Hepatopulmonary Vascular Disorders

1
Hepatopulmonary Vascular Disorders

• Nawaid Shakir, MD
• North Shore University Hospital
• December 13, 2006

2
Case of Ms. AM 54 y/o female with worsening
dyspnea on exertion, platypnea, and fatigue

• Past medical history includes Hepatitis C
  cirrhosis diagnosed 4 years ago
• Physical exam was significant for tachypnea,
  clubbing, a spider nevi on the thorax, and
  splenomegaly
• Arterial blood gas revealed hypoxemia with a PaO2
  of 43 mmHg and patient was placed on 100 oxygen
• CXR was normal and CT Angiogram revealed possible
  dilated peripheral pulmonary vessels but no
  pulmonary embolus

3
Liver-Related Causes of Dyspnea in a Patient with
Chronic Liver Disease

• Pulmonary - Parenchymal
• Alveolar
• Aspiration pneumonia
• Basal atelectasis
• Interstitial lung disease
• Lymphocytic interstitial pneumonia
• Fibrosing alveolitis
• BOOP
• Noncardiogenic pulmonary edema
• Vascular
• Pulmonary hemorrhage
• HPS
• PPHTN

• Extraparenchymal
• Pleural effusions
• Restriction from tense ascites
• Extrapulmonary
• Cirrhotic cardiomyopathy
• Cirrhotic myopathy
• Chronotropic dysfunction
• Muscle wasting
• Deconditioning from impaired mobility

4
Circulatory Changes in Patients with Cirrhosis

• Systemic circulation
• Plasma volume ?
• Total blood volume ?
• Central/arterial volume ?(?)
• Cardiac output (?) ?
• Blood pressure ? ?
• Heart rate ?
• SVR ?
• Pulmonary circulation
• Pulmonary blood flow ?
• PVR ?(?)
• Renal circulation
• Renal blood flow ?
• Renal vascular resistance ?

• Heart
• LA volume ?
• LV volume (?)
• RA volume ? ?
• RV volume ? ?
• RA pressure ?
• RVEDP ?
• PA pressure ??
• PCWP ?
• LVEDP ?
• Cerebral circulation
• Cerebral blood flow ? ?

5
Liver Lung Interaction
Liver Failure
Acute Liver Failure
Chronic Liver Failure
ARDS
Vasodilatation
Vasoconstriction
HPS
Portopulm HTN
6
Hepatopulmonary Syndrome

• Triad of liver disease, hypoxemia, and pulmonary
  vascular dilatations
• Hypoxemia caused by hepatopulmonary syndrome
  ranges from 5 to 20
• Most commonly associated with cirrhosis but also
  reported in noncirrhotic portal hypertension
• No consistent relationship between hepatic
  dysfunction and Child-Pugh classification with
  severity of hypoxemia or shunt

7

• Clinical Manifestations
• Dyspnea
• Platypnea
• Orthodeoxia
• Clubbing
• Liver dysfunction
• Spider nevi
• Elevated Cardiac Output
• Decreased SVR and PVR
• Narrowed A-V O2 difference

• Pathogenesis
• V/Q mismatch
• Intrapulmonary shunting
• Limitation of oxygen diffusion
• Failure to clear and production of circulating
  vasodilators by damaged liver
• Inhibition of vasoconstrictive substance by
  damaged liver

8
Pathogenesis of HPS

• Increased exhaled NO levels in HPS as compared to
  normoxemic cirrhotics and healthy controls and
  normalize after OLT
• Increased NO synthase level following CBD
  ligation in rats

Cremona G et al. Eur Respir J 199581883-1885
Chang SW et al. Am Rev Respir Dis 1992148798-805
9
Hypothesis of Pulmonary Vessel Dilatation in
Hepatopulmonary Syndrome
10
Pathophysiology of Hypoxemia in HPS
Ramsay MA. Int Anesthesiol Clin. 2006
Summer44(3)69-82
11
Pathophysiology of Hypoxemia in HPS
Hoeper MM et al. Lancet 2004 May
1363(9419)1461-8
12
Diagnostic Criteria for Hepatopulmonary Syndrome

