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Published in final edited form as: Endocr Pract. 2017 June ; 23(6): 672-679. doi:10.4158/EP161716.RA.
PRECISION MEDICINE IN ADRENAL DISORDERS: THE NEXT GENERATION
Hans K. Ghayee, DO1, Aaron I. Vinik, MD, PHD, FCP, MACP, FACE2, Karel Pacak, MD, PHD, DSc, FACE3 AACE Adrenal Scientific Committee
1Department of Medicine, Division of Endocrinology, University of Florida and Malcom Randall VA Medical Center, Gainesville, Florida 2Center for Endocrine & Metabolic, Eastern Virginia Medical School, Norfolk, Virginia 3Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
Abstract
Objective: Discuss exciting new research in the area of adrenal disorders that has emerged in the last few years. Advances in genetics, biochemical diagnosis, and imaging modalities that have set new standards for diagnosis and treatment are described.
Methods: A literature review was conducted on adrenal disorders using PubMed.
Results: We highlight new developments in adrenal diseases from new genes discovered in aldosterone-producing adenomas, cortisol-producing tumors to pheochromocytomas/ paragangliomas. In addition, we discuss new information regarding the question of whether nonfunctional adrenal adenomas are really functional or not. In congenital adrenal hyperplasia, emerging steroids that might be helpful in the near future for diagnostic purposes are discussed. New types of imaging are now available to identify endocrine neoplasms to help clinicians find lesions after biochemical conrirmation.
Conclusion: The tremendous knowledge gained thus far in adrenal diseases sets the stage for not only new precision treatment modalities for individualized care but also for prevention.
INTRODUCTION
Functional or malignant adrenal tumors frequently require attention, as patients often develop diabetes and hypertension and experience cardiovascular events. Surgery remains
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Address correspondence to Dr. Hans K. Ghayee, Chief, Endocrinology & Metabolism, Malcom Randall VA Medical Center, Director of Endocrine Neoplasia, University of Florida, 1600 SW Archer Road, Suite H-2, Gainesville, FL 32608,
hans.ghayee@medicine.ufl.edu; Dr. Karel Pacak, Chief, Section on Medical Neuroendocrinology, Professor of Medicine, Eunice Kennedy Shriver NICHD, NIH, Building 10, CRC, 1E-3140, 10 Center Drive, MSC-1109, Bethesda, MD 20892-1109. karel@mail.nih.gov.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
the primary source of treatment, as medical intervention is limited. The previous chapters on adrenal neoplasias, disorders, and precision medicine took advantage of advanced molecular biology techniques, which led to the discovery of important genetic mutations and associated syndromes along with improved radiographic modalities (1). Medical teams took important strides towards personalized medicine when previously identified patients with a genetic mutation were screened for associated tumors and underwent expedited treatment, ultimately saving lives. Furthermore, these discoveries expanded the field of genetic counseling. Asymptomatic family members, including children of index patients, are now diagnosed with adrenal tumor neoplasias or enzyme deficiencies such as congenital adrenal hyperplasia (CAH) much earlier in their lives. Despite these recent developments, surgery and steroid administration continue to remain as central treatment modalities for patients with adrenal neoplasias and disorders. Nevertheless, precision medicine is evolving forward, creating new inroads in genomics as well as in disease risk and prevention for an individual (2). In the following review, we discuss new advances in genetics, biochemical diagnosis, and imaging that are ushering in a new chapter for precision medicine in adrenal diseases, which have the potential to redefine precision medicine for disease prevention.
