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Respiratory symptoms and hypoxemia can complicate chronic liver disease and portal hypertension. Various pulmonary disorders affecting the pleura, lung parenchyma, and pulmonary vasculature are seen in end-stage liver disease, complicating liver transplantation (LT). Approximately 8% of cirrhotic patients in an intensive care unit develop severe pulmonary problems. These disorders affect waiting list mortality and posttransplant outcomes. A thorough history, physical examination, and appropriate laboratory tests help diagnose and assess the severity to risk stratify pulmonary diseases before LT. Hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax (HH) are respiratory consequences specific to cirrhosis and portal hypertension. HPS is seen in 5–30% of cirrhosis cases and is characterized by impaired oxygenation due to intrapulmonary vascular dilatations and arteriovenous shunts. Severe HPS is an indication of LT. The majority of patients with HPS resolve their hypoxemia after LT. When pulmonary arterial hypertension occurs in patients with portal hypertension, it is called POPH. All other causes of pulmonary arterial hypertension should be ruled out before labeling as POPH. Since severe POPH (mean pulmonary artery pressure [mPAP] >50 mm Hg) is a relative contraindication for LT, it is crucial to screen for POPH before LT. Those with moderate POPH (mPAP >35 mm Hg), who improve with medical therapy, will benefit from LT. A transudative pleural effusion called hepatic hydrothorax (HH) is seen in 5–10% of people with cirrhosis. Refractory cases of HH benefit from LT. In recent years, increasing clinical expertise and advances in the medical field have resulted in better outcomes in patients with moderate to severe pulmonary disorders, who undergo LT.
Liver transplantation (LT) is the treatment of choice for end-stage liver disease, a major cause of death in adults and children. Various pulmonary disorders affecting the pleura, lung parenchyma, and pulmonary vasculature are seen in end-stage liver disease, complicating LT. Severe pulmonary complications occur in about 8% of cirrhotic patients in an intensive care unit (ICU) who require an LT.
Anemia of chronic liver disease, tense ascites with the elevated diaphragm, bilateral basilar lung atelectasis, and chest wall edema can interfere with ventilation in cirrhotic patients.
Hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax (HH) occur in cirrhosis and portal hypertension and have a significant impact on quality of life and posttransplant survival. In high endemic areas, pulmonary tuberculosis can complicate cirrhosis.
Also, preexisting lung diseases such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), bronchiectasis, and bronchial asthma can coexist in patients with chronic liver disease.
Most centers would not accept patients with moderate to severe coexisting pulmonary disease with poor functional status and high short-term mortality. Respiratory failure in acute on chronic liver failure (ACLF) often occurs secondary to inflammatory sequelae of ACLF, lung infections, or aspiration.
In ACLF, respiratory failure is defined by the chronic liver failure consortium–organ failure (CLIF-OF) scoring system as a partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2) ratio (P/F ratio) of less than 200 mmHg.
Diagnosing and treating pulmonary disorders pretransplant is essential to ensure optimal functional status, quality of life, tissue oxygenation, and good outcomes posttransplant. In this paper, we aim to review the preoperative pulmonary assessment of LT candidates (Figure 1).
Figure 1Pulmonary evaluation in liver transplantation (LT): Pulmonary evaluation of a liver transplant recipient starts with thorough history and physical examination. Pulse oximetry is a cost-effective method to screen for hypoxemia. All patients undergo CXR, ECG, ABG, 6-MWT, TTE, CE TTE, and HRCT as part of pretransplant evaluation. RHC, 99Tc MAA scan and pulmonary angiography are reserved for select cases. LT, liver transplantation; CXR, chest X-ray; ECG, electrocardiogram; ABG, arterial blood gas; 6-MWT, 6 -min walk test; P [A–a], pulmonary alveolar arterial pressure gradient; RVSP, right ventricular systolic pressure; IPVDs, intrapulmonary vascular dilatations; TTE, transthoracic echocardiogram; CE TTE, contrast-enhanced transthoracic echocardiogram; HRCT, high-resolution computed tomography; RHC, right heart catheterization; 99Tc MAA, scan technetium 99 macroaggregated albumin scintigraphy.