• Portal hypertension with or without cirrhotic
  liver disease
• Arterial hypoxemia
• PaO2 lt 70 mmHg or PA-a, O2 ? 15 mmHg
• Pulmonary vascular dilatation demonstrated by
• Delayed positive contrast enhanced
  transthoracic echocardiography or
• Abnormal brain uptake (gt6) after 99mTcMAA lung
  perfusion scanning

13
Contrast-enhanced Echocardiography

• IV administration of hand-agitated normal saline
  (using 3-way stop cock)
• Microbubbles average 10 to 20 microns (normal
  capillary is 8 microns)
• Diffuse dilatations allows passage of
  microbubbles within 3 to 6 cardiac cycles
• Right-to-left intracardiac shunt if within 3
  cardiac cycles
• Transesophageal echocardiography further
  distinguishes intracardiac and intrapulmonary
  shunting

14
99mTcMAA Lung Perfusion Scanning

• Peripheral injection of 99mTcMAA
• Aggregates are 20 to 90 microns
• Demonstration of abnormal uptake over the brain
  (gt6)
• Does not distinguish between intracardiac and
  intrapulmonary shunts
• May offer complementary information for
  stratification of HPS patients at greater risk of
  OLT mortality

15
Grading of Severity of Hepatopulmonary Syndrome
Stage PA-a,O2 (mmHg) Pa,O2 (mmHg)
Mild ? 15 ? 80
Moderate ? 15 lt 80 - ? 60
Severe ? 15 lt 60 - ? 50
Very Severe ? 15 lt 50 (lt 300 on 100 O2)
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17
Pre-OLT PaO2 in HPS Patients
All HPS N40 Denied OLT N8 Transplant Survivors Nonsurvivors N27 N5 Transplant Survivors Nonsurvivors N27 N5
PaO2 (mmHg) 51 ? 10 47 ? 10 55 ? 10 37 ? 8
Range (mmHg) (29-70) (35-47) (34-70) (29-47)
Krowka MJ et al. Liver Transpl 200410174-82
18
Management of Hepatopulmonary Syndrome

• Pharmacological Treatment
• Somatostatin analogue
• B-blockers
• Cyclooxygenase inhibitor
• Glucocorticoids
• NO inhibitors
• Immunosuppressors
• Vasoconstrictors
• Antimicrobials
• Garlic preparation

• Nonpharmacological Treatment
• Long term oxygen therapy
• Transjugular intrahepatic portosystemic shunts
• Cavoplasty
• Embolization
• Orthotopic Liver Transplantation

19
Survival in HPS Patients and Controls undergoing
OLT

Swanson KL et al. Hepatology 2005411122-9
20
Survival based on Initial PaO2 in 61 Patients
with HPS
Swanson KL et al. Hepatology 2005411122-9
21
Sequential Oxygen Assessment of 14 Patients with
HPS awaiting OLT
Swanson KL et al. Hepatology 2005411122-9
22
The MELD ScoreModel for End-Stage Liver Disease

• Determines priority for Orthotopic Liver
  Transplant
• Uses the following formula
• 3.8 x log (e) (bilirubin mg/dL) 11.2 x log (e)
  (INR) 9.6 log (e) (creatinine mg/dL)
• Scores range from 6 to 40
• Score can be increased if PaO2 lt 60 in patient
  with Hepatopulmonary Syndrome

23
Case of Mr. PB 46 y/o male with progressive
shortness of breath, lower extremity edema, and
syncopal episodes

• Past Medical History
• Cirrhosis diagnosed 3/2000 after liver biopsy
• Alcoholic hepatitis
• Atrial fibrillation
• Congestive heart failure
• Past Surgical History
• None

