STEP 4: Adrenal Venous Sampling

Microadenomas cannot be reliably visualized on CT scans, and imaging does not enable radiologists to distinguish incidentalomas from aldosterone-producing adenomas.

One last step is needed in the diagnosis process — adrenal venous sampling. It is the “gold standard” test to distinguish unilateral from bilateral disease, and to determine the best course of treatment.

It is also a complex test whose success rate largely depends on the case volume handled by diagnostic centers, and on the skills and expertise of their interventional radiologists.

Purpose of AVS and How it is Performed

Adrenal venous sampling addresses whether the autonomous aldosterone production identified in step 2 of the diagnosis process is affecting one (unilateral disease) or both adrenal glands (bilateral disease).

The test consists in collecting cortisol and aldosterone samples at the closest possible source: the adrenal veins.

Because the right adrenal vein originates in the inferior vena cava (IVC), it is usually more difficult to canulate. The left adrenal vein directly originates in the left renal vein, and is usually less challenging to cannulate. Various catheters may be needed to accurately sample both sides.

The procedure is performed by an interventional radiologist in a hospital radiology suite with patients placed under “conscious sedation” (they remain awake, but do not feel any pain).

The radiologist starts with making a small puncture in the femoral vein of the leg, and threads a small catheter through the IVC until it reaches the right adrenal vein. The radiologist then takes a blood sample from the adrenal vein.

The same steps are repeated on the opposite side to sample the left adrenal vein, and a blood sample is also taken from the IVC or femoral vein for reference.

All blood samples are labeled in their individual tubes, and sent to a lab for analysis. Results are usually available within a week.

Purpose of AVS and How it is Performed

Illustration of kidneys, adrenal glands, and important veinsAdrenal venous sampling addresses whether the autonomous aldosterone production identified in step 2 of the diagnosis process is affecting one (unilateral disease) or both adrenal glands (bilateral disease).

The test consists in collecting cortisol and aldosterone samples at the closest possible source: the adrenal veins.

Because the right adrenal vein originates in the inferior vena cava (IVC), it is usually more difficult to canulate. The left adrenal vein directly originates in the left renal vein, and is usually less challenging to cannulate. Various catheters may be needed to accurately sample both sides.

The procedure is performed by an interventional radiologist in a hospital radiology suite with patients placed under “conscious sedation” (they remain awake, but do not feel any pain).

The radiologist starts with making a small puncture in the femoral vein of the leg, and threads a small catheter through the IVC until it reaches the right adrenal vein. The radiologist then takes a blood sample from the adrenal vein.

The same steps are repeated on the opposite side to sample the left adrenal vein, and a blood sample is also taken from the IVC or femoral vein for reference.

All blood samples are labeled in their individual tubes, and sent to a lab for analysis. Results are usually available within a week.

Cosyntropin Stimulation

Adrenal glands do not produce cortisol and aldosterone in a continuous stream, and when one side is sampled after the other, the samples may not represent the actual values.

Sampling both sides at the same time is an option to remediate this risk. Unless performed by a very skilled radiologist, this method is however associated with a risk of adrenal vein thrombosis.

As a result, some diagnostic centers prefer to pharmacologically stimulate the adrenal glands with an infusion of cosyntropin (a synthetic version of ACTH) to ensure that veins are adequately sampled.

Since one has not been proven superior to the other, the choice of method is left at the discretion of the diagnostic center. It is however recommended to consistently use one method or the other, and use higher cutoff values for the selectivity index and lower cutoff values for the lateralization index with pharmacological stimulation.

Call to Action

AVS is the most effective test available to decide whether primary aldosteronism should be treated surgically or medically.

Yet the impact of cosyntropin stimulation on disease outcome remains unknown, and the accuracy of AVS remains a concern. A study published in November 2020 demonstrated that because aldosterone production is highly variable, obtaining multiple measurements may provide more reliable interpretation of AVS results than single measurements.

