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Case 1
45-Year-Old Woman With an

Incidentally Discovered Large
Adrenal Mass
Adrenal tumors >4 cm in diameter represent 17% The baseline laboratory test results are shown in
of adrenal tumors seen in the tertiary endocrine Table 1.1. The serum corticotropin (ACTH) and dehy-
center. The proportion of malignant adrenal tumors droepiandrosterone-sulfate (DHEA-S) concentrations
and pheochromocytomas is high in large adrenal were not low and cortisol suppressed normally with
tumors, representing 31% and 22%, respectively. an overnight 1-mg dexamethasone suppression test
Hounsfield unit (HU) measurement of adrenal (DST) (Table 1.1). Thus, the adrenal adenoma was not
mass on unenhanced computed tomography (CT) secreting cortisol autonomously.
is an important diagnostic step that may distin-
guish benign adrenal mass from malignancy or
Discussion
pheochromocytoma.
In a study of 705 patients with adrenal tumors >4 cm
from Mayo Clinic published in 2018, 31% repre-
Case Report sented benign adrenal cortical adenoma.1 None of
The patient was a 45-year-old woman with history pheochromocytomas (22%) and malignant adrenal
of nephrolithiasis who was incidentally discovered tumors (31%) demonstrated unenhanced CT attenu-
with a 4.9 cm left adrenal mass on abdominal CT ation <10 HU, with the lowest attenuation in malig-
scan performed for abdominal pain. Past medical nant tumors and pheochromocytomas being 14 HU
history included migraines, fibromyalgia, and gas- and 18 HU, respectively.1 As reported in a systematic
tric bypass performed 10 years prior. At the time of review of 2023 patients with adenomas, 2.5% of ade-
presentation, her weight was normal and she did nomas may demonstrate a growth >1 cm depending
not have hypertension or diabetes mellitus type 2. on when in relation to its natural history the tumor is
She denied symptoms consistent with catechol- first discovered.2
amine excess or Cushing syndrome.
INVESTIGATIONS Treatment
On unenhanced CT the left adrenal mass was The patient was counseled that adrenal mass was a
homogeneous and lipid rich, measuring 4.9 cm benign nonfunctioning adrenal adenoma. This was
in the largest diameter and demonstrating a CT concluded based on imaging phenotype of the adre-
attenuation of −13 HU (Fig. 1.1). The right adrenal nal mass with low unenhanced CT attenuation, but
gland appeared normal. Prior imaging from 8 years also based on a low growth rate of only 1.2 cm over
ago was obtained for comparison and revealed a 8 years. The patient was advised that no further endo-
3.7 cm adrenal mass (−14 HU) (Fig. 1.2). crine follow-up was necessary.
5
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6 SECTION A Incidentally Discovered Adrenal Mass
Fig. 1.1 Axial image from an unenhanced computed tomog-

raphy (CT) scan showed a lipid-rich (−13 Hounsfield unit [HU])
4.9 × 3.2 cm left adrenal nodule (arrow). The right adrenal gland
appeared normal on all images.
Fig. 1.2 Axial image from an unenhanced computed tomogra-

phy (CT) scan performed 8 years earlier demonstrated a lipid-
rich (−14 Hounsfield unit [HU]) 3.7 × 3.1 cm left adrenal nodule
(arrow).
TABLE 1.1 Laboratory Tests

Biochemical Test Result Reference Range
1-mg overnight DST, mcg/dL 1.1 <1.8
ACTH, pg/mL 28 7.2–63
DHEA-S, mcg/dL 178 18–284
Aldosterone, ng/dL 6.2 <21
Plasma renin activity, ng/mL per hour 3.2 2.9–10.8
Plasma metanephrine, nmol/L 0.22 <0.5
Plasma normetanephrine, nmol/L 0.7 <0.9
Urine free cortisol, mcg/24 h 21 3.5−45
ACTH, Corticotropin; DHEA-S, dehydroepiandrosterone-sulfate; DST, dexamethasone suppression test.
1 45-Year-Old Woman With an Incidentally Discovered Large Adrenal Mass 7
Key Points REFERENCES

• The risk of malignancy and pheochromocytoma 1. Iniguez-Ariza NM, Kohlenberg JD, Delivanis DA, et al.
Clinical, biochemical, and radiological characteristics
is proportional to tumor size. of a single-center retrospective cohort of 705 large
• In endocrine practice, 30% of adrenal tumors adrenal tumors. Mayo Clin Proc Innov Qual Outcomes.
>4 cm in diameter are malignant and 22% are 2018;2:30–39.
pheochromocytomas. 2. Elhassan YS, Alahdab F, Prete A, et al. Natural history
of adrenal incidentalomas with and without mild
• Unenhanced CT attenuation <10 HU in a autonomous cortisol excess: a systematic review and
homogeneous adrenal mass excludes malignancy meta-analysis. Ann Intern Med. 2019;171:107–116.
and pheochromocytoma.
Case 2
Adrenal Mass in a Patient

With a History of Extraadrenal
Malignancy: The Role of Imaging
Adrenal metastasis should be suspected in any her body mass index (BMI) was 27.38 kg/m2, blood
patient with a history of extraadrenal malignancy pressure was 135/80 mmHg, and heart rate was
presenting with an indeterminate adrenal mass. 98 beats per minute.
Full hormonal workup and assessment of imaging
characteristics are important even when the likeli- INVESTIGATIONS
hood of adrenal metastasis is high.1,2 Pheochromo- Baseline laboratory testing was obtained, and function-
cytoma presents with similar indeterminate adrenal ing pheochromocytoma and primary aldosteronism
imaging, and, if mistaken for an adrenal metas- were excluded. However, the overnight dexametha-
tasis, a biopsy can be inadvertently performed, sone suppression test was abnormal, and the patient
resulting in potentially severe side effects.3,4 Imag- was diagnosed with mild autonomous cortisol secre-
ing characteristics of the adrenal mass can help tion (MACS) (Table 2.1). An unenhanced CT scan
exclude malignancy (as in lipid-rich tumors), and was obtained (Fig. 2.1) and demonstrated that the
avoid additional testing, such as adrenal biopsy.5,6 2.2 × 2.0 × 1.8 cm left adrenal mass had an attenua-
Finally, finding adrenal hormonal excess such as tion of −15 Hounsfield units (HU). A F-18 fluorodeox-
cortisol, androgen, or aldosterone excess can help yglucose (FDG) positron emission tomography (PET)
diagnose an adrenocortical adenoma or carcinoma scan was performed at the same time for breast cancer
and exclude other etiologies of adrenal tumors that staging and revealed that the adrenal mass had FDG
are incapable of steroid production.4 uptake of 5.3 maximum standard unit value (SUVmax)
(Fig. 2.2).
Case Report TREATMENT AND FOLLOW-UP
The patient was a 66-year-old woman who was The patient was advised that she had a lipid-rich
referred for evaluation of a newly found left 2.2 cm adrenal adenoma with autonomous cortisol secre-
adrenal mass discovered on a contrast-enhanced tion. After consideration of management options, she
computed tomography (CT) of the abdomen per- elected conservative follow-up with periodic reevalua-
formed for breast cancer staging. tion for MACS-induced comorbidities.
In addition to a recently diagnosed locally
advanced left breast adenocarcinoma, the patient’s Imaging Follow-Up
past medical history was positive for hypertension Although imaging was not recommended for follow-
and primary hypothyroidism. Her medications up of the adrenal mass, it was available because of
included levothyroxine and hydrochlorothiazide. follow-up of breast cancer for 8 years after the initial
At the time of evaluation, she had no symptoms diagnosis. The adrenal mass was stable in size over
to suggest adrenal hormonal excess and review of 8 years of follow-up and demonstrated stable FDG
systems was negative. On physical examination, uptake over the years.
8
2 Adrenal Mass in a Patient With a History of Extraadrenal Malignancy: The Role of Imaging 9

Biochemical Test Baseline 1 Year Later 2 Years Later 6 Years Later Reference Range
Post 1-mg DST serum cortisol, mcg/dL 2.6 3.1 2.5 2.9 <1.8
ACTH, pg/mL 30 54.2 21 10–60
DHEA-S, mcg/dL 34 51 15–157
Aldosterone, ng/dL 8.1 <21
Renin plasma activity, ng/mL per hour 1.3 <0.6–3
Plasma metanephrine, nmol/L 0.2 <0.5
Plasma normetanephrine, nmol/L 0.63 <0.9
ACTH, Corticotropin; DHEA-S, dehydroepiandrosterone-sulfate; DST, dexamethasone suppression test.
Biochemical Follow-Up later, she developed prediabetes. Her BMI fluctuated

The patient had the 1-mg dexamethasone suppression between 22.4 and 27.6 kg/m2, without an upward
test repeated several times over the years with little trend.
variability and consistent with MACS (Table 2.1).
Clinical Follow-Up Discussion

Bone mineral density was obtained at baseline and Breast adenocarcinoma metastasis in the adrenal gland
repeated 5 years later; it revealed no baseline osteopo- is infrequently seen, representing <2% of all adrenal
rosis or osteopenia and no significant decline of bone metastases.7 Adrenal metastasis should be suspected in
density over 5 years. At baseline the patient was tested any patient with a history of extraadrenal malignancy
for dyslipidemia and diabetes mellitus type 2, with who presents with an indeterminate adrenal mass.
normal results. At the time of last evaluation 6 years Adrenal metastasis can be safely excluded if adrenal
Fig. 2.1 Axial (left) and coronal (right) images from unenhanced computed tomography (CT) scan demonstrated a left adrenal mass (arrows) mea-
suring 2.2 × 2.0 × 1.8 cm and with unenhanced CT attenuation of −16 Hounsfield units (HU).
Fig. 2.2 Axial (left) and coronal (right) images from F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scan demonstrated FDG
uptake in the adrenal mass (arrows) measuring 5.3 maximum standard unit value (SUVmax), and no other foci of activity.
mass is lipid rich (i.e., unenhanced CT attenuation and demonstrates an unenhanced CT attenuation
<10 HU), even if patient has a history of extraadrenal of <10 HU.
malignancy.5,6,8 FDG PET scan is a valuable test for • FDG PET scan may be false positive in function-
diagnosis of malignancy; however, both false-positive ing adrenal adenomas.
(functioning adrenal adenoma, pheochromocytoma) • Patients with MACS due to unilateral adrenal ad-
and false-negative (small metastasis) results occur.5 enoma do not develop overt Cushing syndrome,
In this case, FDG positivity was likely due to autono- but are at higher risk for cardiovascular events,
mous cortisol secretion from the adrenal adenoma. bone fragility, and mortality.
The patient was diagnosed with MACS based on • Clinical monitoring and treatment of MACS-related
an abnormal dexamethasone suppression test.1,2,9 comorbidities should be implemented in patients
She did have mild hypertension and eventually devel- with MACS not treated with adrenalectomy.
oped prediabetes. However, she did not have obesity,
weight gain, osteoporosis, or other manifestations of REFERENCES
MACS. As demonstrated in this case, MACS associ- 1. Fassnacht M, Arlt W, Bancos I, et al. Management
ated with a stable adrenal adenoma does not demon- of adrenal incidentalomas: European Society of
strate worsening in cortisol autonomy and does not Endocrinology Clinical Practice Guideline in collaboration
with the European Network for the Study of Adrenal
progress to overt Cushing syndrome.10 However, Tumors. Eur J Endocrinol. 2016;175(2):G1–G34.
comorbidities associated with MACS frequently do 2. Vaidya A, Hamrahian A, Bancos I, Fleseriu M, Ghayee HK.
progress when compared to those in patients treated The evaluation of incidentally discovered adrenal masses.
with adrenalectomy.10,11 Patients with MACS also Endocr Pract. 2019;25(2):178–192.
have a higher risk of cardiovascular events and mor- 3. Delivanis DA, Erickson D, Atwell TD, et al. Procedural
and clinical outcomes of percutaneous adrenal biopsy
tality.10,12 In this case, the patient decided against in a high-risk population for adrenal malignancy. Clin
adrenalectomy because of mild manifestations of Endocrinol (Oxf). 2016;85(5):710–716.
MACS and individual preference. In patients choos- 4. Iniguez-Ariza NM, Kohlenberg JD, Delivanis DA, et al.
ing conservative follow-up, yearly evaluation for and Clinical, biochemical, and radiological characteristics
of a single-center retrospective cohort of 705 large
treatment of cardiovascular risk factors and bone adrenal tumors. Mayo Clin Proc Innov Qual Outcomes.
health are recommended.1,2 2018;2(1):30–39.
5. Delivanis DA, Bancos I, Atwell TD, et al. Diagnostic
Key Points performance of unenhanced computed tomography and
(18) F-fluorodeoxyglucose positron emission tomography
• Adrenal malignancy and pheochromocytoma can in indeterminate adrenal tumours. Clin Endocrinol (Oxf).
be excluded if the adrenal mass is homogeneous 2018;88(1):306.
2 Adrenal Mass in a Patient With a History of Extraadrenal Malignancy: The Role of Imaging 11
6. Dinnes J, Bancos I, Ferrante di Ruffano L, et al. autonomous cortisol excess: a systematic review and
Management of endocrine disease: Imaging for the meta-analysis. Ann Intern Med. 2019;171(2):107–116.
diagnosis of malignancy in incidentally discovered 11. Bancos I, Alahdab F, Crowley RK, et al. THERAPY OF
adrenal masses: a systematic review and meta-analysis. ENDOCRINE DISEASE: Improvement of cardiovascular
Eur J Endocrinol. 2016;175(2):R51–R64. risk factors after adrenalectomy in patients with
7. Mao JJ, Dages KN, Suresh M, Bancos I. Presentation, adrenal tumors and subclinical Cushing’s syndrome: a
disease progression and outcomes of adrenal gland systematic review and meta-analysis. Eur J Endocrinol.
metastases. Clin Endocrinol (Oxf). 2020;93(5):546–554. 2016;175(6):R283–R95.
8. Ebbehoj A, Li D, Kaur RJ, et al. Epidemiology of 12. Debono M, Bradburn M, Bull M, Harrison B, Ross RJ,
adrenal tumours in Olmsted County, Minnesota, USA: Newell-Price J. Cortisol as a marker for increased mortality
a population-based cohort study. Lancet Diabetes in patients with incidental adrenocortical adenomas. J Clin
Endocrinol. 2020;8(11):894–902. Endocrinol Metab. 2014;99(12):4462–4470.
9. Delivanis DA, Athimulam S, Bancos I. Modern 13. Bancos I, Taylor AE, Chortis V, et al. Urine steroid
management of mild autonomous cortisol secretion. Clin metabolomics for the differential diagnosis of adrenal
Pharmacol Ther. 2019;106(6):1209–1221. incidentalomas in the EURINE-ACT study: a prospective
10. Elhassan YS, Alahdab F, Prete A, et al. Natural history test validation study. Lancet Diabetes Endocrinol.
of adrenal incidentalomas with and without mild 2020;8(9):773–781.
Case 3
Incidentally Discovered Adrenal

Mass in a Patient With a History of
Extraadrenal Malignancy: The Role
of Adrenal Biopsy
Adrenal metastasis should be suspected in any included amlodipine, losartan, metoprolol succinate,
patient with history of extraadrenal malignancy atorvastatin, and metformin. Her body mass index was
presenting with an indeterminate adrenal mass. 42.8 kg/m2, and the physical examination was other-
The most common extraadrenal malignancies that wise unrevealing.
metastasize to adrenal gland include lung, renal,
and gastrointestinal cancers, followed by mela- INVESTIGATIONS
noma, lymphoma, breast, and other cancers.1 In Baseline laboratory testing was obtained and excluded
this case, we illustrate the role of adrenal biopsy in a functioning pheochromocytoma (Table 3.1). Ini-
the workup of adrenal mass and discuss the poten- tial testing also demonstrated possible primary adre-
tial of adrenal insufficiency in these patients. nal insufficiency with elevated serum corticotropin
(ACTH) concentration and low serum cortisol concen-
tration. Follow-up cosyntropin stimulation testing was
Case Report abnormal, with a peak serum cortisol concentration of
The patient was a 77-year-old woman who was 9 mcg/dL.
referred for evaluation of an incidentally discovered The patient was advised that she most likely had
left adrenal mass on a renal ultrasound that was metastatic disease to the adrenal gland. A previous
obtained for workup of hypertension and hyperkale- history of extraadrenal malignancy, a new diagnosis
mia. A subsequent computed tomography (CT) scan of an indeterminate adrenal mass, combined with the
was obtained and demonstrated a heterogeneous biochemical confirmation of primary adrenal insuffi-
left adrenal mass measuring 12.3 × 8.3 × 9.1 cm ciency, supported the preliminary diagnosis of infiltra-
(Fig. 3.1). No other lesions were seen. tive metastatic disease in the setting of contralateral
The patient’s past medical history was positive adrenalectomy. A CT-guided biopsy of the left adrenal
for renal cell carcinoma 12 years prior that was mass was performed and confirmed metastatic renal
treated with right nephrectomy and right adre- cell carcinoma. The neoplastic cells were positive for
nalectomy. Periodic imaging was performed until paired box gene 8 (PAX8) immunostain and negative
5 years prior and was negative for recurrence. At for inhibin and human melanoma black 45 (HMB45).
the time of evaluation, she had no symptoms to
suggest adrenal hormonal excess and the review of TREATMENT AND FOLLOW-UP
systems was negative. The patient was initiated on hydrocortisone replace-
She had a history of hypertension, dyslipidemia, ment therapy for primary adrenal insufficiency. The
and type 2 diabetes mellitus. Her medications metastatic renal cell carcinoma was treated with
12
3 Incidentally Discovered Adrenal Mass in a Patient With a History of Extraadrenal Malignancy: The Role of Adrenal Biopsy 13
Fig. 3.1 Axial (top) and coronal (bottom) images from an unen-
hanced computed tomography (CT) scan demonstrated a large
heterogeneous left adrenal mass measuring 12.3 × 8.3 × 9.1 cm.
Measurement of CT attenuation within the nonnecrotic region
was 41 Hounsfield units. CT also confirmed absence of the right
kidney and right adrenal gland.
pazopanib. One year later, she was treated with sur-