24

• Medications
• Warfarin
• Procrit
• Ranitidine
• Flomax
• Folic acid
• Lactulose
• Furosemide
• Potassium chloride
• Atenolol

25

• Social History
• No use of tobacco or illicit drugs
• H/o alcohol abuse, quit 4 years ago
• Married with 2 daughters
• Family History
• Mother Emphysema
• Father Coronary artery disease
• No family history of Pulmonary Hypertension

26
Physical Examination

• General anxious, no acute distress
• HEENT NCAT, PERRLA, pharynx clear
• Neck supple, JVD
• Chest clear to auscultate bilaterally
• CV S1, S2, irreg. irregular, murmur right
  sternal border
• Abdomen soft, nontender, bowel sounds,
  shifting dullness consistent with ascites,
  splenomegaly
• Extremities edema lower extremities bilaterally

27
Laboratory Data

• WBC 4.8
• Hgb 10.4
• Hct 37.8
• Platelets 98
• Sodium 134
• Potassium 3.9
• Chloride 94
• CO2 23
• BUN 28
• Creatinine 1.2
• Glucose 98
• Calcium 9.3

• AST 26
• ALT 12
• Alk Phos 73
• T. Bili 1.1
• Albumin 4.0
• BNP 349
• TSH 4.2
• Free T4 1.4

28
Chest x-ray showing enlarged pulmonary arteries
29

• CT of Chest/Abdomen/Pelvis
• enlarged pulmonary artery and right chambers of
  the heart
• ascites
• splenomegaly
• cirrhosis and signs of portal hypertension

30

• Electrocardiogram
• Right atrial enlargement
• Right ventricular hypertrophy
• Echocardiogram
• Preserved LV function with ejection fraction of
  60
• Marked enlargement of right heart with PA
  systolic of 60 mmHg
• Severe tricuspid regurgitation
• Dilated inferior vena cava

31
Right Heart Catheterization
Baseline After 40 PPM Nitric Oxide
RA mean 30
RV 102/33
PA mean 56 49
PCWP 19
CO 4.27 6.23
CI 2.31 3.37
PVR 693.2 (8.67) 385.2 (4.82)
32
Portopulmonary Hypertension

• Pulmonary arterial hypertension occuring in the
  setting of portal hypertension
• Prevalence of 5 in hepatic patients
• First described in 1951 in a woman with portal
  vein stenosis and a portocaval shunt thrombus
• 25 sudden death reported due to syndrome

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34

• Clinical Manifestations
• Dyspnea (exertional and at rest)
• Chest pain
• Syncope
• Palpitations
• Split second heart sound
• Right ventricular heave
• Right-sided S3 gallop
• JVD
• Ascites
• LE edema

• Pathogenesis
• Vasoproliferation and obstruction
• Genetics
• Inflammation
• Neurohormones (ET-1)
• Abnormal levels of vasoconstrictors
  (noradrenalin, renin-angiotensin-aldosterone and
  vasopressin) and vasodilators (NO, glucagon, VAP,
  and substance P)

35
Possible Pathogenetic Mechanisms Leading to
Portopulmonary Hypertension
Shear stress from increased pulmonary blood flow
Endothelial cell dysfunction
? Gene mutation
Autoimmunity
Endothelial cell proliferation
Cytokine / Growth factor imbalance
Humoral imbalance
Vascular luminal obliteration
Smooth muscle hypertrophy, Adventitial hypertrophy
Vasoconstriction
Vasoactive compounds escaping hepatic metabolism
Down regulated Potassium channels
Budhiraja R et al. Chest. 2003 Feb123(2)562-76
36
Histological Sample of Lungs in Severe
Portopulmonary Hypertension
Intimal and medial thickening of pulmonary
artery and outspread channel-like structures
forming plexiform lesions
37
Diagnostic Criteria for Portopulmonary
Hypertension