Pulmonary Evaluation of a Liver Transplant Candidate
To diagnose asymptomatic hypoxemia, a thorough history and physical examination are required. Look for risk factors such as smoking, contact with tuberculosis, allergen exposure, and occupational history. Past history and family history aid in the diagnosis of concomitant pulmonary illnesses.
The simplest screening test for hypoxemia is pulse oximetry (SpO2) while breathing ambient room air in a sitting posture. An arterial blood gas (ABG) further characterizes hypoxemia in patients with a SpO2 below 96% in room air.
In our unit, all patients get a chest X-ray, electrocardiogram (ECG), transthoracic echocardiography (TTE), contrast-enhanced transthoracic echocardiogram (CE TTE), pulmonary function test (PFT) and high-resolution computed tomography of the chest (HRCT) as part of the pretransplant evaluation. A 6-min walk test is done to assess exercise capacity. A reduced 6-min walk distance of less than 250 m is associated with a poor post-LT outcome.
Evaluation for liver transplantation in adults: 2013 practice guideline by the American association for the study of liver diseases and the American society of transplantation.
Evaluation for liver transplantation in adults: 2013 practice guideline by the American association for the study of liver diseases and the American society of transplantation.
The contrast-enhanced transesophageal echocardiography (CE TEE) is significantly better for diagnosing intrapulmonary vascular dilatations (IPVDs) as it can differentiate intracardiac from intrapulmonary shunts and has a higher sensitivity.
But it is invasive and is not readily available for screening. Our unit uses TEE for intraoperative monitoring of the patient. In patients with HPS and a coexisting pulmonary parenchymal disease, technetium-labeled macroaggregated albumin (99mTc MAA) scan helps determine the contribution of HPS to hypoxemia. A shunt fraction of more than 6% incriminates HPS as the cause of hypoxemia.
Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99m)Tc MAA lung scanning.
Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99m)Tc MAA lung scanning.
All patients evaluated for LT undergo pulmonary rehabilitation to improve functional status, tissue oxygenation, and prognosis on the waiting list and after LT.
Hepatopulmonary Syndrome (HPS) and Portopulmonary Hypertension (POPH)
Pathogenic processes within the liver and portal venous system impact pulmonary circulation in patients with chronic liver disease and portal hypertension.
Pulmonary vasculature abnormalities result from increased production or failure to clear the circulating inflammatory, vasoactive, proliferative, or angiogenic mediators.
The prolonged stimulation by these mediators leads to the remodeling the pulmonary vascular bed with diffuse or localized vasodilatation in HPS or hyperplastic lesions in POPH (Table 2).
The occurrence of these seemingly unrelated illnesses in the same patient population raises the possibility that disease modifiers have a part in dictating a patient's pulmonary vascular phenotype. These pulmonary vascular abnormalities have distinctive pathogenesis, diagnostic methods, therapeutic modalities, and implications for LT.
Table 2Hepatopulmonary Syndrome and Portopulmonary Hypertension.
HPS
POPH
Symptomatology
Mild cases asymptomatic
Progressive dyspnea
Progressive dyspnoea
Platypnea
Orthodeoxia
Clinical examination
Cyanosis
Chest pain syncope No cyanosis or clubbing RV heave Pronounced P2 component
Finger clubbing
Spider angiomas
Pathophysiology
IPVDs
Pulmonary vasoconstriction. Concentric intimal fibrosis, smooth muscle hyperplasia and hypertrophy. Increased ET-1, 5HT and Thromboxane. Decreased NO and prostacycline
A-V shunts
Angiogenesis
Increased NO, CO, VEGF
ECG findings
None
RBBB Rightward axis RV hypertrophy
Arterial blood gas
Moderate to severe hypoxemia
No/mild hypoxemia
Chest radiography
Normal
Cardiomegaly Hilar enlargement
TTE
Normal
RVSP increased May show impaired right ventricular function
CE TTE
Always positive; bubbles appear in left atrium >3–6 cardiac cycles after right atrial opacification
Usually negative
99mTcMAA shunting
>6%
<6%
Pulmonary hemodynamics
Normal mPAP, Normal/low PVR
mPAP >25 mm Hg, PVR >240 dyn/s/cm−5
Pulmonary angiography
Normal/"spongy" appearance (type I) Discrete AV communications (type II)
Large main pulmonary arteries Distal arterial pruning
OLT
Always indicated in severe HPS (PaO2 <60 mm Hg)
Indicated only if initial mPAP is <35 mm Hg or mPAP is <35 mm Hg and PVR <400. Dyn/sec/cm−5 with treatment or mPAP >35 mmHg and <45 mmHg and PVR <240 dyn/s/cm5 (<3 Wood units (WU)).