If you or someone you know has long-standing and/or hard to control hypertension, we invite you to sign the Foundation’s Open Letter to help us advocate optimum diagnosis and treatment of primary aldosteronism.

How to Prepare for the Test and What to Expect Afterwards

Like ARRs, AVS results are influenced by sodium intake, potassium level, and blood pressure medications. Preparation for AVS is the same as for ARR . Compliance with these recommendations has a direct impact on the accuracy of results, and should be optimized by physicians and patients alike.

The test is usually performed in a couple of hours, and since it only involves mild sedation, patients are discharged within 2 to 4 hours. The AVS involves a puncture in the skin, and it is normal to feel soreness or tenderness at the sites for a short period of time. Upon returning home, patients should not stay alone, and should refrain from taking a shower, driving and operating any equipment for 24 hours.

To prevent undue stress on the procedure sites, it is recommended to rest for 72 hours, to refrain from lifting anything heavier than 10 pounds, and to use caution when climbing stairs or changing positions.

If bleeding occurs, pressure should be applied with a clean towel for 5 minutes uninterrupted. If bleeding is significant or does not stop, it is recommended to promptly call 911, and continue to hold pressure on the site until paramedics arrive.

What Results Mean

AVS results must first show that the adrenal veins were correctly sampled. This is why samples are taken as reference from another vein than the adrenal veins – usually the inferior vena cava. The cortisol level in each adrenal vein (CAV) is compared to the peripheral sample taken from the inferior vena cava (Cperipheral) to produce a ratio equal to CAV/Cperipheral called “Selectivity Index.” The cortisol in the adrenal veins should be several times greater than in the peripheral sample. When AVS is performed with cosyntropin stimulation, a cutoff value of more than 5 is recommended to ensure the procedure was successful. When the AVS is performed without stimulation, a lower cutoff value of more than 2 is recommended.

Lab Results Selectivity Index (SI)

Cortisol – Left Adrenal: 69.2 ug/dL
Cortisol – Right Adrenal: 33.4 ug/dL
Cortisol Random: 9 ug/dL

Left SI: 69.20 / 9.00 = 7.7
Right SI: 33.40 / 9.00 = 3.7

This AVS was performed without cosyntropin stimulation (with cosyntropin the cortisol concentrations are typically 400-800 μg/dL). The ratio on both sides is above 2, so the veins have been sampled properly. Had the ratio been below 2, the samples could not have been used.

Once sampling has been validated, a “Lateralization Index” is used to determine whether one side is responsible for the oversecretion of aldosterone. The aldosterone level in each sample (left: ALAV; right: ARAV) is normalized to the cortisol level in each sample (left: CLAV; right: CRAV) to produce two ratios: ALAV/CLAV, and ARAV/CRAV. Next, the aldosterone to cortisol ratio on the dominant side (i.e. the side with the highest aldosterone to cortisol ratio) is divided by the aldosterone to cortisol ratio on the contralateral side. A result equal or superior to 4 is indicative of unilateral source of aldosterone, while below 4 it is indicative of bilateral disease.

Lab Results Lateralization Index (LI)

Cortisol – Left Adrenal: 69.2 ug/dL
Cortisol – Right Adrenal: 33.4 ug/dL
Aldosterone – Left Adrenal 3651 ng/dL
Aldosterone – Right Adrenal 28 ng/dL

ALAV/CLAV: 3651 / 69.20 = 52.80
ARAV/CRAV: 28 / 33.40 = 0.83
LI: 52.80 / 0.83 = 63.61

CT imaging showed an adenoma on the left adrenal gland of this patient. The lateralization index is above 4. The left adenoma is the cause of aldosterone oversecretion.