GENETICS
For years, pediatricians were primarily diagnosing the generic cases of aldosterone excess associated with glucocorticoid-remediable aldosteronism (GRA) (3) (Fig. 1). Decades later, the same lead investigator for the GRA discovery, Dr. Richard Lifton, was involved in the identification of the KCNJ5 mutation in the zona glomerulosa, which was initially described in adults. For over 50 years, we knew little about the somatic mutations driving aldosterone production in aldosterone-producing adenomas (APAs) until the observation of a mutation in the inwardly rectifying potassium channel called KCNJ5, which comprises over 35% of APAs (4). Since the discovery of this mutation, newer associations with the KCNJ5 mutation are being made with other tumor types. Specifically, a report describing APA with KCNJ5 mutation and familial adenomatous polyposis was described (5). Besides the KCNJ5 mutation, other somatic mutations affecting the Na+/K+ ATPase 1 (ATP1A1), Ca2+-ATPase 3 (ATP2B3), and L-type voltage-gated calcium channel (CACNA1D) were discovered, which comprise the other 15% of somatic APA mutations (6,7). Altogether, over 50% of APAs are associated with specific channel mutations. The cellular origins of APA were questioned following the discovery of these new channel mutations. Rainey and colleagues (8) uncovered clues when they found that normal adrenal cortical tissue contained somatic mutations in ATP1A1, ATP2B3, and CACNA 1D in aldosterone-producing cell clusters (APCCs). Up to 35% of these clusters revealed somatic mutations in ATP1A1 and CACNA1D, which raises the question of whether APCCs could be the precursor to hyperaldosteronism (8) (Fig. 1). Germline mutations in KCNJ5 have shown that affected patients have bilateral adrenal hyperplasia and resistant hyperaldosteronism, which not only affect adults but children as well (9). CACNA1Dhas also been associated with germline mutations where patients not only have hyperaldosteronism but also seizures and neurologic problems (10). Therefore, new opportunities exist to target pathways that may affect aberrant activity of aldosterone production and adrenal hyperplasia. In the coming years, investigators will gain understanding of how to better utilize these genetic advances in
hyperaldosteronism in order to treat a patient effectively with accurate genotype-phenotype correlations.
In terms of hypercortisolism specifically related to bilateral macronodular adrenal hyperplasia and Cushing syndrome, the discovery of armadillo repeat-containing 5 (ARMC5) in tissue samples has taught endocrinologists much about how these tumors function (11). It is believed that ARMC5 functions as a tumor-suppressor gene. In the studied nodules, a gennline ARMC5 and a second specific somatic mutation were identified. Related to this study on bilateral macronodular adrenal hyperplasia, another group described the expression of proopiomelanocortin in bilateral macronodular adrenal hyperplasia tissues (12). From the resected nodules, perfusion studies showed pulsatile corticotropin and cortisol secretion. In vitro studies showed that cortisol production is controlled by corticotropin produced within the adrenocortical tissue and by aberrant G-protein-coupled receptors (12). From a precision medicine point of view, inhibiting adrenal corticotropin receptors might be helpful to some patients afflicted with Cushing syndrome from bilateral macronodular hyperplasia, and as such, the terminology “corticotropin-independent macronodular adrenal hyperplasia” could be considered outdated (13). A list of other important genetic mutations associated with bilateral adrenal disease causing excess in cortisol production is provided in Table 1.
To further define the role of precision medicine, The Cancer Genome Atlas (TCGA) program devoted a tremendous amount of resources to fully characterize the genomic landscape of adrenocortical carcinoma (ACC). Study results identified new driver mutations associated with the Wnt signaling and retinoblastoma pathways (14). Additionally, the authors discovered that in aggressive ACC, there is increased whole-genome doubling consistent with increased telomerase reverse transcriptase expression along with cell cycle progression (14). A subset of tumors were found to have specific methylation signatures that could help identify patients that would be better candidates for a certain types of combination chemotherapy (14).