About 5–30% of cirrhosis patients have HPS. It presents as impaired oxygenation due to the formation of arteriovenous fistulas and IPVDs in the pulmonary vascular bed.
The HPS is defined by the presence of (1) congenital portosystemic shunts, chronic liver disease, or portal hypertension; (2) abnormal arterial oxygenation; and (3) IPVDs (Table 3).
Three processes mostly explain abnormal gas exchange in HPS. (1) In HPS, the pulmonary capillary network has decreased tone and is abnormally dilated (>15 μm), called IPVDs.
The hypoxemia brought on by IPVDs and V/Q mismatch can be partially improved with the help of additional oxygen therapy. True shunt-related hypoxemia is typically resistant to supplemental oxygen.
Human studies in patients with HPS have documented high levels of NO, ET-1, VEGF, intrapulmonary monocytes, and increased expression of endothelin-B receptors in the pulmonary circulation
(Figure 2). Additionally, HPS is linked to single-nucleotide polymorphisms that control angiogenesis, implicating pulmonary angiogenesis as a contributor to HPS.
The fact that two distinct phenotypes (HPS and POPH) occur in the same disease indicates yet-to-be-identified external modifiers that influence the phenotypic presentation.
Figure 2Pathophysiology of hepatopulmonary syndrome: Portal hypertension leads to an increased hyperdynamic circulatory state and shear stress which, along with chronic inflammation and oxidative stress, leads to dysregulation of key regulators of pulmonary vascular tone resulting in pulmonary vasodilatation and intrapulmonary shunts. Excess Vascular endothelial growth factor leads to angiogenesis which contributes to arteriovenous shunts and impaired oxygenation. Chronic inflammation also leads to increased intrapulmonary monocytes, which increase excess NO and CO, further contributing to vasodilatation. Adapted with permission from Machicao VI et al.3 andRodriguez-Roisin R et al.
Patients with moderate to severe HPS will have dyspnea, platypnea (worsening of dyspnea moving from supine to upright), and orthodeoxia (decrease of Pa O2 > 5% or 4 mmHg moving from supine to upright).
As the severity of hypoxemia increases, cyanosis and clubbing occur. Chest examination is usually noncontributory. Even though a prospective multicentric study revealed that a SpO2 <96% has low sensitivity for detecting significant hypoxemia, patients are initially screened with pulse oximetry (SpO2) as it is cost-effective.
Figure 3Approach to hepatopulmonary syndrome (HPS): Pulse oximetry is the simplest and cost-effective method to screen for HPS. All patients undergo CE TTE as part of pretransplant evaluation. When there are competing etiologies for hypoxemia, 99TC MAA scan is done to quantify the shunt fraction and to a confirm HPS as the cause for hypoxemia. Pulmonary angiography is reserved for patients identified to have discrete shunts on CT chest that can be embolized. CE TTE, contrast-enhanced transthoracic echocardiography; ABG, arterial blood gas; IPVD, intrapulmonary vascular dilatations; P [A–a], pulmonary alveolar arterial oxygen gradient; CXR, chest X-ray; PFT, pulmonary function test; CT, computed tomography.