• Liver disease (causing clinical portal
  hypertension
• MPAP gt 25 mmHg
• Mean PAOP lt 15 mmHg
• PVR gt 240 dyn/sec/cm-5
• Transpulmonary gradient gt 10 mmHg

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39
Transthoracic Doppler Echocardiography

• Screening procedure of choice for portopulmonary
  hypertension
• Measures tricuspid systolic peak velocity
• RV systolic pressure calculated using following
  equation
• RVsys RA pressure 4 x TR peak velocity2
• PA systolic pressure gt 50 mmHg should be referred
  for right heart catheterization

40
Transthoracic Doppler Echocardiography

• 958 screened 100 had RVsys gt 50 mmHg 86 with
  PVR gt 120 and 64 with PVR gt240 dyne/sec/cm-5
• PPV of 38 and NPV of 92 in detecting pulmonary
  hypertension on right heart catheterization when
  PAP gt 50 mmHg by echocardiography

Kim WR et al. Liver Transpl 20006453-8
Cotton CL et al. Liver Transpl 200281051-4
41
Pulmonary Hemodynamic Patterns in 101 Patients
with Liver Disease and RVSP gt 50 mmHg on
Echocardiography
MPAP CO PVR PAOP TPG
High flow (?PVR) (n35) 319 8.62.6 14258 166 167
Normal volume (n20) 288 8.22.3 15460 122 177
Increased volume (n15) 3410 9.13.0 12552 214 14?7
PPHTN (?PVR) (n66) 4911 6.12.0 533247 126 3711
Normal volume (n50) 4811 5.92.0 571257 103 3811
Increased volume (n16) 539 6.82.0 407171 215 34?10
Krowka MJ et al. Hepatology. 2006 Nov
2844(6)1502-1510
42
Right Heart Catheterization of Mr. PB
Baseline After 40 PPM Nitric Oxide
RA mean 30
RV 102/33
PA mean 56 49
PCWP 19
CO 4.27 6.23
CI 2.31 3.37
PVR 693.2 (8.67) 385.2 (4.82)
TPG 37
43
Relationship between Cardiac Output and
Transpulmonary Gradient
Rodriguez-Roisen R et al. Eur Respir J
200424861-80
44
Mayo Clinic Classification of Pulmonary
Hypertension in the setting of Portal Hypertension
Type MPAP PAOP CO PVR
Pulmonary artery high-flow state ? N or ? ?? ?
Excess pulmonary venous volume ? ? ? ?
Portopulmonary hypertension with vascular obstruction Normal volume Excess volume ??? ?? N or ? ? ? ? ??? ?
45
Hemodynamic Progression of Pulmonary Arterial
Hypertension
PVR 80 x (MPAP - PCWP ) / CO Normal PVR is
20-120 (dynesec)/cm5 or 0.25 to 1.7 woods
unit (mmHg/ L. min.)
46
Intraoperative Concerns

• Initial diagnosis of PPHTN made in operating room
  at the time of OLT in 28 of 43 cases (65)
• 14 intraoperative and 36 in-hospital mortality
  rate in multicenter database report of 36
  patients with PPHTN who underwent OLT

