Transcript HIV and Lung Disease

Hepatopulmonary Vascular
Disorders
Nawaid Shakir, MD
North Shore University Hospital
December 13, 2006
Case of Ms. AM: 54 y/o female with
worsening dyspnea on exertion,
platypnea, and fatigue
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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
Liver-Related Causes of Dyspnea in a
Patient with Chronic Liver Disease
Pulmonary - Parenchymal
 Alveolar

– Pleural effusions
– Restriction from tense ascites
– Aspiration pneumonia
– Basal atelectasis
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Interstitial lung disease
– Lymphocytic interstitial
pneumonia
– Fibrosing alveolitis
– BOOP
– Noncardiogenic pulmonary
edema

Vascular
– Pulmonary hemorrhage
– HPS
– PPHTN
Extraparenchymal

Extrapulmonary
–
–
–
–
–
Cirrhotic cardiomyopathy
Cirrhotic myopathy
Chronotropic dysfunction
Muscle wasting
Deconditioning from impaired
mobility
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  
Liver Lung Interaction
Liver Failure
Acute Liver Failure
Chronic Liver Failure
ARDS
Vasodilatation
Vasoconstriction
HPS
Portopulm HTN
Hepatopulmonary Syndrome
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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
Clinical
Manifestations
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Dyspnea
Platypnea
Orthodeoxia
Clubbing
Liver dysfunction
Spider nevi
Elevated Cardiac
Output
Decreased SVR and
PVR
Narrowed A-V O2
difference
Pathogenesis
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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
Pathogenesis of HPS
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Increased exhaled NO levels in HPS as
compared to normoxemic cirrhotics and
healthy controls and normalize after
OLT
Cremona G et al. Eur Respir J 1995;8:1883-1885
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Increased NO synthase level following
CBD ligation in rats
Chang SW et al. Am Rev Respir Dis 1992;148:798-805
Hypothesis of Pulmonary Vessel Dilatation in Hepatopulmonary
Syndrome
Pathophysiology of Hypoxemia in
HPS
Ramsay MA. Int Anesthesiol Clin. 2006 Summer;44(3):69-82
Pathophysiology of Hypoxemia in
HPS
Hoeper MM et al. Lancet 2004 May 1;363(9419):1461-8
Diagnostic Criteria for
Hepatopulmonary Syndrome
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Portal hypertension with or without cirrhotic
liver disease
Arterial hypoxemia
PaO2 < 70 mmHg or PA-a, O2  15 mmHg
Pulmonary vascular dilatation demonstrated
by
Delayed “positive” contrast enhanced
transthoracic echocardiography or
Abnormal brain uptake (>6%) after 99mTcMAA
lung perfusion scanning
Contrast-enhanced Echocardiography
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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
99mTcMAA
Lung Perfusion
Scanning
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Peripheral injection of 99mTcMAA
Aggregates are 20 to 90 microns
Demonstration of abnormal uptake
over the brain (>6%)
Does not distinguish between
intracardiac and intrapulmonary shunts
May offer complementary information
for stratification of HPS patients at
greater risk of OLT mortality
Grading of Severity of
Hepatopulmonary Syndrome
Stage
Mild
PA-a,O2 Pa,O2 (mmHg)
(mmHg)
 15
 80
Moderate
 15
< 80 -  60
Severe
 15
< 60 -  50
Very Severe
 15
< 50 (< 300 on 100% O2)
OLT candidates
Hepatic disease patients with dyspnea
Arterial Blood Gases
PaO2 < 80 mmHg
(and/or)
PA-aO2 > 15 mmHg
PaO2 > 80
CEE
No HPS
Negative CEE
No HPS
Positive CEE + PFTs + HRCT
PaO2 >60 - <80 mmHg
(and/or)
PA-aO2 > 15 mmHg
PaO2 >50 - <60 mmHg
PaO2 <50 mmHg
MAA >20%
Follow-up
OLT
OLT
High risk for post-op mortality
Pre-OLT PaO2 in HPS Patients
All HPS
N=40
Denied OLT
N=8
PaO2
(mmHg)
51  10
47  10
Range
(mmHg)
(29-70)
(35-47)
Transplant
Survivors Nonsurvivors
N=27
N=5
55  10
37  8
(34-70)
Krowka MJ et al. Liver Transpl 2004;10:174-82
(29-47)
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
Survival in HPS Patients and Controls
undergoing OLT
Swanson KL et al. Hepatology 2005;41:1122-9
Survival based on Initial PaO2 in 61
Patients with HPS
Swanson KL et al. Hepatology 2005;41:1122-9
Sequential Oxygen Assessment of 14
Patients with HPS awaiting OLT
Swanson KL et al. Hepatology 2005;41:1122-9
The MELD Score:
Model 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 < 60 in
patient with Hepatopulmonary Syndrome
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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
Medications
 Warfarin
 Procrit
 Ranitidine
 Flomax
 Folic acid
 Lactulose
 Furosemide
 Potassium chloride
 Atenolol
