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Liver and LungTreatment of hepatopulmonary diseases
P. Schenk
Department of Internal Medicine 3Medical University Vienna
Hervé et al, Eur Respir J 1998
2-8,5%28%
PVR in patients with portal hypertension & healthy individuals
Definition:
PAPm > 25 mm Hg Rest> 30 mm Hg Exercise
PCP < 15 mm Hg
PVR > 240 dyn.sec.cm-5
Portopulmonary Hypertension
ERS Task Force, Eur Respir J 2004
• elevated portal pressure (> 10 mm Hg)
Staging:
Mild (Early) PAPm > 25 - 34 mm Hg
Moderate PAPm ≥ 35 - 44 mm Hg
Severe PAPm ≥ 45 mm Hg
Chemla et al, Eur Respir J 2002;20:1314Rodriguez-Roisin et al, ERS Task Force, Eur Respir J 2004;24:861
Portopulmonary Hypertension
Prevalence in cirrhosis: 2-8,5% (catheter-based studies)
Haemodynamics & mortality: comparison with IPAH
Kawut el al,Liver Transpl 2005
Multivariatanalysis, adjusted for laboratory values, hemodynamics & treatment:
transplant-free survival
38%
HR = 2,8, 95% CI 1,04-7,4; P=0,04
Portopulmonary Hypertension
21% 30-months survival, n=49; Robalino JACC 1991
28% 5-months survival without OLT, n=66; Swanson et al, Liver Transpl 2005
Treatment
β-blockers for bleeding prophylaxisin patients with esophageal varices
„….could contribute to deterioration of PPHTN“
Rodriguez-Roisin et al, ERS Task Force, Eur Respir J 2004;24:861
Portopulmonary Hypertension
Treatment
Provencher et al, Gastroenterology 2006
prospective study, 10 patients with esophageal varicesβ-blockers for 38 ± 27 months
Portopulmonary Hypertension
Provencher et al, Gastroenterology 2006
+79m +25% +37% +89%
Functional evaluation 2 ± 1 months after β-blocker discontinuation
Portopulmonary Hypertension
Provencher et al, Gastroenterology 2006
+28% -19%
Portopulmonary Hypertension
Hemodynamics 2 ± 1 months after β-blocker discontinuation
n treatment PAPm ↓ PVR ↓ Authortime
4 6-14 months 29-46% 22-71% Kuo et al, Transplant 19977 13 months 33% 68% McLaughlin et al, Ann Intern Med 19997 3 - 30 months 17% 47% Krowka et al, Hepatology 19991 4 months 24% 54% Plotkin et al, Transplant 19981 3 weeks 24% 67% Ramsay et al, Anesthesiology 19992 18 months -4% 52% Rafanan et al, Chest 20003 5 months 24% 40% Kähler et al, Wien Klin Wochenschr 20001 29 months 31% 43% Tan et al, Liver Transpl 20011 4 days 29% 15% Kett et al, Liver Transpl 20011 7 weeks 6% 57% Uchiyama et al, Liver Transpl 20068 6,5 months 23% 53% Sussman et al, Am J Transplant 200619 15 months 25% 55% Fix et al, Liver Transplant 2007
55 patients
Portopulmonary HypertensionTreatment i.v. prostacyclin
Treatment i.v. prostacyclin
Portopulmonary Hypertension
AE: catheter infection, sepsis, gastrointest. bleeding
21% 9% 14% (1 died)McLaughlin et al, Ann Intern Med 1999
progressive splenomegaly with thrombocytopenia(from 149000 47000 G/L in 4 patients)
Findlay et al, Liver Transpl Surg 1999
5% (1 died) Fix et al, Liver Transplant 2007
Hoeper et al, Eur Respir J 2007
Case-series:n=13
8/13 patients died < 3 years
6: right heart failure1: variceal bleeding1: after liver+lung transplant
Change of treatment
5 → iv prostacyclin4 → bosentan
inhaled Iloprost
Portopulmonary Hypertension
p.o. Bosentan
+78 m
Hoeper et al, Eur Respir J 2005
Portopulmonary Hypertension
Treatment
p.o. Bosentan
Hoeper et al, Eur Respir J 2005
Portopulmonary Hypertension
No aminotransferase ↑
Portopulmonary HypertensionBosentan vs. inhaled iloprost
Hoeper et al,Eur Respir J 2007
n=18 n=13retrospectivestudy:
Comparable baseline characteristics
Portopulmonary HypertensionBosentan vs. inhaled iloprost
Events:
deathtransplanttreatment change
Hoeper et al,Eur Respir J 2007
Portopulmonary Hypertension
Hoeper et al, Eur Respir J 2007
Multivariate analysis:
Portopulmonary Hypertensionp.o. Bosentan in Child C cirrhosis ?
