Gastroenterology Hepatology

The liver and systemic disease

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How can I be sure that the patient has hepatopulmunary syndrome or portopulmonary hypertension?

What signs and symptoms are usually found?

In the initial stages of hepatopulmonary syndrome (HPS), the patient complains only of a very mild dyspnea, or can be asymptomatic. In more advanced stages, however, dyspnea, cyanosis, clubbing of the fingers, spider nevi, and hypocapnia are common. Platipnea and orthodeoxia are the typical signs of HPS.

Patients with portopulmonary hypertension (PPHT) present with progressive symptoms that may begin with fatigue, dyspnea, and peripheral edema. The most common symptoms over time include dyspnea on exertion in over 80% of patients, syncope and collapse in approximately 25%, and chest pain in approximately 20%.

What is the usual constellation of clinical features?

Patients with HPS present with symptoms of liver disease in combination with increased alveoloarterial gradient and hypoxemia on room air in relation to intrapulmonary arteriovenous shunts. Therefore, they may present with cyanosis and dyspnea.

In portopulmonary hypertension (PPHT), the most common physical findings include a loud pulmonary heart sound in 65% to 82% of patients and a systolic murmur in up to 69%. Electrocardiographic (ECG) abnormalities include signs of right heart strain in more than 90% of patients. Men and women are equally affected.

A tabular or chart listing of features and signs and symptoms

What other signs and symptoms of hepatopulmonary syndrome and portopulmonary hypertension can be found?

Hepatopulmonary syndrome

Nonspecific symptoms

  • – Shortness of breath exacerbated by sitting up and improved by laying down

  • – Hypoxaemia exacerbated in the upright position

  • – Spider nevi commonly seen but also seen in patients with cirrhosis without HPS

  • – Finger clubbing

  • – Peripheral cyanosis

Portopulmonary hypertension

  • – Often asymptomatic

  • – Shortness of breath as the disease progresses

  • – Signs of right heart failure

What other diseases and conditions might mimic the signs, symptoms, or clinical features of HPS and PPHT and what consideration should be given to alternative diagnoses in the patient?

A large differential diagnosis exists for patients who are short of breath in the context of liver disease. Consideration has to be given to conventional lung disorders, in addition to HPS and PPHT.

Causes of pulmonary abnormalities in patients with liver disease

Intrinsic cardio-pulmonary disease

  • – Chronic obstructive pulmonary disease (COPD)

  • – Pneumonia/Infection

  • – Asthma

  • – Pulmonary fibrosis

Specific to liver disease

  • – Emphysema in association with alpha-one-antitrypsin deficiency

  • – Fibrosing alveolitis in association with autoimmune liver disease

  • – Presence of large volume ascites/hepatic hydrothorax

  • – Hepatopulmonary syndrome

  • – Portopulmonary hypertension

  • – Congestive heart failure

How can I confirm the diagnosis?

What tests should be ordered first in HPS or PPHT?

If the patient is known to have liver disease, the first approach to the diagnosis of HPS is to determine the peripheral oxygen saturation and arterial blood gases to confirm the presence of hypoxemia and increased alveoloarterial gradient.

For patients with PPHT who may be asymptomatic, a high index of suspicion must be present. Suspicion may be raised from clinical findings or, alternatively, from review of ECG in which a pattern of right heart strain may be seen.

What tests should be used to confirm the initial tests?

In HPS, transthoracic echocardiography with microbubble injection can be used in this case. The presence of microbubbles in the left heart chambers is proof of right-to-left shunt. If the bubbles appear after the third heart beat, the shunt is intrapulmonary.

In patients with PPHT, where ECG is suggestive of right heart strain, a transthoracic echo also may be appropriate. An elevated right ventricular systolic pressure higher than 50 mmHg suggests the presence of PPHT and requires further evaluation in the form of right heart catheterization. In transplant candidates, 2D echocardiography may overestimate the degree of pulmonary hypertension.

What tests are useful if the diagnosis is still in doubt?