TCGA not only devoted resources to ACC but also invested efforts to study pheochromocytomas/paragangliomas (PCCs/PGLs). Recent discoveries, including the TCGA data, point to around 20 important genes associated with PCC/PGL (15,16), more than any other endocrine tumor. Like with ACC, PCC/PGL investigators have found increased methylation signatures. Such PCC/PGL tumors have a succinate dehydrogenase subunit B (SDHB) mutation, thereby affecting types of treatment options inpatients presenting with metastases (17). Additional genes that also affect the function of the Krebs cycle have been identified and include fumarate hydratase (FH) and malate dehydrogenase 2 (MDH2) (18,19) (Fig. 1). Not only are FH and MDH2 similar in their link to the Krebs cycle, but they are also associated with a hypermethylation phenotype like SDHx-related tumors (18,19). SDHx, FH, MDH2, and von Hippel-Lindau mutations share a common pathway: the pseudohypoxia pathway with a noradrenergic phenotype (Fig. 1). The other groups of genes, including transmembrane 127 (TMEM127), ret proto-oncogene (RET), and neurofibromatosis type 1 (NF1), associated with PCC/PGL have been linked to the kinase- signaling pathway (20). Patients harboring these mutations tend to have PCCs and mainly produce epinephrine. MYC-associated factor X (MAX) gene mutation tumors can have a
mixed adrenergic and noradrenergic phenotype (21). Like the SDHB gene mutation, MAX mutations are associated with higher malignant potential (22). In addition, the TCGA dataset revealed that a Wnt-altered pathway mutation driven by the master-mind-like transcriptional coactivator 3 (MAML3) fusion gene and transcriptional regulator ATRX (ATRX) somatic mutations is linked with poor clinical outcomes (16). Like ACC, aggressive PCC has been linked to telomerase activity, as demonstrated by the discovery of the somatic ATRX gene mutation (23). In the last few years, a new syndrome associated with multiple PGLs, somatostatinomas, and polycythemia, called the Pacak-Zhuang syndrome, was described (24). In this syndrome, there is an activating mutation of hypoxia-inducible factor 2 (HIF2A, also called EPAS1). This finding is not only clinically important but also provides potential therapeutic opportunities for new treatment targets.
BIOCHEMICAL DIAGNOSIS
The genetics of CAH are well known, with 21-hydroxylase (CYP21A2) deficiency comprising up to 95% of cases (25), and other enzyme deficiencies, including HSD3B2, CYP11B1, and CYP17A1 contributing to the remaining 5%. However, the revelation of the “backdoor pathway” provided a major advancement towards the basic understanding of the biochemical pathways that operate in CAH (26) (Fig. 1). In essence, the accumulated product of 17-hydroxyprogesterone is efficiently converted through 5a-pregnandiol to androsterone in the adrenal and later converted to dihydrotestosterone in peripheral tissues, without the intermediacy of testosterone. Traditionally, elevated 17-hydroxyprogesterone has been utilized in diagnosing CAH associated with 21-hydroxylase deficiency. However, this has been fraught with false-positive and -negative results because the test may not be accurate in distinguishing between the nonclassical and classical forms of 21-hydroxylase deficiency. This issue can be especially critical for all populations, from newborns and young children to adults. For that reason, a detailed analysis of 21-carbon steroids from the serum of CAH patients (19 to 59 years of age) with 21-hydroyxlase deficiency was undertaken by liquid chromatography/tandem mass spectroscopy (LC-MS/MS) (27). The results showed that 16a-hydroxyprogesterone, 11ß-hydroxyprogesterone, 21-deoxycortisol, and 17-hydroxyprogesterone are important in accurately finding all forms of 21-hydroxylase deficiency (27). Further investigation evaluating patients with 21-hydroxylase deficiency has revealed that the 11-oxyandrogens (11ß-hydroxyandrostenedione, 11-ketoandrostenedione, 11ß-hydroxytestosterone, and 11-ketotestosterone) were 3- to 4-fold elevated compared with controls (28). This work suggests that 11-oxyandrogens are specific biomarkers of adrenal- derived androgen excess in classic 21-hydroxylase CAH (28). Larger studies are underway to confirm these interesting findings. Diagnosing the specific forms and subtypes of CAH is the key to better management of these clinically challenging cases.