TABLE 3.1 Laboratory Tests gical resection of the abdominal metastatic disease,
Reference which included resection of a 14-cm adrenal metas-
Biochemical Test Result Range tasis, distal pancreatectomy, and splenectomy. Fludro-
Sodium, mmol/L 134, 138 135–145 cortisone was added to hydrocortisone after the
Potassium, mmol/L 5.0, 5.2 3.6–5.2 surgery. She continues to have a slowly progressive
8 am serum cortisol, mcg/dL 5.3, 8.0 7–25 metastatic disease 3 years after initial presentation.
ACTH, pg/mL 116 10–60
DHEA-S, mcg/dL <15 15–157
Plasma metanephrine, nmol/L <0.2 <0.5
Discussion
Plasma normetanephrine, nmol/L 0.88 <0.9 Adrenal metastasis should be suspected in any patient
ACTH, Corticotropin; DHEA-S, dehydroepiandrosterone-sulfate. with a history of extraadrenal malignancy who presents
with an indeterminate adrenal mass. In a retrospective
study of 579 patients with adrenal metastases, 59% • Primary adrenal insufficiency can occur in 12.4%
were discovered during cancer staging imaging, 36% of patients with bilateral adrenal metastases, and
were incidentally discovered during workup per- 20% of patients with large metastases >4 cm.1
formed for another reason, and 5% were detected due • Primary adrenal insufficiency can occur in a pa-
to other symptoms.1 Adrenal metastases originated tient with unilateral adrenal metastasis and his-
from the lung (39%), genitourinary (28%), gastro- tory of contralateral adrenalectomy.
intestinal (14%), and other (20%) organ systems.1
Notably, bilateral adrenal metastases were diagnosed REFERENCES
at baseline, or developed during follow-up in 43% of 1. Mao JJ, Dages KN, Suresh M, Bancos I. Presentation,
patients. Primary adrenal insufficiency was not rou- disease progression and outcomes of adrenal gland
metastases. Clin Endocrinol (Oxf). 2020;93(5):546–554.
tinely tested for; however, it was diagnosed in 12.4%
2. Fassnacht M, Arlt W, Bancos I, et al. Management
of patients with bilateral adrenal metastases and in of adrenal incidentalomas: European Society of
20% of patients with metastases >4 cm in diameter.1 Endocrinology Clinical Practice Guideline in collaboration
Adrenal biopsy is a procedure that is rarely needed with the European Network for the Study of Adrenal
Tumors. Eur J Endocrinol. 2016;175(2):G1–G34.
in the workup of adrenal masses.2,3 It is reserved only
3. Vaidya A, Hamrahian A, Bancos I, Fleseriu M, Ghayee HK.
for patients with indeterminate adrenal masses (e.g., The evaluation of incidentally discovered adrenal masses.
unenhanced CT attenuation >10 Hounsfield units Endocr Pract. 2019;25(2):178–192.
[HU]), after excluding pheochromocytoma, and in 4. Delivanis DA, Bancos I, Atwell TD, et al. Diagnostic
someone likely to have an adrenal metastasis.2–4 Adre- performance of unenhanced computed tomography and
(18) F-fluorodeoxyglucose positron emission tomography
nal biopsy is not accurate in distinguishing between in indeterminate adrenal tumours. Clin Endocrinol (Oxf).
adrenocortical carcinoma and adrenocortical adenoma 2018;88(1):30–36.
and should not be used with that intent.5–7 The non- 5. Bancos I, Tamhane S, Shah M, et al. Diagnosis of
diagnostic rate for adrenal biopsy is around 5%, and endocrine disease: the diagnostic performance of adrenal
biopsy: a systematic review and meta-analysis. European
complication rate is 3%.5–7 Journal of Endocrinology. 2016;175(2):R65–R80.
6. Delivanis DA, Erickson D, Atwell TD, et al. Procedural
Key Points and clinical outcomes of percutaneous adrenal biopsy
• Adrenal biopsy should be performed only in pain a high-risk population for adrenal malignancy. Clin
Endocrinol (Oxf). 2016;85(5):710–716.
tients with indeterminate adrenal masses (e.g.,
7. Zhang CD, Delivanis DA, Eiken PW, Atwell TD, Bancos
unenhanced CT attenuation >10 HU) and after I. Adrenal biopsy: performance and use. Minerva
excluding pheochromocytoma. Endocrinol. 2019;44(3):288–300.
• Adrenal biopsy is not accurate in distinguishing 8. Bancos I, Taylor AE, Chortis V, et al. Urine steroid
between benign and malignant adrenocortical le- metabolomics for the differential diagnosis of adrenal
incidentalomas in the EURINE-ACT study: a prospective
sions; noninvasive diagnosis should be attempted test validation study. Lancet Diabetes Endocrinol.
in these cases8 or adrenalectomy considered.2 2020;8(9):773–781.
Case 4
Nonfunctioning Lipid-Rich
Adrenocortical Adenoma:
Role of Follow-Up
Any adrenal mass needs evaluation for adrenal heart rate 94 beats per minute. She had no stigmata of
hormonal excess and malignancy.1,2 Imaging char- Cushing syndrome.
acteristics can be helpful to exclude malignancy.3
Workup for adrenal hormone excess includes INVESTIGATIONS
assessment for cortisol, aldosterone, and cat- The baseline laboratory test results are shown in Table
echolamine excess. Here, we present a case of an 4.1. The laboratory tests were normal.
incidentally discovered adrenal mass, which was
determined to be benign and nonfunctioning and OUTCOME AND FOLLOW-UP
where further imaging and biochemical monitoring The patient was counseled that the adrenal mass was
were not required. a benign nonfunctioning adrenal adenoma. This was
concluded based on imaging phenotype of the adre-
nal mass with low unenhanced CT attenuation. The
Case Report patient was advised that no further endocrine follow-
The patient was a 59-year-old woman who pre- up was necessary.
sented for evaluation of an incidentally discovered
right adrenal mass on an abdominal computed
Discussion
tomography (CT) scan performed for investigation
of left-sided abdominal pain. The right adrenal mass CT attenuation measurement on unenhanced CT can
measured 1.6 × 2.0 × 1.2 cm with an unenhanced help clarify the etiology of an adrenal mass. Adre-
CT attenuation of 5.5 Hounsfield units (HU) (see nocortical adenomas can be lipid rich (HU <10) in
Fig. 4.1). She had partial workup at home and was around 60% of cases, demonstrate indeterminate
advised that she did not have a pheochromocy- unenhanced CT attenuation of 10–20 HU in around
toma. She was referred to our institution for further 20%–25% of cases, and be lipid poor (>20 HU) in
evaluation. 15%–20% of cases.4,5 Adrenocortical carcinomas, other
She had a 6-year history of hypertension and malignant adrenal tumors (e.g., sarcomas, metastases),
type 2 diabetes mellitus. She was also diagnosed and pheochromocytomas usually demonstrate unen-
with dyslipidemia 4 years prior. Her bone mineral hanced CT attenuation >20–30 HU and infrequently
density performed several years prior was nor- in the indeterminate zone of 10–20 HU (around
mal. Her medications included lisinopril, hydro- 2%–5%).3–10 Thus, a homogeneous adrenal mass with
chlorothiazide, glipizide, and insulin. She had no an unenhanced CT attenuation of <10 HU excludes
overt signs of adrenal dysfunction or past history malignant adrenal tumors and pheochromocytomas,
of malignancy. She had no change in body weight. and imaging follow-up in these cases is not needed.
On physical examination her body mass index was In addition, workup for pheochromocytoma is not
33.67 kg/m2, blood pressure 132/82 mmHg, and needed in adrenal tumors demonstrating unenhanced
15
Fig. 4.1 Axial (above) and coronal (below) images from an un-
enhanced computed tomography (CT) scan demonstrated a
1.6 × 2.0 × 1.2 cm right adrenal mass (arrows) with an unen-
hanced CT attenuation of 5.5 Hounsfield units. The left adrenal
gland was unremarkable.
TABLE 4.1 Laboratory Tests CT attenuation with <10 HU.5,7,9 As reported in a

Reference systematic review of 2023 patients with adrenal ade-
Biochemical Test Result Range nomas, 2.5% of adenomas may demonstrate growth
4 pm serum cortisol, mcg/dL 2.5 1.4–7 >1 cm depending on when in relation to its natural
1 mg DST serum cortisol, mcg/dL <1 <1.8 history the tumor is first discovered.11 However, the
ACTH, pg/mL 40 10–60 risk of malignant transformation was 0%.11 In patients
Aldosterone, ng/dL 8.5 ≤21 with either nonfunctioning adrenal adenomas (serum
Plasma renin activity, ng/mL/hr 15.3 ≤0.6–3 cortisol concentration after the 1-mg dexamethasone
DHEA-S, mcg/dL 95 16–195 suppression test <1.8 mcg/dL) or those with mild
Plasma metanephrine, nmol/L 0.1 <0.5 autonomous cortisol secretion (MACS) (serum corti-
Plasma normetanephrine, nmol/L 0.56 <0.9 sol concentration after the 1-mg dexamethasone sup-
pression test >1.8 mcg/dL), overt hormone excess
ACTH, Corticotropin; DHEA-S, dehydroepiandrosterone-
sulfate, DST, dexamethasone suppression test. (primary aldosteronism, catecholamine excess, or
4 Nonfunctioning Lipid-Rich Adrenocortical Adenoma: Role of Follow-Up 17
Cushing syndrome) developed in approximately 0.2% 2. Vaidya A, Hamrahian A, Bancos I, Fleseriu M, Ghayee HK.
The evaluation of incidentally discovered adrenal masses.
(6 of 2745 patients).11 The proportion of patients with Endocr Pract. 2019;25(2):178–192.
nonfunctioning adrenal adenomas who developed 3. Dinnes J, Bancos I, Ferrante di Ruffano L, et al.
new MACS during a mean follow-up of 20.3 months Management of endocrine disease: Imaging for the
was 4.3% (149 of 2083).11 Repeating dexamethasone diagnosis of malignancy in incidentally discovered
adrenal masses: a systematic review and meta-analysis.
suppression tests in patients with bilateral nodular Eur J Endocrinol. 2016;175(2):R51–R64.
disease or in those with new symptoms potentially 4. Ebbehoj A, Li D, Kaur RJ, et al. Epidemiology of
related to MACS could be considered. adrenal tumours in Olmsted County, Minnesota, USA:
a population-based cohort study. Lancet Diabetes
Key Points Endocrinol. 2020;8(11):894–902.
5. Iniguez-Ariza NM, Kohlenberg JD, Delivanis DA, et al.
• Unenhanced CT attenuation <10 HU in a homo- Clinical, biochemical, and radiological characteristics
geneous adrenal mass excludes malignancy and of a single-center retrospective cohort of 705 large
pheochromocytoma. adrenal tumors. Mayo Clin Proc Innov Qual Outcomes.
2018;2(1):30–39.
• Growth of >1 cm can be seen in 2.5% of adre-
6. Bancos I, Taylor AE, Chortis V, et al. Urine steroid
nal adenomas; however, the risk of malignant metabolomics for the differential diagnosis of adrenal
transformation is 0%; thus imaging follow-up of incidentalomas in the EURINE-ACT study: a prospective
homogeneous lipid-rich adenomas is not needed. test validation study. Lancet Diabetes Endocrinol.
2020;8(9):773–781.
• The risk of new overt hormone excess in a patient
7. Canu L, Van Hemert JAW, Kerstens MN, et al. CT
with nonfunctioning unilateral adrenal adenoma Characteristics of pheochromocytoma: relevance for the
is around 0.2%. evaluation of adrenal incidentaloma. J Clin Endocrinol
• The risk of new MACS is 4.3%; thus repeating Metab. 2019;104(2):312–318.
dexamethasone suppression tests in selected pa- 8. Delivanis DA, Bancos I, Atwell TD, et al. Diagnostic
performance of unenhanced computed tomography and
tients could be considered, especially in those (18) F-fluorodeoxyglucose positron emission tomography
with bilateral adrenal adenomas, bilateral mac- in indeterminate adrenal tumours. Clin Endocrinol (Oxf).
ronodular hyperplasia, or in those who develop 2018;88(1):30–36.
comorbidities potentially related to MACS (e.g., 9. Gruber LM, Strajina V, Bancos I, et al. Not all adrenal
incidentalomas require biochemical testing to exclude
osteoporosis, diabetes mellitus, hypertension, pheochromocytoma: Mayo Clinic experience and a meta-
obesity). analysis. Gland Surg. 2020;9(2):362–371.
10. Mao JJ, Dages KN, Suresh M, Bancos I. Presentation,
REFERENCES disease progression and outcomes of adrenal gland
1. Fassnacht M, Arlt W, Bancos I, et al. Management metastases. Clin Endocrinol (Oxf). 2020;93(5):546–554.
of adrenal incidentalomas: European Society of 11. Elhassan YS, Alahdab F, Prete A, et al. Natural history
Endocrinology Clinical Practice Guideline in collaboration of adrenal incidentalomas with and without mild
with the European Network for the Study of Adrenal autonomous cortisol excess: a systematic review and
Tumors. Eur J Endocrinol. 2016;175(2):G1–G34. meta-analysis. Ann Intern Med. 2019;171(2):107–116.
Case 5
54-Year-Old Woman With

an Incidentally Discovered
Adrenal Mass and Abnormal
Dexamethasone Suppression Test:
Role of Adrenalectomy
Mild autonomous cortisol secretion (MACS) is INVESTIGATIONS

defined as an abnormal cortisol concentration follo On unenhanced CT of adrenal glands, the left adrenal
wing dexamethasone suppression test (post-DST cor- mass was lipid rich (6 Hounsfield units [HU]), mea-
tisol >1.8 mcg/dL) and is detected in up to 50% of suring 2.2 cm in the largest diameter (see Fig. 5.1).
patients with adrenal cortical adenomas. Patients with The right adrenal gland appeared normal. The base-
MACS present with a higher prevalence of cardiovas- line laboratory test results are shown in Table 5.1. The
cular risk factors and events, osteopenia and osteopo- serum corticotropin (ACTH) and dehydroepiandros-
rosis, and increased risk of fractures. Adrenalectomy terone-sulfate (DHEA-S) concentrations were low, and
leads to improvement of comorbidities in 20%–70% of cortisol did not suppress normally with an overnight
patients; however, estimating the degree of improve- 1-mg dexamethasone suppression test (DST) (see
ment prior to adrenalectomy is challenging. Table 5.1). MACS was diagnosed.
TREATMENT
Case Report The patient was counseled that the adrenal mass was
The patient was a 54-year-old woman who pre- a benign adrenal adenoma that was producing cortisol
sented for evaluation of continuous weight gain of autonomously. Malignancy was excluded based on the
50 pounds over 5–7 years. In addition, she had imaging phenotype (<10 HU). MACS was diagnosed
prediabetes (glycosylated hemoglobin = 6%, not based on an abnormal DST (cortisol >1.8 mcg/dL), as
on medications) and hypertension treated with well as low ACTH and DHEA-S. The patient was coun-
metoprolol tartrate 25 mg twice a day and nifedip- seled about possible relationship of MACS and cardio-
ine 30 mg daily. Two years prior, she was diagnosed vascular comorbidities (e.g., hypertension, prediabetes,
with osteoporosis. Several months prior, she was obesity), and conservative management versus adrenal-
incidentally discovered with a 2.2-cm left adre- ectomy was discussed. A decision on adrenalectomy
nal mass initially visualized on chest computed was made. Pathology demonstrated an adrenocortical
tomography (CT) and further better characterized adenoma forming a 3.1 × 2.5 × 1.7 cm adrenal nodule.
on abdominal CT (Fig. 5.1). Physical exam was
positive for body mass index of 39.8 kg/m2 and FOLLOW-UP
blood pressure of 138/86 mmHg, but no features Postoperative adrenal insufficiency was diagnosed
of Cushing syndrome. based on cortisol of 5.7 mcg/dL the morning after
18
5 54-Year-Old Woman With an Incidentally Discovered Adrenal Mass and Abnormal Dexamethasone Suppression Test 19
Unenhanced Contrast enhanced Delayed contrast enhanced

HU=6 HU=43 HU=22
Fig. 5.1 Axial images from an unenhanced and contrast enhanced computed tomography (CT) scan showed a lipid-rich 2.2 × 1.4–cm left adrenal
mass. (A) Unenhanced Hounsfield units (HU) of 6. (B) Contrast-enhanced HU of 43. (C) Delayed contrast-enhanced HU of 22.
surgery. Hydrocortisone supplementation was initiated 48% of patients with adenoma and available DST
with a plan to reassess adrenal function. At the 6-month had MACS.2 Patients with MACS demonstrate higher
follow-up, the patient’s hypothalamic-pituitary-adrenal prevalence of cardiovascular risk factors (hyperten-
axis recovered and hydrocortisone was stopped. Clini- sion, diabetes mellitus type 2, obesity, dyslipidemia),
cally, the patient lost 15 pounds of body weight and cardiovascular events and mortality, osteopenia, osteo-
her blood pressure measurements improved. porosis, and fractures.3–5 In a systematic review and
meta-analysis of adrenalectomy versus conservative
management in MACS, patients undergoing adrenal-
Discussion ectomy experienced improvement in hypertension and
As reported in a prospective study of 601 unselected diabetes mellitus type 2.6 However, studies included in
patients undergoing CT scans, with a 7% prevalence of this systematic review were of low to moderate quality
incidental adrenal tumors, MACS can be diagnosed in and had heterogeneous definitions of both MACS and
up to 50% of patients.1 In a larger multicenter study comorbidity improvement. Identifying patients most
of adrenal tumors evaluated in the adrenal practice, likely to experience improvement in long-term out-
comes is challenging, and thus the decision regarding
TABLE 5.1 Laboratory Tests adrenalectomy needs to be individualized.
Reference
Biochemical Test Result Range Key Points
1-mg overnight DST, mcg/dL 2.3 <1.8 • DST is required in any patient with adrenal mass,
ACTH, pg/mL <5 7.2–63 regardless of symptoms.
• MACS (DST >1.8 mcg/dL) is diagnosed in up to
50% of patients with adrenal adenoma.
Aldosterone, ng/dL 8 <21
• Patients with MACS have higher prevalence of
Plasma renin activity, ng/mL per 4.1 2.9–10.8 cardiovascular risk factors, cardiovascular events,
hour
osteopenia, osteoporosis, and fractures.
Urine metanephrines, mcg/24 h 236 <400 • Adrenalectomy leads to improvement in cardio-
Urine normetanephrine, mcg/24 h 712 <900 vascular risk factors; however, individual degree
Urine free cortisol, mcg/24 h 7.5 3.5–45 of improvement varies.
ACTH, Corticotropin; DHEA-S, dehydroepiandrosterone- • Decision on adrenalectomy versus conservative
sulfate; DST, dexamethasone suppression test. managements needs to be individualized to the
patient’s age, comorbidities, tumor imaging phe- 3. Elhassan YS, Alahdab F, Prete A, et al. Natural history
of adrenal incidentalomas with and without mild
notype, local surgical expertise, and the patient’s autonomous cortisol excess: a systematic review and
preference. meta-analysis. Ann Intern Med. 2019;171:107–116.
4. Delivanis DA, Athimulam S, Bancos I. Modern
management of mild autonomous cortisol secretion.
REFERENCES Clin Pharmacol Ther. 2019;106:1209–1221.
1. Reimondo G, Castellano E, Grosso M, et al. Adrenal 5. Athimulam S, Bancos I. Evaluation of bone health in
Incidentalomas are tied to increased risk of diabetes: patients with adrenal tumors. Curr Opin Endocrinol
findings from a prospective study. J Clin Endocrinol Diabetes Obes. 2019;26:125–132.
Metab. 2020:105. 6. Bancos I, Alahdab F, Crowley RK, et al. Therapy of
2. Bancos I, Taylor AE, Chortis V, et al. Urine steroid endocrine disease: improvement of cardiovascular
metabolomics for the differential diagnosis of adrenal risk factors after adrenalectomy in patients with
incidentalomas in the EURINE-ACT study: a prospective adrenal tumors and subclinical Cushing’s syndrome: a
test validation study. Lancet Diabetes Endocrinol. systematic review and meta-analysis. Eur J Endocrinol.
2020;8:773–781. 2016;175:R283–R295.
Case 6
Lipid-Poor Adrenal Masses: The