Figure 4Pathogenesis of portopulmonary hypertension: Portal hypertension leads to an increased hyperdynamic circulatory state and shear stress along with chronic inflammation and oxidative stress leading to dysregulation of key regulators of pulmonary vascular tone resulting in pulmonary vasoconstriction. At the same time, damage to the pulmonary endothelium and the underlying smooth muscle along with genetic factors, results in permanent vascular remodeling, ultimately leading to the development of pulmonary hypertension. Adapted with permission from Thomas C et al.
A CE TTE is a sensitive technique to identify IPVDs and rule out structural cardiac anomalies, intracardiac shunts, and coexisting pulmonary hypertension.
CE TTE (bubble contrast study) is done by injecting agitated saline intravenously. The normal pulmonary capillaries (diameter of 8–15 um) trap the saline bubbles and do not permit entry to the left heart.
When an intracardiac shunt is present, bubbles often appear in the left heart 1–2 cycles after it appears in the right atrium. In intrapulmonary shunting, bubbles will appear in the left heart in 3–6 cardiac cycles after it appears in the right atrium.
But it is invasive and is not readily available for screening. Our unit uses TEE for intraoperative monitoring of the patient. The 99mTc MAA lung perfusion scan is reserved for patients with HPS and coexisting lung parenchymal disease.
A 99mTc MAA lung perfusion scan with a high brain shunt index fraction (>6%) would argue for HPS being the predominant cause of hypoxemia than lung parenchymal disease.
Patients with severe hypoxemia (PaO2 <60 mm Hg) whose high-resolution chest computed tomography is suspicious for discrete pulmonary arteriovenous malformations or those in whom PaO2 does not rise to >200 mm Hg with 100% inhaled oxygen undergo a pulmonary angiography to detect discrete arteriovenous malformations that can be embolized.
In the absence of LT, patients with HPS have twice the risk of dying compared to those with cirrhosis of comparable severity without HPS. HPS also worsens the quality of life of patients with cirrhosis.
There is no evidence that medical treatment for HPS increases survival, and LT remains the standard of care for patients with severe HPS (PaO2 <60 mm Hg).
HPS has been successfully treated in children by stenting spontaneous inferior vena cava to portal vein shunts and ligating/coiling congenital portosystemic shunts in the Abernethy malformation.
Rarely, discrete pulmonary arteriovenous anomalies may be detected on high-resolution chest computed tomography or pulmonary angiography, and coil embolization may improve hypoxemia.
Numerous medications, including methylene blue, cyclooxygenase inhibitors, N(G)-nitro-l-arginine methyl ester (l-NAME), somatostatin, propranolol, inhaled prostacyclin derivatives, almitrine, and withdrawal of chronic methadone, have been tried in uncontrolled studies; none have been proven to be beneficial in HPS (Table 4).
Sorafenib, a tyrosine kinase inhibitor that prevents angiogenesis or norfloxacin used for gut decontamination, did not show benefit in the pilot research.
In a randomized placebo-controlled trial, patients with HPS who received high-dose garlic (1–2 mg/m2) had a more significant increase in PaO2 (24.66% vs. 7.37%; P < 00.1).
Recently, better oxygenation in experimental HPS has been attributed to pentoxifylline, a phosphodiesterase inhibitor with known modest TNF-α and NO inhibition. Small uncontrolled studies using pentoxifylline on human HPS have produced conflicting outcomes.
Overall, no intervention other than LT has proven beneficial in HPS. These medical therapies should only be resorted to in critically ill patients with hypoxemia who have no LT options.
Table 4Drugs Used in HPS.
Drugs
Mechanism of action
Methylene blue
Causes vasoconstriction by inhibiting NO and also decrease angiogenesis.
NG-nitro-l-arginine methyl ester
Inhibit nitric oxide synthase
Pentoxifylline
Tumor necrosis factor-alpha inhibitor with vasodilator and anti-angiogenesis actions
Norfloxacin
Decreases bacterial translocation
Garlic
Contains allicin which is a potent vasodilator and anti-angiogenesis.