The vast majority of adrenal tumors are nonfunctional. As a result, diagnosis is often difficult, unless discovered incidentally. For patients harboring an ACC, this is vital, as the tumor may not manifest with any physical exam abnormalities. Under current biochemical guidelines, many incidental ACCs that do not cause any physical exam findings found at an early stage are dismissed as nonfunctional tumors, unless the clinician continues to monitor the patient. To alter the paradigm of how endocrinologists view nonfunctional tumors, investigators have turned to mass spectroscopy to analyze early steroid precursors to
determine the difference between benign and malignant adrenal masses (29). Promising results identified early stage precursors such as tetrahydro-11-deoxycortisol, which is able to distinguish between noncancerous and cancerous lesions (29); however, more studies are needed to confirm tins finding. In examining steroid profiling by LC-MS/MS between nonsecreting and subclinical cortisol-secreting (SCS) adrenocortical adenomas, researchers found patients with SCS had lower basal and adrenocorticotropic hormone (ACTH)- stimulated levels of dehydroepiandrosterone and androstenedione than those with nonsecreting adenomas. In addition, SCS patients also showed increased production of 21- deoxycortisol and 11-deoxycorticosterone after ACTH stimulation (30). Delving further into the functionality of adrenal tumors, a recent population-based study called into question whether benign nonfunctional adrenal adenomas are secreting hormones, as many of these patients were found to have diabetes (31). Related to this issue is the understanding that the Wnt signaling pathway is known to play a key role for normal adrenal cortical development (32). Thus, it is not surprising that somatic mutations associated with Wnt signaling have been discovered in adrenal cortical adenomas and carcinomas such as catenin beta 1 (CTNNB1) (33). However, adrenal adenomas that were found to have CTNNB1 were considered nonfunctional until Teo et al (34) described 3 patients with hyperaldosteronism along with a CTNNB1 mutation. Since 2 patients were pregnant and the other was postmenopausal, this report raised the question, if the nonfunctional tumors with CTNNB1 are exposed to the right stimulus, do they become functional? When APAs of all 3 patients were analyzed, all 3 tumors expressed high levels of gonadal receptors luteinizing hormone- chorionic gonadotropin receptor and gonadotropin-releasing hormone receptor (34). Hence, elevated gonadotropins and human chorionic gonadotropin may have led to the activation of aldosterone synthesis in the initially nonfunctioning adrenal tumors (34). Perhaps what we currently consider to be nonfunctional adrenal adenomas just need the right stimulus for hormone production, in addition to detection of hormones that are not currently being tested for.
Besides evaluating new steroids in patients with adrenal disorders, utilizing receptors that are the end targets from hormone excess may be the upcoming wave of the future in evaluating patients with primary hyperaldosteronism. More specifically, mineralocorticoid (MR) overactivation can possibly be assessed. With the demonstration of MR-induced proteins such as the subunits of the epithelial sodium channel (ENaC) in urine samples, an understanding of the degree of aldosterone excess can possibly be deduced in the future (35).
PCC/PGL precision medicine underwent a tremendous transformation with the introduction and implementation of plasma metanephrine biochemical testing to diagnose these tumors (36). Utilizing the stable breakdown product of epinephrine to metanephrine and norepinephrine to normetanephrine by catechol-O-methyltransferase (COMT), clinicians were able to identify patients with PCC/PGL with 95% sensitivity (37). Furthermore, scientists discovered that many PGLs do not produce epinephrine or norepinephrine and may only make dopamine. In further expansion of catecholamine breakdown products, Eisenhofer and colleagues (38) determined that the breakdown product of dopamine via COMT is 3-methoxytramine, which can be used as an important biomarker for aggressive PGLs. What were previously described as nonfunctional PGLs can now be identified and
treated, or closely followed, due to the precise identification of their biochemical phenotype. Ongoing investigations in PCC/PGL research are also examining Krebs cycle metabolites. Recent studies examined the metabolic perturbations characteristic of tissues harboring SDHB mutations (39-41). These and other studies showed that diminished SDHx activity made cells addicted to extracellular pyruvate, which sustains cellular bioenergetic features. Pyruvate carboxylation diverts glucose-derived 3-carbons into aspartate biosynthesis and supports cell proliferation (42,43).
IMAGING
In the last 3 decades, imaging has enhanced our ability to characterize adrenal tumors by measuring Hounsheld units, contrast medium wash out, and derilling imaging qualities that differentiate benign versus malignant lesions on computed tomography (CT). Nuclear imaging techniques have also improved with positron emission tomography (PET)/CT scans. ACCs show high 18F-fluorodeoxyglucose (FDG) uptake (44), which indicates that the tumor is metabolically active and likely to be cancerous. Taking advantage of recently gained metabolomics knowledge, the next phase of precision imaging involves designing new radiotracers for a more accurate diagnosis. New research in hyperaldosteronism indicates that the tracer metomidate ([11C]-MTO) can be useful in identifying a unilateral aldosterone- producing adenoma, as it binds to CYP11B1 and CYP11B2 enzymes in the steroidogenic pathway (45). Another possible application for metomidate in precision medicine is in the detection of ACCs (46).