Case for Aggressive Management
Lipid-poor adrenal masses are the landmines of INVESTIGATIONS

adrenal disorders. Although lipid-poor adrenal The baseline laboratory test results are shown in
masses may be benign nonfunctional cortical ade- Table 6.1. The laboratory tests were normal with the
nomas, it can be difficult to make the distinction exception of a positive case detection test for primary
from more concerning diagnoses such as a small aldosteronism and minimal elevations in serum total
adrenocortical carcinoma (ACC) (see Case 23) and testosterone and plasma normetanephrine.
prebiochemical pheochromocytoma (see Case 36).
Choosing nonsurgical management can carry a TREATMENT
clinically significant risk. Herein we present such The patient was advised that she may have an adrenal
a case. malignancy, and right adrenalectomy was strongly rec-
ommended. However, her spouse was recovering from
an illness, and she opted to care for the spouse over
Case Report the subsequent months.
The patient was an 82-year-old woman who
5 months previously presented with community- OUTCOME AND FOLLOW-UP
acquired pneumonia. To exclude pulmonary embo- The patient did not return for medical evaluation
lism, a chest computed tomography (CT) angiogram for an additional 9 months. An abdominal CT with-
was performed and a right adrenal mass was noted out (see Fig. 6.1) and with contrast (Fig. 6.2) was
incidentally. An adrenal-dedicated CT scan showed obtained. The right adrenal mass had increased fur-
the mass to measure 2.3 × 2.5 × 3.2 cm with an ther in size (5.2 × 4.1 × 4.5 cm), and there was associ-
unenhanced CT attenuation of 28 Hounsfield units ated metastatic disease to the liver and lymph nodes
(HU) (Fig. 6.1). Follow-up CT scan was obtained (see Fig. 6.2). Biopsy of the liver confirmed metastatic
5 months later, and the right adrenal mass increased adrenocortical carcinoma (ACC). The patient died
in size (2.8 × 2.5 × 3.5 cm) (see Fig. 6.1). She had 17 months after the first CT scan.
a history of hypertension and type 2 diabetes mel-
litus. Her antihypertensive medications included a Key Points
calcium channel blocker (amlodipine 10 mg daily) • ACC is the most aggressive of all malignances
and a β-adrenergic blocker (metoprolol 12.5 mg seen by endocrinologists.
twice daily). She had no overt signs of adrenal dys- • All ACCs are small at the beginning.
function or past history of malignancy. She had no • Lipid-poor adrenal masses should either be re-
change in body weight. On physical examination sected or followed closely with serial imaging.1,2
her body mass index was 32 kg/m2, blood pressure • Findings from F-18 fluorodeoxyglucose posi-
161/81 mmHg, and heart rate 81 beats per minute. tron emission tomography and high-resolution
She had no stigmata of Cushing syndrome. accurate-mass mass spectrometry urine steroid
21
Fig. 6.1 Axial images from serial unenhanced computed tomography (CT) scans.
Top, the initial scan showed a 2.3 × 2.5 × 3.2 cm right adrenal mass (arrow) with
an unenhanced CT attenuation of 28 Hounsfield units (HU). Middle, the CT scan
performed 5 months after the first scan showed that the adrenal mass (arrow)
had increased in size (2.8 × 2.5 × 3.5 cm) and had an unenhanced CT attenuation
of 34 HU. Bottom, the CT scan performed 14 months after the initial scan showed
further enlargement of the right adrenal mass (arrow) (5.2 × 4.1 × 4.5 cm) and
metastatic disease to the liver (see Fig. 6.2).
6 Lipid-Poor Adrenal Masses: The Case for Aggressive Management 23
Fig. 6.2 Axial (top) and coronal (bottom) contrast-enhanced computed tomography (CT) scan images, obtained 14 months after the initial CT scan
(see Fig. 6.1), showed an increased size of a large heterogeneous right adrenal mass (large arrows) and a large (9.8 × 8.6 cm) mass (small arrows) in
the right hepatic lobe. In addition, there were multiple prominent retroperitoneal and mesenteric lymph nodes, including a right pericaval 1.5 × 0.8–cm
retroperitoneal lymph node.
TABLE 6.1 Laboratory Tests profiling may help the clinician when there is un-
certainty on whether to resect a lipid-poor adre-
Reference
nal mass.3,4
Biochemical Test Result Range
Sodium, mmol/L 144 135–145
Potassium, mmol/L 3.6 3.6–5.2 REFERENCES
Fasting plasma glucose, mg/dL 123 70–100 1. Young Jr WF. Clinical practice. The incidentally discovered
Creatinine, mg/dL 0.9 0.6–1.1 adrenal mass. N Engl J Med. 2007;356(6):601–610.
8 am serum cortisol, mcg/dL 12 7–25 2. Young Jr WF. Conventional imaging in adrenocortical
carcinoma: update and perspectives. Horm Cancer.
ACTH, pg/mL 23 10–60 2011;2(6):341–347.
Aldosterone, ng/dL 21 ≤21 3. Delivanis DA, Bancos I, Atwell TD, et al. Diagnostic
Plasma renin activity, ng/mL per performance of unenhanced computed tomography and
hour <0.6 ≤0.6–3 (18) F-fluorodeoxyglucose positron emission tomography
DHEA-S, mcg/dL in indeterminate adrenal tumours. Clin Endocrinol (Oxf).
47.3 15–157 2018;88(1):30–36.
Total testosterone, ng/dL 80 8–60 4. Hines JM, Bancos I, Bancos C, et al. High-resolution,
Androstenedione, ng/dL 172 30–200 accurate-mass (HRAM) mass spectrometry urine steroid
Plasma metanephrine, nmol/L 0.35 <0.5 profiling in the diagnosis of adrenal disorders. Clin Chem.
Plasma normetanephrine, nmol/L 2017;63(12):1824–1835.
1.0 <0.9
24-hour urine:
Metanephrine, mcg 119 <400
Normetanephrine, mcg 396 <900
Norepinephrine, mcg 72 <80
Epinephrine, mcg 3.5 <20
Dopamine, mcg 170 <400
Cortisol, mcg 28 3.5–45
ACTH, Corticotropin; DHEA-S, dehydroepiandrosterone-
sulfate.
SECTION A
Incidentally Discovered
Adrenal Mass
tumors and pheochromocytomas is high in large adre-
Adrenal Incidentaloma
nal tumors, representing 31% and 22%, respectively.7
Adrenal incidentaloma is an adrenal mass discov- Accelerated tumor growth (>20% in 3–6 months)
ered incidentally on cross-sectional abdominal imag- is suggestive of a malignant adrenal mass, while no
ing performed for indications other than suspected or minimal tumor growth suggests a benign adrenal
adrenal mass. Over the preceding two decades, the mass. Pheochromocytomas usually grow slowly, <1 cm
incidence rate of adrenal tumors increased 10-fold, per year. As reported in a systematic review of 2023
most likely as a result of the widespread use of com- patients with adrenocortical adenomas, 2.5% of adeno-
puted tomography (CT) imaging.1 In a prospective mas may demonstrate a growth >1 cm over 3–5 years,
study of adults undergoing abdominal CT imaging, depending on when in relation to its natural history
the prevalence of adrenal tumors was 7%.2 Adrenal the tumor is first discovered.8 However, the risk of
tumors are rare in childhood and young adults and malignant transformation was 0%.8
are usually diagnosed in the sixth decade.1 The eti-
ology of adrenal tumors can be broadly separated IMAGING CHARACTERISTICS
into five categories: (1) adrenocortical adenomas Hounsfield unit (HU) measurement of adrenal mass
(85%), (2) other benign adrenal masses (4%–6%), on unenhanced CT is an important diagnostic step that
(3) pheochromocytomas (1%–3%), (4) adrenocorti- may distinguish benign adrenal mass from malignancy
cal carcinomas (<1%–3%), and (5) other malignant or pheochromocytoma. Adrenocortical adenomas
adrenal masses (3%–8%)1 (Table A.1). In any patient can be lipid rich (with unenhanced CT attenuation
with an adrenal mass, workup needs to determine <10 HU) in approximately 60% of cases, demonstrate
whether the adrenal mass is malignant and whether an unenhanced CT attenuation between 10 and 20 HU
it is hormonally active. in approximately 20%–25% of cases, and >20 HU (lipid
poor) in 15%–20% of cases.1,7 Adrenocortical carcino-
mas (ACCs), other malignant adrenal tumors (sarcomas,
Diagnosis of Malignant Adrenal Mass metastases), and pheochromocytomas usually demon-
Tumor size, tumor growth, history of extraadrenal strate an unenhanced CT attenuation of >20–30 HU, and
malignancy, and imaging characteristics are helpful infrequently 10–20 HU (approximately 2%–5%).1,4–7,9–11
in diagnosing adrenal malignancy3–6 (see Table A.1). Thus a homogeneous adrenal mass with an unenhanced
CT attenuation of <10 HU excludes malignant adrenal
TUMOR SIZE AND TUMOR GROWTH tumors and pheochromocytomas, and imaging follow-
Adrenal tumors >4 cm in diameter represent 17% up in these cases is not needed in most cases. Lipid-poor
of adrenal tumors seen in the tertiary endocrine adrenal masses should either be resected or followed
center.7 The proportions of malignant adrenal closely with serial imaging.1,2
1
TABLE A.1 Presentation of Adrenal Tumors

Benign Adrenal Mass Malignant Adrenal Mass Pheochromocytoma
Prevalence (population) 90% 9% 1%
Prevalence (endocrine clinic) 80%–85% 5%–10% 5%–10%
Mode of discovery Most: incidental Incidental: 40% Incidental: 60%
Nonincidental (cancer Hormone excess: 30%
staging, hormone excess, Genetic screening: 10%
abdominal pain, B
symptoms1): 60%
Tumor size Usually <4 cm Adrenal cortical carcinoma: Usually >4 cm, variable
usually >6 cm (smaller when genetic
Other malignancy: Variable screening and preclinical)
Tumor laterality 15%–20% bilateral Adrenal cortical carcinoma 5%–10% bilateral (if genetic
<0.1% bilateral predisposition, e.g., VHL,
Other malignancy: 20%–40% MEN2, NF1.)
bilateral
Unenhanced computed HU <10: 50%–60% HU>20 (usually >30 HU) HU>20 (usually >30 HU)
tomography attenuation, HU HU 10–20: 20%–30%
HU >20: 10%–20%
Magnetic resonance imaging Chemical shift: present – Chemical shift: absent Chemical shift: absent
60–80%
Chemical shift: absent –
20–40%
1FDG-18 positron emission FDG-18 uptake – FDG-18 uptake – present FDG-18 uptake – present
tomography usually absent
Tumor growth Usually <1 cm in 1 year Usually >1 cm in 3–6 months Usually <1 cm in 1 year
1a B symptom is a common way to describe fever, weight loss, and other symptoms related to malignancy. FDG-18, F-18
fluorodeoxyglucose; HU, Hounsfield units; MEN2, multiple endocrine neoplasia type 2; NF1, neurofibromatosis type 1; VHL, von
Hippel-Lindau.
Magnetic resonance imaging (MRI) chemical shift characteristics for diagnostic purposes, and can avoid
analysis is similar in accuracy to the unenhanced CT unnecessary biopsy or surgery.12
attenuation.5 F-18 fluorodeoxyglucose (FDG) posi-
tron emission tomography (PET) can also be used in ADRENAL BIOPSY
diagnosis of malignant adrenal tumors, with positive Adrenal biopsy is a procedure that is rarely needed
FDG uptake in the adrenal mass that is greater than in the workup of adrenal masses.13,14 It is reserved
the uptake in liver suggestive of malignancy. However, for patients with indeterminate adrenal masses (e.g.,
FDG PET demonstrates sensitivity and specificity of unenhanced CT attenuation >10 HU), after excluding
approximately 85%–90%, with both false-positive pheochromocytoma, and in someone likely to have an
(functioning adrenal adenoma, pheochromocytoma) adrenal metastasis.10,13,14 Adrenal metastasis should
and false-negative (small metastasis) results.5,10 be suspected in any patient with a history of extraadre-
nal malignancy who presents with an indeterminate
URINE STEROID PROFILING adrenal mass. In a retrospective study of 579 patients
Urine steroid profiling has been recently validated as with adrenal metastases, 59% were discovered during
an accurate diagnostic test for ACC.9 It is most useful cancer staging imaging, 36% were incidentally discov-
in larger adrenal tumors with indeterminate imaging ered during workup performed for another reason,
SECTION A Incidentally Discovered Adrenal Mass 3
TABLE A.2 Hormonal Workup in Patients With Adrenal Tumors

Adrenal Hormone Excess Indication for Testing First-Line Testing Additional or Confirmatory Testing
Adrenal hypercortisolism Anyone with adrenal 1-mg overnight ACTH, DHEA-S, 24-hour urine cortisol
(overt or mild) mass dexamethasone Repeat 1-mg or perform 8-mg
suppression test dexamethasone suppression test
(abnormal: >1.8 mcg/dL)
Adrenal hyperaldosteronism Anyone with Morning PAC and PRA Unnecessary if spontaneous
hypertension or or PRC (abnormal: hypokalemia, PAC >20 ng/dL, and
spontaneous aldosterone >10 ng/dL and PRA <1.0 ng/mL per hour
hypokalemia suppressed renin) Oral sodium loading test or saline
infusion test
Catecholamine excess Anyone with Plasma or 24-hour Usually not needed unless interfering
indeterminate urine fractionated medications are suspected
adrenal mass metanephrines
(HU>10)
ACTH, Corticotropin; DHEA-S, dehydroepiandrosterone sulfate; HU, Hounsfield units; PAC, plasma aldosterone concentration;
PRA, plasma renin activity; PRC, plasma renin concentration.
and 5% were detected as a result of other symptoms.11 patients with adrenal cortical adenomas.2,13,14 Patients
Adrenal metastases originated from the lung (39%), with MACS demonstrate a higher prevalence of car-
genitourinary (28%), gastrointestinal (14%), and diovascular risk factors (e.g., hypertension, diabetes
other (20%) organ systems.11 mellitus type 2, obesity, dyslipidemia), cardiovascular
Adrenal biopsy is not accurate in distinguishing events and mortality, osteopenia, osteoporosis, and
between adrenocortical carcinoma and adrenocortical fractures.8,18,19 In a systematic review and metaanal-
adenoma and should not be used with that intent.15–17 ysis of adrenalectomy versus conservative manage-
The nondiagnostic rate for adrenal biopsy is around ment in MACS, patients undergoing adrenalectomy
5%, and complication rate is 3%.15–17 experienced improvement in diabetes mellitus type
2 and hypertension.20 However, studies included in
this systematic review were of low to moderate quality
Diagnosis of Adrenal Hormonal Excess and had heterogeneous definitions of both MACS and
Every patient with adrenal mass needs a careful evalua- comorbidity improvement. Identifying patients most
tion for adrenal hormonal excess. Assessment includes likely to experience improvement in long-term out-
workup for autonomous cortisol secretion, workup comes is challenging, and thus the decision of adre-
for primary aldosteronism, and workup for catechol- nalectomy needs to be individualized. The decision
amine excess (Table A.2). on adrenalectomy versus conservative managements
Later sections in this book will address pri- needs to be individualized to patient age, comorbidi-
mary aldosteronism, overt Cushing syndrome, and ties, tumor imaging phenotype, local surgical expertise,
pheochromocytoma. and patient preference.
MILD AUTONOMOUS CORTISOL SECRETION REFERENCES