Mycophenolate mofetil
An inhibitor of angiogenesis and nitric oxide production
Sorafenib
Tyrosine kinase inhibitor that can reduce angiogenesis.
Letrozole
Nonsteroidal inhibitor of aromatase which effectively blocks estrogen synthesis.
The decision to accept candidates with very severe HPS for LT is center specific. No specific PaO2 threshold has been agreed upon as an absolute contraindication to LT.
Intraoperative management of HPS is supportive. Most HPS patients can obtain sufficient oxygen saturation with 100% inspired oxygen.
The goal should be to extubate as soon as possible to reduce infectious problems. In patients with HPS, severe posttransplant hypoxemia—defined as the need for 100% inspired oxygen to maintain an oxygen saturation level of 85%—develops in 6–21% of cases and is linked to longer ICU stays and a death rate of 45%.
Trendelenburg positioning, 100% inspired high-flow oxygen, inhaled vasodilators such as epoprostenol or nitric oxide (by increasing the transit time of erythrocytes it enables sufficient oxygen binding to take place and improves V-Q mismatch), and intravenous methylene blue (with or without inhaled vasodilators) are all options for treating severe posttransplant hypoxemia.
The oxygenation of patients with extremely severe HPS has also been shown to improve with venovenous (VV)-extracorporeal membrane oxygenation (ECMO), both before and after LT, and to help with the transition to LT or recovery after LT.
Nearly, all cases of HPS-related hypoxemia improve after LT. However, the degree of pretransplant hypoxemia may determine how long it takes to recover.
Following surgery, patients are routinely monitored using pulse oximetry, and when room air oxygen saturation is above 88%, stopping the use of supplemental oxygen is considered.
The diagnosis of POPH requires a RHC showing an increased mean pulmonary artery pressure (mPAP >25 mm Hg) due to increased pulmonary vascular resistance (PVR > three wood units or 240 dyn/s per cm−5) in the setting of a normal pulmonary capillary wedge pressure (PCWP <15 mm Hg) (Table 3).
This new definition has not been incorporated in hepatology literature. Before diagnosing POPH, other causes of pulmonary artery hypertension (PAH), such as high flow state, fluid overload, diastolic dysfunction, obstructive/restrictive lung disease, and obstructive sleep apnea, should be ruled out.
Evaluation for liver transplantation in adults: 2013 practice guideline by the American association for the study of liver diseases and the American society of transplantation.
In this situation, an elevated transpulmonary gradient (mPAP-PCWP of >12 mm Hg) indicates the presence of true precapillary pulmonary hypertension (POPH).
The pathologic alterations in POPH, such as the muscularization of the arterioles, smooth muscle hypertrophy, intimal thickening, in situ thrombosis, and plexiform lesions, are comparable to those in other types of PAH.
Portal hypertension leads to a hyperdynamic circulatory state, and the resulting shear stress triggers the pulmonary vascular proliferative process, which results in POPH (figure 4).
Excess circulating growth hormones, mediators of smooth muscle proliferation, and the imbalance between vasoconstrictors and vasodilators contribute to the POPH phenotype. In clinical studies, people with POPH have elevated endothelin-1, low prostacyclin, and low NO in their pulmonary circulation.
POPH may be asymptomatic and diagnosed during liver transplant evaluation. Depending on the severity, some patients may have dyspnea on exertion, chest pain, syncope, or evidence of right heart failure.
Typically, the lung examination is unremarkable. As POPH's duration and severity increase, the chest X-ray shows enlarged pulmonary arteries and cardiomegaly. When POPH is severe, the electrocardiogram could exhibit a right-axis deviation, a right bundle branch block pattern, and T wave inversion in the precordial V1–V4 leads. PFTs are usually nonspecific in POPH.
In patients with portal hypertension, the RVSP is calculated using tricuspid regurgitant peak velocity, the modified Bernoulli equation, and an estimation of the right atrial pressure (RVSP = 4(V)2 + RAP).
