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Extrahepatic Complications in
Cirrhosis: What Happens in the
Lung?
Michael B. Fallon, MD. Professor of Medicine and Division Director,
Gastroenterology, Hepatology & Nutrition,
The University of Texas Medical School at Houston
“The blind men and the elephant”
PORTAL HYPERTENSION MECHANISMS
PORTAL HYPERTENSION MECHANISMS
Endothelial cell
Stellate cell
Nitric oxide
Constriction Fibrosis
Intrahepatic Vasoconstriction
Inflammatory cells
PORTAL HYPERTENSION MECHANISMS
Endothelial cell
Stellate cell
Nitric oxide
Constriction Fibrosis
Nitric oxide Vasodilation Angiogenesis Splanchnic
Systemic Vasodilation
Intrahepatic Vasoconstriction
Inflammatory cells
PORTAL HYPERTENSION MECHANISMS
CARDIAC
Endothelial cell
Stellate cell
Nitric oxide
Constriction Fibrosis
Nitric oxide Vasodilation Angiogenesis Splanchnic
Systemic Vasodilation
Intrahepatic Vasoconstriction
Inflammatory cells
PORTAL HYPERTENSION MECHANISMS
VARICES
CARDIAC
Endothelial cell
Stellate cell
Nitric oxide
Constriction Fibrosis
Nitric oxide Vasodilation Angiogenesis Splanchnic
Systemic Vasodilation
Intrahepatic Vasoconstriction
Inflammatory cells
PORTAL HYPERTENSION MECHANISMS
VARICES
CARDIAC
Endothelial cell
Stellate cell
Nitric oxide
Constriction Fibrosis
Nitric oxide Vasodilation Angiogenesis Splanchnic
Systemic Vasodilation
Intrahepatic Vasoconstriction
Inflammatory cells
PSE
PORTAL HYPERTENSION MECHANISMS
VARICES
CARDIAC
Endothelial cell
Stellate cell
Nitric oxide
Constriction Fibrosis
Nitric oxide Vasodilation Angiogenesis Splanchnic
Systemic Vasodilation
Intrahepatic Vasoconstriction
Inflammatory cells
ASCITES HRS
PSE
PORTAL HYPERTENSION MECHANISMS
VARICES
CARDIAC
Endothelial cell
Stellate cell
Nitric oxide
Constriction Fibrosis
Nitric oxide Vasodilation Angiogenesis Splanchnic
Systemic Vasodilation
Intrahepatic Vasoconstriction
Inflammatory cells
ASCITES HRS
PSE
Pulmonary HPS, POPH
63 year old female with HCV cirrhosis seen 12/11: Transfusion age 28 HCV dx: 2001 genotype 2 (treated three times 2001-2006) Biopsy 2006 cirrhosis Progressive exertional dyspnea over 18 months Oxygen saturation on room air 89% (placed on oxygen)
Chest CT Prominent lower lobe vasculature
PFTs Mild obstruction low DLCO (40% predicted)
Contrast echo Moderate TR
RVSP 41 Delayed shunting
RHC RA 9
MPAP 24 PCWP 16 PVR 87
Clubbing, no varices, ascites MELD 13 RA Arterial Blood Gas PaO2 59
PaCO2 29 A-aPO2 54
QUESTIONS: 1) How common is this?
2) What is the outcome?
3) Are there medical treatments?
4) What is the role of transplantation?
QUESTIONS: 1) How common is this?
2) What is the outcome?
3) Are there medical treatments?
4) What is the role of transplantation?
INTRINSIC LUNG DISEASE
RELATED TO LIVER DISEASE
Chronic obstructive pulmonary disease
Congestive heart failure
Asthma
Pulmonary vascular disorders
Ascites, hepatic hydrothorax
Specific liver diseases
Deconditioning
INTRINSIC LUNG DISEASE
RELATED TO LIVER DISEASE
Pulmonary vascular disorders 20-30%
Chronic obstructive pulmonary disease 17%
Asictes, hepatic hydrothorax 5%
Congestive heart failure 5%
Specific liver diseases 3%
Deconditioning 2%
Asthma 1%
Fallon et al, Gastro 2008;135:1168-1175
LUNG HPS POPH
Vasodilatation and Angiogenesis in microvasculature
Vasoconstriction and remodeling in resistance vessels
Cirrhosis Hepatic injury
Portal hypertension
v Portal Hypertension v Cirrhosis v Portosystemic shunting
HPS
Pulmonary vasodilatation
? Angiogenesis
Normal Pulmonary Microvasculature
Abnormal ABGs
40-50% 40-60%
50%
Rodriguez-Roisin et al , Thorax 1992, Eur Respir J 2004
46% (14)
36% (12)
18% (5)
PaO2 in HPS patients at LT evaluation
(31% of patients had HPS)
UAB Columbia Mayo Clinic UNC U. Colorado Tufts-NEMC
LT EVALUATION Pulse
Oximetry ≥ 96%
TTE
≤ 95%
CTTE
Shunt No shunt
ABGs CXR, PFTs, Chest CT
Other causes
PaO2 ≤ 60 PaO2>60
MELD ABG 3-6m
Monitor Treat
Low PO2 HPS
Abrams, Liver Transpl. 2002:8;391-6 Roberts, Liver Transpl. 2007:13:206-14
Arguedas, Clin Gastro Hepatol. 2007:5;749-54
Kochar, Dig Dis Sci. 2011:56;1862-8
QUESTIONS: 1) How common is this?