The most common hormonal abnormality diagnosed 1. Ebbehoj A, Li D, Kaur RJ, et al. Epidemiology of
adrenal tumours in Olmsted County, Minnesota, USA:
in patients with adrenal incidentalomas is mild auton- a population-based cohort study. Lancet Diabetes
omous cortisol secretion (MACS). MACS is defined as Endocrinol. 2020;8(11):894–902.
abnormal overnight 1-mg dexamethasone suppression 2. Reimondo G, Castellano E, Grosso M, et al. Adrenal
test (DST >1.8 mcg/dL) and is detected in up to 50% of incidentalomas are tied to increased risk of diabetes:
findings from a prospective study. J Clin Endocrinol 11. Mao JJ, Dages KN, Suresh M, Bancos I. Presentation,
Metab. 2020;105(4). disease progression and outcomes of adrenal gland
3. Bancos I, Arlt W. Diagnosis of a malignant adrenal mass: metastases. Clin Endocrinol (Oxf). 2020;93(5):546–554.
the role of urinary steroid metabolite profiling. Curr Opin 12. Chortis V, Bancos I, Nijman T, et al. Urine steroid
Endocrinol Diabetes Obes. 2017;24(3):200–207. metabolomics as a novel tool for detection of recurrent
4. Canu L, Van Hemert JAW, Kerstens MN, et al. CT adrenocortical carcinoma. J Clin Endocrinol Metab.
Characteristics of pheochromocytoma: relevance for the 2020;105(3).
evaluation of adrenal incidentaloma. J Clin Endocrinol 13. Fassnacht M, Arlt W, Bancos I, et al. Management
Metab. 2019;104(2):312–318. of adrenal incidentalomas: European Society of
5. Dinnes J, Bancos I, Ferrante di Ruffano L, et al. Endocrinology Clinical Practice Guideline in collaboration
management of endocrine disease: imaging for the with the European Network for the Study of Adrenal
diagnosis of malignancy in incidentally discovered adrenal Tumors. Eur J Endocrinol. 2016;175(2):G1–G34.
masses: a systematic review and meta-analysis. Eur J 14. Vaidya A, Hamrahian A, Bancos I, Fleseriu M, Ghayee HK.
Endocrinol. 2016;175(2):R51–R64. The evaluation of incidentally discovered adrenal masses.
6. Gruber LM, Strajina V, Bancos I, et al. Not all adrenal Endocr Pract. 2019;25(2):178–192.
incidentalomas require biochemical testing to exclude 15. Bancos I, Tamhane S, Shah M, et al. diagnosis of endocrine
pheochromocytoma: Mayo Clinic experience and a meta- disease: the diagnostic performance of adrenal biopsy: a
analysis. Gland Surg. 2020;9(2):362–371. systematic review and meta-analysis. European Journal of
7. Iniguez-Ariza NM, Kohlenberg JD, Delivanis DA, et al. Endocrinology. 2016;175(2):R65–R80.
Clinical, biochemical, and radiological characteristics 16. Delivanis DA, Erickson D, Atwell TD, et al. Procedural
of a single-center retrospective cohort of 705 large and clinical outcomes of percutaneous adrenal biopsy
adrenal tumors. Mayo Clin Proc Innov Qual Outcomes. in a high-risk population for adrenal malignancy. Clin
2018;2(1):30–39. Endocrinol (Oxf). 2016;85(5):710–716.
8. Elhassan YS, Alahdab F, Prete A, et al. Natural history 17. Zhang CD, Delivanis DA, Eiken PW, Atwell TD,
of adrenal incidentalomas with and without mild Bancos I. Adrenal biopsy: performance and use. Minerva
autonomous cortisol excess: a systematic review and meta- Endocrinol. 2019;44(3):288–300.
analysis. Ann Intern Med. 2019;171(2):107–116. 18. Delivanis DA, Athimulam S, Bancos I. Modern
9. Bancos I, Taylor AE, Chortis V, et al. Urine steroid management of mild autonomous cortisol secretion. Clin
metabolomics for the differential diagnosis of adrenal Pharmacol Ther. 2019;106(6):1209–1221.
incidentalomas in the EURINE-ACT study: a prospective 19. Athimulam S, Bancos I. Evaluation of bone health in
test validation study. Lancet Diabetes Endocrinol. patients with adrenal tumors. Curr Opin Endocrinol
2020;8(9):773–781. Diabetes Obes. 2019;26(3):125–132.
10. Delivanis DA, Bancos I, Atwell TD, et al. Diagnostic 20. Bancos I, Alahdab F, Crowley RK, et al. therapy of
performance of unenhanced computed tomography and endocrine disease: improvement of cardiovascular risk
(18) F-fluorodeoxyglucose positron emission tomography factors after adrenalectomy in patients with adrenal tumors
in indeterminate adrenal tumours. Clin Endocrinol (Oxf). and subclinical Cushing's syndrome: a systematic review and
2018;88(1):30–36. meta-analysis. Eur J Endocrinol. 2016;175(6):R283–R295.
Case 8
Primary Aldosteronism With

Unilateral Adrenal Nodule on
Computed Tomography
Cross-sectional computed imaging lacks the neces- (PRA) <1.0 ng/mL per hour.1 Due to lack of sponta-
sary accuracy to determine if a patient has unilat- neous hypokalemia, formal confirmatory testing with
eral adrenal versus bilateral adrenal disease as the oral sodium loading was performed.1,2 The patient was
cause of primary aldosteronism (PA). If abdominal counseled on a high-sodium diet over 3 days, and the
computed tomography (CT) does not reveal a large 24-hour urine was collected from day 3 to day 4. The
adrenal mass consistent with adrenocortical can- patient monitored her blood pressure daily and serum
cer, adrenal venous sampling (AVS) is an essential potassium was checked daily. PA was confirmed with
localization step in patients with confirmed PA who the 24-hour urinary aldosterone excretion of 20 mcg
want to pursue surgical management. The only and a urinary sodium excretion of 190 mEq (the lat-
exception to this rule is the patient who is young, ter confirming compliance with the high-sodium diet).
has marked PA, and a unilateral solitary adrenal Clinicians frequently ask what to do if the 24-hour
macroadenoma is documented on adrenal CT (see urine sodium is <200 mEq. The 200 mEq cutoff serves
Case 7). as a guide—it is not an absolute, and clinical judg-
ment should be used. In this patient’s case a 24-hour
urine sodium of 190 mEq was “close enough” and a
Case Report repeat test was not needed. The baseline dehydroepi-
The patient was a 68-year-old woman who had androsterone sulfate (DHEA-S) was normal, and cor-
been hypertensive for 40 years. However, she had tisol suppressed normally with the 1-mg overnight
accelerated hypertension and new-onset diuretic- dexamethasone suppression test (DST) (see Table 8.1).
induced hypokalemia over the past 6 months. Pre- An unenhanced adrenal-dedicated CT scan showed
viously her blood pressure was under good control a lipid-rich 1.6-cm left adrenal nodule (Fig. 8.1).
with an angiotensin-converting enzyme inhibitor After a thorough discussion with her, the patient
and hydrochlorothiazide. Due to the hypokale- was keen to pursue a surgical cure of hypokalemia and
mia, her local physician changed her antihyperten- better control of her hypertension on less medication.
sive program to metoprolol (12.5 mg twice daily) She understood that a cure of her hypertension with
and amlodipine (5 mg daily). She took potassium surgery was not a reasonable goal in view of the dura-
20 mEq twice daily to correct the hypokalemia. She tion of hypertension of >10 years.1,3
had no signs or symptoms of Cushing syndrome. AVS was performed as the next step. AVS was
successful based on adrenal vein-to-inferior vena
INVESTIGATIONS cava (IVC) cortisol gradients of more than 5-to-1
The baseline laboratory test results are shown in (Box 8.1).4,5 With the continuous cosyntropin infusion
Table 8.1. The patient had positive case detection protocol (cosyntropin 50 mcg/h administered intrave-
testing for PA with a plasma aldosterone concen- nously starting 30 minutes before AVS and continued
tration (PAC) >10 ng/dL and plasma renin activity throughout the procedure), the adrenal-to-IVC cortisol
31
32 SECTION B Primary Aldosteronism

Sodium 138 135–145
Potassium 4.2 3.6–5.2
Creatinine 0.8 0.8–1.3
eGFR >60 >60 mL/min/BSA
Aldosterone 18 ≤21 ng/dL
Plasma renin activity <0.6 ≤0.6–3 ng/mL per hour
DHEA-S 48.9 9.7–159 mcg/dL
1-mg overnight DST <1.0 <1.8 mcg/dL
24-hour urine aldosterone 20 <12 mcg if 24-hour urine sodium >200 mEq
24-hour urine sodium 190 Goal for oral sodium loading >200 mEq
BSA, Body surface area; DHEA-S, dehydroepiandrosterone-sulfate; DST, dexamethasone suppression test; eGFR, estimated
glomerular filtration rate.
Fig. 8.1 An unenhanced adrenal-dedicated computed tomogra-

phy scan (axial image) showed a lipid-rich (−1 Hounsfield unit)
1.6-cm left adrenal nodule (arrow).
gradients are typically well above the 5-to-1 cutoff (in adrenal nodule in the left adrenal gland was not the
this case, 25-to-1 on the right and 9.2-to-1 on the source of aldosterone excess, and AVS prevented surgi-
left). Each adrenal vein aldosterone (A) concentration cal mismanagement based on CT scan findings.
is divided by the respective cortisol (C) concentration
for the A/C ratio (see Box 8.1). The A/C ratio from the TREATMENT
dominant adrenal is divided by the A/C ratio from the The patient was advised to start treatment with spi-
nondominant adrenal to determine the aldosterone ronolactone 50 mg daily. Treatments with potassium
lateralization ratio. In this case, an A/C ratio of 5.4 on chloride and metoprolol were discontinued. The
the right is divided by an A/C ratio of 3.3 on the left, patient was advised to monitor blood pressure daily
yielding an aldosterone lateralization ratio of 1.7-to-1 and follow up with her primary care physician for
(right to left).When the aldosterone lateralization ratio medication adjustments with a target average blood
is <3-to-1 and the A/C ratio from each adrenal vein pressure of <135/85 mmHg. The dosage of spirono-
is greater than the A/C ratio in the IVC, the patient is lactone was not guided by blood pressure but rather
presumed to have bilateral idiopathic hyperplasia and by serum potassium concentration. She was advised to
medical management is advised.1,4 Thus the 1.6-cm have serum potassium checked weekly and the dose of
8 Primary Aldosteronism With Unilateral Adrenal Nodule on Computed Tomography 33
BOX 8.1 ADRENAL VEIN SAMPLINGa was advised to have no further imaging follow-up of
Right AV IVC Left AV the nonfunctioning lipid-rich left adrenal adenoma.
Aldosterone, ng/dL 3110 38 690
Key Points
Cortisol, mcg/dL 576 23 212
A/C ratiob 5.4 1.7 3.3 • Computed cross-sectional imaging of the adre-
Aldosterone lateralization ratio 1.7-to-1 (right-to-left) nal glands is not accurate in determining if PA is
A/C ratios from both adrenal veins (5.4 on RT and 3.3 on LT) caused by unilateral or bilateral adrenal disease.
> A/C ratio in IVC (1.7) Bottom line: don’t trust CT!
aSequential AVS completed under continuous cosyntropin infu-
• Use common sense in interpreting confirmatory
sion 50 mcg/h. testing for PA.
bEach adrenal aldosterone concentration is divided by the re-
• The correct dosage of a mineralocorticoid antago-
spective cortisol concentration for the A/C ratio. The A/C ratio
from the dominant adrenal is divided by the A/C ratio from the
nist is whatever it takes to achieve a target serum
nondominant adrenal for the aldosterone lateralization ratio. In potassium of 4.5 mEq/L without the aid of potas-
this case, 5.4 on the right is divided by 3.3 on the left, yield- sium supplements.
ing an aldosterone lateralization ratio of 1.7-to-1 (right to left).
When the aldosterone lateralization ratio is <3-to-1 and the A/C
ratios from both adrenal veins are greater than the A/C ratio in REFERENCES
the IVC, the data are consistent with bilateral idiopathic adrenal
1. Young WF Jr. Diagnosis and treatment of primary
hyperplasia.
aldosteronism: practical clinical perspectives. J Intern Med.
A, Aldosterone; AV, adrenal vein; C, cortisol; LT, left; RT, right;
2019;285(2):126–148.
IVC, inferior vena cava.
2. Funder JW, Carey RM, Mantero F, et al. The
management of primary aldosteronism: case detection,
diagnosis, and treatment: an Endocrine Society
spironolactone increased as needed for a target serum Clinical Practice Guideline. J Clin Endocrinol Metab.
potassium concentration of 4.5 mEq/L. 2016;101(5):1889–1916.
3. Sawka AM, Young WF, Thompson GB, et al. Primary
OUTCOME AND FOLLOW-UP aldosteronism: factors associated with normalization
of blood pressure after surgery. Ann Intern Med.
To achieve a target serum potassium of 4.5 mEq/L, 2001;135(4):258–261.
the patient’s dose of spironolactone was increased to 4. Young WF, Stanson AW, Thompson GB, Grant CS, Farley
100 mg daily. With improved blood pressure control, DR, van Heerden JA. Role for adrenal venous sampling in
primary aldosteronism. Surgery. 2004;136(6):1227–1235.
the dosage of amlodipine was decreased to 2.5 mg daily.
5. Young WF, Stanson AW. What are the keys to successful
CT without contrast and 1-mg DST performed 1 year adrenal venous sampling (AVS) in patients with primary
later showed no change in the size of the left adrenal aldosteronism? Clin Endocrinol (Oxf). 2009;70(1):14–17.
adenoma and normal cortisol suppression. The patient
Case 11
Primary Aldosteronism in a Patient

With Bilateral Macronodular
Adrenal Hyperplasia and Associated
Clinically Important Cortisol
Cosecretion
Bilateral macronodular adrenal hyperplasia (BMAH) angiotensin receptor blocker (losartan 100 mg daily),
is typically a computed tomography (CT)-based and a diuretic (chlorthalidone 25 mg daily). Blood
diagnosis. When patients present with primary pressure control was not optimal. At the time of refer-
aldosteronism (PA) and BMAH is found on the CT ral to Mayo Clinic he was taking 40 mEq of potas-
scan, the aldosterone hypersecretion is bilateral and sium chloride daily in an effort to maintain a normal
usually associated with cortisol cosecretion, result- serum potassium concentration. Beyond hypertension
ing in either clinically evident Cushing syndrome and hypokalemia, the patient was healthy. He had no
or subclinical Cushing syndrome (also referred to signs or symptoms of overt Cushing syndrome. He
as “mild autonomous cortisol secretion”). Adrenal did not have diabetes mellitus or osteoporosis. He had
venous sampling (AVS) is usually not needed in one first-degree relative who had been diagnosed with
this setting because, by definition, the disorder is hypertension.
bilateral. Treatment is surgical. If the patient has
subclinical Cushing syndrome (mild autonomous INVESTIGATIONS
cortisol secretion), then there is the opportunity The baseline laboratory test results are shown in Table
to resect the larger adrenal gland to debulk the 11.1. The patient had positive case detection testing
disease. If the patient has clinically overt Cushing for PA with plasma aldosterone concentration (PAC)
syndrome, bilateral adrenalectomy is the best treat- >10 ng/dL and plasma renin activity (PRA) <1.0 ng/mL
ment option. per hour.1 In addition, PA was confirmed because
when a patient has spontaneous hypokalemia (noted
prior to diuretic therapy) and PAC >20 ng/dL, there
Case Report are no other differential diagnostic possibilities
The patient was a 69-year-old man with a 34-year beyond PA.1,2 Thus formal confirmatory testing with
history of hypertension; PA was diagnosed 9 years oral sodium loading or a saline infusion test was not
previously when he presented with spontaneous needed for this patient. The diagnosis of glucocorti-
hypokalemia. His visit to Mayo Clinic was triggered coid secretory autonomy was based on low serum cor-
by accelerated hypertension 6 months prior. He was ticotropin (ACTH) concentration, low-normal serum
treated with a four-drug program: calcium chan- dehydroepiandrosterone sulfate (DHEA-S) concentra-
nel blocker (nifedipine 30 mg daily), β-adrenergic tion, mild elevation in 24-hour urinary free cortisol
blocker (carvedilol 12.5 mg twice daily), an excretion, and lack of complete suppression in serum
42
11 Aldosterone and Cortisol Co-secreting Bilateral Macronodular Adrenal Hyperplasia 43

Reference
Potassium, mmol/L 4.0 3.6–5.2
Creatinine, mg/dL 1.0 0.8–1.3
Aldosterone, ng/dL 24 ≤21 ng/dL
Plasma renin activity, ng/mL per
hour <0.6 ≤0.6–3
ACTH, pg/mL 13 10–60
24-hour urine cortisol, mcg 84 <45
ACTH, Corticotropin; DHEA-S, dehydroepiandrosterone sul-
fate; DST, dexamethasone suppression test.
cortisol with an overnight 8-mg dexamethasone sup-

pression test (DST) (see Table 11.1).3 An unenhanced
abdominal CT scan showed bilateral macronodular
hyperplasia (Fig. 11.1).
The patient was informed that both adrenal glands
were producing aldosterone and cortisol. He under-
stood that because he had subclinical Cushing syn-
drome (mild autonomous cortisol excess), we had the
opportunity to start with a debulking operation by
resecting his larger right adrenal gland, and if that did
not provide a clinically significant remission, comple-
tion adrenalectomy would be needed.
TREATMENT
With perioperative glucocorticoid coverage (100 mg
hydrocortisone administered intravenously on call
to the operating room and again 8 hours later), the
patient underwent laparoscopic right adrenalectomy.
Fig. 11.1 Serial axial images of the adrenal glands (cranial images at top and caudal
images at bottom) from an unenhanced abdominal computed tomography (CT) scan.
Bilateral multinodular adrenal glands are shown (arrows). The largest nodule in the
right adrenal gland was 5.3 cm in diameter and had an unenhanced CT attenuation
of −4 Hounsfield units (HU). The largest nodule in the left adrenal gland was 4.2 cm
in diameter and had an unenhanced CT attenuation of 9 HU.
blood pressure control on a three-drug program:

β-adrenergic blocker (carvedilol 12.5 mg twice daily),
an angiotensin receptor blocker (valsartan 160 mg
daily), and a mineralocorticoid receptor antagonist
(eplerenone 50 mg daily). His serum potassium con-
centrations were high-normal. Measurements of aldo-
sterone and cortisol were normal, and the patient was
extremely pleased with the surgical outcome.
Key Points
• When a patient with PA has a CT-based diagnosis
of BMAH, the aldosterone hypersecretion is uni-
formly bilateral and AVS is not needed.
• The 8-mg overnight DST has a role to absolutely
confirm glucocorticoid secretory autonomy in
patients with an abnormal 1-mg overnight DST.
A normal serum cortisol concentration following
8-mg of dexamethasone is undetectable.
• Autonomous cortisol cosecretion is present in
most patients PA who have BMAH. If the patient
has ACTH-independent Cushing syndrome, bi-
lateral adrenalectomy is the treatment of choice,
Fig. 11.2 Gross pathology cut section of the right adrenal gland shows whereas if the patient has subclinical Cushing
diffuse nodular hyperplasia.
syndrome (mild autonomous cortisol excess),
a debulking operation by resecting the larger
adrenal gland is a reasonable first operation—
The right adrenal gland weighed 39 g (normal, 4–5 g)
recognizing that completion adrenalectomy may
and on serial sectioning it had a golden-yellow mul-
be needed in the future.
tinodular cut surface (nodules ranging from 0.3 to
• Patients with BMAH who have aldosterone and
3.0 cm in greatest dimension) (Fig. 11.2). The PAC
cortisol cosecretion should have perioperative
the day after surgery was <4 ng/dL and consistent with
stress glucocorticoid coverage and on discharge
a surgical cure. Treatment with potassium chloride,
should be prescribed a morning dose of hydrocor-
losartan, nifedipine, and chlorthalidone was stopped
tisone until the hypothalamic-pituitary-adrenal
the day after surgery. On discharge from the hospital
axis recovers.
the patient was prescribed carvedilol and advised to
monitor his blood pressure daily, and blood pressure
medications were adjusted as needed for high-normal REFERENCES
blood pressure for the first month after surgery. The 1. Young WF Jr. Diagnosis and treatment of primary
patient was discharged from the hospital with instruc- aldosteronism: practical clinical perspectives. J Intern Med.
2019;285(2):126–148.
tions to take 20 mg of hydrocortisone every morning
and to decrease the dosage to 15 mg every morning management of primary aldosteronism: case detection,
in 2 weeks. diagnosis, and treatment: an Endocrine Society
Clinical Practice Guideline. J Clin Endocrinol Metab.
OUTCOME AND FOLLOW-UP 2016;101(5):1889–1916.
3. Tokumoto M, Onoda N, Tauchi Y, et al. A case of
The patient’s serum cortisol was normal 2 weeks after Adrenocoricotrophic hormone-independent bilateral
surgery, and hydrocortisone was discontinued. Four- adrenocortical macronodular hyperplasia concomitant
teen months after surgery the patient had excellent with primary aldosteronism. BMC Surg. 2017;17(1):97.
Case 7
Primary Aldosteronism: When

Adrenal Venous Sampling Is
Not Needed Before Unilateral
Adrenalectomy
There is a small subset of patients (≈5%) with INVESTIGATIONS

primary aldosteronism (PA) in whom surgical man- The baseline laboratory test results are shown in
agement can proceed without the need for adre- Table 7.1. The patient had positive case detection
nal venous sampling (AVS). This subset includes testing for PA with a plasma aldosterone concentra-
those patients with the following characteristics: tion (PAC) >10 ng/dL and plasma renin activity (PRA)
young (≤35 years), marked PA as demonstrated by <1.0 ng/mL per hour.1 In addition, PA was confirmed
spontaneous hypokalemia and plasma aldosterone because when a patient has spontaneous hypokale-
concentration >30 ng/dL, and unilateral macroad- mia and the PAC >20 ng/dL, there are no other dif-
enoma on adrenal computed tomography (CT) ferential diagnostic possibilities beyond PA.1,2 Thus
scan. formal confirmatory testing with oral sodium load-
ing or a saline infusion test was not needed for this
patient. The serum dehydroepiandrosterone sulfate
Case Report (DHEA-S) concentration was mid-normal and cor-
The patient was a 35-year-old man with a 4-year tisol suppressed normally with an overnight 1-mg
history of hypertension. He was treated with a dexamethasone suppression test (DST) (Table 7.1).
three-drug program: central α2-agonist (clonidine Thus the adrenal adenoma was not cosecreting
0.2 mg daily), calcium channel blocker (amlodipine cortisol.
10 mg daily), and an angiotensin receptor blocker An unenhanced adrenal-dedicated CT scan showed
(valsartan 80 mg daily). Blood pressure control a lipid-rich 2.0 × 1.0–cm right adrenal nodule (Fig. 7.1).
with these three medications was good. However, The left adrenal gland appeared normal on CT.
spontaneous hypokalemia had become a major The patient was informed that in view of his young
problem requiring hospitalization on two occa- age and severe PA, it was very likely (>95% probabil-
sions for potassium chloride infusions. At the time ity) that his right adrenal nodule was indeed an aldo-
of referral to Mayo Clinic he was taking 80 mEq sterone-producing adenoma (APA). This conclusion
of potassium chloride daily to maintain a normal was based on the understanding that nonfunctioning
serum potassium concentration. Beyond hyperten- adrenal nodules are uncommon in young people, and
sion and hypokalemia, the patient was healthy. He severe PA requires a large factory—typically an adre-
had no signs or symptoms of Cushing syndrome. nal macroadenoma.3,4 In a study from Mayo Clinic
He had no first-degree relatives who had been diag- published in 2014, although the overall accuracy
nosed with hypertension. of CT and magnetic resonance imaging in detecting
28
7 Primary Aldosteronism: When Adrenal Venous Sampling Is Not Needed Before Unilateral Adrenalectomy 29
with mineralocorticoid receptor blockade.7 In a ret-

rospective case series from 12 centers with data for
Reference 705 patients with PA who were treated surgically,
259 (37%) were cured of hypertension and 334
Sodium, mmol/L 142 135–145 (47%) were improved; complete clinical success was
Potassium, mmol/L 4.1 3.6–5.2 more likely in female and younger patients.8 Preop-
Creatinine, mg/dL 1.2 0.8–1.3 erative factors predictive of some degree of persis-
Aldosterone, ng/dL 54 ≤21 ng/dL tent hypertension after adrenalectomy include: more
Plasma renin activity ng/mL <0.6 ≤0.6–3 than one first-degree relative with hypertension, use
per hour
of more than two antihypertensive agents, older age,
increased serum creatinine level, and longer duration
1-mg overnight DST <1.0 <1.8
of hypertension.5
DHEA-S, Dehydroepiandrosterone-sulfate; DST, dexamethasone The patient underwent laparoscopic right adrenal-
suppression test.
ectomy. The right adrenal gland weighed 7.9 g (nor-
mal adrenal gland weight is 4–5 g) and contained
unilateral adrenal disease in patients with PA was poor a 2.3 × 1.6 × 1.1 cm yellow cortical adenoma (Fig.
at 58.6%, adrenal imaging performed well in those 7.2). The PAC the day after surgery was 1.2 ng/dL
patients younger than 35 years of age, with 100% accu- and consistent with a surgical cure. Treatment with
racy when an adrenal mass was detected.4 The patient potassium chloride and losartan was stopped the day
understood that a cure of his hypertension with sur- after surgery. The dosages of amlodipine and cloni-
gery was a reasonable goal in view of his short dura- dine were decreased by 50%. The patient was advised
tion of hypertension and lack of a family history of to monitor his blood pressure daily and blood pres-
hypertension.1,5 sure medications adjusted as needed for high-normal
blood pressure for the first month after surgery.
TREATMENT
The optimal treatment of APA or unilateral hyperpla- OUTCOME AND FOLLOW-UP
sia is curative surgery, because hypertension control The patient’s weekly blood potassium concentrations
is improved in all patients and no blood pressure remained high-normal over 4 weeks after surgery.
medications are required in 30%–60% of individu- Serum creatinine remained normal. Two years postop-
als.4–6 In addition, quality-of-life outcomes are supe- eratively the patient had normal blood pressure with-
rior with surgical cure versus medical management out the need for antihypertensive medications.
Fig. 7.1 Axial (A) and coronal (B) images from an unenhanced adrenal-dedicated computed tomography (CT) scan showed a lipid-rich (0.4 Houn-
sfield units) 1.0 × 2.0 cm right adrenal nodule (arrow). The left adrenal gland appeared normal on all images.
Fig. 7.2 The right adrenal gland weighed 7.9 g (normal adrenal
weight is 4–5 g) and contained a 2.3 × 1.6 × 1.1 cm yellow corti-
cal adenoma shown in the cut section.
Key Points REFERENCES

• Nearly all patients with PA who want to pursue 1. Young WF Jr. Diagnosis and treatment of primary
aldosteronism: practical clinical perspectives. J Intern Med.
the surgical option should undergo AVS. How- 2019;285(2):126–148.
ever, there are exceptions to this rule. 2. Funder JW, Carey RM, Mantero F, et al. The
• In general, patients with PA due to an APA have management of primary aldosteronism: case detection,
more severe manifestations than those with bilat- diagnosis, and treatment: an Endocrine Society
eral idiopathic hyperplasia. 2016;101(5):1889–1916.
• There is an age-related prevalence of nonfunc- 3. Young WF Jr. Clinical practice. The incidentally discovered
tional adrenal nodules: they are rare in individu- adrenal mass. N Engl J Med. 2007;356(6):601–610.
als ≤35 years old but relatively common in those 4. Lim V, Guo Q, Grant CS, et al. Accuracy of adrenal
>70 years old. imaging and adrenal venous sampling in predicting
surgical cure of primary aldosteronism. J Clin Endocrinol
• In the setting of a young (≤35 years) patient with Metab. 2014;99(8):2712–2719.
PA who presents with severe PA (defined as spon- 5. Sawka AM, Young WF, Thompson GB, et al. Primary
taneous hypokalemia and PAC >30 ng/dL) and a aldosteronism: factors associated with normalization
unilateral adrenal macroadenoma (>1 cm) on CT of blood pressure after surgery. Ann Intern Med.
2001;135(4):258–261.
scan, the clinician may consider bypassing AVS
6. Benham JL, Eldoma M, Khokhar B, Roberts DJ, Rabi
and proceeding to unilateral laparoscopic adre- DM, Kline GA. Proportion of patients with hypertension
nalectomy (assuming that the contralateral adre- resolution following adrenalectomy for primary
nal gland is morphologically normal on CT). aldosteronism: a systematic review and meta-analysis.
J Clin Hypertens (Greenwich). 2016;18:1205–1212.
• Preoperative factors in favor of a cure of hyper-
7. Velema M, Dekkers T, Hermus A, et al. Quality of life in
tension following unilateral adrenalectomy in primary aldosteronism: a comparative effectiveness study
patients with PA include no family history of hy- of adrenalectomy and medical treatment. J Clin Endocrinol
pertension, use of two or fewer antihypertensive Metab. 2018;103(1):16–24.
agents, younger age, normal serum creatinine 8. Williams TA, Lenders JWM, Mulatero P, et al. Outcomes
after adrenalectomy for unilateral primary aldosteronism:
level, and shorter duration of hypertension (e.g., an international consensus on outcome measures and
<10 years). analysis of remission rates in an international cohort.
Lancet Diabetes Endocrinol. 2017;5:689–699.
Case 9
Primary Aldosteronism With

Bilateral Adrenal Nodules on
Computed Tomography
The differential diagnosis in a patient with primary At the time of referral to Mayo Clinic he was taking
aldosteronism (PA) when bilateral adrenocortical 160 mEq of potassium chloride daily to maintain a
nodules are found on adrenal computed tomogra- normal serum potassium concentration. Beyond
phy (CT) scan includes bilateral idiopathic nodular hypertension and chronic kidney disease (CKD), the
hyperplasia, bilateral aldosterone-producing adre- patient was healthy. He had no signs or symptoms of
nal adenomas, unilateral aldosterone-producing Cushing syndrome.
adenoma and contralateral nonfunctioning nodule,
and a mix of aldosterone- and cortisol-producing INVESTIGATIONS
adrenal adenomas. All patients who have an adre- The baseline laboratory test results are shown in
nal nodule on CT should be evaluated for cortisol Table 9.1. The serum creatinine concentration was
secretory autonomy with baseline blood dehydro- consistent with stage 3a CKD—likely the result of
epiandrosterone sulfate (DHEA-S) concentration long-standing untreated PA.1–3 The patient had positive
and an overnight dexamethasone suppression test case detection testing for PA with a plasma aldoste-
(DST). Whether to pursue subtype evaluation with rone concentration (PAC) >10 ng/dL and plasma renin
adrenal venous sampling (AVS) is based on a shared activity (PRA) <0.6 ng/mL per hour.1 In addition, PA
decision-making discussion with the patient. If the was confirmed because when a patient has spontane-
patient would like to pursue the surgical treatment ous hypokalemia and the PAC >20 ng/dL, there are no
option and is a reasonable surgical candidate, then other differential diagnostic possibilities beyond PA.1,2
AVS is the best next step. Thus formal confirmatory testing with oral sodium
loading or a saline infusion test was not needed.
The low-normal levels of DHEA-S and corticotropin
Case Report (ACTH) suggested that there may be a component
The patient was a 69-year-old African American of subclinical glucocorticoid secretory autonomy—a
man with a 15-year history of hypertension. He was suggestion that was confirmed with lack of normal
treated with a three-drug program: β-adrenergic suppression of the serum cortisol concentration with
blocker (carvedilol 25 mg twice daily), direct vaso- the overnight 2-mg DST (see Table 9.1).
dilator (hydralazine 100 mg three times per day), An unenhanced adrenal-dedicated CT scan showed
and an angiotensin receptor blocker (losartan 50 mg a lipid-rich 1.2 × 1.6 cm right adrenal nodule and a
daily). Blood pressure control was not optimal, lipid-poor 1.0-cm left adrenal nodule (Fig. 9.1).
with systolic blood pressures typically in the mid- After a thorough discussion with the patient, it was
150s mmHg. Spontaneous hypokalemia was first clear that the patient was keen to pursue a surgical
noted 7 years previously with serum potassium cure of hypokalemia and better control of his hyper-
concentrations of 3.2 mmol/L and 3.1 mmol/L, but tension on less medication. He understood that a cure
remarkably, he was not tested for PA until recently. of his hypertension with surgery was not a reasonable
34
9 Primary Aldosteronism With Bilateral Adrenal Nodules on Computed Tomography 35
TABLE 9.1 Laboratory Tests the serum creatinine will rise after effective treatment
with either surgery or treatment with a mineralocorti-
coid receptor antagonist.1,5
Sodium 146 135–145 AVS was performed as the next step. The patient
Potassium 4.5 3.6–5.2 was well hydrated with intravenously administered
Creatinine 1.6 0.8–1.3 saline. In addition, care was taken to limit the use of
eGFR 52 >60 mL/min per BSA contrast dye. AVS was successful based on adrenal
Aldosterone 71 ≤21 ng/dL vein-to-inferior vena cava (IVC) cortisol gradients of
Plasma renin activity <0.6 ≤0.6–3 ng/mL per hour more than 5-to-1 (Box 9.1).6,7 With the continuous
DHEA-S 37.3 25–131 mcg/dL cosyntropin infusion protocol (cosyntropin 50 mcg/h
ACTH 12 7.2–63 pg/mL administered intravenously starting 30 minutes before
2-mg overnight DST 2.6 <1.8 mcg/dL AVS and continued throughout the procedure), the
ACTH, Corticotropin; BSA, body surface area; DHEA-S, dehy- adrenal-to-IVC cortisol gradients are typically well
droepiandrosterone-sulfate; DST, dexamethasone suppression above the 5-to-1 cutoff (in this case, 22.8-to-1 on the
test; eGFR, estimated glomerular filtration rate.
right and 13.1-to-1 on the left). Each adrenal aldoste-
rone concentration is divided by the respective corti-
goal in view of the duration of hypertension of >10 sol concentration for the A/C ratio (see Box 9.1). The
years and the presence of CKD.1,4 He was also coun- A/C ratio from the dominant adrenal is divided by the
seled that patients with PA hyperfiltrate at the kid- A/C ratio from the nondominant adrenal for the aldo-
ney the degree of renal insufficiency is actually worse sterone lateralization ratio. In this case, 46.8 on the
than it appears—PA “masks” the degree of underlying left is divided by 1.9 on the right, yielding an aldo-
CKD.1,5 This is not a reason to avoid effective therapy sterone lateralization ratio of 24.6-to-1 (left-to-right).
for a patient, but rather something that the patient and When the aldosterone lateralization ratio is >4-to-1,
all of his or her physicians need to understand because unilateral adrenalectomy will be curative.1,6 It is also
Fig. 9.1 An unenhanced adrenal-dedicated computed tomog-

raphy scan showed a lipid-rich (−1.9 Hounsfield units [HU])
1.2 × 1.6 cm right adrenal nodule (arrow) and a lipid-poor (22.2 HU)
1.0-cm left adrenal nodule (arrow).
BOX 9.1 ADRENAL VEIN SAMPLINGa by the A/C ratio from the IVC.1,6 In this case, the A/C
ratio of 1.9 on the right was divided by 9.4 from the
Right AV IVC Left AV
IVC, yielding a value of 0.2. Contralateral adrenal sup-
Aldosterone, ng/dL 790 170 11,000
pression is confirmed when this value is <1.0. Thus
Cortisol, mcg/dL 411 18 235
the larger adrenal nodule in the right adrenal gland
A/C ratiob 1.9 9.4 46.8
was not the source of aldosterone excess.
Aldosterone lateralization ratio 24.6-to-1
Contralateral suppression index 0.2 TREATMENT
aSequential AVS completed under continuous cosyntropin infu- The patient underwent laparoscopic left adrenalec-
sion 50 mcg/h.
bEach adrenal aldosterone concentration is divided by the re- tomy. The left adrenal gland weighed 9 g and con-
spective cortisol concentration for the A/C ratio. The A/C ratio tained a 1.5 × 1.0 × 0.9 cm yellow cortical adenoma
from the dominant adrenal is divided by the A/C ratio from the (Fig. 9.2). The PAC the day after surgery was <4 ng/dL
nondominant adrenal for the aldosterone lateralization ratio. In
this case, 46.8 on the left is divided by 1.9 on the right, yield- and consistent with a surgical cure. In view of the mild
ing an aldosterone lateralization ratio of 24.6-to-1 (left to right). degree of glucocorticoid secretory autonomy, he was
When the aldosterone lateralization ratio is >4-to-1, unilateral given perioperative glucocorticoid coverage and was
adrenalectomy will be curative. An additional predictor of uni-
lateral disease is when the nondominant adrenal vein A/C ratio sent home on prednisone 5 mg every morning with
is less than that in the IVC and this is termed the contralateral the plan to check a morning serum cortisol 2 weeks
suppression index. later. Treatment with potassium chloride and losar-
AV, Adrenal vein; IVC, inferior vena cava.
tan was stopped the day after surgery. The patient
was advised to monitor his blood pressure daily and
reassuring to confirm relative suppression of aldo- blood pressure medications adjusted as needed for
sterone secretion from the nondominant adrenal by high-normal blood pressure for the first month after
dividing the A/C ratio from the nondominant adrenal surgery.
Fig. 9.2 The left adrenal gland weighed 9 g (normal adrenal