Krowka MJ et al. Liver Transp 20006443-50
Krowka MJ et al. Liver Transpl 200410174-82
47
Mayo Clinic Intraoperative Guidelines Concerning
Hemodynamics in Patients with Portopulmonary
Hypertension
Mean Pulmonary Artery Pressure Intraoperative Guideline Reported Mortality
lt 35 mmHg Proceed with OLT 0/14 (0)
35-50 mmHg If PVR lt 250 proceed with OLT If PVR ? 250 cancel OLT 0/6 (0) 7/14 (50)
? 50 mmHg Cancel OLT 6/6 (100)
Krowka MJ et al. Liver Transp 20006443-50
48
Outcome and Pulmonary Hemodynamic Subgroups in
PPHTN Patients
Denied OLT (N30) Following OLT Died Survived (N13) (N23) Following OLT Died Survived (N13) (N23)
MPAP lt 35 0 1 5
35 ? MPAP ? 50 15 8 12
50 lt MPAP 15 4 6
Krowka MJ et al. Liver Transpl 200410174-82
49
Reperfusion of Liver Graft in Patient with PPHTN
Ramsay M. Adv Pulmon Hypertens 200429-18
50
Mean Pre-orthotopic Liver Transplant Pulmonary
Hemodynamics in Patients with Portopulmonary
Hypertension
Parameter All PortoPH (N66) Denied OLT (N30) Transplanted
Parameter All PortoPH (N66) Denied OLT (N30) Survivors (N23) Nonsurvivors (N13)
MPAP 48 11 53 11 45 14 44 8
PVR 462 202 614 288 341 181 322 139
CO 7.3 3.1 6.2 3.3 8.2 2.7 8.6 4.3
RA 10 6 11 7 8 3 7 3
PCWP 11 6 10 6 11 5 14 6
Krowka MJ et al. Liver Transpl 200410174-82
51
Management of Portopulmonary Hypertension

• Pharmacological Treatment
• Diuretics
• Digoxin
• B-blockers
• Calcium channel blockers
• Nitrates
• Prostacyclin analogues (epoprostenol,
  treprostinil, iloprost, and beraprost)
• Endothelin receptor antagonists (bosentan)
• Sildenafil

• Nonpharmacological Treatment
• Long term oxygen therapy
• Transjugular intrahepatic portosystemic shunt
• Orthotopic liver transplantation

52
Deleterious Effects of B-Blockers on Exercise
Capacity and Hemodynamics in Patients with PPHTN
Provencher S et al. Gastroenterology. 2006
Jan130(1)120-6
53
Epoprostenol

• Prostacyclin or Prostaglandin I2
• Potent systemic and pulmonary vasodilator
• Powerful inhibitor of platelet aggregation
• Increased permeability of the peritoneal membrane
  possibly leading to worsening ascites
• Significant and favorable changes in Ppa, PVR,
  CO, and 6MWD

54
Survival in Portopulmonary Hypertension with the
use of Epoprostenol
Swanson KL et al. Am J Respir Crit Care Med
2003167A683
55
Pulmonary Hemodynamics in a Patient with
Cirrhosis and Severe PPHTN
Krowka MJ et al. Clin Chest Med. 2005
Dec26(4)587-97
56
Hemodynamic and Echocardiographic Profile of a
Patient before and after OLT
Pre-OLT Pre-OLT Post-OLT Post-OLT Post-OLT Post-OLT
Baseline Iloprost Iloprost Iloprost Iloprost No therapy
Baseline Iloprost Day 1 Month 1 Month 4 No therapy
HR beats/min 68 64 80 82 68 70
BP mmHg 104/54 100/46 120/85 130/90 130/80 120/75
Ppa mmHg 54 38 45
PAOP mmHg 8 10 9
Cardiac index L/min/m2 3.7 3.9 4.2
PVR dyn.s.cm-5 524 302 361
SVO2 74 77 76
RVSP mmHg 74 68 27 29
6MWD m 462 579 570 572 582
Minder S et al. Eur Respir J 2004 Oct24(4)703-7
57
Pulmonary Hemodynamics and Outcomes of Patients
Treated with Prostaglandins prior to OLT
First Author Baseline Baseline Preoperative Preoperative Postoperative Postoperative Epoprostenol Epoprostenol Epoprostenol Status Survival months
First Author Ppa mmHg PVR dyn.s.cm-5 Ppa mmHg PVR dyn.s.cm-5 Ppa mmHg PVR dyn.s.cm-5 Dose ng.kg.min-1 Therapy months Therapy months Status Survival months
First Author Ppa mmHg PVR dyn.s.cm-5 Ppa mmHg PVR dyn.s.cm-5 Ppa mmHg PVR dyn.s.cm-5 Dose ng.kg.min-1 Pre-OLT Post-OLT Status Survival months
PLOTKIN 47 678 26 271 28 253 23 4 3 Alive 3
KROWKA 39 358 40 187 NA NA 11 3 4 Alive 8
RAMSAY 38 587 29 193 NA NA 7 1 3 Alive 3
TAN 48 472 33 248 32 355 50 36 10 Alive 12
MAIR 46 960 39 240 47 520 6 Died 1
MINDER 54 524 38 302 45 361 Ilo-prost 8 3 Alive 25
Minder S et al. Eur Respir J 2004 Oct24(4)703-7
58
Endothelin Receptor Antagonists (Bosentan)

