SEARCHING IN VEIN

1

? ? ? ? ? ? ? ? ? ? ? ? ?

SEARCHING IN VEIN FOR THE CONN MAN
Department of Endocrinology
M-96-4896
S-24-8967
R-35-9064
2
Suspect 1

• May 2004
• A suspicious case of hypertension was reported to
  Dr Martin T. Epstein of Lindsay St, Hamilton.
• Suspect first identified by LMO in Nov 2003
• 48 yr old Caucasian male, fair complexion, large
  build
• Inhabitant of mid-north coast.

3
Suspect 1

• Records
• Hypertension for 10 yrs, poorly controlled
• Abdominally obese, hypercholesterolaemia,
  impaired fasting glucose.
• Previous angio for investigation of chest pain
• Otherwise fit, occasional dyspnoea, no angina
• Metoprolol 200 mg bd, prazosin 5/2.5/2.5 mg,
  amlodipine 10mg
• Previously on Irbesartan and Irbesartan HCT,
  hypokalaemic on the latter.

4
Suspect 1

• March 04 Preliminary Investigations
• BP 210/140 mmHg
• Urea 8 mmol/L, Creatinine 118 umol/L
• Creatinine clearance 105 ml/min
• Low K (3.1 mmol/L) despite cessation of
  hydrochlorothiazide
• ECG LVH, lateral T wave changes
• Albumin excretion rate 746.1 ug/min

5
Suspect 1

• Renal artery doppler and ultrasound normal
• 24 hr urinary catechols
• adrenaline 15 (0-80mmol/d)
• noradrenaline 156 (100-420mmol/d)
• CT abdomen (8th April 04)
• rounded 2cm mass of uniform density in right
  adrenal.

6
Suspect 1

• Therapy
• Ceased amlodipine and prazosin
• Commenced telmisartan 80mg daily, clonidine 200mg
  bd
• Added spironolactone 25mg tds

7
Suspect 1

• 2nd April 04
• Urea 8 mmol/L, Creatinine 140 nmol/L, K 3.5
  mmol/L
• Spironolactone increased to 100mg bd, then 200mg
  bd
• 3rd May 04
• Urea 12 mmol/L, Creatinine 190 nmol/L
• K 5.9 mmol/L
• Ceased telmisartan and spironolactone

8
The Metabolic Syndrome

• Different organisations have different criteria
  for diagnosis, generally includes 3 of the
  following
• Abdominal obesity (based on waist circumference)
• Low HDL
• High triglycerides
• Impaired glucose metabolism
• Hypertension

9
Secondary Hypertension

• Risk Factors for Secondary Hypertension
• Poor response to therapy (resistant hypertension)
  
• Worsening of control in previously stable
  hypertensive patient
• Stage 3 hypertension (systolic blood pressure gt
  180 mm Hg or diastolic blood pressure gt110 mm Hg)
  
• Onset of hypertension in persons younger than age
  20 or older than age 50
• Significant hypertensive target organ damage
• Lack of family history of hypertension
• Findings on history, physical examination, or
  laboratory testing that suggest a secondary cause
  

10
Causes of Secondary Hypertension
11
Secondary Hypertension

• Routine Screening Laboratory Tests for
  Hypertension
• Urinalysis
• Complete blood count
• Blood chemistries (potassium, sodium, creatinine,
  fasting glucose)
• Fasting lipid profile (LDL, HDL, triglycerides,
  total cholesterol)
• 12-lead electrocardiogram
• Information from Joint National Committee. The
  sixth report of the Joint National Committee on
  Prevention, Detection, Evaluation, and Treatment
  of High Blood Pressure. Arch Intern Med
  19971572413-46

12

Adrenal Incidentaloma

• 2 to 15 of people have adrenal cortical tumours
  at autopsy
• As the power of CT images improves and more CTs
  are done, incidental adrenal lesions are more
  commonly identified
• In the late 1980s approximately 1.3 of all
  abdominal CT scans had clinically unsuspected
  adrenal masses
• Approximately 10 are hyperfunctional/autonomous
• lt3 are adrenocortical carcinoma and 98 of these
  are bigger than 4cm in size.

13
Suspect 1

• Dr Epstein review
• Ceased all medications except amlodipine and
  prazosin
• Home BP monitoring confirmed persistent BP
  elevation
• 3 weeks later (31st May 04)
• Aldosteronerenin ratio 3.2 (0.4 - 1.5)
• Aldosterone 1042 pmol/L (80-1040)
• Renin activity 255 fmol/L/sec (130-2350)
• Review July 04
• Still hypertensive despite prazosin 5mg tds,
  hydralazine 50mg, verapamil SR 120mg bd, Slow K
  iii tds.