In HPS, contrast transesophageal echocardiography is more sensitive than the transthoracic approach. If there are doubts about the origin of hypoxemia, the injection of macroaggregates of labeled albumin with a brain uptake 6% higher than the lung uptake is an evidence of right-to-left shunt. Contrast CT can also be performed, with images of nodular dilatations in terminal pulmonary vessels. Pulmonary arteriography is generally not necessary but can be indicated if the patient has no improvement in PaO2 despite being on 100% oxygen or if there is a suggestion of arteriovenous communication on CT.

For patients with PPHT, as part of the diagnostic pathway, it is appropriate to determine during the right heart catheterization whether it is possible to modulate the degree of pulmonary hypertension. In assessing patients with pulmonary hypertension for liver transplantation, an infusion of prostacyclin may be given during the cardiac catheterization to determine whether it is possible to reduce the pulmonary pressure. If a fall in pressure can be demonstrated, this may facilitate the ongoing prescription of oral therapy in the form of sildenefil or bosentan.

Although symptoms are common in patients with PPHT and correlate with disease severity, a high index of suspicion is required. Screening of PPHT is performed using a chest X-ray, ECG, and transthoracic echocardiography. Using Doppler echocardiography it is possible to estimate right ventricular systolic pressure in most patients. An elevated right ventricular systolic pressure higher than 50mm Hg (normal, <30 mmHg) suggests the presence of PPHT and requires further evaluation.

Diagnostic criteria for HPS and PPHT

Hepatopulmonary syndrome

  • – Chronic liver disease*

  • – PaO2 <70 mmHg or alveolar-arterial oxygen gradient >20 mmHg**

  • – Intrapulmonary vascular dilatations documented by either:

    • —Demonstration of delayed shunt on contrast-enhanced transthoracic echocardiogram (bubble echocardiography) or

    • —Brain uptake of >6% following lung perfusion scanning with 99mTc macroaggregated albumin

Notes:

*Portal hypertension, irrespective of whether the patient has cirrhosis or not (i.e., this may arise in patients with portal vein block/thrombosis, nodular regenerative hyperplasia, granulomatous liver disease where cirrhosis is not confirmed histologically. However, this is more commonly seen in cirrhotic patients).

**Some investigators suggest an alveolar-arterial oxygen gradient > 15 mmHg.

Portopulmonary hypertension

  • – Portal hypertension

  • – Mean pulmonary artery pressure (MPAP) >25 mmHg

  • – Pulmonary capillary wedge pressure (PCWP) <15 mmHg

  • – Pulmonary vascular resistance (PVR) >120 dynes/s/cm-5

PVR = (MPAP-PCWP)/cardiac output. This criterion helps to discern increased pulmonary artery pressures from high flow/hyperdynamic circulatory states (low PVR) caused by vasoconstriction (high PVR).

What other diseases, conditions, or complications should I look for in patients with hepatopulmonary syndrome or portopulmonary hypertension ?

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What is the right therapy for the patient with hepatopulmonary syndrome or portopulmonary hypertension?

What treatment options are effective for HPS and PPHT?

Hepatopulmonary syndrome

The only proven and most effective treatment for HPS is liver transplantation. It is particularly indicated in patients with severe HPS, when PaO2 is less than 60 mmHg, as prognosis of these patients is particularly poor.

In the past, transjugular intrahepatic portosystemic stent (TIPS) was performed for this indication, with poor results and, therefore, is no longer reccommended without an alternative appropriate indication. Even then, TIPS may be contraindicated, and liver transplantation remains the most appropriate therapy.

In the context of a large shunt on CT, pulmonary angiography can be performed and it can be successfully treated with embolization; however, this practice is restricted only to case reports and does not represent standard treatment.

No medical therapy has proved to be effective in the treatment of HPS. Experience with somatostatin analogs, β-blockers, cyclooxygenase inhibitors,glucocorticoids and immunosuppressants, pulmonary vasoconstrictors, almitrine bismesylate, plasma exchange, and antibiotics have all been disappointing.