2) What is the outcome?
3) Are there medical treatments?
4) What is the role of transplantation?
QUESTIONS: 1) How common is this?
2) What is the outcome?
3) Are there medical treatments?
4) What is the role of transplantation?
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48
Per
cent
Sur
vivi
ng
Follow up time in months
HPS: SURVIVAL PRIOR TO LT
Adapted from: Schenk et al Gastroenterology 2003 125:1042-52
HPS (n=27)
Non HPS (n=84)
P = 0.018
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48
Per
cent
Sur
vivi
ng
Follow up time in months
Adapted from: Swanson et al 2005 Hepatology 41: 1122-1129
HPS (n=37)
Non HPS (n=47)
P = 0.0003
HPS: SURVIVAL PRIOR TO LT
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48
Per
cent
Sur
vivi
ng
Follow up time in months
UAB Columbia Mayo Clinic UNC U. Colorado Tufts-NEMC
Adapted from: Fallon et al Gastroenterology 2008 135: 1168-75
HPS (n=72)
Non HPS (n=146)
P = 0.013 (adjusted for age, gender, BMI, MELD, LT, PaO2)
HPS: SURVIVAL PRIOR TO LT
50
60
70
80
90
100
-20 0 20 40 60 80 100
Wak
e tim
e P
aO2
mm
Hg
TST-SpO2<90%
Controls (n=10)
HPS (n=10)
Median TST-SpO2 <90% HPS (25%) vs. Controls (0%) p = 0.0005
Nocturnal pulse oximetry and HPS
Palma et al. Hepatology 47: 1257-63, 2008
QUESTIONS: 1) How common is this?
2) What is the outcome?
3) Are there medical treatments?
4) What is the role of transplantation?
QUESTIONS: 1) How common is this?
2) What is the outcome?
3) Are there medical treatments?
4) What is the role of transplantation?
Cirrhosis Portal
Hypertension
Lung microvessel
Vasodilation
Angiogenesis
PATHOPHYSIOLOGY
Shear Translocation
ET-1 TNF-
NO
Mononuclear cell
Endothelial cell
ETBR
ET-1 iNOS HO-1
CO
VEGF
eNOS
Cirrhosis Portal
Hypertension
Lung microvessel
Vasodilation
Angiogenesis
PATHOPHYSIOLOGY
Shear Translocation
ET-1 TNF-
NO
Mononuclear cell
Endothelial cell
ETBR
ET-1 iNOS HO-1
CO
VEGF Norfloxacin
PTX
ET Receptor Blockers NOS Inhibitors Garlic
eNOS
Liver Transplantation
Oxygen
Oxygen
TIPS
Anti-Angiogenics
Natures Way garlicin (2 tablets daily with PPI) RA Arterial Blood Gas
12/8/11 3/29/12 PaO2 59 68 PaCO2 29 34 A-aPO2 54 36
QUESTIONS: 1) How common is this?
2) What is the outcome?
3) Are there medical treatments?
4) What is the role of transplantation?
QUESTIONS: 1) How common is this?
2) What is the outcome?
3) Are there medical treatments?
4) What is the role of transplantation?
Study Study design
Sample Size
Mean PaO2
mmHg
Length of follow-up (months)
Survival
Arguedas (2003) Prospective 24 54 12 71%
Taille (2003) Retrospective
23 51 17 69%
Schenk (2003) Prospective 7 68 58%
Swanson (2005) Retrospective
24 57 60 79%
Schiffer (2006) Prospective 9 60 6 67%
Deberaldini (2008)
Retrospective
25 77 49 60%
Gupta (2009) Retrospective
21 50 20 95%
HPS: OUTCOME AFTER OLT
(2003)
(2008)
(2006)
(2003) (2003)
(2005)
(2009)
40
50
60
70
80
50 60 70 80 90 100
PaO
2 (m
mH
g)
1 Year Survival (%)
HPS: OUTCOME AFTER OLT
0
20
40
60
80
100
0 3 6 9 12
Su
rviv
al (
%)
Follow up (months)
0
10
20
30
40
50
60 50
9
59
18
53
9
43 41
Alive Expired
* *
HPS FEATURES AND LT OUTCOME
Arguedas Hepatol. 2003:37;192-197
HPS:SUMMARY
• Common cause of hypoxemia (20-30%)
• Increased mortality
• No proven medical therapies (garlic?)