Echocardiographic assessment of the right ventricle, from the conventional approach to speckle tracking and three-dimensional imaging, and insights into the "right way" to explore the forgotten chamber.
It is an indirect measure of pulmonary artery systolic pressure (PASP) (Figure 4). With the aid of this screening method, it is possible to choose the patients who should have RHC (Figure 5). In most institutions, the cutoff value for proceeding with a RHC is an RVSP >50 mm Hg even though AASLD recommends RHC if RVSP is >45 mm Hg.
Evaluation for liver transplantation in adults: 2013 practice guideline by the American association for the study of liver diseases and the American society of transplantation.
In our unit, any patient with RVSP >45 mm Hg or evidence of RV strain/dysfunction undergoes an RHC. POPH is classified as mild (mPAP 25–35 mm Hg), moderate (mPAP 35–45 mm Hg), and severe (mPAP >45 mm Hg) based on RHC findings.
Other indirect measures of PAH include tricuspid regurgitant velocity >2.8 m/s l, RV/LV basal diameter/area ratio >1.0, flattening of the interventricular septum (LVEI >1.1 in systole and/or diastole), RVOT acceleration time <105 ms, TAPSE/PASP ratio <0.55 mm/mmHg, and early diastolic pulmonary regurgitation velocity >2.2 m/s.
Echocardiographic assessment of the right ventricle, from the conventional approach to speckle tracking and three-dimensional imaging, and insights into the "right way" to explore the forgotten chamber.
Echocardiography also help to assess the right ventricular function. The features of RV dysfunction on echocardiography include the tricuspid annular plane systolic excursion (TAPSE) <18 mm, RV fractional area change (RV-FAC) <35%, RV free-wall strain, tricuspid annulus velocity (S′ wave) <9.5 cm/s, and RV ejection fraction (RVEF) <45%.
Echocardiographic assessment of the right ventricle, from the conventional approach to speckle tracking and three-dimensional imaging, and insights into the "right way" to explore the forgotten chamber.
The diagnosis of POPH requires a RHC showing an increased mean PA pressure (mPAP >25 mm Hg) with an increased pulmonary vascular resistance (PVR > three wood units or 240 dyn/s per cm−5) in the setting of a normal pulmonary capillary wedge pressure (PCWP <15 mm Hg).
Evaluation for liver transplantation in adults: 2013 practice guideline by the American association for the study of liver diseases and the American society of transplantation.
Some patients with cirrhosis and elevated RVSP have changes indicative of hyperdynamic circulation or volume overload with normal PVR (Figure 6). These patients don't seem to be at risk for adverse results with LT.
Right-sided heart failure and decompensated cirrhosis are responsible for mortality in POPH. Patients with POPH with an mPAP of more than 35 mm Hg are at risk for poor results with LT and require PAH-specific medicines.
In a study of 43 patients with PoPH (confirmed by RHC) not on medical treatment and underwent LT, 100% of the patients with severe (mPAP > 50 mm Hg) and 50% of the patients with moderate POPH (mPAP 35–50 mm Hg) died due to cardiopulmonary events in the peritransplant period.
Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation.
Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation.
Patients with POPH are treated with general measures that target portal hypertension and the complications of PAH. Diuretics are used as the fluid overload is frequently present in patients with POPH from right heart failure and liver dysfunction.
To minimize pulmonary vasoconstriction, supplementary oxygen should be utilized to maintain oxygen saturation >89%. Anticoagulants are not recommended in POPH.
Medications with vasodilator, antiplatelet, and antiproliferative characteristics help to improve pulmonary hemodynamics and restore normal right ventricular function.
Effect of PAH specific therapy on pulmonary hemodynamics and six-minute walk distance in portopulmonary hypertension: a systematic review and meta-analysis.
Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): a study of 15 patients with moderate to severe portopulmonary hypertension.
Phosphodiesterase-5 inhibitors, such as tadalafil and sildenafil, and soluble guanylate cyclase stimulators, such as riociguat, target the nitric oxide pathway.