PCC/PGL tumors with metastatic potential, such as those with the SDHB mutation, utilize aerobic glycolysis and are therefore likely to express more glucose transporters, hence the success of 18F-FDG uptake in aggressive PCC/PGL tumors (47). However, since PCCs/ PGLs express somatostatin receptors, the utility of radiolabeled compounds such as 68Ga bound to a chelating agent such as [68Ga]-DOTA(0)-Tyr(3)-octreotate (DOTATATE) or other somatostatin analogues has gained momentum as the new standard of imaging in neuroendocrine tumors (48,49). This not only allows for accurate imaging but also for targeted treatment for those patients that express specific types of somatostatin receptors (50). As a proof-of-concept study, 20 patients with head and neck PGLs underwent [68Ga] DOTATATE PET/CT, [18F]-FDOPA PET/CT, [18F]-FDG PET/CT, and CT/magnetic resonance imaging (MRI). Interestingly, [18F]-FDOPA PET/CT identified 37 of 38 lesions in the 20 patients, and CT/MRI identified 22 of 38 lesions (P <. 01). All 38 lesions and 7 extra lesions (likely representing head and neck PGL manifestations) (P= . 016) were detected on [68Ga]-DOTATATE PET/CT. Far fewer tumors were identified by [18F]-FDG (51). With the continued advancement of precision imaging and identification of novel biomarkers, diagnostic abilities will steadily expand until eventually, imaging is indeed tumor specific. Tins will lead to individualized treatment and follow-up plans and even the ability to determine which patients responded to therapy and may no longer require intervention.
PREVENTION
Understanding the subtype of adrenal disorder and creating a unique treatment plan will become the next paradigm of precision medicine in adrenal disorders. With the above-
Endocr Pract. Author manuscript; available in PMC 2020 August 28.
described advances, endocrinologists will have the ability to test for more steroids than ever before in order to precisely manage a CAH patient without inducing the metabolic syndrome by steroid over replacement, especially in children transitioning into adulthood. Physicians will have better tools to test for hypertension due to aldosterone excess, perhaps by urinary ENaC proteins or evaluating for evidence of secretion of steroid precursors, which can also lead to the development of impaired glucose tolerance. Finally, they will have the ability to measure various Krebs cycle and other metabolites that are particularly associated with aggressive behavior in PCC/PGL. Advancements in metabolomics and genomics are not the only areas under development. Transcriptomics are currently emerging (52) and will provide a precision approach to diagnostic and treatment options. In essence, clinicians will be able to measure a new “Adrenal Chem Panel” to prevent complications in patients, which could also produce behavioral changes in patients. With the Adrenal Chem Panel, clinicians will not only assess the usual steroid products such as cortisol, aldosterone, and metanephrines, but they will also be able to assess steroid precursors such as 16a-hydroxyprogesterone, 11ß-hydroxyprogesterone, or MR receptor overactivation, whether in the brain or kidney. Levels of many other metabolites, such as succinate, fumarate, citrate, isocitrate, and glutamate, will provide further insight into the patient’s tumor pathway predilection, providing precise decisions for diagnosis and treatment. As an example, more accurate diagnosis of CAH will allow a patient to undergo improved family planning. Those at risk for hyperaldosteronism due to APCCs will be aggressively counseled on diet/lifestyle modification in addition to earlier mineralocorticoid antagonist treatment. Patients with HIF2A or SDHx mutations will be encouraged from an earlier age to forego tobacco use, which can worsen hypoxia, or relocate to lower altitudes to reduce hypoxia and therefore the chance of PCC/PGL development. Diet may be considered another key factor that would affect energy metabolism and change the course of tumor development.