Portopulmonary hypertension

A number of novel therapies exist to treat PPHT, including liver transplantation. In general, transplantation is appropriate if MPAP is less than 35 mmHg. The primary risk, however, is the development of acute right heart failure and circulatory collapse either intra-operatively or within the first month post transplantation. It is difficult to predict who will succumb to these effects and, indeed, in many studies, there is no significant difference in measured hemodynamic parameters between survivors and nonsurvivors (MPAP in survivors was 45 ± 14 mmHg compared to 44 ± 8 mmHg in nonsurvivors in one study), although pulmonary vascular resistance was measured at more than 250 dynes/s/cm-5 in 8/13 patients who died.

It is also important to note that among patients who died following transplantation, pharmacological intervention in the form of epoprostenol (prostacyclin) therapy for more than 3 months was used in only one patient. Therefore, optimum pretransplant management of portopulmonary hypertension remains problematic in that mortality predominantly occurs as a consequence of right heart failure, but it is logical to suggest that earlier treatment with pulmonary vascular modulators followed by transplantation may result in significant improvement in outcome.

What are the therapy options for HPS and PPHT?

Hepatopulmonary syndrome

Domicilary oxygen therapy. Improves symptoms of dyspnea.

Liver transplantation. Efficacious in highly selected cases

Portopulmonary hypertension

Medical therapy

  • – Oral sildenafil

  • – Oral bosentan

  • – Oral ambrisentan

  • – Inhaled prostacyclin

Combinations of these agents may be necessary to facilitate successful transplantation and also may be required post transplant for a period of months to years.

Liver transplantation

What is the most effective initial therapy?

In HPS, oxygen therapy is the preferred treatment choice.

In PPHT, vasodilator therapy is most effective in modulating pressure. Based on patient tolerability, nebulized prostacycline, sildenafil, or bosentan may be used.

In more severe, cases, combinations of all three drug classes may be utilized.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

What therapy is best if initial therapy fails, including definitions of failure?

Sildenafil

Sildenefil is frequently used and well tolerated as an oral agent. Initial dosing is 20 mg twice daily and can be escalated according to response and tolerability. It should be prescribed cautiously in the context of hypotension, intravascular volume depletion, cardiovascular disease or autonomic dysfunction.

It is contraindicated in the context of recent myocardial infarction or cerebrovascular accident. It is also contraindicated with a history of nonarteritic anterior ischaemic optic neuritis and degenerative retinal disorders and should not be used in patients who are receiving nitrates.

Typical side-effects include GI disturbance, dry mouth, oedema, bronchitis cough, headache, paraesthesiae myalgia, visual disturbance. Doses of up to 50 mg three times daily have been reported to be tolerated.

Bosentan

In common with the other vasodilators, bosentan should not be initiated if blood pressure is below 80 to 85 mmHg. It should be withdrawn slowly. A concern in relation to this class of drugs is the fact that it can accumulate within the liver, and there has been some fear that significant hepatotoxicity can exist in patients with cirrhosis.

It is contraindicated in patients with acute porphyria.

Common side effects include dry mouth, GI disturbance, rectal bleeding, hepatic enzyme abnormalities, flushing, low blood pressure, palpitation, and oedema. It is also associated with hypersensitivity reactions and anaphylaxis.

Ambrisentan

In a pilot study using doses of up to 10 mg daily, ambrisentan was associated with responsiveness in the majority of patients with moderate to severe PPHT.

Similar class effects exist involving bosentan.

Iloprost

Iloprost or prostacyclin is often used in a nebulizer solution in the context of PPHT. Initial doses of 2.5 µg escalated to 5 µg, 6 to 9 times daily, are used according to response. A lower dose of 2.5 µg, 6 to 9 times daily, can be utilized if a higher dose is not tolerated.