weight is 4 g) and contained a 1.5 × 1.0 × 0.9–cm yellow cortical
adenoma shown in the cut section on the right.
9 Primary Aldosteronism With Bilateral Adrenal Nodules on Computed Tomography 37
OUTCOME AND FOLLOW-UP • When a patient with PA has bilateral adrenal nod-
The patient’s weekly blood potassium concentrations ules, AVS is mandatory if the patient wants to
remained normal (3.7, 4.4, 4.4, and 4.2 mmol/L), and pursue a surgical cure.
treatment with fludrocortisone was not needed. The • Due to the hyperfiltration associated with un-
8 am serum cortisol was checked before his morning treated PA, renal function appears better than it is
dose of prednisone 2 weeks after surgery and was and serum creatinine will rise with effective treat-
normal (15.2 mcg/dL). Prednisone was discontinued. ment of PA.
One month after surgery, as predicted, the serum cre- • Reasonable surgical treatment goals in those pa-
atinine rose to 1.9 mg/dL with an estimated glomerular tients with PA who have had hypertension for
filtration rate (eGFR) of 43 (stage 3b CKD). One year more than 10 years are resolution of hypokalemia
postoperatively the adrenal magnetic resonance imag- and improved hypertension control on 50% less
ing scan showed no change in the right adrenal nod- medication.
ule. Two years postoperatively the patient had good
blood pressure control on amlodipine 10 mg daily,
REFERENCES
carvedilol 6.25 mg daily, and hydralazine 50 mg twice
daily. His serum potassium concentration remained aldosteronism: practical clinical perspectives. J Intern Med.
normal at 4.1 mmol/L and the serum creatinine was 2019;285(2):126–148.
slightly higher at 2.15 mg/dL (eGFR 37). The 1-mg 2. Funder JW, Carey RM, Mantero F, et al. The management
overnight DST was normal. of primary aldosteronism: case detection, diagnosis, and
treatment: an endocrine society clinical practice
guideline. J Clin Endocrinol Metab. 2016;101(5):
Key Points 1889–1916.
• Most patients with PA remain undiagnosed for 3. Nishiyama A. Pathophysiological mechanisms of
years. What was remarkable in this case was that mineralocorticoid receptor-dependent cardiovascular
and chronic kidney disease. Hypertens Res.
despite chronic hypokalemia, it was 7 years be- 2019;42(3):293–300.
fore case detection testing for PA was performed 4. Sawka AM, Young WF, Thompson GB, et al. Primary
for this patient. aldosteronism: factors associated with normalization
• To prevent PA-related cardiac disease and renal of blood pressure after surgery. Ann Intern Med.
2001;135(4):258–261.
dysfunction, all patients with hypertension should
5. Kim IY, Park IS, Kim MJ, et al. Change in kidney
have case detection testing for PA at least once. function after unilateral adrenalectomy in patients
• In the setting of spontaneous hypokalemia, PAC with primary aldosteronism: identification of risk
>20 ng/dL, and PRA <1 ng/mL per hour, formal factors for decreased kidney function. Int Urol Nephrol.
2018;50(10):1887–1895.
confirmatory testing for PA is not needed.
6. Young WF, Stanson AW, Thompson GB, Grant CS, Farley
• All patients with PA who have an adrenal nod- DR, van Heerden JA. Role for adrenal venous sampling in
ule on CT should be screened for subclinical glu- primary aldosteronism. Surgery. 2004;136(6):1227–1235.
cocorticoid secretory autonomy with a baseline 7. Young WF, Stanson AW. What are the keys to successful
DHEA-S and an overnight DST. adrenal venous sampling (AVS) in patients with primary
aldosteronism? Clin Endocrinol (Oxf). 2009;70(1):14–17.
• Subclinical glucocorticoid secretory autonomy,
when mild, does not interfere with the interpreta-
tion of AVS.
Case 10
Primary Aldosteronism Caused by

Unilateral Adrenal Hyperplasia
There are six subtypes of primary aldosteronism formal confirmatory testing was not needed.1,2 The
(PA). The most common subtype of PA is bilateral baseline dehydroepiandrosterone sulfate (DHEA-S)
idiopathic adrenal hyperplasia (IHA) (≈60% of was normal (see Table 10.1). An enhanced adrenal-
patients) (see Case 8). The second most common dedicated CT scan showed nodular thickening of the
subtype of PA, in approximately 30% of patients, is left adrenal gland (Fig. 10.1).
caused by a unilateral aldosterone-producing ade- After a thorough discussion with him, the patient
noma (APA) (see Cases 7, 9, 12, 13, 14, and 15). was keen to pursue a surgical cure of hypokalemia and
The third most common subtype of PA is unilateral better control of his hypertension on less medication.
or primary adrenal hyperplasia (referred to as UAH He understood that a cure of his hypertension with
or PAH). The diagnosis of UAH is based on (1) surgery was not a reasonable goal in view of the dura-
unilateral adrenal localization with adrenal venous tion of hypertension of >10 years.1,3
sampling (AVS), (2) lack of an adrenal adenoma AVS was performed as the next step (Fig. 10.2).
and the presence of zona glomerulosa hyperplasia AVS was successful based on adrenal vein-to–inferior
on pathology, and (3) long-term cure of PA with vena cava (IVC) cortisol gradients of more to 5-to-1
unilateral adrenalectomy. (Box 10.1).4,5 With the continuous cosyntropin
infusion protocol (cosyntropin 50 mcg/h adminis-
tered intravenously starting 30 minutes before AVS
Case Report and continued throughout the procedure), the adre-
The patient was a 65-year-old man who had been nal-to-IVC cortisol gradients are typically well above
hypertensive for 20 years. He had spontaneous the 5-to-1 cutoff (in this case, 55.5-to-1 on the right
hypokalemia for the past 4 years. He was treated and 30-to-1 on the left). Each adrenal vein aldoste-
with 60 mEq of potassium chloride per day along rone (A) concentration is divided by the respective
with five antihypertensive drugs including cloni- cortisol (C) concentration for the A/C ratio (see Box
dine (0.3 mg twice daily), doxazosin (8 mg daily), 10.1). The A/C ratio from the dominant adrenal
lisinopril (40 mg daily), verapamil (240 mg twice is divided by the A/C ratio from the nondominant
daily), and hydralazine (100 mg three times per day). adrenal to determine the aldosterone lateralization
He had a subarachnoid hemorrhage 6 years previ- ratio. In this case, an A/C ratio of 13.8 on the left
ously that left him with left-sided weakness. He had is divided by an A/C ratio of 0.5 on the right, yield-
no signs or symptoms of Cushing syndrome. ing an aldosterone lateralization ratio of 25.5-to-1
(left to right). When the aldosterone lateralization
INVESTIGATIONS ratio is >4-to-1, unilateral adrenalectomy will be
The baseline laboratory test results are shown in curative.1,6 It is also reassuring to confirm relative
Table 10.1. The patient had positive case detection suppression of aldosterone secretion from the non-
testing for PA with a plasma aldosterone concen- dominant adrenal by dividing the A/C ratio from
tration (PAC) >10 ng/dL and plasma renin activity the nondominant adrenal by the A/C ratio from the
(PRA) <1.0 ng/mL per hour.1 Because the patient had IVC.1,6 In this case, the A/C ratio of 0.2 on the right
spontaneous hypokalemia and a PAC >20 ng/dL, was divided by 2.4 from the IVC, yielding a value
38
10 Primary Aldosteronism Caused by Unilateral Adrenal Hyperplasia 39
TABLE 10.1 Laboratory Tests cure. His home-going medications included clonidine
(0.3 mg twice daily), doxazosin (8 mg daily), lisino-
pril (20 mg daily), verapamil (240 mg twice daily),
Sodium 146 135–145 and hydralazine (50 mg three times per day). Treat-
Potassium 3.8 3.6–5.2 ment with potassium chloride and doxazosin was
Creatinine 1.0 0.8–1.3 discontinued. The patient was advised to monitor his
eGFR >60 >60 mL/min per BSA blood pressure daily and blood pressure medications
Aldosterone 36 ≤21 ng/dL adjusted as needed for high-normal blood pressure for
Plasma renin activity <0.6 ≤0.6–3 ng/mL per hour the first month after surgery.
DHEA-S 146 12–227 mcg/dL
BSA, Body surface area; DHEA-S, dehydroepiandrosterone OUTCOME AND FOLLOW-UP
sulfate; eGFR, estimated glomerular filtration rate. The patient’s weekly blood potassium concentrations
over 4 weeks were normal, and treatment with fludro-
cortisone was not needed. The underlying pathophysi-
of 0.08. Contralateral adrenal suppression is con- ology of UAH is unknown. In our Mayo Clinic series
firmed when this value is <1.0. of 203 patients with PA published in 2004, UAH was
diagnosed in 8 patients (4%).4 Postoperatively, with a
TREATMENT mean follow-up of 6.2 years, six of the eight patients
The patient underwent laparoscopic left adrenalec- (75%) were normotensive without the aid of antihy-
tomy. The left adrenal gland weighed 13.2 g (normal, pertensive drugs, and none had recurrent PA.4 In a
4–5 g), and the cut surface of the adrenal gland was more recent surgical series from Mayo Clinic pub-
uniform yellow-brown in color, soft, and no adenoma lished in 2019, UAH was diagnosed in 33 of 206
was present. Microscopic examination showed corti- patients with PA who were sent to surgery.6 Patients
cal hyperplasia (Table 10.2). The PAC the day after with UAH were more likely to be male, undergo left-
surgery was <4 ng/dL and consistent with a surgical sided adrenalectomy, and had lower median AVS
Fig. 10.1 An enhanced abdominal computed tomography scan (axial image) showed nodular thickening of the left adrenal gland. A, Superior limb
of the left adrenal gland is thickened (arrow). B, Inferior limb of the left adrenal gland is also thickened (arrow).
Fig. 10.2 Radiographs from adrenal venous sampling. A, Right adrenal venous anatomy is shown with contrast administration. B, Left adrenal vein
venous anatomy is shown.
BOX 10.1 ADRENAL VEIN SAMPLINGa

TABLE 10.2 Forms of Primary
Right AV IVC Left AV Aldosteronism
Aldosterone, ng/dL 654 53 9280 Estimated
Cortisol, mcg/dL 1220 22 673 Proportion of
A/C ratiob 0.5 2.4 13.8 All Patients
Aldosterone lateralization ratio 25.5-to-1 Subtype of Primary Aldosteronism (PA) with PA
Contralateral suppression index 0.2 Aldosterone-producing adenoma (APA) 30%
aSequential AVS completed under continuous cosyntropin infu- Bilateral idiopathic hyperplasia (IHA) 60%
sion 50 mcg/h. Unilateral (primary) adrenal hyperplasia 4%
bEach adrenal aldosterone concentration is divided by the re-
(UAH/PAH)
spective cortisol concentration for the A/C ratio. The A/C ratio
from the dominant adrenal is divided by the A/C ratio from the Aldosterone-producing adrenocortical <1%
nondominant adrenal for the aldosterone lateralization ratio. In carcinoma
this case, 13.8 on the left is divided by 0.5 on the right, yielding Familial hyperaldosteronism (FH)
an aldosterone lateralization ratio of 25.5-to-1 (left to right). When
the aldosterone lateralization ratio is >4-to-1, unilateral adrenalec- Glucocorticoid-remediable <1%
tomy will be curative. An additional predictor of unilateral disease aldosteronism (FH type I) (germline
is when the nondominant adrenal vein A/C ratio is less than that CYP11B1/CYP11B2 chimeric gene)
in the IVC and this is termed the contralateral suppression index.
A, Aldosterone; AV, adrenal vein; C, cortisol; IVC, inferior vena FH type II (APA or IHA) (germline <6%
cava; LT, left; RT, right. CLCN2 pathogenic variants)
FH type III (germline KCNJ5 <1%
pathogenic variants)
aldosterone lateralization ratios (9.8 versus 19.8,
FH type IV (germline CACNA1H <0.1%
P = .04) compared to patients with APA. No signifi-
pathogenic variants)
cant differences in the rates of hypertension cure or
Ectopic aldosterone-producing neoplasm <0.1%
improvement were observed between patients with
10 Primary Aldosteronism Caused by Unilateral Adrenal Hyperplasia 41
UAH versus APA.6 Thus detecting and surgically man- REFERENCES

aging UAH is just as important and successful as that 1. Young WF Jr. Diagnosis and treatment of primary
for APAs. Five years after surgery our patient was nor- aldosteronism: practical clinical perspectives. J Intern Med.
2019;285(2):126–148.
mokalemic, and hypertension was well controlled on
only two antihypertensive medications (lisinopril and management of primary aldosteronism: case detection,
verapamil). diagnosis, and treatment: an Endocrine Society
2016;101(5):1889–1916.
Key Points 3. Sawka AM, Young WF, Thompson GB, et al. Primary
• Although UAH is less common than IHA or APA, aldosteronism: factors associated with normalization
of blood pressure after surgery. Ann Intern Med.
it is important to identify patients with UAH be- 2001;135(4):258–261.
cause they have a long-term cure with unilateral 4. Young WF, Stanson AW, Thompson GB, Grant CS, Farley
adrenalectomy (see Table 10.2). DR, van Heerden JA. Role for adrenal venous sampling in
• The diagnosis of UAH is made postoperatively primary aldosteronism. Surgery. 2004;136(6):1227–1235.
and is based on (1) localization to one adrenal 5. Young WF, Stanson AW. What are the keys to successful
adrenal venous sampling (AVS) in patients with primary
gland with AVS, (2) lack of an adrenal adenoma aldosteronism? Clin Endocrinol (Oxf). 2009;70(1):14–17.
and the presence of zona glomerulosa hyperplasia 6. Shariq OA, Mehta K, Thompson GB, et al. Primary
on pathology, and (3) long-term cure of PA with aldosteronism: does underlying pathology impact
unilateral adrenalectomy. clinical presentation and outcomes following unilateral
adrenalectomy? World J Surg. 2019;43(10):2469–2476.
Case 12

With an Adrenal Macroadenoma
and Clinically Important Cortisol
Cosecretion
Unlike aldosterone-producing adenomas (APAs) enzyme inhibitor (enalapril 10 mg daily). Blood pres-
that can be <1 cm in diameter and cause the full sure control was not optimal. He was referred to Mayo
syndrome of primary aldosteronism (PA), clinically Clinic for AVS. At the time of referral to Mayo Clinic
important cortisol-secreting adenomas require a he was taking 40 mEq of potassium chloride daily in
“big factory” (e.g., typically >2 cm in diameter). an effort to maintain a normal serum potassium con-
Thus when a patient with PA has a large adrenal ade- centration. Beyond hypertension and hypokalemia,
noma (>1.5 cm), clinicians should screen for corti- the patient was healthy. His body mass index was
sol cosecretion. If autonomous cortisol cosecretion 29.2 kg/m2. He had no signs or symptoms of overt
is present in a patient with PA who has a unilateral Cushing syndrome. He did not have diabetes mellitus
adrenal macroadenoma, then adrenal venous sam- or osteoporosis. He had two first-degree relatives who
pling (AVS) is not needed. Usually in this setting had been diagnosed with hypertension.
the macroadenoma is cosecreting aldosterone and
cortisol. However, even if the patient has PA caused INVESTIGATIONS
by bilateral idiopathic hyperplasia (IHA) or a con- The baseline laboratory test results are shown in Table
tralateral adrenal microadenoma, we do not have a 12.1. The patient had positive case detection test-
good long-term viable medical treatment option for ing for PA with plasma aldosterone concentration
hypercortisolism, whereas mineralocorticoid recep- (PAC) >10 ng/dL and plasma renin activity (PRA)
tor antagonists are an excellent treatment option for <1.0 ng/mL per hour.1 In addition, PA was confirmed
PA if it proves to persist following unilateral adre- because when a patient has spontaneous hypokalemia
nalectomy. Thus if AVS is performed in the setting and a PAC >20 ng/dL, there are no other differential
described in the preceding text, the findings do not diagnostic possibilities beyond PA.1,2 Thus formal
guide surgical management. confirmatory testing with oral sodium loading or a
saline infusion test was not needed for this patient.
A baseline 24-hour urine for sodium showed that this
Case Report patient was on a daily high sodium diet, which was
The patient was a 46-year-old man with a 15-year contributing to his resistant hypertension and hypo-
history of hypertension, which accelerated 10 years kalemia. Serum corticotropin (ACTH) was undetect-
ago. He was treated with a three-drug program: cal- able and the serum dehydroepiandrosterone sulfate
cium channel blocker (amlodipine 10 mg daily), (DHEA-S) concentration was low-normal, and cortisol
combined β- and α-adrenergic blocker (labetalol did not suppress with an overnight 8-mg dexametha-
400 mg twice daily), and an angiotensin-converting sone suppression test (DST) (see Table 12.1).
45
TABLE 12.1 Laboratory Tests glucocorticoid secretory autonomy and hopefully PA

too.
Reference
Biochemical Test Result Range TREATMENT
With perioperative glucocorticoid coverage (40 mg of
Potassium, mmol/L 3.3 3.6–5.2
methylprednisolone administered intramuscularly on
Creatinine, mg/dL 1.3 0.8–1.3
call to the operating room and again 12 hours later),
Aldosterone, ng/dL 26 ≤21 ng/dL
the patient underwent laparoscopic left adrenalec-
Plasma renin activity, ng/mL per <0.6 ≤0.6–3
tomy. The left adrenal weighed 36.3 g (normal, 4–5 g)
hour
and contained a 3.5 × 3.5 × 2.2–cm yellow cortical
DHEA-S, mcg/dL 62.9 48–244
adenoma. The PAC the day after surgery was <4 ng/dL
ACTH, pg/mL <5.0 10–60
and consistent with a surgical cure. Treatment with
potassium chloride and enalapril was stopped the
24-hour urine sodium, mmol 343 40–217
day after surgery. The patient was advised to monitor
24-hour urine aldosterone, mcg 28 <12 if urine
sodium his blood pressure daily and blood pressure medica-
>200 tions adjusted as needed for high-normal blood pres-
mmol sure for the first month after surgery. On discharge
ACTH, Corticotropin; DHEA-S, dehydroepiandrosterone-sulfate; from the hospital the patient was prescribed 20 mg
DST, dexamethasone suppression test. of hydrocortisone every morning with instructions
to decrease the dosage to 15 mg every morning in
An unenhanced adrenal-dedicated CT scan showed 2 weeks.
an indeterminate 4.2-cm left adrenal mass (Fig. 12.1).
The right adrenal gland appeared atrophic on CT. OUTCOME AND FOLLOW-UP
The patient was informed that the left adrenal mass The patient’s weekly blood potassium concentrations
was the source of glucocorticoid secretory autonomy, remained high-normal weekly for 4 weeks after sur-
and that it was also likely the source of aldosterone gery. Serum creatinine remained normal. He had good
hypersecretion. He understood that regardless of what blood pressure control on lower dosages of amlodipine
an AVS study might show, the left indeterminate adre- and labetalol. The 8 am serum cortisol concentration
nal mass should be resected with the goal curing the obtained before his morning dose of hydrocortisone
Fig. 12.1 Axial image from an unenhanced adrenal-dedicated

computed tomography (CT) scan showed an indeterminate (15.6
Hounsfield units [HU]) 4.2-cm left adrenal mass (arrow). The right
adrenal gland appeared atrophic.
12 Primary Aldosteronism in a Patient With an Adrenal Macroadenoma and Clinically Important Cortisol Cosecretion 47
was >10 mcg/dL at 6 weeks after surgery, and hydro- macroadenoma is cosecreting aldosterone and
cortisone was discontinued. cortisol.
• Patients with aldosterone and cortisol cosecreting
Key Points adenomas should have perioperative stress glu-
• When a patient with PA has a large (>1.5 cm) cocorticoid coverage and on discharge from the
adrenal adenoma, clinicians should screen for hospital prescribed a morning dose of hydrocor-
cortisol cosecretion with baseline DHEA-S and tisone until the hypothalamic-pituitary-adrenal
overnight DST. axis recovers.
• The 8-mg overnight DST has a role to absolutely
confirm glucocorticoid secretory autonomy in
REFERENCES
patients with an abnormal 1-mg overnight DST.
A normal serum cortisol concentration following aldosteronism: practical clinical perspectives. J Intern Med.
8-mg of dexamethasone is undetectable. 2019;285(2):126–148.
• If autonomous cortisol cosecretion is present in 2. Funder JW, Carey RM, Mantero F, et al. The
a patient with PA who has a unilateral adrenal management of primary aldosteronism: case detection,
diagnosis, and treatment: an Endocrine Society
macroadenoma, then adrenal venous sampling Clinical Practice Guideline. J Clin Endocrinol Metab.
(AVS) is not needed. Usually in this setting the 2016;101(5):1889–1916.
Case 13