(Table 5) These agents have been used to manage POPH, based mainly on clinical experience in idiopathic pulmonary artery hypertension (IPAH). A prospective cohort study from the French Pulmonary Hypertension Registry (FPHR) examined data on 637 patients with POPH. It showed that PAH-specific therapies improved WHO functional class, 6-min walk distance, and hemodynamic parameters.
Effect of PAH specific therapy on pulmonary hemodynamics and six-minute walk distance in portopulmonary hypertension: a systematic review and meta-analysis.
Dual ETA and ETB receptor subtypes antagonist. Specifically, inhibition of ET-1 receptors.
Ambrisentan
5 mg o.d
10 mg o.d
Highly selective ETA receptor inhibition.
Macitentan
10 mg o.d
10 mg o.d
High affinity ETA than ETB antagonist.
Phosphodiesterase-5 inhibitors
Sildenafil
20 mg t.i.d
20 mg t.i.d
High selectivity for PD5 vs PD2, 3 and 4.
Tadalafil
20 mg o.d
40 mg o.d
High selectivity for PD5 compared with PD1, 4, 7 and 10.
Vardenafil
10 mg o.d
20 mg o.d
20 times more potent than sildenafil for inhibiting PD5
Prostanoids
Epoprostenol
2 ng/kg/mt
16–30 ng/kg/mt
Synthetic prostacyclin with potent effects of vasodilatation and platelet aggregator inhibitor.
Treprostinil
1.25 ng/kg/mt
25–60 ng/kg/mt
Long acting tricyclic benzindene synthetic analog of prostacyclin. Vasodilator and inhibits platelet inhibition.
Inhaled Iloprost
2.5mcg 6-9times/d
5mcg 6–9 times/d
Orally, intravenously, or as an inhaler.
Selexipag
200mcg b.i.d
1600mcg b.i.d
Oral prostacyclin receptor agonist with vasodilatory, antiproliferative and antiplatelet action.
Beraprost
20mcg t.i.d
40mcg t.i.d
Oral prostacyclin analog binding to prostacyclin membrane receptors inhibit the release of Ca2+ leading to relaxation of the smooth muscle cells and vasodilation
Soluble guanylate cyclase stimulator
Riociguat
2.5mcg 6-9times/d
5mcg 6-9times/d
Riociguat has a dual mode of action, acting in synergy with endogenous nitric oxide and also directly stimulating soluble guanylate cyclase, independent of nitric oxide availability
In patients with a poor initial response to monotherapy, combination therapy with PDE5i, and ERA or riociguat with ERA may be used. Inhaled or s/c prostacyclin analogs may be added in nonresponders.
Only patients who require hastened LT or have severe signs of POPH like syncope, right heart failure, or dyspnea at rest should receive intravenous prostacyclin therapy.
Ambrisentan and macitentan do not require regular monitoring of liver function tests. Still, it is recommended that patients have baseline liver function tests, and generally, ERAs are not recommended for individuals with moderate to severe liver function impairment and transaminases that are more than three times the upper limit of normal.
They aid in qualifying for LT and improve survival.
Liver transplantation
POPH is not considered an indication of LT in the absence of decompensated liver disease. Patients with properly managed POPH and good RV function can safely undergo LT. POPH improves after the transplant in about 29–64% of patients.
As per retrospective studies, moderate-to-severe POPH (mPAP >35 mmHg) is associated with a higher mortality rate after LT and LT are contraindicated in patients with an mPAP >50 mmHg as perioperative mortality reaches 100%.
Recent case series using current PAH-specific therapy have shown favorable short-term post-LT outcomes in individuals with moderate POPH who respond to treatment by achieving an mPAP <35 mm Hg and a PVR <400 dyn/s per cm−5 (<5 WU) before surgery or mPAP greater than or equal to 35 mmHg and less than 45 mmHg and PVR less than 240 dyn/s/cm5 (or less than 3 Wood units [WU]).
Mending the model for end-stage liver disease: an in-depth review of the past, present, and future portopulmonary hypertension model for end-stage liver disease exception.
