests may still result from elevated endogenous catecholamine levels because of stress, medication and ingestions, or diet. Stress reactions as a result of nicotine, trauma, hypoglycaemia, cold or anxiety and pain may elevate catecholamines and thus be observed in plasma and urine tests.
Illnesses known to elevate plasma catecholamines include both acute e. A dietary ingestion such as coffee may not only induce release of catecholamines, but also one of its ingredients, caffeic acid, may interfere with some assays for catecholamines. Medications can also induce false-positive results, such as acetaminophen, which may interfere with the assay for metanephrines. Also problematic are ingestions of catecholamines possibly surreptitious , alpha-methyldopa, l -DOPA, labetalol or sympathomimetic amines, which release endogenous catecholamines from their stores and can result in false-positive elevations of catecholamines.
False-positive metanephrine elevations may occur from the use of MAO inhibitors or tricyclic antidepressants. To minimize false-positive results, plasma catecholamines are best sampled from a resting and fasting patient who is lying supine with an indwelling antecubital venous cannula in place for at least 15 minutes.
Factors that diminish plasma catecholamines include drugs clonidine, reserpine and alpha-methylparatyrosine , autonomic neuropathy and congenital deficiency of dopamine beta-hydroxylase activity. Sampling plasma or performing urine biochemical tests during a paroxysmal attack of hypertension is valuable. Because only extreme elevations of plasma noradrenaline perturb blood pressure, the finding of normal plasma catecholamines while blood pressure is elevated argues strongly against phaeochromocytoma as the cause.
Chromogranin A is not substantially elevated by acute venipuncture, nor is it affected by drugs used in the treatment or diagnosis of phaeochromocytoma Hsiao et al. Chromogranin A is released by a variety of neuroendocrine secretory vesicles, and therefore plasma concentration may be elevated in other cases of neuroendocrine neoplasia Taupenot et al.
Chromogranin A immunoreactive fragments are retained in patients with renal insufficiency, leading to potential false-positive results Hsiao et al. Measurement of chromogranin A is also useful in cases of suspected factitious or feigned phaeochromocytoma Kailasam et al.
Pharmacological tests for phaeochromocytoma are generally not necessary because the diagnosis can usually be confirmed by urine and plasma biochemical measurements at rest or during spontaneous blood pressure surges. The clonidine suppression test can be performed if the biochemical tests in a patient with highly suspected phaeochromocytoma are equivocal.
Because phaeochromocytoma chromaffin cells, unlike normal adrenal medullary chromaffin cells, are not innervated, catecholamine release from phaeochromocytoma cells is autonomous and not susceptible to manipulation by drugs that decrease efferent sympathetic outflow, such as the central alphaagonist clonidine Bravo et al. Blood is obtained for plasma catecholamines before and 3 hours after a single oral dose of 0.
A positive test failure of catecholamines to decline after clonidine is sensitive but may not be entirely specific for phaeochromocytoma. Beta-blockers should be discontinued 48 hours before the test as they may diminish circulating noradrenaline clearance. Tumour localization should occur only after compelling evidence of catecholamine excess Pacok et al. The location is crucial to plan the proper surgical route. Ninety-five per cent of phaeochromocytomas are in the abdomen, and the majority of these can be visualized by one of three modalities: computed tomography CT , magnetic resonance imaging MRI or [ I]-meta-iod-obenzylguanidine MIBG scintigraphy.
Ultrasound may also be utilized in cases where radiation must be minimized, such as in pregnancy, infants and children, but is not optimal for adult patients. Computed tomography and MRI are highly sensitive, although they are non-specific because they visualize any mass lesion. MRI may be more effective in differentiating adrenal adenoma from phaeochromocytoma.
MIBG is transported into chromaffin cells by the reuptake cell membrane catecholamine carrier and accumulates in chromaffin cells to confirm tumour tissue that has been localized via CT scan or MRI. It is especially useful for metastatic, recurrent or extra-adrenal tumours. Positron emission tomography PET using 6-[ 18 F]-fluorodopamine, [ 18 F]-fluorodeoxyglucose, [ 18 F]-dihydroxyphenylalanine, [ 11 C]-hydroxyephedrine or [ 11 C]-adrenaline have been evaluated as improved localization techniques for undetectable phaeochromocytoma or metastases, but are not yet widely available Ilias et al.