Treated With Spironolactone
Mineralocorticoid receptor antagonists (MRAs) 1 year previously when her serum potassium level
(e.g., spironolactone and eplerenone) prevent was 2.2 mEq/L. Her home blood pressures averaged
aldosterone from activating the receptor, resulting, 117/72 mmHg. Before the hypokalemia was treated,
sequentially, in sodium loss, a decrease in plasma she had frequent nocturia, which improved with res-
volume, and an elevation in renin. If plasma renin toration of her serum potassium to normal. She had
activity (PRA) or plasma renin concentration (PRC) been treated with spironolactone for the past 1 year.
is not suppressed in a patient treated with a MRA, There was a strong family history of hypertension in
then no further primary aldosteronism (PA)-related both parents and her son, as well as the paternal aunts
testing can be performed, and the MRA should be and uncles. She had no other major medical health
discontinued for 6 weeks before retesting. How- issues. She had no signs or symptoms of Cushing
ever, if the patient is hypokalemic despite treatment syndrome.
with a MRA, then the mineralocorticoid receptors
are not fully blocked, and PRA or PRC should be INVESTIGATIONS
suppressed in such a patient with PA. In addition, The baseline laboratory test results are shown in
most patients with PA are treated with suboptimal Table 13.1. The patient had positive case detection
dosages of MRAs, and the mineralocorticoid recep- testing for PA with a PAC >10 ng/dL and the PRA
tors are not fully blocked. Thus for case detection <0.6 ng/mL per hour.1 In addition, PA was confirmed
testing, blood pressure medications, including because when a patient has spontaneous hypokalemia
MRAs, should not be discontinued. In the setting and the PAC >20 ng/dL, there are no other differen-
of suppressed PRA or PRC, clinicians can proceed tial diagnostic possibilities beyond PA.1,2 Thus formal
with case detection testing in all patients treated confirmatory testing with oral sodium loading or a
with MRAs, and the MRA does not need to be dis- saline infusion test was not needed.
continued for confirmatory or subtype testing with An unenhanced adrenal-dedicated computed
adrenal venous sampling (AVS). tomography (CT) scan showed an indeterminate
attenuation 1.2-cm right adrenal nodule and a 0.3-cm
left adrenal nodule (Fig. 13.1).
Case Report After a thorough discussion with the patient, she
The patient was a 57-year-old woman with an was keen to pursue a surgical cure of hypokalemia and
11-year history of hypertension. She was treated better control of her hypertension on less medication.
with a four-drug program: β-adrenergic blocker She understood that a complete cure of her hyperten-
(atenolol 50 mg daily), calcium channel blocker sion with surgery was not a reasonable goal in view of
(nifedipine extended release 60 mg per day), an the duration of hypertension of >10 years.1
angiotensin-converting enzyme inhibitor (lisino- AVS was already attempted elsewhere and the right
pril 20 mg daily), and a mineralocorticoid recep- adrenal vein was not successfully catheterized. The
tor antagonist (spironolactone 100 mg daily). aldosterone and cortisol values from the left adrenal
She was also taking 60 mEq of potassium chlo- vein and inferior vena cava (IVC) were not provided
ride twice daily. Hypokalemia was first noted in the outside records. Repeat AVS at Mayo Clinic was
48
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The Project Gutenberg eBook of Rachel Dyer
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Title: Rachel Dyer

A North American story
Author: John Neal
Release date: September 30, 2023 [eBook #71766]
Language: English
Original publication: US:
Credits: Alan, Steve Mattern and the Online Distributed Proofreading

Team at https://www.pgdp.net (This book was produced
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*** START OF THE PROJECT GUTENBERG EBOOK RACHEL

DYER ***
RACHEL DYER:
A NORTH AMERICAN STORY.
BY JOHN NEAL.
PORTLAND:
PUBLISHED BY SHIRLEY AND HYDE.
1828.
DISTRICT OF MAINE.... TO WIT:
DISTRICT CLERK’S OFFICE.
B E IT REMEMBERED, That on the eighth day of October, A.D. 1828, and in