14
Suspect 1

• Where to from here?
• What is the significance of the aldorenin ratio?
• When should an aldo/renin ratio be performed?
• What are some of the pitfalls of testing?
• How can the diagnosis of primary
  hyperaldosteronism be confirmed?

15
The Aldo/Renin Ratio

• The Aldo/Renin ratio
• Recommended screening test for primary
  hyperaldosteronism

Excess adrenal aldosterone production ? BP
elevation salt retention ? suppression of renin
activity ? elevated aldorenin ratio.
16
When to use the ARR?

• The ARR is the best initial investigation for
  Conns Syndrome
• Traditionally, screening with the aldo/renin
  ratio was reserved for hypertensive population
  with
• a) treatment refractory disease
• b) hypokalaemia
• c) adrenal incidentalomas
• Some tertiary centres now argue for universal
  screening of hypertensives
• The cost vs benefit of this approach is still
  unclear.

17
When to use the ARR?

• Prevalence of primary aldosteronism amongst
  hypertensives has been hotly debated.
• 1955, Dr Conn first described the syndrome of
  aldosterone producing adenoma (APA) and estimated
  its prevalence at 20 of hypertensives.
• Subsequent investigators reported APA in fewer
  than 1 of unselected hypertensives
• A second form of primary aldosteronism, bilateral
  adrenal hyperplasia was later described, thought
  to be less common.
• In last 10 yrs with introduction of new screening
  techniques, apparent epidemic of PA in the
  literature.

18
When to use the ARR?

• Discrepancy of reports
• Referral centres report prevalence of PA of up to
  20
• Primary centres report 4-6
• Differences between referred and primary
  populations more refractory hypertension,
  unexplained hypokalaemia?
• Differences in accuracy of testing using
  commercial vs research assays, false negatives
  from antihypertensive use.
• Bilateral adrenal hyperplasia (BAH) has overtaken
  APA as commonest cause of PA
• Due to more sensitive testing, able to pick up
  milder forms of disease?
• Over-interpretation of results, BAH actually
  essential HT with low renin?

19
When to use the ARR?

• Mulatero et al (5 continent study JCEM 2004)
• widespread introduction of ARR as screening test
  led to 5 15 fold increase in identification of
  pts with primary aldosteronism
• Only 9-37 of these pts were hypokalaemic
• Annual detection rate of APAs increased by 1.3
  6.3 times
• Increasing evidence of the deleterious role of
  aldosterone in vascular and cardiotoxicity,
  independent of blood pressure effects.
• Pts with surgically treated APAs report improved
  quality of life
• Diagnoses would have been missed without
  implementation of routine screening

20
When to use the ARR?

• Kaplan (J. of Hypertension 2004)
• Opposes recommendation for routine screening
• ARR is non-specific and non-sensitive test, often
  mandates more expensive/invasive testing such as
  adrenal venous sampling
• Leads to massive increases in cost and morbidity,
  providing benefit to only a few.
• With increasing diagnosis of BAH, are you making
  a difference by identifying people with mild
  disease who you would treat with medical therapy
  anyway?

21

Lateralised ratio Ratio of dominant A/C ratio
to non-dominant A/C ratio Ipsilateral ratio
Ratio of dominant A/C ratio to peripheral A/C
ratio Contralateral ratio Ratio of non-dominant
A/C ratio to peripheral A/C ratio
22
Suspect 1
Pitfalls of the ARR

• Aldosterone Renin ratio
• Schwartz et al (Clin Chem 2002), 505 pts.
• Sensitivity 66, Specificity 67
• Ratio varies with posture of patient, dietary
  salt intake, K
• Ratio varies with diuretic therapy (HCT for 4
  weeks)
• Ratio is strongly and inversely dependent on PRA
  (just about anyone with a low PRA will have high
  ARR)
• Tanabe et al (JCEM 2003)
• 71 pts with proven APA undergoing repeated ARR
  testing
• Only 1/3 of pts had an abnormal ARR on 3
  successive tests.