Case-report:
Barth et al, Eur J Gastroenterol Hepatol 2006
41 y, HCV+alcohol
6 MWT:0 290m 400m
4 weeks 8 weeks
RVEF (MRT):7% 14%
Child C Child B
Treatment p.o. Sildenafil
Portopulmonary Hypertension
Reichenberger et al, Eur Respir J 2006
n=14, NYHA III-IV, Sildenafil 3x 50 mg/day
Treatment p.o. Sildenafil
Portopulmonary Hypertension
Reichenberger et al, Eur Respir J 2006
n=14, NYHA III-IV, Sildenafil 3x 50 mg/day
Treatment p.o. Sildenafil
Portopulmonary Hypertension
Reichenberger et al, Eur Respir J 2006
Sidenafil monotherapy
Sidenafil + inhaledProstanoids
Prognosis for OLT
● no increased periop. risk when PAPm ≤ 35 mm Hg
Castro et al, Mayo Clin Proc 1996;71:543Krowka et al, Liver Transpl 2000;6:443
● PAPm > 35 mm Hg & PVR >250 dyn.s.cm-5
↓periop. mortality > 50% Krowka et al, Liver Transpl 2000;6:443
40% Krowka et al, Liver Transpl 2004:10:174
OLT for Portopulmonary Hypertension
Why is OLT so dangerous for PH-patients ?
Acosta et al, Transpl Proc 2005
RV-preload ↑
OLT for Portopulmonary Hypertension
Portopulmonary Hypertension
Ashfaq et al, Am J Transplant 2007
Prognosis of OLT under vasodilator therapy ?
16 patients, PAPm ≥ 35 mm Hg:
Recommendations of ERS Task Force:
Screening of OLT-candidates with echo
RVsyst > 40-50 mm Hg
Confirmation with catheter
Medical treatment (PAPm > 35 mm Hg = CI for OLT)
Rodriguez-Roisin et al, Eur Respir J 2004
Portopulmonary Hypertension
Hepatopulmonary Syndrome
Definition
1) liver disease
2) abnormal arterial oxygenation
3) intrapulmonary vasodilatationKrowka, Hepatology 1990 Rodriguez-Roisin, Thorax 1992Rodriguez-Roisin, Eur Respir J 2004
Triad
Prevalence in Cirrhosis: 5-32%Schenk et al, Gut 2002
Potential mechanism and treatment in experimental HPS
Palma, FallonJ Hepatol 2006
Months
% c
umul
ativ
e su
rviv
al
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
0 6 12 18 24 30 36 42 48 54 60 66
without HPS, median 40.8 months
with HPS, median 10.6 months
p=0.018
111 patients with cirrhosis, 27 with HPS
without HPS, median 40,8 months
with HPS, median 10,6 months
Months
% c
umul
ativ
esu
rviv
al
Schenk et al, Gastroenterology 2003
Prognosis of patients with HPS ?
Months
% c
umul
ativ
e su
rviv
al
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
0 6 12 18 24 30 36 42 48 54 60 66
P = 0.00472
mit HPS, PaO2 > 60 mm Hg
mit HPS, PaO2 ≤ 60 mm Hg
Prognosis according to the severity of HPS
Parameter Regression-coefficient (β) P
BUN 0.021576 0.000222Age 0.041554 0.002103HPS 0.708367 0.014151Child-class -0.403450 0.039510 Schenk et al,
Gastroenterology 2003
O2-long-term therapy for HPS
→ recommended for patients with PaO2 < 60 mm Hg ERS Task ForceEur Respir J 2004
63-y ♀, HCV-cirrhosis Child C, PaO2 63 mm Hg
PT
Albumin
Child-Pugh score
after 1 year:
Child Ano ascites
Influence on liver function ?
Fukushima et al,J Gastroenterol 2007
Hypoxemia in patients with HPS is no CI for OLT
high risk: PaO2 < 50 mm Hg: 30% postop. mortality
high shunt (> 40%): 50% postop. mortality
Krowka et al, Mayo Clin Proc 1997Egawa et al, Transplantation 1999
OLT improves HPS in most patients: 86% Battaglia et al, Hepatology 1997
82% Krowka et al, Mayo Clin Proc 1997
OLT for HPS
Medical therapies for HPS
No established medical therapies ….
Sympathomimetic agentsSomatostatinAlmitrineIndomethacinPlasma exchangeAspirinGarlicMethylene blueL-NAME
Schenk et al, Ann Intern Med 2000
Medical therapies for HPS
Sympathomimetic agentsSomatostatinAlmitrineIndomethacinPlasma exchangeAspirinGarlicMethylene blueL-NAME
No established medical therapies ….