• ETA and ETB receptor antagonist
• 14 transient increase in hepatic enzyme levels
  have been reported
• Severe cases of acute hepatitis with one fatality
  reported with sitaxsentan, an ETA receptor
  selective antagonist
• Reduction of PVR and and increased 6MWD in 11
  patients with cirrhosis and severe PPHTN after 1
  year therapy with bosentan without liver injury

Barst RJ et al. Chest 20021211860-1868
Hoeper MM et al. Eur Respir J 2005 25502-508
59
Sildenafil

• Phosphodiesterase type 5 inhibitor
• Enhances effects of nitric oxide-activated
  increases in cGMP
• Used as monotherapy and as combination therapy
  for reduction of Ppa
• Increased 6MWD and reduction in Pro-BNP in 14
  PPHTN patients (8 as monotherapy, 5 with
  iloprost, and 1 with treprostinil)

Reichenberger F et al. Eur Respir J 2006
28563-567
60
Case of Mr. PB

• Started on Treprostinil with improvement in
  quality of life
• Two years later develops worsening shortness of
  breath and switched to Iloprost with improvement
• Liver Transplant?

61
HPS PPHTN
Symptoms Progressive dyspnea Progressive dyspnea
Clinical Exam Cyanosis, finger clubbing, spider angiomas No cyanosis, RV heave, pronounced P2 component
ECG findings None RBBB, RAD, RV hypertrophy
ABG Mod/severe hypoxemia No/mild hypoxemia
Chest x-ray Normal CMG, hilar enlargement
CEE Always , left atrial opac for gt3-6 cardiac cycles Usually -, lt3 cardiac cycles if ASD or PFO
99mTcMAA index ?6 lt6
Pulmonary hemodynamics Normal/low PVR Elevated PVR, normal mPAOP
Pulmonary angiography Normal/spongy (type I) Discrete arteriovenous communications (type II) Large main PA, distal arterial pruning
OLT Always indicated in severe stages Only indicated in mild to moderate stages
62
Summary of Liver Transplant Considerations
Hepatopulmonary syndrome Portopulmonary hypertension
High risk for OLT (?mortality) PaO 2lt50 mm Hg MPAPgt35 mm Hg
High risk for OLT (?mortality) 99mTcMAA brain uptake gt20 MPAPgt35 mm Hg
UNOS indication for OLT Yes No
Higher priority for OLT Yes, if PaO 2lt60 mmHg No
Syndrome deterioration awaiting OLT Yes Yes
Sudden death due to syndrome No 25
5-Year survival without OLT 23 30
Pharmacologic treatment before OLT helpful Not proven Strongly suggested
Intraoperative death Not reported Yes
Transplant hospitalization mortality 16 35
Syndrome resolution after OLT Common Extremely variable
63
Recommendations for HPS and PPHTN

• Diagnose it early, transplant early
• Pulse oximetry and Arterial blood gas to screen
  for HPS
• Annual screening echocardiography for patients on
  the OLT waiting list to evaluate for PPHTN
• Use of anti-pulmonary hypertension meds as a
  bridge to transplantation in PPHTN
• Close monitoring of patients after OLT because
  recurrence of HPS and conversion to PPHTN have
  been reported

64
I can breath better now that I got a new liver!