INSUFICIENCIA SUPRARRENAL DEL CIRRÓTICO

J. Fernández, Liver Unit, Hospital Clinic of Barcelona, Spain

III Curso Residentes. Diagnóstico y tratamiento de las enfermedades hepáticas. AEEH

Barcelona 2011

Biological effects of cortisol

- Catabolism of glycogen, fat and proteins- Delay in anabolic pathways

- Retention of intravascular fluid- Increases the cardiac/ vascular response to cathecolamins and angiotensin

Essential to survivecritical illness

CORTISOL

IMMUNE &INFLAMATORY

REACTIONS

METABOLICEFFECTS

CARDIOVASCULARSYSTEM

Potent immunossupresive hormone: cytokines, nitric oxide…

HYPOTHALAMUS

PITUITARY GLAND

ADRENAL CORTEX

ADHCRH

ACTH

HIGH FREE PLASMA CORTISOL LEVELS

++ +

+

Cytokines, bacterial products

STRESS

Decrease in cortisol-binding protein levels

Increased adrenalcortisol secretion

Decreased hepatic/ renal inactivation of cortisol

Upregulation of glucocorticoid receptors

INCREASED EFFECTS OF CORTISOL IN PERIPHERAL TISSUES

Hypothalamic-pituitary-adrenal axis in the acute phase of critical illness

Definition and clinical impact of relative adrenal insufficiency on critical illness

• Definition: inadequate production of cortisol, although high in terms of absolute value, with respect to the peripheral demands (functional adrenal insufficiency).

• Incidence in septic shock: 20-65%.

• Importance: it is associated with a poor outcome in critically ill patients:

- Resistance to vasoconstrictor drugs- refractory shock.- Higher mortality.

• Diagnosis: It is not possible on clinical grounds and nowadays relies on the determination of total/free cortisol levels.

Gold standard diagnostic criteria of relative adrenal insufficiency in critical illness

Cooper et al, N Engl J Med 2003; Grinspoon et al, J Clin Endocrinol Metabol 1994 Hamrahian et al N Engl J Med 2004

hour0 1

Baseline serum total

cortisol levels

250 μgr ACTH IV Peak serumtotal cortisol

levels

Low baseline levels:< 9 or 15 µg/dL

Response to the corticotropin test:

- Increase < 9 µg/dL - Peak cortisol < 18-20 µg/dL

Major problem: Free cortisol (active fraction): 10% of serum total cortisol (70-80% linked to CBG and 10-20% to albumin)

40% of critically-ill patients with subnormal total cortisol have normal adrenal function

Serum free cortisol diagnostic criteria of relative adrenal insufficiency in critical illness

Hamrahian et al, N Engl J Med 2004

hour0 1

Baseline serum free

cortisol levels

250 μgr ACTH IV Peak serumfree cortisol

levels

Low baseline levels:< 2.0 µg/dL

Response to the corticotropin test:

Peak cortisol < 3.1 or 4.5 µg/dL

Diagnostic criteria of relative adrenal insufficiency based on salivary cortisol

Deutschbein et al. Eur J Endocrinol 2009

hour0 1

Salivarycortisol levels

250 μgr ACTH IV Salivary cortisol levels

Response to the corticotropin test: - Increase < 3 ng/ml

- Peak cortisol < 12.7 ng/ml

Low basal values < 1.8 ng/dL

* Low applicability in ICU* No blood in the mouth, refrain from eating,smoking, brushing teeth 1h before sampling

Other diagnostic criteria of relative adrenal insufficiency

The low dose short synacthen test

Abdu et al, J Clin Endocrinol Metabol 1999; Tordjman et al Clinical Endocrinology 2000

minutes0 20-30

Baseline serumtotal cortisol

levels

1 μgr ACTH IV Peak serumtotal cortisol

levels

Response to the low dose corticotropin test:

Peak cortisol < 18-20 µg/dL

Effects of low doses of steroids on shock reversal

Minnecci et al. Ann Intern Med 2004

Bollaert et al., 1998 3.24 (1.50-7.01)

Briegel et al., 1999 1.13 (0.86-1.46)

Chawla et al., 1999 2.09 (1.14-3.83)

Annane et al., 2002 1.54 (1.10-2.16)