23
Pitfalls of the ARR

• Confounding factors
• Beta blockers increase false positives (decrease
  PRA)
• AIIRB increases false negatives
• Elderly, blacks have low PRA
• Some investigators therefore add S. Aldosterone
  to diagnostic criteria.
• 20 of 54 pts with documented primary
  aldosteronism had aldosterone lt 416 pmol/L

24
Primary Aldosteronism

• Confirmatory Tests
• If the Aldo/Renin ratio is elevated, the
  diagnosis of primary hyperaldosteronism can be
  confirmed by further testing
• As an endocrinological principle, many hormone
  levels will fluctuate according to numerous
  variables.
• To confirm hormonal deficiency perform a
  stimulation test
• To confirm hormonal excess perform a
  suppression test.

25
Primary Aldosteronism

• Normally, aldosterone acts to increase salt
  retention in the urine in exchange for potassium
  loss.
• Administering salt should therefore turn off
  aldosterone production, allowing the excess salt
  to be excreted.
• Oral salt suppression test
• IV salt suppression test
• Fludrocortisone suppression test

Na
K
26
Suspect 1

• 2L saline infusion over 4 hrs (23rd July 04)

27
Suspect 1

• What are the different aetiologies of primary
  hyperaldosteronism?
• How do we differentiate between them?
• What is our ongoing management plan?

28
Aetiologies

• Aetiologies of primary hyperaldosteronism
• bilateral adrenal hyperplasia (BAH)
• unilateral aldosterone producing adenoma (APA)
• primary adrenal hyperplasia (PAH)
• Glucocorticoid remediable aldosteronism (GRA)
• Familial hyperaldosteronism type II
• Aldosterone producing carcinoma

29
Aetiologies

• Important to differentiate between unilateral and
  bilateral disease
• Unilateral ? adrenalectomy can cure
• Bilateral ? medical management with
  spironolactone
• Main techniques include
• Postural testing
• Adrenal imaging
• Adrenal vein sampling

30
Lateralisation

• Postural Test
• Espiner (JCEM 2003)
• Response of plasma cortisol and aldosterone to 4
  hrs morning ambulation
• Expect fall in plasma cortisol due to normal
  circadian rhythm, ensures that ACTH is not an
  interfering factor
• A fall in plasma aldosterone is supportive of
  APA. (positive test)
• However 40 of APA actually had a rise in aldo
  (negative test) ie, remain angiotensive
  responsive
• No BAH had a positive test (n7)
• Suggest that in presence of single focal adenoma
  on CT and a positive posture test, AVS is not
  needed before surgery.

31
Lateralisation

• Imaging
• Majority of APA are smaller than 10-15mm diameter
• unilateral
  bilateral
• solitary nodule
  micronodular hyperplasia
• pathological continuum
• Prevalence of nonfunctioning adrenal adenoma as
  high as 10
• Large nonfunctioning adenoma can occur
  concurrently with smaller CT-negative
  contralateral APA.

32
Lateralisation

• Imaging
• CT has reported sensitivity of 58-75, perhaps
  more with high resolution CT. (Doppman et al,
  Radiology 1992)
• Sheaves et al (Eu.J.Endo 1996) claim 100
  sensitivity and advocate CT alone if diagnosis
  can be made on imaging.
• Harper et el (QJM 1999) reported that 1/3 of
  provisional diagnosis made on CT were changed
  after further investigations.

33
Lateralisation

• Adrenal Venous Sampling
• the gold standard pre-op method of localisation
• Many studies publish very decent sensitivity and
  specificity
• No consensus on criteria for lateralisation
• No standardisation in use of ACTH stimulation
• Centre-dependent

34
Adrenal Vein Sampling
Catheters inserted via femoral vein into the
right and left adrenal vein. Simultaneous
peripheral samples also taken. Blood is sampled
for aldosterone and cortisol.
35
Adrenal Vein Sampling

• Adrenal Venous Sampling (Rossi et al JCEM 2001)
• The right adrenal vein is much more difficult to
  cannulate
• The ratio of cortisol in the adrenal vein vs
  peripheral vein is used to confirm accurate
  placement. (selectivity)
• Different investigators use different ratios
• Using cut-off of gt1.1, selective in 85.7 on
  right, 94.1 on left.
• Bilaterally selective in 80.6
• Blumenfeld gt2, Young gt5, Gordon gt2.7
• Complications
• Adrenal vein rupture, thrombosis, adrenal
  infarction
• Very low rate (1 in 105)

36
Adrenal Vein Sampling

• Adrenal Venous Sampling
• The aldocortisol ratio for each sample is used
  to determine if the excess aldosterone production
  is unilateral or bilateral.
• This is called lateralisation
• Lateralised ratio (A/C)dominant side
  (A/C)non-dom side
• Rossi et al. used ROC curve analysis
  lateralised ratio cut-off of 2.0 or more was best
  compromise of sensitivity and false positive rate
• Correctly classified 80 of all pts, provided
  bilaterally selective.
• Young et al (Surgery 2004) found that most
  unilateral disease had lateralised ratio gt4,
  bilateral disease ratio lt3. With grey area in
  between.