Lab Results Lateralization Index (LI)

Aldosterone R adrenal vein: 90.8 ng/dl;
L adrenal vein: 52.9 ng/dl
Cortisol R 12.5 mcg/dL; cortisol L 12.5 mcg/dL

ALAV/CLAV: 52.90 / 12.50 = 4.23
ARAV/CRAV: 90.80 / 12.50 = 7.26
LI: 7.26 / 4.23 = 1.72

An adenoma had been previously seen during CT imaging on the right adrenal gland of this patient. The lateralization index is below 4. The adenoma is not causing excess aldosterone. The patient has bilateral disease.

Most diagnostic centers use the Lateralization Index to diagnose unilateral disease. Contralateral gland suppression can also confirm the diagnosis. In this case, the aldosterone to cortisol ratio of the non-affected side (i.e. the side with the lowest aldosterone to cortisol ratio) is divided by the peripheral aldosterone to cortisol ratio. A result less than 1 on the side without adrenal nodule is indicative of suppression on this same side with overproduction originating in the opposite side.

AVS Calculator

The Foundation’s calculator was designed to help you understand your AVS results. It uses the cutoff values recommended by the Endocrine Society Guidelines. It is built for the sole purpose of helping you visualize how AVS results are computed. It is not a substitute for medical interpretation. Only your physicians can provide advice and recommendations about your health based on your results. Mathematical operations are run directly on your local computer. None of your data can be accessed over the Internet or collected by the Primary Aldosteronism Foundation, either when you enter it or when the calculator returns results.

  Right Adrenal Vein Left Adrenal Vein Inferior Vena Cava Units
Cortisol μg/dL or nmol/L
Aldosterone ng/dL or pmol/L
Cosyntropin Stimulation  No  Yes    
Aldosterone-Cortisol Ratio ratio
Selectivity Index (SI)    
Lateralization Index (LI)    
Contralateral Suppression Index (CSI)    
Interpretation
   

How to Use the Calculator

  1. Enter the cortisol values for your right and left adrenal glands, and inferior vena cava or femoral vein
  2. Enter the aldosterone values in the same way
  3. Select whether cosyntropin stimulation was used during your procedure
  4. Press the “Submit” button, and the values for your AVS together with their standard interpretation will display. If the adrenal veins were not sampled correctly, the calculator will indicate that results are inconclusive.

Note

On your lab report, aldosterone and cortisol results may be listed in the middle of other tests. Cortisol measurements may be listed as μg/dL, mcg/dL, or nmol/L. Aldosterone measurements will be listed as either ng/dL or pmol/L.

Risks Associated with AVS

Radiologist inserting catheter

Adrenal venous sampling is an invasive test that involves a complex technique that only skilled and experienced interventional radiologists can perform with a satisfactory success rate of 90% or more.

Other than Centers of Excellence, very few diagnostic centers achieve such a rate consistently for their patient population.

This poses a significant risk to patients:

  • Erroneous results lead to erroneous diagnosis;
  • More often, AVS results are found to be inconclusive. Patients have to undergo the procedure multiple times, or seek care at a different center far from home to repeat the test.

The correct location of the catheters is confirmed with injection of a contrast agent. Radiation exposure is thus inherent to adrenal venous sampling. Notable differences exist among diagnostic centers, and patients should enquire whether their center applies standard operating procedures to limit radiation exposure.

At Centers of Excellence, the complication rate is believed to be 2.5% or less. The most common complications include symptomatic groin hematoma, adrenal hemorrhage, and dissection of an adrenal vein. Nerve damage, infarction, adrenal vein thrombosis, hypertensive crisis, and adrenal insufficiency have been reported.

Rupture of an adrenal vein and subsequent hemorrhage are considered a major complication. The literature suggests it is more frequent on the right side, is likely due to increased vein fragility caused by Conn and/or Cushing syndromes, and may actually occur in 5 to 10% of AVS procedures. The complication may cause extensive retroperitoneal adhesions which, in turn, may make laparoscopic adrenalectomy more difficult.

Patients should not undergo AVS unless they have the certainty that their diagnostic center handles a high enough case volume, and employs skilled radiologists who have a robust track record of successful AVS procedures.

