1. Case Conference
Samer Bani-Hani
PGY-5

2. Nephrology Consultation
Reason for the Consult: Persist HypoKalemia
H/P:
52 year-old male referred to nephrology clinic for hypokalemia. His onset of hypokalemia began in Pt was started on KCL 20 meq/day and increased to 80 meq/day and HCTZ was discontinued however K level persist low.

3. PMH:
HTN DM
Allergic rhinitis
Medication
Lisinopril 40 mg QD
Atenolol 50 mg QD
Amlodipine 10 mg QD
KCL 40 meq BID
Spirolactone 25 mf QD

4. Physical Examination Vital signs 135/75 , 70 , Afebrile , 18
HEENT:   NCAT, PERRL, EOMi, Thyroid normal in size and texture
Chest:   CTAB
CV:      Regular rythm, no M/R/G
Abd:    soft, NTND, +BS
Ext:     no CCEx4, DTRs brisk w/nl relaxation phase

5. Labs 6/2011: 2007 before HCTZ CT: 2010: CT: 6/2011 On HCTZ
144 | 95 | /
3.1 | 37 | 0.85 \
On HCTZ
144 | 106| /
2.5 | 33 | 0.85 \
After starting Spirolactone
141 | 104 | 7 /
4.3 | 29 | 1.0 \
CT: 2010:
1.4 cm left adrenal nodule that has low attenuation.
CT: 6/2011
A 2 cm x 1.4 cm x 1 cm oval nodule on the inferior aspect of the anterior limb of the left adrenal gland with characteristics
6/2011:
Rennin <0.15 ng/ml/hr
Aldosterone 14.8 ng/dl

6. Primary Aldosteronism

7. Prevalence of Primary Aldosteronism
Most common form of secondary hypertension.
Hypertension associated with low renin and increased aldosterone levels that are not suppressed by appropriate testing
Conn, 1955: 34-year-old woman with hypertension, intermittent paralysis, hypokalemia and metabolic alkalosis.
Prevalence among nonselected hypertensive  5% and 13%.
With an estimated prevalence of 10%  8.5 million people in the US have primary aldosteronism.
Mosso L et al. Primary aldosteronism and hypertensive disease. Hypertension 2003

8. Prevalence of Primary Aldosteronism According to HTN severity
The prevalence of primary aldosteronism increases with severity of hypertension.
Mosso and colleagues showed that prevalence was 1.99% in subjects with STAGE 1 HTN(according to the Joint National Committee 6); 8.02% in STAGE 2 HTN; and 13.2% in STAGE 3 HTN
Mosso L et al. Hypertension 2003; 42(2):

9. Prevalence of PA inpatients with resistant hypertension
Resistant hypertension is defined as BP that remains elevated despite use of three antihypertensive agents, ideally one of which is a diuretic
Among patients with resistant hypertension, the prevalence of primary aldosteronism has been reported to be 17–22%.
David A. Calhoun Aldosteronism and Hypertension CJASN 2006

10. Aldosterone Synthesis
Aldosterone, produced in the ZONA GLOMERULOSA, is synthesized and released mainly in response to renin-dependent production of ANGIOTENSIN II; however, adreno corticotropic hormone (ACTH), serum potassium, and dopamine also affect its production and secretion.

11. Aldosterone Action

12. Inhibition and Stimulation
Aldosterone is stimulated by a number of factors but the most important include angiotensin II, hyperkalemia, and ACTH.
Angiotensin II and hyperkalemia stimulate both the synthesis and stimulation of aldosterone synthase in the zona glomerulosa.
Aldosterone inhibition occurs predominantly by ANP and hypokalemia

13. Aldosterone regulates blood pressure through a number of mechanisms

14. Aldosterone and Kidney Fibrosis
Serum and glucocorticoid induced kinase 1
Nuclear factor-KB
Reactive oxygen species
Brem AS , Am J Kidney Dis. 2011