37
Primary Aldosteronism

• Adrenal Venous Sampling
• ACTH infusion
• Aldosterone release may be pulsatile
• ACTH may smooth out the minute to minute
  variations
• Magill et al JCEM 2001 reported no significant
  benefit of ACTH when given at 50 ug/hr.
• Phillips et al JCEM 2000 found that ACTH (250ug
  bolus then 0.5 pg/ml/min infusion) increased the
  aldo/cort differential in APA, but decreased it
  in BAH.
• For left sided tumours, some right adrenal glands
  had A/C ratios higher than peripheral initially,
  but suppressed to below peripheral after ACTH

38
Management

• Proposed Algorithm
• Primary aldosteronism

CR Contralateral (ACnondom/A Cperiph) IR
ipsilateral (ACdom/ACperiph) LR
lateralised (ACdom/ACnondom)
Adrenal CT
-ve
CR lt1 ve LR gt4
ve
AVS with ACTH
Surgery
IR gt1.4 Single vein access
-ve
ve
Posture test
39
Suspect 1

• Postural test 9th August 2004
• 10th August 2004
• Urine aldosterone 123 nmol/d (17 69)
• Urine creatinine 22.4 mmol/d (6 22)

40

• Adrenal venous sampling (25th Aug 2004)

41
Suspect 1

• Adrenal venous sampling (25th Aug 2004)
• High cortisol levels on both sides compared to
  periph confirms catheter position.
• Ratios for matching LAV and RAV are similar and
  lower than periph
• Average LAV ratio is 0.9
• Average RAV ratio is 0.9
• Average Periph ratio is 2.9
• High peripheral to adrenal AV ratios

42

• Adrenal venous sampling (10th Feb 2005)
• Pre ACTH study

43

• Adrenal venous sampling (10th Feb 2005)
• Post ACTH

44
Test 1
Test 2 pre ACTH
post ACTH
45
Suspect 1

• High cortisol confirms good position, although
  post ACTH more dilute.
• Pre ACTH
• high LAV ratios with contralateral suppression
• Average LAV ratio 7.9
• Average RAV ratio 0.375
• Average periph ratio 1.5
• Post ACTH
• LAV samples not as high as pre-ACTH, average 1.3
• RAV samples comparable to pre-ACTH, average 0.43
• Peripheral ratios higher than both adrenal veins,
  average 2.3
• SRV similar to LAV.
• Similar to 1st attempt but difference between L
  and R is greater.

46
Suspect 1

47
Suspect 1

• Laparascopic left adrenalectomy arranged
• 3rd May 05 First attempt to apprehend the
  suspect thwarted by Anaesthetics, operation
  cancelled due to renal failure, hyperkalaemia
• Surgeons advised of significant potential threat
  if the culprit remained at large.
• Spironolactone decreased to 50 mg daily.
• 28th June 05 culprit finally apprehended at Lake
  Macquarie Private Hospital
• Subsequent scrutiny revealed an 11 ? 6 ? 9 mm
  pigmented nodule at the centre of a 35 mm adrenal
  gland, consistent with an adrenal cortical
  adenoma.

48
Management

• Medical therapy
• Over 5-7 yr period of follow-up, pts medically
  managed with spironolactone showed no evidence of
  escape or malignant transformation
• Side effect of gynaecomastia
• Potential role of eplerenone lesser side effect
  profile
• Surgical therapy
• In patients with APA, adrenalectomy had mean cost
  saving of US20,472 per patient cf lifetime
  medical treatment
• Long term cure of HT and hypokalaemia in 69 with
  APA
• More favourable regression of LVH in surgically
  vs medically treated patients.