the fifty-third year of the Independence of the United States of America,
Shirley & Hyde of said District, have deposited in this office, the title of a book, the
right whereof they claim as proprietors, in the words following, to wit.
“Rachel Dyer: A North American Story. By John Neal. Portland.”
In conformity to the act of the Congress of the United States, entitled “An Act for
the encouragement of learning, by securing the copies of maps, charts and books,
to the authors and proprietors of such copies, during the times therein mentioned;”
and also, to an act, entitled “An Act supplementary to an act, entitled An Art for the
encouragement of learning, by securing the copies of maps, charts and books, to
the authors and proprietors of such copies, during the times therein mentioned;
and for extending the benefits thereof to the arts of designing, engraving and
etching historical and other prints.”
J. MUSSEY, Clerk of the District of Maine.
A true copy as of record,
Attest, J. MUSSEY, Clerk D. C. Maine.
PREFACE.
I have long entertained a suspicion, all that has been said by the
novel-writers and dramatists and poets of our age to the contrary
notwithstanding, that personal beauty and intellectual beauty, or
personal beauty and moral beauty, are not inseparably connected
with, nor apportioned to each other. In Errata, a work of which as a
work, I am heartily ashamed now, I labored long and earnestly to
prove this. I made my dwarf a creature of great moral beauty and
strength.
Godwin, the powerful energetic and philosophizing Godwin, saw a
shadow of this truth; but he saw nothing more—the substance
escaped him. He taught, and he has been followed by others, among
whom are Brown, Scott and Byron, (I observe the chronological
order) that a towering intellect may inhabit a miserable body; that
heroes are not of necessity six feet high, nor of a godlike shape, and
that we may be deceived, if we venture to judge of the inward by the
outward man. But they stopped here. They did not perceive, or
perceiving, would not acknowledge the whole truth; for if we consider
a moment, we find that all their great men are scoundrels. Without
one exception I believe, their heroes are hypocrites or misanthropes,
banditti or worse; while their good men are altogether subordinate
and pitiable destitute of energy and wholly without character.
Now believing as I do, in spite of such overwhelming authority, that a
man may have a club-foot, or a hump-back, or even red hair and yet
be a good man—peradventure a great man; that a dwarf with a
distorted shape may be a giant in goodness of heart and greatness
of temper; and that moral beauty may exist where it appears not to
have been suspected by the chief critics of our age, and of past ages
—namely, in a deformed body (like that of Æsop,) I have written this
book.
Let me add however that although such was my principal, it was not
my only object. I would call the attention of our novel-writers and our
novel-readers to what is undoubtedly native and peculiar, in the early
history of our Fathers; I would urge them to believe that though there
is much to lament in that history, there is nothing to conceal; that if
they went astray, as they most assuredly did in their judgments, they
went astray conscientiously, with what they understood to be the law
of God in their right hands. The “Salem Tragedie” is in proof—that is
the ground-work of my story; and I pray the reader to have patience
with the author, if he should find this tale rather more serious in
parts, and rather more argumentative in parts, than stories, novels
and romances generally are.
I do not pretend to say that the book I now offer to my countrymen, is
altogether such a book as I would write now, if I had more leisure,
nor altogether such a book as I hope to write before I die; but as I
cannot afford to throw it entirely away, and as I believe it to be much
better, because more evidently prepared for a healthy good purpose,
than any other I have written, I have concluded to publish it—hoping
it may be regarded by the wise and virtuous of our country as some
sort of atonement for the folly and extravagance of my earlier writing.
The skeleton of this tale was originally prepared for Blackwood, as
the first of a series of North-American Stories: He accepted it, paid
for it, printed it, and sent me the proofs. A misunderstanding
however occurred between us, about other matters, and I withdrew
the story and repaid him for it. It was never published therefore; but
was put aside by me, as the frame-work for a novel—which novel is
now before the reader.
JOHN NEAL.
Portland, October 1, 1828.
P.S. After some consideration, I have concluded to publish a preface,
originally intended for the North American Stories alluded to
above. It was never published, nor has it ever been read by any
body but myself. Among those who are interested for the
encouragement of our native literature, there may be some who will
not be sorry to see what my ideas were on the subject of novel-
writing, as well as what they are. Changes have been foretold in my
views—and I owe it to our people to acknowledge, that in a good
degree, the prediction has been accomplished I do not feel now as I
did, when I wrote Seventy-Six, Randolph, and the rest of the works
published in America; nor even as I did, when I wrote those that
were published over seas. The mere novel-reader had better skip
the following pages and go directly to the story. The introductory
chapter in all human probability will be too much for him.
J. N.
UNPUBLISHED PREFACE
TO THE NORTH-AMERICAN STORIES, ALLUDED TO IN PAGE V.
The author of this work is now under the necessity of bidding the novel-
readers of the day, on both sides of the water, farewell, and in all
probability, forever. By them it may be considered a trivial affair—a time
for pleasantry, or peradventure for a formal expression of what are called
good wishes. But by him, who does not feel like other men—or does not
understand their language, when they talk in this way, it will ever be
regarded as a very serious thing. He would neither conceal nor deny the
truth—he would not so affront the feeling within him—and he says
therefore without affectation or ceremony, that it goes to his heart even to
bid the novel-readers of the age, the few that have read his novels, it
were better to say—farewell.
These volumes are the last of a series which even from his youth up, he
had been accustomed to meditate upon as a worthy and affectionate
offering to his family and to those who have made many a long winter day
in a dreary climate, very cheerful and pleasant to him—the daughters of a
dear friend—of one who, if his eye should ever fall upon this page, will
understand immediately more than a chapter could tell, of the deep
wayward strange motives that have influenced the author to say thus
much and no more, while recurring for the last time to the bright vision of
his youth. And the little that he does say now, is not said for the world;—
for what care they about the humble and innocent creatures, whose
gentleness and sincerity about their own fire-side, were for a long time all
that kept a man, who was weary and sick of the great world, from leaving
it in despair? No, it is not said for them; but for any one of that large family
who may happen to be alive now, and in the way of remembering “the
stranger that was within their gates”—when to the world he may be as if
he never had been. Let them not be amazed when they discover the truth;
nor afraid nor ashamed to see that the man whom they knew only as the
stranger from a far country, was also an author.
In other days, angels were entertained in the shape of travellers and way-
faring men; but ye—had ye known every stranger that knocked at your
door to be an angel, or a messenger of the Most High, could not have
treated him more like an immortal creature than ye did that unknown man,
who now bears witness to your simplicity and great goodness of heart.
With you it was enough that a fellow-creature was unhappy—you strove
to make him happy; and having done this, you sent him away, ignorant
alike of his people, his country and his name.
* * * * *
This work is the last of the sort I believe—the very last I shall ever write.
Reader—stop!—lay down the book for a moment and answer me. Do you
feel no emotion at the sight of that word? You are surprised at the
question. Why should you feel any, you ask. Why should you?—let us
reason together for a moment. Can it be that you are able to bear of the
final consummation of a hope which had been the chief stay of a fellow-
creature for many—many years?—Can it be that you feel no sort of
emotion at hearing him say, Lo! I have finished the work—it is the last—no
sensation of inquietude? Perhaps you now begin to see differently;
perhaps you would now try to exculpate yourself. You are willing to admit
now that the affair is one of a graver aspect than you first imagined. You
are half ready to deny now that you ever considered it otherwise. But
mark me—out of your own mouth you are condemned. Twice have I said
already—three times have I said already, that this was the last work of the
sort I should ever write, and you have read the declaration as you would,
the passing motto of a title-page. You neither cared for it, nor thought of it;
and had I not alarmed you by my abruptness, compelled you to stop and
think, and awed you by steadfastly rebuking your inhumanity, you would
not have known by to-morrow whether I had spoken of it as my last work
or not. Consider what I say—is it not the truth?—can you deny it? And yet
you—you are one of the multitude who dare to sit in judgment upon the
doings of your fellow men. It is on what you and such as you say, that
authors are to depend for that which is of more value to them than the
breath of life—character. How dare you!—You read without reflection, and
you hear without understanding. Yet upon the judgment of such as you—
so made up, it is that the patient and the profound, the thoughtful and the
gifted, are to rely for immortality.
To return to what I was about saying—the work now before you, reader, is
the last of a series, meditated as I have already told you, from my youth. It
was but a dream at first—a dream of my boyhood, indefinite, vague and
shadowy; but as I grew up, it grew stronger and braver and more
substantial. For years it did not deserve the name of a plan—it was
merely a breathing after I hardly knew what, a hope that I should live to do
something in a literary way worthy of my people—accompanied however
with an inappeasable yearning for the time and opportunity to arrive. But
so it was, that, notwithstanding all my anxiety and resolution, I could not
bring myself to make the attempt—even the attempt—until it appeared no
longer possible for me to do what for years I had been very anxious to do.
The engagement was of too sacred a nature to be trifled with—perhaps
the more sacred in my view for being made only with myself, and without
a witness; for engagements having no other authority than our moral
sense of duty to ourselves, would never be performed, after they grew
irksome or heavy, unless we were scrupulous in proportion to the facility
with which we might escape if we would.
This indeterminate, haunting desire to do what I had so engaged to do, at
last however began to give way before the serious and necessary
business of life, and the continually augmenting pressure of duties too
solemn to be slighted for any—I had almost said for any earthly
consideration. Yea more, to confess the whole truth, I had begun to
regard the enterprise itself—so prone are we to self-deception, so ready
at finding excuses where we have a duty to perform—as hardly worthy of
much power, and as altogether beneath an exalted ambition. But here I
was greatly mistaken; for I have an idea now, that a great novel—such a
novel as might be made—if all the powers that could be employed upon it
were found in one man, would be the greatest production of human
genius. It is a law and a history of itself—to every people—and throughout
all time—in literature and morals—in character and passion—yea—in
what may be called the fire-side biography of nations. It would be, if rightly
managed, a picture of the present for futurity—a picture of human nature,
not only here but every where—a portrait of man—a history of the human
heart—a book therefore, written not only in a universal, but in what may
be considered as an everlasting language—the language of immortal,
indistructable spirits. Such are the parables of Him who spoke that
language best.
Again however, the subject was revived. Sleeping and waking, by night
and by day, it was before me; and at last I began to perceive that if the
attempt were ever to be made, it must be made by one desperate,
convulsive, instantaneous effort. I determined to deliberate no longer—or
rather to stand no longer, shivering like a coward, upon the brink of
adventure, under pretence of deliberation; and therefore, having first
carefully stopped my ears and shut my eyes, I threw myself headlong
over the precipice. Behold the result! If I have not brought up the pearls, I
can say at least that I have been to the bottom—and I might have added
—of the human heart sometimes—but for the perverse and foolish
insincerity of the world, which if I had so finished the sentence, would
have set their faces forever against my book; although that same world,
had I been wise enough—no, not wise enough but cunning enough, to
hold my peace, might have been ready to acknowledge that I had been
sometimes, even where I say—to the very bottom of the human heart.
I plunged. But when I did, it was rather to relieve my own soul from the
intolerable weight of her own reproach, than with any hope of living to
complete the design, except at a sacrifice next in degree to that of self-
immolation. Would you know what more than any other thing—more than
all other things determined me at last? I was an American. I had heard the
insolent question of a Scotch Reviewer, repeated on every side of me by
native Americans—“Who reads an American Book?” I could not bear this
—I could neither eat nor sleep till my mind was made up. I reasoned with
myself—I strove hard—but the spirit within me would not be rebuked.
Shall I go forth said I, in the solitude of my own thought, and make war
alone against the foe—for alone it must be made, or there will be no hope
of success. There must be but one head, one heart in the plan—the
secret must not even be guessed at by another—it must be single and
simple, one that like the wedge in mechanics, or in the ancient military art,
must have but one point, and that point must be of adamant. Being so it
may be turned aside: A thousand more like itself, may be blunted or
shivered; but if at last, any one of the whole should make any impression
whatever upon the foe, or effect any entrance whatever into the sanctity
and strength of his tremendous phalanx, then, from that moment, the day
is our own. Our literature will begin to wake up, and our pride of country
will wake up with it. Those who follow will have nothing to do but keep
what the forlorn hope, who goes to irretrievable martyrdom if he fail, has
gained.
Moreover—who was there to stand by the native American that should go
out, haply with a sling and a stone, against a tower of strength and the
everlasting entrenchments of prejudice? Could he hope to find so much
as one of his countrymen, to go with him or even to bear his shield?
Would the Reviewers of America befriend him? No—they have not
courage enough to fight their own battles manfully.[1] No—they would
rather flatter than strike. They negociate altogether too much—where
blows are wanted, they give words. And the best of our literary
champions, would they? No; they would only bewail his temerity, if he
were the bold headlong creature he should be to accomplish the work;
and pity his folly and presumption, if he were any thing else.
[1] Or had not before this was written. Look to the North-American
Review before 1825, for proof.
After all however, why should they be reproached for this? They have
gained their little reputation hardly. “It were too much to spend that little”—
so grudgingly acquiesced in by their beloved countrymen—“rashly.” No
wonder they fight shy. It is their duty—considering what they have at stake
—their little all. There is Washington Irving now; he has obtained the
reputation of being—what?—why at the best, of being only the American
Addison, in the view of Englishmen. And is this a title to care much for?
Would such a name, though Addison stood far higher in the opinion of the
English themselves, than he now does, or ever again will, be enough to
satisfy the ambition of a lofty minded, original thinker? Would such a man
falter and reef his plumage midway up the altitude of his blinding and
brave ascent, to be called the American Addison, or even what in my view
were ten thousand times better, the American Goldsmith.[2] No—up to the
very key stone of the broad blue firmament! he would say, or back to the
vile earth again: ay, lower than the earth first! Understand me however. I
do not say this lightly nor disparagingly. I love and admire Washington
Irving. I wish him all the reputation he covets, and of the very kind he
covets. Our paths never did, never will cross each other. And so with Mr.
Cooper; and a multitude more, of whom we may rightfully be proud. They
have gained just enough popular favor to make them afraid of hazarding
one jot or tittle of it, by stepping aside into a new path. No one of these
could avail me in my design. They would have everything to lose, and
nothing to gain by embarking in it. While I—what had I to lose—nay what
have I to lose? I am not now, I never have been, I never shall be an
author by trade. The opinion of the public is not the breath of life to me;
for if the truth must be told, I have to this hour very little respect for it—so
long as it is indeed the opinion of the public—of the mere multitude, the
careless, unthinking judgment of the mob, unregulated by the wise and
thoughtful.
[2] I speak here of Goldsmith’s prose, not of his poetry. Heaven forbid!
To succeed as I hoped, I must put everything at hazard. It would not do
for me to imitate anybody. Nor would it do for my country. Who would care
for the American Addison where he could have the English by asking for
it? Who would languish, a twelvemonth after they appeared, for Mr.
Cooper’s imitations of Sir Walter Scott, or Charles Brockden Brown’s
imitations of Godwin? Those, and those only, who after having seen the
transfiguration of Raphael, (or that of Talma,) or Dominichino’s St.
Jerome, would walk away to a village painting room, or a provincial
theatre, to pick their teeth and play the critic over an imitation of the one
or a copy of the other. At the best, all such things are but imitations. And
what are imitations? Sheer mimicry—more or less exalted to be sure; but
still mimicry—wherever the copies of life are copied and not life itself: a
sort of high-handed, noon-day plagiarism—nothing more. People are
never amazed, nor carried away, nor uplifted by imitations. They are
pleased with the ingenuity of the artist—they are delighted with the
closeness of the imitation—but that is all. The better the work is done, the
worse they think of the workman. He who can paint a great picture,
cannot copy—David Teniers to the contrary notwithstanding; for David
never painted a great picture in his life, though he has painted small ones,
not more than three feet square, which would sell for twenty-five thousand
dollars to day.
Yes—to succeed, I must imitate nobody—I must resemble nobody; for
with your critic, resemblance in the unknown to the known, is never
anything but adroit imitation. To succeed therefore, I must be unlike all
that have gone before me. That were no easy matter; nor would be it so
difficult as men are apt to believe. Nor is it necessary that I should do
better than all who have gone before me. I should be more likely to
prosper, in the long run, by worse original productions—with a poor story
told in poor language, (if it were original in spirit and character) than by a
much better story told in much better language, if after the transports of
the public were over, they should be able to trace a resemblance between
it and Walter Scott, or Oliver Goldsmith, or Mr. Addison.
So far so good. There was, beyond a doubt, a fair chance in the great
commonwealth of literature, even though I should not achieve a miracle,
nor prove myself both wiser and better than all the authors who had gone
before me. And moreover, might it not be possible—possible I say—for
the mob are a jealous guardian of sepulchres and ashes, and high-
sounding names, particularly where a name will save them the trouble of
judging for themselves, or do their arguments for them in the shape of a
perpetual demonstration, whatever may be the nature of the controversy
in which they are involved—might it not be possible then, I say, that, as
the whole body of mankind have been growing wiser and wiser, and
better and better, since the day when these great writers flourished, who
are now ruling “our spirits from their urns,” that authors may have
improved with them?—that they alone of the whole human race, by some
possibility, may not have remained altogether stationary age after age—
while the least enquiring and the most indolent of human beings—the
very multitude—have been steadily advancing both in knowledge and
power? And if so, might it not be possible for some improvements to be
made, some discoveries, even yet in style and composition, by lanching
forth into space. True, we might not be certain of finding a new world, like
Columbus, nor a new heaven, like Tycho Brahe; but we should probably
encounter some phenomena in the great unvisited moral sky and ocean;
we should at least find out, after a while—which would of itself be the next
greatest consolation for our trouble and anxiety, after that of discovering a
new world or a new system,—that there remained no new world nor
system to be discovered; that they who should adventure after us, would
have so much the less to do for all that we had done; that they must
follow in our steps; that if our health and strength had been wasted in a
prodigious dream, it would have the good effect of preventing any future
waste of health and strength on the part of others in any similar
enterprize.
Islands and planets may still be found, we should say, and they that find
them, are welcome to them; but continents and systems cannot be
beyond where we have been; and if there be any within it, why—they are
neither continents nor systems.
But then, after all, there was one plain question to be asked, which no
honest man would like to evade, however much a mere dreamer might
wish to do so. It was this. After all my fine theory—what are my chances
of success? And if successful, what have I to gain? I chose to answer the
last question first. Gain!—of a truth, it were no easy matter to say. Nothing
here, nothing now—certainly nothing in America, till my bones have been
canonized; for my countrymen are a thrifty, calculating people—they give
nothing for the reputation of a man, till they are sure of selling it for more
than they give. Were they visited by saints and prophets instead of gifted
men, they would never believe that they were either saints or prophets, till
they had been starved to death—or lived by a miracle—by no visible
means; or until their cast-off clothes, bones, hair and teeth, or the furniture
of the houses wherein they were starved, or the trees under which they
had been chilled to death, carved into snuff-boxes or walking-sticks,
would sell for as much as that sympathy had cost them, or as much as it
would come to, to build a monument over—I do not say over their
unsheltered remains, for by that time there would be but little or no
remains of them to be found, unmingled with the sky and water, earth and
air about them, save perhaps in here and there a museum or college
where they might always be bought up, however, immortality and all—for
something more than compound interest added to the original cost—but
to build a monument or a shed over the unappropriated stock, with certain
privileges to the manufacturer of the walking-sticks and snuff-boxes
aforesaid, so long as any of the material remained; taking care to provide
with all due solemnity, perhaps by an act of the legislature, for securing
the monopoly to the sovereign state itself.
Thus much perhaps I might hope for from my own people. But what from
the British? They were magnanimous, or at least they would bear to be
told so; and telling them so in a simple, off-hand, ingenuous way, with a
great appearance of sincerity, and as if one had been carried away by a
sudden impulse, to speak a forbidden truth, or surprised into a prohibited
expression of feeling by some spectacle of generosity, in spite of his
constitutional reserve and timidity and caution, would be likely to pay well.
But I would do no such thing. I would flatter nobody—no people—no
nation. I would be to nobody—neither to my own countrymen, nor to the
British—unless I were better paid for it, than any of my countrymen were
ever yet paid either at home or abroad.
No—I choose to see for myself, by putting the proof touch like a hot iron
to their foreheads, whether the British are indeed a magnanimous people.
But then, if I do all this, what are my chances of reward, even with the
British themselves? That was a fearful question to be sure. The British are
a nation of writers. Their novel-writers are as a cloud. True—true—but
they still want something which they have not. They want a real American
writer—one with courage enough to write in his native tongue. That they
have not, even at this day. That they never had. Our best writers are
English writers, not American writers. They are English in every thing they
do, and in every thing they say, as authors—in the structure and moral of
their stories, in their dialogue, speech and pronunciation, yea in the very
characters they draw. Not so much as one true Yankee is to be found in
any of our native books: hardly so much as one true Yankee phrase. Not
so much as one true Indian, though you hardly take up a story on either
side of the water now, without finding a red-man stowed away in it; and
what sort of a red-man? Why one that uniformly talks the best English the
author is capable of—more than half the time perhaps out-Ossianing
Ossian.
I have the modesty to believe that in some things I am unlike all the other
writers of my country—both living and dead; although there are not a few,
I dare say who would be glad to hear of my bearing a great resemblance
to the latter. For my own part I do not pretend to write English—that is, I
do not pretend to write what the English themselves call English—I do
not, and I hope to God—I say this reverently, although one of their
Reviewers may be again puzzled to determine “whether I am swearing or
praying” when I say so—that I never shall write what is now worshipped
under the name of classical English. It is no natural language—it never
was—it never will be spoken alive on this earth: and therefore, ought
never to be written. We have dead languages enough now; but the
deadest language I ever met with or heard of, was that in use among the
writers of Queen Anne’s day.
At last I came to the conclusion—that the chances were at least a
thousand to one against me. A thousand to one said I, to myself, that I
perish outright in my headlong enterprise. But then, if I do not perish—if I
triumph, what a triumph it will be! If I succeed, I shall be rewarded well—if
the British are what they are believed to be—in fair proportion to the toil
and peril I have encountered. At any rate, whether I fail or not, I shall be,
and am willing to be, one of the first hundred to carry the war into the very
camp, yea among the very household gods of the enemy. And if I die, I
will die with my right arm consuming in the blaze of their altars—like
Mutius Scævola.
But enough on this head. The plan took shape, and you have the
commencement now before you, reader. I have had several objects in
view at the same time, all subordinate however to that which I first
mentioned, in the prosecution of my wayward enterprise. One was to
show to my countrymen that there are abundant and hidden sources of
fertility in their own beautiful brave earth, waiting only to be broken up;
and barren places to all outward appearance, in the northern, as well as
the southern Americas—yet teeming below with bright sail—where the
plough-share that is driven through them with a strong arm, will come out
laden with rich mineral and followed by running water: places where—if
you but lay your ear to the scented ground, you may hear the perpetual
gush of innumerable fountains pouring their subterranean melody night
and day among the minerals and rocks, the iron and the gold: places
where the way-faring man, the pilgrim or the wanderer through what he
may deem the very deserts of literature, the barren-places of knowledge,
will find the very roots of the withered and blasted shrubbery, which like
the traveller in Peru, he may have accidentally uptorn in his weary and
discouraging ascent, and the very bowels of the earth into which he has
torn his way, heavy with a brightness that may be coined, like the soil
about the favorite hiding places of the sunny-haired Apollo.
Another, was to teach my countrymen, that these very Englishmen, to
whom as the barbarians of ancient story did by their gods when they
would conciliate them, we are accustomed to offer up our own offspring,
with our own hands, whenever we see the sky darkening over the water—
the sky inhabited of them; ay, that these very Englishmen, to whom we
are so in the habit of immolating all that is beautiful and grand among us
—the first born of our youth—our creatures of immortality—our men of
genius, while in the fever and flush of their vanity, innocence and passion
—ere they have had time to put out their first plumage to the sky and the
wind, all above and about them—that they, these very Englishmen, would
not love us the less, nor revere us the less, if we loved and revered
ourselves, and the issue of our blood and breath, and vitality and power, a
little more. No—the men of England are men. They love manhood. They
may smile at our national vanity, but their smile would be one of
compassionate benevolence and encouragement, if we were wise
enough to keep our young at home, till their first molting season were well
over—and then, offer to pair them, even though there would be a little
presumption in it, high up in the skies, and the strong wind—with their
bravest and best: not, as we do now, upon the altars of the earth—upon
the tables of our money-changers—half fledged and untrained—with their
legs tied, and wings clipped; or, peradventure, with necks turned, and
heads all skewered under their tails—a heap of carrion and garbage that
the braver birds, even among their enemies, would disdain to stoop at.
Such would be their behavior, if we dealt as we ought with our own; there
would be no pity nor disdain with them. They would cheer us to the
conflict—pour their red wine down our throats if we were beaten; and if
their birds were beaten, they would bear it with temper—knowing that
their reputation could well afford an occasional trumph, to the young of
their favorite brood. The men of England are waiting to do us justice: but
there is a certain formality to be gone through with, before they will do it.
We must claim it. And why should we not? I do not mean that we should
claim it upon our knees as the condemned of their courts of justice are
compelled to claim that mercy, which the very law itself, has
predetermined to grant to him—but will not, unless that idle and unworthy
formality has been submitted to; no—I mean no such thing. We do not
want mercy: and I would have my countrymen, when they are arraigned
before any mere English tribunal—not acting under the law of nations in
the world of literature, to go at once, with a calm front and untroubled eye,
and plead to their jurisdiction, with a loud clear voice, and with their right
hand upon the great book of English law, and set them at defiance. This,
they have the right, and the power to do; and why should they not, when
some of the inferior courts, of mere English criticism, have the audacity at
every little interval, to call upon a sovereign people, to plead before them
—without counsel—and be tried for some infringement of some paltry
municipal provision of their statute book—some provincialism of language
—or some heresy in politics—or some plagiarism of manner or style; and
abide the penalty of forgery—or of ecclesiastical censure—or the reward
of petit-larceny; re-transportation—or re-banishment to America.
It is high time now, that we should begin to do each other justice. Let us
profit by their good qualities; and let them, by ours. And in time, we shall
assuredly come to feel like brothers of the same parentage—an elder and
a younger—different in temper—but alike in family resemblance—and
alike proud of our great ancestry, the English giants of olden time. We
shall revere our brother; and he will love his. But when shall this be?—
not, I am sorely afraid—till we have called home all our children, from the
four corners of the earth; from the east and from the west; from the north
and from the south—and held a congress of the dead—of their fathers,
and of our fathers—and published to the world, and to posterity—
appealing again to Jehovah for the rectitude of our intentions—another
Declaration of Independence, in the great Republic of Letters. And,
yet this may soon be. The time is even now at hand. Our representatives
are assembling: the dead Greek, and the Roman; the ancient English,
and the fathers of literature, from all the buried nations of all the earth,
and holding counsel together, and choosing their delegates. And the
generation is already born, that shall yet hear the heavens ringing with
acclamations to their decree—that another state has been added to the
everlasting confederacy of literature!
And now the author repeats to the people of America, one and all,
farewell; assuring them that there is very little probability of his ever
appearing before them again as a novel-writer. His object has been, if not
wholly, at least in a great degree accomplished. He has demonstrated that
a bold and direct appeal to the manhood of any people will never be
made in vain. Others may have been already, or may hereafter be incited
to a more intrepid movement; and to a more confident reliance upon

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45-Year-Old Woman With an

Fig. 1.1 Axial image from an unenhanced computed tomog-

Fig. 1.2 Axial image from an unenhanced computed tomogra-

TABLE 1.1 Laboratory Tests

Key Points REFERENCES

Adrenal Mass in a Patient

TABLE 2.1 Laboratory Tests

Biochemical Follow-Up later, she developed prediabetes. Her BMI fluctuated

Clinical Follow-Up Discussion

Incidentally Discovered Adrenal

pazopanib. One year later, she was treated with sur-

TABLE 4.1 Laboratory Tests CT attenuation with <10 HU.5,7,9 As reported in a

54-Year-Old Woman With

Mild autonomous cortisol secretion (MACS) is INVESTIGATIONS

Unenhanced Contrast enhanced Delayed contrast enhanced

Lipid-Poor Adrenal Masses: The

Lipid-poor adrenal masses are the landmines of INVESTIGATIONS

TABLE A.1 Presentation of Adrenal Tumors

TABLE A.2 Hormonal Workup in Patients With Adrenal Tumors

MILD AUTONOMOUS CORTISOL SECRETION REFERENCES

Primary Aldosteronism With

TABLE 8.1 Laboratory Tests

Fig. 8.1 An unenhanced adrenal-dedicated computed tomogra-

Primary Aldosteronism in a Patient

TABLE 11.1 Laboratory Tests

cortisol with an overnight 8-mg dexamethasone sup-

blood pressure control on a three-drug program:

Primary Aldosteronism: When

There is a small subset of patients (≈5%) with INVESTIGATIONS

with mineralocorticoid receptor blockade.7 In a ret-

Key Points REFERENCES

Primary Aldosteronism With

Fig. 9.1 An unenhanced adrenal-dedicated computed tomog-

Fig. 9.2 The left adrenal gland weighed 9 g (normal adrenal

Primary Aldosteronism Caused by

BOX 10.1 ADRENAL VEIN SAMPLINGa

UAH versus APA.6 Thus detecting and surgically man- REFERENCES

Primary Aldosteronism in a Patient

TABLE 12.1 Laboratory Tests glucocorticoid secretory autonomy and hopefully PA

Fig. 12.1 Axial image from an unenhanced adrenal-dedicated

Primary Aldosteronism in a Patient

Title: Rachel Dyer

Author: John Neal

Release date: September 30, 2023 [eBook #71766]

Original publication: US:

Credits: Alan, Steve Mattern and the Online Distributed Proofreading

*** START OF THE PROJECT GUTENBERG EBOOK RACHEL

A NORTH AMERICAN STORY.

PUBLISHED BY SHIRLEY AND HYDE.

B E IT REMEMBERED, That on the eighth day of October, A.D. 1828, and in

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