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
Physical Examination
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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
Laboratory Data
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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
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AST 26
ALT 12
Alk Phos 73
T. Bili 1.1
Albumin 4.0
BNP 349
TSH 4.2
Free T4 1.4
Chest x-ray showing
enlarged pulmonary
arteries
CT of Chest/Abdomen/Pelvis
 enlarged pulmonary artery and
right chambers of the heart
 ascites
 splenomegaly
 cirrhosis and signs of portal
hypertension
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
Right Heart Catheterization
Baseline
RA mean
RV
After 40 PPM
Nitric Oxide
30
102/33
PA mean
56
PCWP
19
49
CO
4.27
6.23
CI
2.31
3.37
693.2 (8.67)
385.2 (4.82)
PVR
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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Clinical
Manifestations
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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
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Vasoproliferation and
obstruction
Genetics
Inflammation
Neurohormones (ET-1)
Abnormal levels of
vasoconstrictors
(noradrenalin, reninangiotensin-aldosterone
and vasopressin) and
vasodilators (NO,
glucagon, VAP, and
substance P)
Possible Pathogenetic Mechanisms
Leading to Portopulmonary Hypertension
Shear stress from increased pulmonary blood flow
? Gene mutation
Humoral imbalance
Endothelial cell dysfunction
Endothelial cell proliferation
Autoimmunity
Cytokine / Growth
factor imbalance
Vascular luminal obliteration
Smooth muscle hypertrophy,
Adventitial hypertrophy
Vasoactive compounds
escaping hepatic metabolism
Vasoconstriction
Down regulated
Potassium channels
Budhiraja R et al. Chest. 2003 Feb;123(2):562-76
Histological Sample of Lungs in
Severe Portopulmonary Hypertension
Intimal and medial
thickening of
pulmonary artery
and outspread
channel-like
structures forming
plexiform lesions
Diagnostic Criteria for
Portopulmonary Hypertension
Liver disease (causing clinical portal
hypertension
 MPAP > 25 mmHg
 Mean PAOP < 15 mmHg
 PVR > 240 dyn/sec/cm-5
 Transpulmonary gradient > 10 mmHg
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PPHTN suspected
Conduct screening transthoracic
doppler echocardiography
RVsys > 50 mmHg or abnormal RV
Conduct RHC and establish
PPHTN diagnosis
Determine risk profile for OLT
(pre- and intra-operatively)
and treatment options
Mild (early)
Ppa < 35 mmHg
Good cardiac function
Moderate
Ppa > 35 - 45 mmHg
Good cardiac function
Severe
Ppa > 45 mmHg
Cancel OLT
Proceed to OLT
Consider pulmonary
vasodilator therapy
prior to OLT
Consider pulmonary
vasodilator therapy
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 > 50 mmHg should be
referred for right heart catheterization
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Transthoracic Doppler
Echocardiography
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958 screened; 100 had RVsys > 50 mmHg;
86% with PVR > 120 and 64% with PVR
>240 dyne/sec/cm-5
Kim WR et al. Liver Transpl 2000;6:453-8
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PPV of 38% and NPV of 92% in detecting
pulmonary hypertension on right heart
catheterization when PAP > 50 mmHg by
echocardiography
Cotton CL et al. Liver Transpl 2002;8:1051-4
Pulmonary Hemodynamic Patterns in
101 Patients with Liver Disease and
RVSP > 50 mmHg on Echocardiography
MPAP
CO
High flow (PVR)
(n=35)
31+9
Normal volume (n=20)
28+8
PAOP
TPG
8.6+2.6 142+58
16+6
16+7
8.2+2.3 154+60
12+2
17+7
Increased volume (n=15) 34+10
9.1+3.0 125+52
21+4
147
PPHTN (PVR) (n=66) 49+11
6.1+2.0 533+247 12+6
37+11
Normal volume (n=50)
5.9+2.0 571+257 10+3
38+11
6.8+2.0 407+171 21+5
3410
48+11
Increased volume (n=16) 53+9
PVR
Krowka MJ et al. Hepatology. 2006 Nov 28;44(6):1502-1510
Right Heart Catheterization of Mr. PB
Baseline
RA mean
RV
After 40 PPM
Nitric Oxide
30
102/33
PA mean
56
PCWP
19
49
CO
4.27
6.23
CI
2.31
3.37
693.2 (8.67)
37
385.2 (4.82)
PVR
TPG
Relationship between Cardiac Output
and Transpulmonary Gradient
Rodriguez-Roisen R et al. Eur Respir J 2004;24:861-80
Mayo Clinic Classification of Pulmonary
Hypertension in the setting of Portal Hypertension
Type
MPAP
PAOP
Pulmonary artery high-flow
state

N or  

Excess pulmonary venous
volume
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

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N or  
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Portopulmonary hypertension
with vascular obstruction
a) Normal volume
b) Excess volume
CO