At present, UNOS policy allows for a MELD exception for POPH, awarding a MELD score of 22 to POPH patients with baseline mPAP values > 35 mmHg, provided that an RHC documented mPAP values < 35 mmHg, PVR values < 400 dyn/s per cm−5 (<5 WU) or mPAP greater than or equal to 35 mmHg and less than 45 mmHg and PVR less than 240 dyn/s/cm5 (or less than 3 WU) and normal right ventricular function following medical therapy.
Mending the model for end-stage liver disease: an in-depth review of the past, present, and future portopulmonary hypertension model for end-stage liver disease exception.
We use intraoperative TEE to monitor RV function. During LT, wide fluctuations in pulmonary pressure occur due to changes in CO. PAH-targeted therapy should be continued throughout the perioperative and immediate posttransplant period.
Other therapeutic options during and after LT include inhaled vasodilators, such as nitric oxide or epoprostenol, intravenous prostacyclin analogs, and continuing a patient's preoperative PAH-targeted therapy.
Rarely, venoarterial (VA)–extracorporeal membrane oxygenation (ECMO) has been used as a rescue option to support cardiovascular function throughout the transplant surgery and the posttransplant recovery period.
Planned initiation of venoarterial extracorporeal membrane oxygenation prior to liver transplantation in a patient with severe portopulmonary hypertension.
During VA-ECMO, blood is extracted from the right atrium and returned to the arterial system, bypassing the heart and lungs and providing respiratory and hemodynamic support. This process provides indirect support to the RV by reducing preload, reducing RV wall tension, and delivering oxygenated blood to the coronary circulation.
Planned initiation of venoarterial extracorporeal membrane oxygenation prior to liver transplantation in a patient with severe portopulmonary hypertension.
Invasive hemodynamic monitoring is continued in the ICU to help manage pulmonary hypertension. ICU care for POPH entails avoiding hypoxia, hypercapnia, hypovolemia, and hypotension.
Inotropes, such as dobutamine or milrinone, may increase contractility in individuals who develop right ventricular failure, and vasopressors may be required to prevent hypotension.
,. Following the transplant, PAH medication should be continued, and weaning should be considered based on symptoms, the results of echocardiography, and pulmonary hemodynamics.
Major alterations are typically not recommended during the initial posttransplant period. Weaning or stopping therapy after a transplant may take up to 3 months or longer.
Case reports and series suggest that 29–64% of patients with moderate to severe POPH under long-term follow-up posttransplant have been able to discontinue therapy over time.
POPH patients have worse 1-year mortality or graft failure than patients without POPH.
Hepatic hydrothorax
HH is a transudative pleural effusion typically higher than 500 mL in a patient with portal hypertension with no other underlying major cardiac or pulmonary etiology.
Azygous vein hypertension with plasma leakage, peritoneal fluid leakage through the lymphatics, lymphatic leakage from the thoracic duct, and hypoalbuminemia that reduces oncotic pressure are few more reasons of HH.
It is recommended to perform a thoracentesis to determine the etiology of pleural effusion, rule out infection in the fluid, and alleviate the symptoms.
In uncomplicated HH, the polymorphonuclear cell count (PMN) is 250 cells/mm3, the pleural fluid total protein is 2.5 g/dL, and the serum-to-pleural fluid albumin gradient (SPAG) is > 1.1 (Table 3).
The evaluation of the pleural fluid should include cell count and differential, Gram stain, culture, cytology, protein concentrations, albumin concentrations, and lactate dehydrogenase concentrations.
Depending on the clinical circumstances, further tests to rule out chylothorax, pancreatitis, malignancy, tuberculosis, heart or renal failure, and other etiology of pleural effusion are done.
The following conditions are necessary for the diagnosis of SBPL (Table 3): (1) a positive pleural fluid culture and a neutrophil cell count of more than 250 cells/mm3; (2) a negative pleural fluid culture and a neutrophil cell count of more than 500 cells/mm3; and (3) the absence of pneumonia on chest imaging.
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