• LT reverses, ? Increased mortality
Definition
Clinical Importance
Diagnosis
Pathogenesis
Treatment
POPH
Definition
Clinical Importance
Diagnosis
Pathogenesis
Treatment
POPH
PORTOPULMONARY HYPERTENSION (POPH): DEFINITION
• Portal hypertension
• Mean pulmonary artery pressure: >25 mmHg
• Pulmonary capillary wedge pressure: NL
• PVR > 240 dynes/sec/cm5
Definition
Clinical Importance
Diagnosis
Pathogenesis
Treatment
POPH
Definition
Clinical Importance
Diagnosis
Pathogenesis
Treatment
POPH
PULMONARY VASCULATURE IN LT EVALUATIONS
0
20
40
60
80
100
0 12 24 36 48 60
Per
cent
Sur
vivi
ng
Follow up time in months
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96
Follow up time in months
POPH: NATURAL HISTORY
Kawut, Liver Transplantation, 2005
Le Pavec, Am J Res Crit Care Med, 2008
POPH without cirrhosis (N=18)
POPH with cirrhosis (N=136)
IPAH (N=33)
POPH (N=13)
P = 0.04 P = 0.03
---- POPH (N=153) ---- IPAH (N=1190) P<0.001
Krowka, Chest, 2012
POPH: LIVER TRANSPLANTATION SURVIVAL
<35 >35 >50 MPAP
52%
0%
Krowka, 2000
(n = 43)
(6)
(23)
(14)
Definition
Clinical Importance
Diagnosis
Pathogenesis
Treatment
POPH
Definition
Clinical Importance
Diagnosis
Pathogenesis
Treatment
POPH
LT EVALUATION AASLD Practice Guidelines
Transthoracic Echocardiograpy
RV systolic pressure (RVSP) Pulmonary artery systolic pressure (PASP)
> 40-50 mm Hg
Right Heart Catheterization (RHC)
Systolic estimate
Mean measured
Pre TIPS Pulm sxs, edema
mPAP CI PVR PCWP
Hyperdynamic (20%)
NL NL /
Volume (25%)
NL
POPH (50%)
NL
RHC: PORTAL HYPERTENSION
Definition
Clinical Importance
Diagnosis
Pathogenesis
Treatment
POPH
Definition
Clinical Importance
Diagnosis
Pathogenesis
Treatment
POPH
Cirrhosis Portal
Hypertension
Resistance vessel in the Lung
PATHOGENESIS OF POPH
Endothelial cell
NOS
ETB R Vasoconstriction Remodeling
ETA R
NO
Clinical and Genetic
Risk Factors
PGIS
PGI2
Smooth muscle cell
Epoprostenol Treprostinil Ilosprost
Bosentan ET-1
Sildenafil Ambrisentan
cGMP cAMP
Vasorelaxation Vasoconstriction Remodeling
PATHOGENESIS OF POPH
POPH
Female gender (OR=2.9)
Autoimmune Hepatitis (OR=4)
Estrogen signaling
Kawut, Hepatology, 2008:48;196-203
Roberts, Am J Resp Crit Care, 2009:179;835-42
Roberts et al Chest. 2009 :135 ;1470-5
Portosystemic shunting
Talwalkar et al Gastroenterol 2011
Definition
Clinical Importance
Diagnosis
Pathogenesis
Treatment
POPH
Definition
Clinical Importance
Diagnosis
Pathogenesis
Treatment
POPH
• POPH mPAP > 35 mmHg
and
• Medical treatment for 12 wks
MPAP <35mmHg
PVR < 400 dynes/sec/cm5
Adequate right ventricular function
POPH: MELD EXCEPTION
Krowka, Liver Transplantation, 2006
36
19 6 2 0
20 16 12 11 5
11 10 3 1 0
POPH: REVERSAL WITH OLT?
8 8 6 4 2
90%
27%
9%
53% 17
% 5%
75%
60%
55%
25%
100%
75%
50%
25%
mPAP>35 Therapy mPAP<35 OLT Off therapy
Gough (2009)
Fix (2007)
Ashfaq (2007)
Sussman (2006)
POPH: SUMMARY
• 4-8% of LT evaluations
• increased pre and post-op mortality
• Gender, disease and estrogen signaling
• Medical therapies effective
• LT may reverse a subset, MELD exception