15. Cardiovascular Events and Primary Aldosteronism
Rate of Cardiovascular Events and Cardiac Structure in Primary Aldosteronism
Primary Aldo (n=124)
Essential HTN (n=465)
Odds ratio (95% CI)
p value
Stroke (%)
12.9
3.4
4.2 ( )
< 0.001
Myocardial infarction (%)
4.0
0.6
6.5 (1.5–27.4)
< 0.005*
Atrial fibrillation
7.3
12.1 ( )
<0.0001*
Echo LVH (%) 34 24
1.6 ( )
< 0.01
EKG LVH (%) 32 14
2.9 ( )
Cardiovascular events (stroke, myocardial infarction and atrial fibrillation) are more common in patients with primary aldosteronism than in subjects with essential hypertension, a finding that is inde pendent of blood pressure.
Milliez P et al. J Am Coll Cardiol 2005; 45(8):

16. Clinical Features Hypertension HypoKalemia Metabolic alkalosis
Due to increased urinary H+ excretion mediated both by direct stimulatory effect of aldosterone on distal acidification
Muscle weakness 
It is primarily due to hypokalemia

17. Lack of edema:
Although aldosterone initially induces sodium and water retention, this is followed within a few days by a spontaneous diuresis (called aldosterone escape) that returns excretion to the level of intake and partially lowers the extracellular fluid volume toward normal .
The mechanisms responsible for the escape phenomenon are incompletely understood, but at least three factors may be important:
increased secretion of atrial natriuretic peptide (ANP) induced by the hypervolemia
decreased abundance of the thiazide-sensitive Na-Cl cotransporter that mediates sodium reabsorption in the distal tubule
pressure natriuresis .

18. Hypokalemia: an inconsistent finding
With increasing use of the plasma aldosterone to plasma renin activity ratio as a case detection test from PA in HTN patients, more normokalemic patients are being identified
In a multicenter review using this approach, approximately 60 percent of patients with primary aldosteronism were not hypokalemic
Mulatero et al J Clin Endocrinol Metab, March 2004

19. Subtypes

20. DDx of Aldosteronism from Essential Hypertension
Aldo-Producing
Adenoma
Adrenal Hyperplasia
Low-renin essential HTN
Age
Middle-aged
Older
Hypokalemia
Frequent
Less common
Uncommon
Plasma renin levels
Very low
Low
Plasma aldo levels
Very high
High-normal
Normal
Plasma aldo suppressibility to volume
Minimal
Partial
Complete

21. Glucocorticoid Remediable Aldosteronism
The mutation is fusion of the promoter region of the gene for CYP11B1 and the coding sequences of CYP11B2
resulting in ACTH-dependent activation of the aldosterone synthase effect on cortisol, corticosterone, and cortisol precursors

22. Who to Screen?
Hypertension and spontaneous or low dose diuretic-induced hypokalemia
Severe hypertension (>160 mmHg systolic or >100 mmHg diastolic) or drug-resistant hypertension (defined as suboptimally-controlled hypertension on a three-drug program that includes an adrenergic inhibitor, vasodilator, and diuretic)
Hypertension with adrenal incidentaloma
Hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years)
All hypertensive first-degree relatives of patients with primary aldosteronism
Endocrine Society guidelines 2008

23. Screening for PA : ARR
Aldosterone-Renin Ratio (ARR)>20 and Aldosterone level>15 ng/dl
Morning testing
K+ repletion
Mineralocorticoid receptor antagonists (spironolactone and eplerenone) and high-dose amiloride (e.g. >5 mg daily) should be dis continued 6 weeks before blood sampling to avoid direct interference with the results
Confirmatory testing should be performed

25. Factors May affect ARR

27. Confirmatory test for Primary Aldosteronism

28. CT
Initial study to determine subtype (adenoma versus hyperplasia) and exclude adrenal carcinoma
The diagnosis of an adrenal carcinoma should be suspected when a unilateral large (>4 cm) adrenal mass is found on CT
An abnormality in both glands suggests adrenal hyperplasia; however, patients with hyperplasia may also have normal appearing adrenal glands on CT

29. Limitations Lots of False Positives Only can image adenoma if > 1cm
Of these, 1/3 are incidentaloma (no lateralization on adrenal vein sampling)
Lots of False Negatives
Up to 1/3 of adenomas are missed because of small size (lateralize on adrenal vein sampling)