Magnifying glass and document

References

  • John W. Funder, Robert M. Carey, Franco Mantero, M. Hassan Murad, Martin Reincke, Hirotaka Shibata, Michael Stowasser, William F. Young, The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 5, 1 May 2016, Pages 1889–1916, DOI: 10.1210/jc.2015-4061
  • Williams, Tracy Ann, and Martin Reincke. “MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary aldosteronism: the Endocrine Society guideline 2016 revisited”,  European Journal of Endocrinology 179.1 (2018): R19-R29, DOI: 10.1530/EJE-17-0990
  • Martin J. Wolley, Richard D. Gordon, Ashraf H. Ahmed, Michael Stowasser, Does Contralateral Suppression at Adrenal Venous Sampling Predict Outcome Following Unilateral Adrenalectomy for Primary Aldosteronism? A Retrospective Study, The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 4, 1 April 2015, Pages 1477–1484, DOI: 10.1210/jc.2014-3676
  • Irakoze Laurent, Manirakiza Astère, Fengfan Zheng, Xiangjun Chen, Jun Yang, Qingfeng Cheng, Qifu Li, Adrenal Venous Sampling With or Without Adrenocorticotropic Hormone Stimulation: A Meta-Analysis, The Journal of Clinical Endocrinology & Metabolism, Volume 104, Issue 4, April 2019, Pages 1060–1068, DOI: 10.1210/jc.2018-01324
  • Gian Paolo Rossi, Marlena Barisa, Bruno Allolio, Richard J. Auchus, Laurence Amar, Debbie Cohen, Christoph Degenhart, Jaap Deinum, Evelyn Fischer, Richard Gordon, Ralph Kickuth, Gregory Kline, Andre Lacroix, Steven Magill, Diego Miotto, Mitsuhide Naruse, Tetsuo Nishikawa, Masao Omura, Eduardo Pimenta, Pierre-François Plouin, Marcus Quinkler, Martin Reincke, Ermanno Rossi, Lars Christian Rump, Fumitoshi Satoh, Leo Schultze Kool, Teresa Maria Seccia, Michael Stowasser, Akiyo Tanabe, Scott Trerotola, Oliver Vonend, Jiri Widimsky, Kwan-Dun Wu, Vin-Cent Wu, Achille Cesare Pessina, The Adrenal Vein Sampling International Study (AVIS) for Identifying the Major Subtypes of Primary Aldosteronism, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 5, 1 May 2012, Pages 1606–1614, DOI: 10.1210/jc.2011-2830
  • Nicholas Yozamp, Gregory L Hundemer, Marwan Moussa, Johnathan Underhill, Tali Fudim, Barry Sacks, Anand Vaidya, Variability of Aldosterone Measurements During Adrenal Venous Sampling for Primary Aldosteronism, American Journal of Hypertension, hpaa151, DOI: 10.1093/ajh/hpaa151
  • Giacomo Rossitto, Laurence Amar, Michel Azizi, Anna Riester, Martin Reincke, Christoph Degenhart, Jiri Widimsky, Jr, Mitsuhide Naruse, Jaap Deinum, Leo Schultzekool, Tomaz Kocjan, Aurelio Negro, Ermanno Rossi, Gregory Kline, Akiyo Tanabe, Fumitoshi Satoh, Lars Christian Rump, Oliver Vonend, Holger S Willenberg, Peter Fuller, Jun Yang, Nicholas Yong Nian Chee, Steven B Magill, Zulfiya Shafigullina, Marcus Quinkler, Anna Oliveras, Chin-Chen Chang, Vin Cent Wu, Zusana Somloova, Giuseppe Maiolino, Giulio Barbiero, Michele Battistel, Livia Lenzini, Emilio Quaia, Achille Cesare Pessina, Gian Paolo Rossi, Subtyping of Primary Aldosteronism in the AVIS-2 Study: Assessment of Selectivity and Lateralization, The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 6, June 2020, Pages 2042–2052, DOI: 10.1210/clinem/dgz017