49
Suspect 2

• 51 yo Caucasian male
• First diagnosed with HT aged 47 yrs, commenced
  Telmisartan
• Previous contact with Endocrine service in 2002
  during admission with fever and thyrotoxicosis.
• Thyroid disease
• May 02 Hyperthyroidism, low uptake on scan, ESR
  67
• June Aug 02 Hypothyroidism, TSH up to 110
  mU/L, T4 treatment.
• Feb 03 Hyperthyroidism, toxic multinodular
  goitre. Antibody negative. Treated with
  neomercazole, then I131 May 03
• June 03 Hypothyroidism, commenced thyroxine
• Sep 03 Graves eye disease. TSI gt125

50
Suspect 2

• Dec 03
• Ulcerative Colitis
• Treated with salazopyrine, salofalk enemas,
  prednisone 25 mg daily
• July 04
• Ongoing Graves ophthalmopathy
• Azathioprine used to treat both conditions
• Steroid sparing, but ceased after 2 mths due to
  LFT abnormality
• August 04
• Prednisone 12.5 mg daily
• K 3.0 mmol/L, commenced on oral Slow K

51
Suspect 2

• Oct 04
• BP 160/100 mmHg, amlodipine 5mg added
• Still on 10 mg prednisone daily
• Persistent hypokalaemia, Slow K increased to 10
  per day.
• Came under investigation for Conns syndrome
• Nov 04
• 24 hr urinary Na 288 mmol/day (50-200)
• 24 hr urinary K 208 mmol/day (25 125)
• Prednisone decreased to 7.5 mg daily

52
Suspect 2

• Dec 04
• BP 180/110 mmHg
• Plasma renin 0.3ng/ml/hr (1.2-2.8)
• aldosterone 809 pmol/L (80-1040)
• Ratio 97.2 (0-30)
• Serum K 3.4 mmol/L, Na 147 mmol/L
• Feb 05
• Prednisone reduced to 5 mg daily

53
(No Transcript)
54
Suspect 2

• Jan 05 CT abdomen
• small nodule in left adrenal 1 ? 1.2cm
• Soft tissue density 45- 50 HU
• K tablets seen in small bowel
• March 05 Adrenal Vein Sampling
• Extremely painful
• RAV catheter came out of position during sampling
  for RAV1.

55

• Adrenal venous sampling 10th March 2005

56
Suspect 2

• High cortisol levels in all but RAV 1 confirm
  adequate position.
• Average LAV ratio 1.3
• Average RAV ratio 0.2 (disregarding RAV 1)
• Average peripheral ratio 2.05
• ratios for LAV equivocal (possible aberrant
  draining of vein) so cannot distinguish between a
  discrete adenoma and bilateral hyperplasia.

57
Suspect 2

• April 05
• Prednisone 2.5 mg daily
• PRA 0.2 ng/ml/hr
• Aldo 729 pmol/L (80-1040)
• Aldo/renin ratio 131.4
• U. aldo 161 nmol/day (17-69)
• U. K 118 mmol/day (30-100)
• U. Na 161 mmol/day (60-200)
• U. Creat 19.5 mmol/day (6-22)

58
Suspect 2

• Expert advice sought from Dr Stowasser
• Repeat adrenal venous sampling under ACTH
  stimulation after overnight admission
• Low dose Spironolactone 12.5 mg is adequate.
• Serum K responds quickly, BP takes a month or
  two.
• Risk of gynaecomastia at this dose is low.

59
Suspect 2

• Options discussed with patient
• Repeat procedure in Brisbane with Dr Stowasser
• Medical therapy with spironolactone
• Laparascopic left adrenalectomy
• Opinion sought from Dr Gani
• Reluctant to offer surgery unless all other
  avenues explored
• Support repeat venous sampling in Brisbane /-
  therapeutic trial of aldosterone.

60
Suspect 2

• Postural Test

What should we advise?
61
Summary

• Primary hyperaldosteronism is not an uncommon
  cause of secondary hypertension
• It should be suspected in the presence of
  hypokalaemia which may only be unmasked by
  diuretic therapy
• The aldorenin ratio is the best screening test,
  some recommend routine use for all hypertensives.
• False positives and negatives occur with the ARR
  and confirmation with a suppression test is
  recommended

62
Summary

• Once diagnosis confirmed, need to differentiate
  between the 2 most common aetiologies
• aldosterone producing adenoma
• bilateral adrenal hyperplasia
• Adrenal vein sampling is the gold standard for
  lateralisation, but not without its problems
• Postural testing and adrenal imaging may assist

63
Summary

• Laparoscopic adrenalectomy is the preferred
  treatment for aldosterone producing adenomas
• Spironolactone is recommended medical therapy,
  large doses should be avoided.
• Appreciate the limitations of endocrinological
  testing which yield a number, not a direct answer
  to the clinical problem.
• As in any investigation, multiple modes of
  interrogation may be required.

64
Endocrine Department John Hunter Hospital
The culprit undergoes cross-examination