30. Adrenal vein sampling
It is a Measurement of aldosterone in samples of adrenal venous blood, obtained by an experienced radiologist
is the criterion standard test to distinguish between unilateral adenoma and bilateral hyperplasia.
Unilateral disease is associated with a marked (usually fourfold greater than contralateral adrenal) increase in PAC on the side of the tumor, whereas there is little difference between the two sides in patients with bilateral hyperplasia.
Indications — The Endocrine Society recommends AVS to confirm unilateral disease in all patients with primary aldosteronism who would like to pursue surgical management (unilateral adrenalectomy).
Other centers approach is slightly different, they recommend AVS in such patients when the CT scan is normal, shows bilateral abnormalities, or shows a unilateral abnormality, but the patient is over age 40.

31. Procedure
Some centers perform AVS with or without cosyntropin stimulation.
Why Cosyntropin?
To minimize stress-induced fluctuations in aldosterone secretion during nonsimultaneous AVS, which could potentially confound the interpretation of lateralization data.
To maximize the gradient in cortisol from adrenal vein to inferior vena cava (IVC) and thus confirm successful sampling of the adrenal vein.
To maximize the secretion of aldosterone from an APA
Aldosterone and cortisol concentrations are measured in the blood from all three sites (right adrenal vein, left adrenal vein, and IVC).
The complication rate in published studies is 2.5 percent or less .
The most common complication is groin hematoma; adrenal hemorrhage and adrenal vein dissection are rare.

32. Confirming successful catheterization — The cortisol concentrations from the adrenal veins and IVC are used to confirm successful cannulation of both adrenal veins. With cosyntropin infusion, the adrenal vein to IVC cortisol ratio is typically more than 10:1; a ratio of at least 5:1 is required to be confident that the adrenal veins were successfully catheterized
Cortisol-corrected ratios — Dividing the right and left adrenal vein plasma aldosterone concentrations (PAC) by their respective cortisol concentrations corrects for the dilutional effect of the inferior phrenic vein flow into the left adrenal vein
At Mayo Clinic, where AVS is performed with cosyntropin infusion, the mean cortisol-corrected aldosterone ratio (APA-side PAC/cortisol to normal adrenal PAC/cortisol) in patients with confirmed APA is 18:1
In patients with presumed IHA, the mean cortisol-corrected aldosterone ratio is 1.8:1 ; a ratio less than 3:1 is suggestive of bilateral aldosterone hypersecretion

34. Cont Limitation
The limitations of adrenal CT were illustrated in a study of 203 patients with primary aldosteronism who were evaluated with both CT and AVS
CT correctly identified unilateral or bilateral disease in 103 (53.0%) of 194 patients that had successful AVS
CT falsely suggested APA in 48 patient
CT finding inaccurately suggested bilateral hyperplasia in 43 patients with unilateral disease
When CT and AVS results both suggested unilateral disease, CT indicated the wrong adrenal gland in 12 (21.2%) of 57 patients
AVS inaccurately predicted bilateral disease in 4 patients with APA and in 1 patient with PAH
William F. Role for adrenal venous sampling in primary aldosteronism. Surgery. 2004

35. Subtype Evaluation of Primary Aldosteronism

36. Treatment of primary aldosteronism
GENERAL PRINCIPLES — Establishing the correct subtype diagnosis is essential since the treatment of primary aldosteronism is based upon whether the adrenal aldosterone hypersecretion is unilateral (adenoma, unilateral hyperplasia, or carcinoma) or bilateral (idiopathic adrenal hyperplasia or glucocorticoid-remediable aldosteronism).
Surgery is curative only in patients with unilateral disease.
Patients with bilateral idiopathic adrenal hyperplasia are treated with a mineralocorticoid antagonist.
Patients with glucocorticoid-remediable aldosteronism should receive physiologic doses of a glucocorticoid