The genetic revolution as seen in the held of hyperaldosteronism, macronodular adrenal hyperplasia, ACC, and PCC/PGL has created opportunities beyond early diagnosis and syndromic discovery. This era of genetic revolution can translate into important opportunities in individualized pharmacotherapy. Patients with hyperaldosteronism with a certain “chamielopathy” mutation can be treated with specific inhibitors that can target specific channels that cause constant zona glomemlosa cell depolarization. This is important as a preventative medicine measure so the patient does not suffer the effects of prolonged hypertension leading to cardiovascular events. Another important example of individualized phannacotherapy is when a patient is found to have a specific pathway defect, such as in Wnt signaling; whether it is ACC or adrenal adenomas, the expansion of analysis of ectopic receptors creates opportunities for individualized drug targets. In PCC/PGL, metabolites produced as a result of an aberrant Krebs cycle will create new waves of drugs that can be given to patients earlier to possibly correct an “error in metabolism and energy production” to prevent tumor formation.
The next generation of genomic discovery has brought attention to exciting new molecular research and clinical observations. Novel diagnostic and treatment approaches for adrenal disorders could bring about the most invigorating time in our profession’s history-a phenomenon directly tied to precision medicine.
CONCLUSION
In this review, a number of important advances have been described from genetics, biochemical diagnosis, imaging modalities, and new possibilities of prevention that will enhance endocrine patient care in the future. Table 1 summarizes key aspects of this review for the practicing clinician.
ACKNOWLEDGMENT
The authors would like to acknowledge the participation in this endeavor by the remaining members of the Adrenal Scientific Committee: Dr. Richard Auchus, Dr. Tobias Else, Dr. Maria Fleseriu, Dr. Amir Hamrahian, Dr. Christian Koch, Dr. Carl Malchoff, Dr. Barbara S. Miller, Dr. Phyllis Speiser, and Dr. Anand Vaidya. The authors are indebted to Dr. Garima Gupta and Katherine Wolf for their efforts in figure illustration and editing this manuscript.
Abbreviations:
| ACC | adrenal cortical carcinoma |
| APA | aldosterone-producing adenoma |
| APCC | aldosterone-producing cell cluster |
| CAH | congenital adrenal hyperplasia |
| CT | computed tomography |
| DOTATATE | [68Ga]-DOTA(0)-Tyr(3)-octreotate |
| FDG | fluorode-oxyglucose |
| FH | fumarate hydratase |
| MR | mineralocorticoid |
| MDH2 | malate dehydrogenase 2 |
| PCC | pheochromocytoma |
| PET | positron emission tomography |
| PGL | paraganglioma |
| SCS | subclinical cortisol-secreting |
| SDHB | succinate dehydrogenase subunit B |
| TCGA | The Cancer Genome Atlas |
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Physiological stimulation
GRA (EH-))
Mutated KCNJS
EH-III
PASNA/FH-IV
Mateted NYA
Somatic mutations
Ca2+
channe
ACTH
Cal* channel
K* channel
W
Mutated CACNAID/ CACNAIH
ATPAOLO
Naº/Call+ exchanger
Angiotensin 1
Mutated CACNAID
Na
Cal
Mitoted Cole APPne 2
K* channel
Cala
MCR2
AT1R
Na
ŤCa?»
K* ATIR Aldosterone
Ca ?:
Mutated KCIUJS
Depolarization
TCa?
K
Na”
ATIR
Depolarization
Aldosterone/ Hybrid Steroids
Cal
Aldosterone
Depolarization
Aldosterone
Aldosterone
CYP1182
CYP1182
CYPLI81
CN
maeric
CYP1182
CYP1182
CYP1182
Ng*
Cholesterol
SIAR
Glucocorticoid precursors
Mineralocorticoid precursors
Mineralocorticoids
CYPHAI
ZG
Pregnenolone
38HSD2
Progesterone
CYP21A2
Adrenal Cortex
11-Deoxycorticosterone POR
CYPIIB2
18OH-Corticosterone
CYP11B2
Aldosterone
POR
CYP17AI
Glucocorticoids
ZF
17a-(OH)Pregnenolone
36HSD2
17a-OHP
CYP21A2
11-Deoxycortisol
CYPIIBI
POR
Cortisol
118HSD2
HIBHSDI
Cortisone
POR(b5)
CYP17A1
Sa-Pregnan- 17a-ol-3.20-dione
Sa-Pregnan-3a 17a-diol-20-one
ZR
CYP17A1
Androsterone
Backdoor or alternate pathway
DHEA
35HSD2
Androstenedione
17BHSD2
Testosterone
Sa-Reductase2
DHT
Androstanediol
Androgen precursors
Androgens
Normoxia
Hypoxia
MOH2
Oxaloacetate
cs
HIF-C
Malate
Citrate
PHD
PHD
FH
ACO Isøcitrate
Fumarate
OH
OH
IDH
Adrenal Medulla
SOM
&-KG
HIF-O
Succinate
SULO
Saccamys-CoA KGOH
PVHL
pVHL
Dedifferentiation
PVHL
HIF-CX
UIQ
HIF-a
HIF-O
HIF-B
Angiogenesis
OH
OH
Proliferation
Proteasomal degradation
Transcriptional activation of target genes
Invasion
Nucleus Tumor progenitor cell
Metastasis
factor (HIF) levels increase, which cause the activation of target genes causing tumorigenesis.
