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Depts of 1 Internal Medicine, 2 Anaesthesiology and 3 Surgery, University Hospital, Zurch, Switzerland.
CORRESPONDENCE: R. Speich, Dept of Internal Medicine, University Hospital, Raemistrasse 100, CH-8091, Zurich, Switzerland. Fax: 41 12554451. E-mail: klinspr@usz.unizh.ch
Keywords: Epoprostenol, iloprost, liver cirrhosis, liver transplantation, portopulmonary hypertension, pulmonary hypertension
Received: December 2, 2003
Accepted April 8, 2004
Abstract
Portopulmonary hypertension (PPHTN) is associated with poor prognosis and high perioperative mortality after orthotopic liver transplantation.
This study documents the first case of a patient with PPHTN who was successfully bridged to orthotopic liver transplantation with i.v. iloprost, a stable prostacyclin analogue. The PPHTN had resolved completely 4 months after successful transplantation.
In conclusion, portopulmonary hypertension is a relative contraindication to orthotopic liver transplantation, which should be attempted only if pulmonary haemodynamics improve with prostanoids. In this context, iloprost may be a valuable alternative to epoprostenol.
). Most centres consider the syndrome to be an indication for orthotopic liver transplantation (OLT) 2. Complete resolution of the syndrome is well documented 4. PPHTN is a specific condition characterised by an elevated mean pulmonary arterial pressure (Ppa), increased pulmonary vascular resistance (PVR), and a normal pulmonary artery occlusion pressure (PAOP) in the presence of portal hypertension and absence of other potential causes of pulmonary hypertension, such as chronic thromboembolic disease, valvular disease, collagen vascular disease, HIV infection, and ingestion of certain toxins or appetite suppressants. In the World Health Organization (WHO) classification, PPHTN represents a subset of pulmonary arterial hypertension 5. There are only a few case reports of patients with the coexistence of PPHTN and hepatopulmonary syndrome 1. Right-to-left intracardiac shunts through a patent foramen ovale, as a cause of hypoxaemia, should be excluded in this situation.
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4–9% 6–8. Prognosis is poor, with a mean survival of 15 months after diagnosis 9. Perioperative mortality in patients who undergo OLT is extremely high, andseems to correlate with the degree of increase in Ppa. Although patients with mild-to-moderate PPHTN (Ppa 25–35 mmHg) can safely undergo transplantation without increased risk 6–8, 10, in patients with a Ppa of 35–49 mmHg, the perioperative mortality rate is 50%, and reaches 70–100% in those with a Ppa of >50 mmHg 10. The high perioperative mortality results primarily from right ventricular dysfunction. Thus, severe PPHTN has been considered to be a contraindication to OLT. Nevertheless, thereduction in Ppa and PVR, as well as the improvement in right ventricular function during continuous infusion of epoprostenol, may facilitate successful OLT 11–15. The disadvantage of epoprostenol is its very short half-life and the rapid development of tolerance, necessitating increasing doses of the drug to achieve the same effects. Thus, the more stable prostacyclin analogue iloprost might be an alternative treatment option. Case report
In August 1996, a 48-yr-old patient underwent laparotomy for a perforated gastric ulcer. Routine laboratory examinations revealed elevated liver enzyme levels and liver cirrhosis as a result of chronic hepatitis C, and chronic alcohol abuse was subsequently diagnosed. After a second episode of variceal bleeding in January 1998, the patient successfully stopped drinking alcohol. The clinical course was complicated by several episodes of ascites and jaundice, and, in December 1999, the patient was evaluated for OLT. At that time, no contraindications were found. Echocardiography revealed a normal rightventricular systolic pressure (RVSP; 27 mmHg), measured over right atrial pressure, and the patient was listed for transplantation. In September 2000, a routine control examination revealed a multifocal hepatocellular carcinoma with three nodules, located in segments IV and VIII. Three transarterial segmental hepatic chemoembolisations were performed between September 2000 and July 2001, and they resulted in partial tumour remission.