PVR


Hemodynamic Progression of
Pulmonary Arterial Hypertension
Pre-symptomatic
Symptomatic /Stable
Progressive/Declining
Level
Pulmonary pressure
Cardiac output
Time
PVR = 80 x (MPAP - PCWP ) / CO
Normal PVR is 20-120 (dyne*sec)/cm5
or 0.25 to 1.7 woods unit (mmHg/
L. min.)
Intraoperative Concerns
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Initial diagnosis of PPHTN made in
operating room at the time of OLT in 28 of
43 cases (65%)
Krowka MJ et al. Liver Transp 2000;6:443-50
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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 Transpl 2004;10:174-82
Mayo Clinic Intraoperative Guidelines
Concerning Hemodynamics in Patients
with Portopulmonary Hypertension
Mean Pulmonary
Artery Pressure
Intraoperative
Guideline
Reported
Mortality
< 35 mmHg
Proceed with OLT
0/14 (0)
35-50 mmHg
If PVR < 250
proceed with OLT
If PVR  250
cancel OLT
Cancel OLT
0/6 (0)
 50 mmHg
Krowka MJ et al. Liver Transp 2000;6:443-50
7/14 (50)
6/6 (100)
Outcome and Pulmonary Hemodynamic
Subgroups in PPHTN Patients
Denied OLT
(N=30)
Following OLT:
Died
Survived
(N=13)
(N=23)
1
5
MPAP < 35
0
35  MPAP  50
15
8
12
50 < MPAP
15
4
6
Krowka MJ et al. Liver Transpl 2004;10:174-82
Reperfusion of Liver Graft in
Patient with PPHTN
Ramsay M. Adv Pulmon Hypertens 2004;2:9-18
Mean Pre-orthotopic Liver Transplant
Pulmonary Hemodynamics in Patients with
Portopulmonary Hypertension
Transplanted
All
PortoPH
(N=66)
Denied OLT
(N=30)
Survivors
(N=23)
Nonsurvivors
(N=13)
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
Parameter
MPAP
Krowka MJ et al. Liver Transpl 2004;10:174-82
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
Deleterious Effects of B-Blockers on
Exercise Capacity and Hemodynamics in
Patients with PPHTN
Provencher S et al. Gastroenterology. 2006 Jan;130(1):120-6
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
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Survival in Portopulmonary Hypertension
with the use of Epoprostenol
Swanson KL et al. Am J Respir Crit Care Med 2003;167:A683
Pulmonary Hemodynamics in a Patient
with Cirrhosis and Severe PPHTN
Krowka MJ et al. Clin Chest Med. 2005 Dec;26(4):587-97
Hemodynamic and Echocardiographic
Profile of a Patient before and after OLT
Pre-OLT
Baseline
Post-OLT
Iloprost
Iloprost
Day 1
HR beats/min
No therapy
Month 1
Month 4
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
570
572
582
579
Minder S et al. Eur Respir J 2004 Oct;24(4):703-7
Pulmonary Hemodynamics and Outcomes of
Patients Treated with Prostaglandins prior to OLT
First
Author
Baseline
Preoperative
Postoperative
Epoprostenol
Ppa
mm
Hg
PVR
dyn.s
.cm-5
Ppa
mm
Hg
PVR
dyn.s.
cm-5
Ppa
mm
Hg
PVR
dyn.s.
cm-5
Dose
ng.kg
.min-1
PLOTKIN
47
678
26
271
28
253
KROWKA
39
358
40
187
NA
RAMSAY
38
587
29
193
TAN
48
472
33
MAIR
46
960
MINDER
54
524
Status Survival
months
Therapy
months
PreOLT
PostOLT
23
4
3
Alive
3
NA
11
3
4
Alive
8
NA
NA
7
1
3
Alive
3
248
32
355
50
36
10
Alive
12
39
240
47
520
6
Died
1
38
302
45
361
Iloprost
Alive
25
Minder S et al. Eur Respir J 2004 Oct;24(4):703-7
8
3
Endothelin Receptor
Antagonists (Bosentan)
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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
Barst RJ et al. Chest 2002;121:1860-1868
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Reduction of PVR and and increased 6MWD in
11 patients with cirrhosis and severe PPHTN
after 1 year therapy with bosentan without
liver injury
Hoeper MM et al. Eur Respir J 2005; 25:502-508
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 ProBNP in 14 PPHTN patients (8 as
monotherapy, 5 with iloprost, and 1 with
treprostinil)

Reichenberger F et al. Eur Respir J 2006; 28:563-567
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?

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 >3-6 cardiac cycles
Usually -, + <3 cardiac
cycles if ASD or PFO
99mTcMAA
index 6%
<6%
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
Summary of Liver Transplant Considerations
High risk for OLT (↑mortality)
Hepatopulmonary
syndrome
Portopulmonary
hypertension
PaO 2<50 mm Hg
MPAP>35 mm Hg
99mTcMAA
>20%
brain uptake
UNOS indication for OLT
Yes
No
Higher priority for OLT
Yes, if PaO 2<60 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
Recommendations for HPS
and PPHTN
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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
I can breath better
now that I got a
new liver!