Table 1.
Summary of Recent Genetic, Biochemical, and Imaging Advances in Adrenal Disorders. Related Syndromes to These Adrenal Disorders Are Also Included
| Adrenal disorder | Advances in genetics | Biochemical assays of today and for tomorrow's precision medicine | Imaging of today and for tomorrow's precision medicine | Syndromes |
|---|---|---|---|---|
| Hyperaldosteronism | CYP11B1, KCNJ5, ATP1A1, ATP2B3, CACNA1D | ªAldosterone and renin, salt suppression test "Subunits of the epithelial sodium channel in urine | aCT to rule out ACC "Metomidate ([1]C] MTO) PET/CT | FHA1 (GRA), FHA2, FHA3, FHA4, FAP |
| Macronodular adrenal hyperplasia | ARMC5, APC, FH, MC2R, MEN1, PDE11A, GNAS1, PRKARIA | "Dexamethasone suppression test, 24-h urinary free cortisol, midnight salivary cortisol | ªCT or MRI | MEN1, FAP, Carney complex |
| Adrenocortical carcinoma | TP53, CDKN2A, ZNRF3, CDK4, MDM2, RBI, CCNE1, APC, CTNNB1, MEN1, PRKARIA | "May or may not have elevation of all adrenal cortical hormones: aldosterone, cortisol, DHEAS, androstenedione PT etrahydro-11-deoxy cortisol | ªCT, PET/CT, or MRI PMetomidate ([11C] MTO) | Li-Fraumeni, MEN1, Carney complex |
| Pheochromocytoma/ paraganglioma | MEN2, VHL, NF1, SDHA, SDHAF2, SDHB, SDHC, SDHD, HIF2A (EPAS1), MAX, TMEM127, FH, MDH2, ATRX, HRAS, KIF1B, IDH, EGLN1, EGLN2, CSDE1, MAML3 | ªPlasma/urine metanephrines; 24-h urine catecholamines "Methoxytramine, succinate, fumarate, isocitrate, glutamate | ªCT, MRI, PET/CT D[68Ga]-DOTATATE PET/CT | MEN2, VHL, NF1, PGL1, PGL2, PGL3, PGL4, Pacak-Zhuang syndrome |
| Congenital adrenal hyperplasia | CYP21A2(most common), HSD3B2, CYP11B1, CYP17A1 | ªElevated 17-OHP, cortisol, aldosterone, renin P16a-OHP, 116-OHP, 21-deoxycortisol, 11-oxyandrogens | Not used for diagnosis | No specific syndrome |
Abbreviations: ACC = adrenal cortical carcinoma; CT = computed tomography; DHEAS = dehydroepiandrosterone sulfate; DOTATATE = [68Ga]-DOTA(0)-Tyr(3)-octreotate; FAP = familial adenomatous polyposis; FHA = familial hyperaldosteronism; GRA = glucocorticoid-remediable aldosteronism; MEN = multiple endocrine neoplasia; MRI = magnetic resonance imaging; MTO = metomidate; NF = neurofibromatosis; OHP= hydroxyprogesterone; PET = positron emission tomography; PGL = paraganglioma; VHL = von Hippel-Lindau.
“Standard laboratory testing in current use
“Techniques in development, more data needed to confirm.