In January 2001, the patient was admitted for transplantation when a donor organ became available. Induction of anaesthesia was unremarkable, except for right heart catheterisation, which revealed severe pulmonary hypertension with a Ppa of 50 mmHg. In view of this unexpected major risk factor, the transplantation was cancelled. Further diagnostic work-up excluded diseases of the respiratory system, thromboembolism, heart failure and valvular heart diseases. The alveolar–arterial oxygen tension gradient was 16 mmHg (normal <20 mmHg). Thus, severe PPHTN was diagnosed. Not even retrospectively, reviewing the video sequence of the first echocardiographic examination in December 1999, were there any signs of elevated pulmonary arterial pressure, and the examination performed at the same time showed an RVSP of 74 mmHg and the distinctive pattern of severe pulmonary hypertension.
The patient complained only of slight dyspnoea on exertion (WHO functional class II). Analogous to the protocol of Kuo et al. 16, invasive haemodynamic testing was performed (table 2), and continuous i.v. therapy with iloprost started at a gradually increasing infusion rate of 
200 µg·day–1 (1.8 ng·kg body weight–1·min–1). Iloprost was chosen since it is routinely used instead of epoprostenol in the present authors' pulmonary hypertension programme, primarily because of its longer half-life, its possible lesser tendency to tolerance development, and the need for lower doses and, therefore, lower costs. After 3 months of iloprost infusion, the patient's 6-min walking distance improved, and a significant reduction in RVSP to <40 mmHg could be achieved.
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Postoperative recovery was favourable and without any major complications. The patient was extubated on postoperative day 1, transferred to the ward on day 3, and discharged from hospital on day 13. Treatment with iloprost was continued. The explanted cirrhotic liver showed a moderately differentiated hepatocellular carcinoma in the left lobe and two circumscribed completely necrotic areas in the right lobe, as well as signs of chronic hepatitis with minimal inflammatory activity. In December 2001, 4 months after liver transplantation, all echocardiographic signs of pulmonary hypertension had disappeared, and the RVSP was 27 mmHg. The patient was completely asymptomatic, and the continuous i.v. therapy with iloprost was stopped. The patient is still doing well 25 months after OLT. Echocardiographic results remain normal. Meanwhile, reinfection with hepatitis C virus has been documented and treatment with pegylated interferon alpha-2a and ribavirin has begun. There are no signs of tumour recurrence.
Discussion
The first patient with severe PPHTN successfully bridged to OLT with continuous i.v. iloprost, a stable prostacyclin analogue, is presented. Pulmonary hypertension resolved 4months after successful transplantation and, subsequently, vasodilator therapy could be stopped. The patient's clinical course >2 yrs after OLT is excellent, and there is no recurrence of pulmonary hypertension.
Until the mid-1990s, severe PPHTN was considered to beanabsolute contraindication to OLT. When the Ppa is >50 mmHg, perioperative mortality is 70–100% 10. In 1997, after encouraging results from the continuous administration of epoprostenol in idiopathic pulmonary arterial hypertension 17, Kuo et al. 18 demonstrated a favourable haemodynamic effect of this treatment in four cases of PPHTN, with a 22–71% decrease in PVR. One year later, the same group reported the first case undergoing successful OLT after 4 months of preoperative treatment with i.v. epoprostenol 11. The patient was taken off epoprostenol 3 months aftertransplantation with near normal pulmonary haemodynamics.
To date, only four other cases who bridged to OLT with continuous i.v. epoprostenol have been described (table 3) 12–15. Although one patient died due to right heart failure 28 days after OLT, the other three are alive and successfully weaned from vasodilator therapy.
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A recent case series has cast doubt on the efficacy of epoprostenol, since six of the 10 patients died after a mean follow-up time of 9 months, at least two of them possibly due to PPHTN after 5 and 6 months, respectively 12. The same group recently reported a peculiar syndrome of progressive splenomegaly with worsening thrombocytopenia and leukopenia in four patients on continuous i.v. epoprostenol 21. One of them died as a result of sepsis following splenic embolisation and subsequent splenectomy. Thus, the present finding that iloprost has a comparable effect to that of epoprostenol suggests that iloprost might become a valuable treatment alternative in severe PPHTN.