The differential diagnosis is broad, and includes any medication or disease state that results in elevated catecholamine levels. Medications, especially surreptitious use of adrenaline or isoproterenol, can emulate catecholamine excess. Also withdrawal of clonidine abruptly or ingestion of tyramine-rich foods while taking a monoamine oxidase inhibitor can result in catecholamine surges. Disease states causing or simulating catecholamine excess and hypertension include thyrotoxicosis, acute intracranial disturbances, such as subarachnoid haemorrhage or posterior fossa masses, and hypoglycaemia, especially in the presence of beta-blockade.
Damage to carotid sinus baroreceptors by surgery or tumour may result in baroreflex failure and result in episodic blood pressure and plasma catecholamine surges Ketch et al. Some patients with symptomatic blood pressure surges have underlying unrecognized emotional trauma. Although circulating catecholamine excess is the ultimate cause of hypertension in patients with phaeochromocytoma, the correlation of blood pressure with plasma catecholamines is modest.
Keller will go over the adrenals and what they do, some common adrenal issues, and whether they actually do get worn out and cause adrenal fatigue. The adrenals are little glands that sit right on the tops of your kidneys. In fact, that's where their name comes from: Ad , which means, on or to, and renal , or kidneys. One of the most important hormones produced by the adrenals is adrenaline which gets its name from the adrenals.
You may also know this hormone as epinephrine. Adrenaline and epinephrine are the same thing; they just have names derived from Latin and Greek origins, respectively.
When the adrenals are working well, we feel great, but they are such an important gland to our bodily function that if they're not working, it has serious repercussions.
They're very important. This might get a little technical, but stick around; understanding how your body works can really make you feel empowered to address issues that may arise. This is the outer layer, and it produces a bunch of things called steroids. The full name of these are corticosteroids — they derive their name from the cortex.
The cortex, and the steroids it produces, are further divided into three important layers:. After the cortex layer, the adrenal gland has another area called the medulla. This is the marrow, or the inner part. These are hormones like epinephrine and norepinephrine or adrenaline. That means it's not hyperactive, and causing us to be stressed out all the time, but is ready for an appropriate response if we sense danger. That's a lot of things that the adrenals do.
The whole body can be affected when our adrenals aren't working. When our adrenals aren't working well, some pretty bad things can happen. There are many diseases of the adrenal glands that have been studied, and which can be treated and cured.
When our adrenals are making too much cortisol, that's the disease often referred to as Cushing's Syndrome or Cushing's Disease, depending on the origin of the problem. When that happens, cortisol is going through the roof, which, as we said, affects blood sugar, and can cause weight gain and lead to issues like diabetes.
It can also lead to other problems, like osteoporosis. That's usually caused by some kind of tumor, either of the adrenal gland itself or the pituitary, which is a part of the brain that influences the adrenal. If our cortisol levels were too low , it could be a condition called Addison's disease.
You can actually go into something called hypovolemic shock , meaning you don't have enough fluid in your body to really maintain yourself. This can also result in hyperpigmentation of the skin. So, if you're someone who has a tan even though you never go in the sun, you might want to think about this particular condition, which is often caused by an autoimmune disease that's attacking the adrenal glands. This is a condition where your body didn't make a certain enzyme because of a genetic mutation, which means that the adrenals just get out of whack; certain systems are working in overdrive and certain aren't working at all.
And it just creates a big mess. It can create problems with all the different areas of the body that we talked about, that are influenced by the adrenals. You can get tumors of the adrenal glands themselves, or the pituitary, which again is the part of the brain that affects the adrenal glands.
They can be classified into disorders that occur when too much hormone is produced or when too little hormone is produced. These disorders can occur if there is a problem with the adrenal gland itself, such as a disease, genetic mutation, tumor, or infection.
Or, sometimes the disorder results from a problem in another gland, such as the pituitary, which helps to regulate the adrenal gland. In addition, some medications can cause problems with how the adrenal glands function.
When the adrenal glands produce too little or too many hormones, or when too many hormones come into the body from an outside source, serious health problems can develop. Overall, adrenal gland disorders are generally rare.
The number of people affected and at risk depends on the specific type of adrenal gland disorder.
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