The drug should not be used in the context of advanced cardiac failure and hypotension, and should be not initiated if systolic blood pressure is below 80 to 85 mmHg. It is contraindicated in unstable angina, myocardial infarction, or decompensated cardiac failure. Its elimination is reduced in hepatic impairment.

Specific side-effects include vasodilatation, hypotension syncope jaw pain headache and bronchospasm.

Typical side-effects include GI disturbance, dry mouth, oedema, bronchitis cough, headache, paraesthesiae myalgia, visual disturbance. Doses of up to 50 mg, 3 times daily, have been reported to be tolerated. Initial dosing is 62.5 mg twice daily, increased after 4 weeks if tolerated to 125 g twice daily. Maximal dosing is 250 mg twice daily.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Combinations of these drugs in PPHT may be appropriate and guided by response to therapy, either measured by echocardiography or right heart catheterization.

Listing of these, including any guidelines for monitoring side effects.

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How should I monitor the patient with disease hepatopulmonary syndrome or portopulmonary hypertension?

How should I monitor complications and progression of HPS and PPHT?

The natural history of HPS is that most patients develop progressive shunting and have worsening gas exchange over time. Second, spontaneous regression is rare and mortality, when established, is significant. Moderate to severe HPS may be noted in patients with Child-Pugh class A or B cirrhosis.

Over time, it also has become apparent that liver transplantation is an effective long-term therapeutic option for HPS with more than 80% of patients having regression of intrapulmonary shunting following surgery, albeit with an increased risk of morbidity and mortality in the perioperative period. Therefore, establishment of the diagnosis preoperatively is important, so that the condition can be more effectively managed in the post-transplant period.

Moreover, it is important to distinguish HPS from PPHT because the response to liver transplantation is much less dramatic, particularly if advanced disease is unrecognized, and severe PPHT may be a contraindication to liver grafting.

How should I monitor progress of stages of the disease in HPS and PPHT?

Hepatopulmonary syndrome

A retrospective study of patients with HPS described a mortality of 41% after a mean time of 2.5 years following diagnosis. In a prospective study with a comparable observation period of 2.5 years, mortality reached 63% and, therefore, is substantially higher than that often reported heretofore. From a total cohort of 111 patients with cirrhosis undergoing transplant assessment, patients with HPS showed a 3.8-times lower median survival time compared with those patients without the syndrome.

Subgroup analysis according to liver disease severity showed a clear survival disadvantage in HPS patients among Child-Pugh class C patients (5 times lower median survival, 2.5 months). In cirrhotic patients with Child-Pugh class B, the difference in survival was less substantial (median survival, 35.3 months in HPS vs. 44.5 months without HPS) and did not reach statistical significance.

Survival for patients with earlier stage disease has not been evaluated fully, but it is clear that most patients have progressive intrapulmonary vasodilatation and worsening gas exchange over time. This can be monitored through measurement of oxygen saturation and blood gas analysis over time.

Portopulmonary hypertension

In patients with primary pulmonary hypertension, the response to inhaled nitric oxide or intravenous epoprostenol is frequently measured and if a decrease in MPAP and pulmonary vascular resistance is measured, then administration of calcium channel blockers has been shown to prolong survival. Although, no randomized data exists for patients with PPHT, similar strategies have been applied with some success. As outlined earlier, the alternative agents gaining acceptance in the treatment of primary pulmonary hypertension include the endothelin receptor antagonist bosentan, which is approved for use in functional class III to IV pulmonary arterial hypertension.

Monitoring recommendations following diagnosis, including timing and interpretation

Hepatopulmonary syndrome

Repeated monitoring of peripheral oxygen saturation may be helpful in identifying the evolving progression of HPS even in asymptomatic patients. A recent review of a cohort of patients with cirrhosis confirms this utility.

Portopulmonary hypertension

Having performed a complete history review and comprehensive clinical evaluation, the screening tests of most value are a chest X-ray, ECG, and arterial blood gas measurements. Following this, if an echocardiogram demonstrates normal cardiac function, including satisfactory right-sided pressures, then, the patient should be listed for liver transplantation.