Harm No effect Benefit

■

-2 0 2-1 1

Relative shock reversalbenefit (95%CI)

■

■

■

0.14 1.0 7.390.37 2.72HR for shock

reversal (95%CI)

Effects of low doses of steroids on survival in septic shock

Minnecci et al. Ann Intern Med 2004

Bollaert et al., 1998 1.85 (1.01-3.40)

Briegel et al., 1999 1.06 (0.80-1.42)

Yildiz et al., 2002 1.50 (0.79-2.83)

Total 1.23 (1.01-1.50)

Relative survival benefit Harm No effect Benefit

Annane et al., 2002 1.17 (0.89-1.52)

0.37 1.0 2.70.22 0.61 1.64.5

■

Relative survivalBenefit (95%CI)

■

■

■

■

Sprung C et al. N Engl J Med 2008;358:111-124

Corticus Study Kaplan-Meier Curves for Survival at 28 days

Relative adrenal insufficiency in critically-ill patients with chronic liver failure

Number of patients Critical illness Incidence

Harry et al (2003) 20 Acute or chronic 69%liver failure andseptic shock

Marik et al (2005) 147 Chronic liver 66%disease

Tsai et al (2006) 101 Cirrhosis and 51%severe sepsis or shock

Fernandez et al (2006) 25 Cirrhosis and 68%septic shock

Thierry et al (2007) 14 Cirrhosis and shock 77%

Cheyron et al (2008) 50 Cirrhosis 62%

Renal, hepatic and adrenal function in severe

sepsis and septic shock in cirrhosis

Tsai et al. Hepatology 2006

25

50 50

25

75

0

RENAL FAILURE (%)

100

Adrenalinsufficiency

Normalfunction

CHILD-PUGH CLASS C (%)

0

100

75

Adrenalinsufficiency

Normal function

p=0.01

p<0.001

Impact of adrenal insufficiency on clinical outcome

in critically-ill cirrhotic patients

Tsai et al. Hepatology 2006

25

50 50

25

75

0

ICU MORTALITY (%)

100

Adrenalinsufficiency

Normalfunction

HOSPITAL MORTALITY (%)

0

100

75

Adrenalinsufficiency

Normal function

p<0.001p<0.001

Resolution of septic shock, hospital and ICU mortality

75 PATIENTS WITH CIRRHOSIS AND SEPTIC SHOCK

GROUP 1 (n=25)Prospective series

Evaluation of adrenal function Hydrocortisone 50mg/6h IV

GROUP 2 (n=50) Retrospective series

No evaluation of adrenal function

Adrenal insufficiency in septic shock in cirrhosis. Effects of hydrocortisone on survival

Fernández et al. Hepatology 2006

Impact of steroid treatment on resolution of septic shock

p=0.001

Fernández et al. Hepatology 2006

%

Days

6050403020100

1,0

,8

,6

,4

,2

0,0

Pro

babi

lity

of h

ospi

tal s

urvi

val

Group 2 (n=50)

Group 1 (n=25)

p=0.003

Impact of steroid treatment on hospital survival

Fernández et al. Hepatology 2006

Prospective Retrospective

p series (n=25) series (n=50)

Refractory shock 0 20 0.001Type-1 HRS 2 3 nsLiver failure 4 4 nsVariceal bleeding 0 4 ns Fungal infection 2 0 ns

Fernández et al. Hepatology 2006

Causes of death in the ICU

Impact of steroid treatment on hospital survival . RCT

Arabi et al. CMAJ 2010

Conclusions

• Relative adrenal insufficiency (RAI) has a negative impact on prognosis in critically-ill cirrhotic patients (refractory shock, mortality).

• The effects of low dose steroids on survival are unclear. Final answer: RCT under design

Non-critically ill cirrrhotic patientsQuestions

• Is RAI an underlying condition or a triggered event (i.e sepsis, variceal bleeding) in cirrhosis?

• Which is its clinical impact on decompensated cirrhosis?

REAL CLINICAL PROBLEM?