37. Bilateral Adrenal Hyperplasia
— There are two forms of primary aldosteronism due to bilateral adrenal zona glomerulosa hyperplasia:
Idiopathic adrenal hyperplasia —
 is generally a milder disease than adrenal adenoma, with less hypersecretion of aldosterone and less hypokalemia.
Such patients should be treated with an aldosterone (mineralocorticoid receptor) antagonist.
Glucocorticoid-remediable aldosteronism:
Chronic treatment with physiologic doses of a glucocorticoid normalizes blood pressure and corrects hypokalemia

38. Cont Medical Therapy MR affinity 20 X > spironolactone
Potency of effect 75% of spironolactone
Binding affinity for androgen and progesterone receptors 1000-fold lower than spironolactone

39. Unilateral Adrenal Adenoma or Hyperplasia
Responsible for the hypersecretion of aldosterone in 30 to 60 % of cases of primary aldosteronism , while unilateral hyperplasia is less common (about 3 percent)
Surgery:
Preferred therapy
Hypertension improved in all and is cured in 35 to 60 % of patients
Preferred laparoscopic adrenalectomy over open adrenalectomy
Preoperatively, hypertension should be controlled and hypokalemia should be corrected with a mineralocorticoid receptor antagonist (eg, spironolactone or eplerenone).
The blood pressure response to spironolactone preoperatively often predicts the blood pressure response to unilateral adrenalectomy in patients with aldosterone-producing adenoma

40. Failure of Surgical Treatment
Persistent hypertension may be related to
underlying essential hypertension and/or
the development of nephrosclerosis after a prolonged period of uncontrolled hypertension .
It is also possible that an error in subtype assignment has been made and that the patient has bilateral adrenal hyperplasia, a disorder that should be treated medically, not with unilateral adrenalectomy. As many as one-third of patients thought to have a unilateral lesion on imaging studies have bilateral adrenal hyperplasia on adrenal vein sampling

41. Aldosteronoma Resolution Score (ARS)
is a scoring system that has been proposed to help identify patients at low or high likelihood of complete resolution of hypertension after adrenalectomy
In a study of 100 patients with primary aldosteronism seen at a single tertiary center, four clinical features provided the best predictive model for complete resolution of hypertension after adrenalectomy and was externally validated using an independent series of 67 patients from another center
The likelihood of complete resolution of hypertension for patients with ARS scores of 0 to 1, 2 to 3, and 4 to 5 was 27, 46, and 75 percent, respectively
Zarnegar R et Ann Surg. 2008

42. Medical therapy
Aldosterone antagonists — Although laparoscopic adrenalectomy is more cost-effective over time , the administration of an aldosterone (mineralocorticoid receptor) antagonist is an effective alternative in patients who refuse or are not candidates for surgery.
The efficacy of this approach was illustrated in a study of 24 patients with adenomas who were treated medically for at least five years . We
discuss 24 patients who chose medical management
instead of surgical excision of the aldosteroneproducing
adenoma. No patient had a history of
myocardial infarction, congestive heart failure, or
diabetes mellitus. To be included in this analysis,
patients had to have had at least 5 continuous years
of medical management and follow-up sufficient to
allow assessment of compliance with the medical
regimen (follow-up at 3- to 6-month intervals in our
nephrology department).

43. DESIGN: Retrospective cohort study.
OBJECTIVE: To demonstrate the efficacy of medical management of aldosterone-producing adenomas in terms of blood pressure and serum potassium concentration and to discuss morbidity associated with medical management
DESIGN: Retrospective cohort study.
PATIENTS: 24 patients with documented aldosterone-producing adenomas who were treated medically for at least 5 years
RESULTS: From the time of diagnosis to the time of last follow-up, systolic blood pressure decreased from 175 mm Hg to 129 mm Hg (95% CI for difference, 37.1 to 53.8 mm Hg) and diastolic blood pressure decreased from 106 mm Hg to 79 mm Hg (CI for difference, 20.8 to 33.9 mm Hg). Serum potassium concentration increased from 3.0 mmol/L to 4.3 mmol/L (CI for difference, 1.1 to 1.5 mmol/L)
Ghose RP et al .Medical management of aldosterone-producing adenomas. Ann Intern Med. 1999