On the other hand, if the echocardiogram demonstrates right ventricular dysfunction or elevated right-sided pressures, then, right heart catheterization is appropriate. If mean pulmonary artery pressure is less than 35 mmHg, the patient should be listed for liver transplantation. If mean pulmonary auditory pressure is measured between 35 and 50 mmHg, a trial of prostaglandin, sildenefil, or bosentan or a combination of these drugs should be undertaken. Repeat echocardiogram and right heart catheterization should be undertaken after an interval of 3 months and if mean pulmonary artery pressure is less than 35mm Hg, then, the patient should be listed for liver transplantation. If there is no change in pulmonary artery pressure, liver transplant and should not be undertaken.

Similarly, if the original mean pulmonary artery pressure, is above 50 mmHg, there is an argument for not proceeding with listing for liver transplantation, although one could argue that a trial of vasodilator therapy would be appropriate with monitoring performed again on a 3-monthly basis in the form of echocardiography and right heart catheterization. If MPAP is reduced sufficiently, a decision to proceed with transplantation can be made. However, in general, such patients are rare.

What is the Evidence?

Fallon, MB, Krowka, MJ, Brown, RS. "Pulmonary Vascular Complications of Liver Disease Study Group. Impact of hepatopulmonary syndrome on quality of life and survival in liver transplant candidates". Gastroenterology. vol. 135. 2008. pp. 1168-75.

(Review of 72 patients with HPS compared with a large cohort of patients without. Study defined that both quality and quantity of life were significantly diminished in patients with HPS.)

Arguedas, MR, Singh, H, Faulk, DK, Fallon, MB. "Utility of pulse oximetry screening for hepatopulmonary syndrome". Clin Gastroenterol Hepatol. vol. 5. 2007. pp. 749-54.

(An evaluation of the utility of measurement of pulse oximetry in screening patients in our consultation. This study identified the prevalence of HPS as in excess of 30% in patients being assessed in our consultation. It demonstrated that this method was a cost-efficient and highly satisfactory way of identifying patients with HPS.)

Gupta, S, Castel, H, Rao, RV. "Improved survival after liver transplantation in patients with hepatopulmonary syndrome". Am J Transplant. vol. 10. 2010. pp. 354-63.

(Study of patients with HPS undergoing liver transplantation. Improvement in outcomes with appropriate patient selection.)

Talwalkar, JA, Swanson, KL, Krowka, MJ. "Prevalence of spontaneous portosystemic shunts in patients with portopulmonary hypertension and effect on treatment". Gastroenterology. vol. 141. 2011. pp. 1673-9.

(This study demonstrated that large pulmonary shunts in excess of 1 cm were associated with poor prognosis and low likelihood of response.)

Swanson, KL, Wiesner, RH, Nyberg, SL. "Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups". Am J Transplant. vol. 8. 2008. pp. 2445-53.

(Single-center experience of outcome of liver consultation in patients with PPHT. This study categorized patients according to the treatment received prior to transplantation. It demonstrated that therapy improved survival.)

Cartin-Ceba, R, Swanson, K, Iyer, V. "Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension". Chest. vol. 139. 2011. pp. 109-14.

(A report on the use of a novel agent in a pilot study performed over 2 years in patients with PPHT. This drug was well tolerated and safe in Child's class A patients with moderate to severe pulmonary hypertension.)

Le Pavec, J, Souza, R, Herve, P. "Portopulmonary hypertension: survival and prognostic factors". Am J Respir Crit Care Med. vol. 178. 2008. pp. 637-43.

(A review of a large series of patients with regard to natural history of PPHT.)

Gough, MS, White, RJ. "Sildenafil therapy is associated with improved hemodynamics in liver transplantation candidates with pulmonary arterial hypertension". Liver Transpl. vol. 15. 2009. pp. 30-6.

(One of a series of single-center experiences in patients with PPHT who receive sildenafil prior to liver transplantation.)
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