Adrenal insufficiency as an underlying condition in cirrhosis. First evidences

• McDonald et al, J Gastroenterol Hepatol 2003: - N= 51 patients with end-stage non-alcoholic cirrhosis.- 64% reduction in peak plasma cortisol to indirect adrenal stimulation(insulin-induced hypoglycemia) compared to healthy controls. - 39% reduction to direct adrenal stimulation by ACTH. - Significant negative correlation between Child-Pugh score and peak plasma cortisol levels.

• Marik et al, Crit Care Med 2005 : - 92% of patients submitted to recent liver transplantation with a steroid-free regimen had RAI.

Adrenocortical reserve in stable cirrhosis

101 Patientswithout infection/instability

Adrenal Insufficiency(n=38)

Normal Adrenal Function(n=73)

p

Ascites (%) 68 37 0.01

Bilirubin (μmol/L) 51 31 <0.05

Serum albumin (g/l) 28±0.8 33±0.7 0.0001

INR 1.6 1.2 0.0001

Child-Pugh score (points) 10 7 0.0001

MELD score (points) 17 12 0.0001

Basal total cortisol (μg/dl) 7.6 14.9 0.01

Total cholesterol (mg/dl) 120 142 <0.05

• Definition of AI: serum total cortisol <18 μg/dl at 20 or 30 min after 1μg of ACTH. • Weak point: no direct free cortisol assessment. • Good correlation between total cortisol and calculated free cortisol.

Fede et al. J Hepatol 2011

RAI: 38% (frequent event related to the severity of liver disease)

No data on clinical impact!

RAI in decompensated cirrhosis

RAI according to serum total cortisol*

RAI according to salivary cortisol**

P

RAI according to Δ, n (%) 19 (22%) 3 (3%) 0.001

Any criteria of RAI, n (%) 29/88 (33%) 8/88 (9%) 0.001

Serum total cortisol overestimates RAI compared to salivary cortisol

* RAI using serum total cortisol: basal value (T0) < 9 µg/dL or peak value (T60) < 18 µg/dL or Δ < 9µg/dL; ** RAI using salivary cortisol was defined as T0 < 1.8 ng/mL or T60 < 12.7 ng/mL or Δ < 3 ng/mL.

Galbois A, et al. J Hepatol 2010

- Eighty-eight patients with decompensated cirrhosis (68% Child-Pugh C) without hemodynamic instability.

- Assessment of salivary and serum total cortisol before and 1h after 250µg of ACTH.

Aims

• To evaluate the prevalence and clinical impact of RAI on decompensated cirrhosis.

• Prospective observacional study (2008-2010).• Inclusion criteria: hospitalization for

complications related to cirrhosis• Exclusion criteria:

– HIV infection, use of steroids, history of pituitary/adrenal disease, advanced CHC, other advanced diseases that could affect short-term prognosis.

– Septic shock (hemodynamic inestability).

Study design

Study protocol

• Within the 1st 24h of hospitalization: – Standard laboratory tests.– Short synacthen test (8:00-9:00 AM): serum total cortisol before and 1h

after the administration of 250 µg of ACTH. – Vasoactive hormones, cytokines, NO, CBG and choleterol levels (total, HDL

and LDL).

• Definition of RAI: delta of cortisol < 9 µg/dL.• Follow-up during hospitalization.

Prevalence

168 patients with decompensated cirrhosisMain cause of admission Frequency

(n/%)RAI(%)

Ascites 25 (15%) 36

Encephalopathy 14 (8%) 29

Variceal bleeding 30 (18%) 27

SBP 29 (17%) 14

Other infections 42 (25%) 26

Hepatorenal syndrome 16 (10%) 31

Other 12 (7%) 33

TOTAL 168 (100%) 45 (27%)

* In a group of 11 compensated patients 2 (18%) presented RAI.