The excessive perioperative mortality in patients with severe PPHTN undergoing OLT suggests that early diagnosis is crucial. Since, as in the present case, patients with even severe PPHTN are not infrequently asymptomatic 10, 22, 23, and PPHTN is a serious but treatable disorder, screening for pulmonary hypertension plays a key role in the management of OLT candidates. For the detection of pulmonary hypertension, ECG and plain chest radiography are unreliable, as their sensitivity is only 60% and 80%, respectively 23. Transthoracic echocardiography is a sensitive noninvasive diagnostic method. It is considered the screening modality of choice for all forms of pulmonary hypertension, including PPHTN. In a study of 165 OLT candidates 24, thesensitivity and specificity of RVSP at a relatively low cut-off of >30 mmHg (including a right atrial pressure of 5 mmHg), with respect to a Ppa of >25 mmHg, were 100 and96%, respectively. However, half of these patients with invasively confirmed PPHTN had a Ppa of <40 mmHg and could thus undergo OLT without additional treatment. In another study of 74OLT candidates using a higher RVSP cut-off of 
50 mmHg, sensitivity and specificity were 97 and 72%, respectively 25. Only one patient with an RVSP of<50 mmHg had a Ppa of 35 mmHg, but the invasively determined systolic pulmonary arterial pressure was only 55 mmHg. Thus, Doppler echocardiography is an accurate screening test, and all OLT candidates with an RVSP of 50 mmHg should undergo right heart catheterisation. Although rare, PPHTN can develop after evaluation for OLT, as was the case in the present patient. In their large series, Colle et al. 24 describe three patients who developed PPHTN within only 3–5 months after the initial evaluation for OLT. In their retrospective review of 43 patients, Krowka et al. 10 found that, in 65%, PPHTN was diagnosed in the operating room immediately prior to OLT. Thus, regular echocardiographic examinations of OLT candidates on the waiting list are necessary, although the optimal screening frequency remains to be determined. Inaccordance with the Mayo Clinic Liver Transplantation Program (M.J. Krowka, Division of Pulmonary and Critical Care, The Mayo Clinic, Rochester, MN, USA, personal communication), the patients on the current authors' waiting list are screened every 12 months if the first echocardiography is normal,and every 6 months if the RVSP is 35–50 mmHg. Patients with an RVSP of >50 mmHg undergo right heart catheterisation and initiation of vasodilator therapy, with theaim of decreasing Ppa to <35–40 mmHg and PVR to<400 dyn·s·cm–5 with good cardiac output before listing them for OLT.
Since the aetiology of PPHTN is unknown 26, it is difficult to predict whether pulmonary hypertension will resolve after OLT. Literature data indicate that, as in the present case, almost all patients with PPHTN show improved or normalised pulmonary artery pressures within 6 months after OLT 27–30, but this may take up to 2 yrs 31. In literature reviews, it was found that 19 out of 25 (76%) patients ever transplanted for PPHTN showed improved or resolved pulmonary hypertension 6, 8, 10. In individual cases, persistence 6, 14, 32, 33, progression 6, 34, recurrence 35 or even de novo evolution 36 of pulmonary hypertension after OLT have been observed. A comparison of the preoperative haemodynamics revealed that patients who showed improved or resolved pulmonary hypertension had a lower Ppa (43 mmHg; 95% confidence interval (CI) 39–47 mmHg) compared with those who did not (51 mmHg; 95% CI 42–61 mmHg). This difference, however, was not significant (p=0.1). Thus, owing to the large overlap between the two groups, the individual postoperative course cannot be predicted from the severity of PPHTN. It is noteworthy that the present case represents the one with the highest preoperative Ppa of those who showed improved or normalised haemodynamics postoperatively.
In conclusion, it has been shown that iloprost is a valuable alternative for the successful bridging to orthotopic liver transplantation of patients with severe portopulmonary hypertension. Regular echocardiographic screening of orthotopic livertransplantation candidates on the waiting list is mandatory, since portopulmonary hypertension may develop at any time.
Acknowledgements
The candid feedback provided to the authors by M.J. Krowka (Division of Pulmonary and Critical Care, The Mayo Clinic, Rochester, MN, USA) during the preparation of this manuscript is gratefully acknowledged.
References
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