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