Baseline clinical characteristics

Adrenal Insufficiency

(n=45)

Normal Adrenal Function

(n=123)

p

Ascites (%) 76 70 0.57

Infection (%) 38 49 0.23

SBP 9 20 0.11

Other infections 29 29 1.00

Variceal bleeding (%) 20 20 1.00

Encephalopathy (%) 38 33 0.59

Hepatorenal syndrome (%) 11 9 0.77

MAP (mmHg) 77 ± 11.3 82 ± 13.2 0.02

Heart rate (bpm) 83.5 ± 10.8 82.3 ± 15.5 0.59

SIRS (%) 54 27 0.004

ICU admission* (%) 29 21 0.31* Variceal bleeding (24), severe hepatic encephalopathy (5), HRS (3),acute-on-chronic liver failure (3), severe sepsis (2), secondary peritonitis (1), respiratory failure (1)

Baseline analytical data

Adrenal Insufficiency

(n=45)

Normal Adrenal Function

(n=123)

p

Bilirubin (mg/dL) 6.7 ± 9.2 4.9 ± 5.9 0.24

Albumin (mg/dL) 27.4 ± 4.5 29.0 ± 5.5 0.08

Prothrombin time (%) 48.5 ± 14.8 49.7 ± 14.0 0.64

Creatinine (mg/dL) 1.4 ± 1.1 1.3 ± 1.0 0.35

Serum sodium (mEq/L) 131 ± 7.6 134 ± 5.4 0.049

Total cholesterol (mg/dL) 87.0 ± 30.2 99.8 ± 36.3 0.046

HDL (mg/dL) 18.3 ± 12.5 22.6 ± 12.1 0.052

LDL (mg/dL) 52.5 ± 22.4 61.8 ± 27.8 0.055

Child-Pugh (points) 9.8 ± 2.2 9.3 ± 2.1 0.19

MELD (points) 20.1 ± 8.4 18.5 ± 6.8 0.20

Baseline hormonal, proinflammatory and cortisol/CBG profile

Adrenal Insufficiency

(n=45)

Normal Adrenal Function

(n=123)

p

Vasoactive hormones

PRA (mg/mL.h-1) 1.7 (0.4-12.8) 1.3 (0.2-4.3) 0.07

Noradrenaline (pg/mL) 492 (284-742) 367 (216-536) 0.03

Cytokines and nitric oxide

TNF (pg/mL) 20 (16-40) 20 (13-33) 0.21

IL-6 (pg/mL) 103 (74-409) 112 (53-206) 0.30

Nitric oxide (nMol/mL) 34.6 (17.7-64.0) 26.1 (18.7-45.1) 0.33

Cortisol/transcortin levels

Basal total cortisol (mg/dL) 17.7 ± 7.3 15.7 ± 6.9 0.12

Post ACTH cortisol (mg/dL) 23.1 ± 7.4 30.6 ± 8.3 <0.001

Transcortin (µg/dL) 29.3 ± 10.2 27.4 ± 9.1 0.25

Clinical evolution during hospitalization

Clinical eventAdrenal

Insufficiency(n=45)

Normal Adrenal Function(n=123)

P(probability)

Variceal bleeding 1 (2%) 0 0.27

Type 1 or 2 HRS 4 (9%) 4 (3%) 0.23

New bacterial infections 11 (24%) 15 (12%) 0.07

SBP 4 (9%) 3 (2%) 0.24

Non SBP infections 7 (16%) 12 (10%) 0.10

Septic shock 6 (24%) 1 (1%) 0. 006

Death 10 (22%) 9 (7%) 0.004

Probability of remaining free of septic shock during hospitalization in infected patients

p< 0.001

Normal adrenal function=69

Adrenal insufficiency=26

Probability of survival during hospitalization

p=0.004

Adrenal insufficiency=45

Normal adrenal function=123

Probability of septic shock after nosocomial infection

p=0.04

RAI (n=11)

No RAI (n=16)

Causes of death during hospitalization

Clinical eventAdrenal

Insufficiency(n=45)

Normal Adrenal Function(n=123)

P

Variceal bleeding 1 1 ns

Respiratory failure 1 2 ns

Other 1 1 ns

Refractory shock 1 0 ns

Acute on chronic liver failure

6 6 ns

Conclusions

• RAI is relatively common in decompensated cirrhosis and it is associated with circulatory dysfunction and SIRS.

• RAI (delta of cortisol < 9 µg/dL) seems to be independent from the degree of liver failure (marker of another failing organ).

• RAI seems to predispose patients who develop bacterial infections to septic shock and has a negative impact on hospital survival.

0

20

40

60

80

100

120

140

0 8 16 24 32 40 48

MAP (mmHg)

Heart rate(b.p.m)Noradrenaline(microgr/Kg/h)

hours

ICUadmission

Hydrocortisone