Different substances have been used to treat HPS. Nevertheless the majority of studies have been carried out on animals and the studies carried out on humans lack the necessary design and sufficient sample numbers to allow them to be applied to clinical practice. Substances which have been tested without producing any clearly favourable results include somatostatin analogues[100,110], norfloxacin[12,13,111], inhaled nitric oxide, cyclooxygenase inhibitors such as aspirin and indomethacin, immunosuppressants such as mycophenolate mofetil, cyclophosphamide and sorafenib[117,118], quercetin[20,119], beta blockers, paroxetine, rosuvastatin, caspase-3 inhibitors, methylene blue[26,123,124] and inhaled iloprost. Amongst the substances used in human tests are pentoxifylline and garlic. Pentoxifylline, which has been seen to yield positive results in animal tests[11,17], has also been tried on adults and children. However, samples in each study have been fewer than 10 patients, with contradictory results in terms of improvements in oxygenation and frequent gastrointestinal side effects[126-128]. The use of garlic as a treatment for HPS has not been tested on animals and its active mechanism is not understood. Nevertheless, in a comparative study using garlic oil capsules and a salt capsule placebo, with a total sample of 41 HPS patients, and in another study without a placebo involving 15 patients, favorable results were observed, with improvements in oxygenation and other symptoms[129,130]. For pharmaceutical studies it would be necessary to carry out multicentre controlled trials using these and other substances against placebos. A study is currently taking place to evaluate the safety of sorafenib vs placebo, and its effects in blood oxygenation (ClinicalTrials.gov Identifier: NCT02021929).
The most widely studied treatment is LT. At the moment it is the only effective treatment for HPS and is proven to improve survival rates[68,86].
When evaluating a patient listed for LT, it is recommended that they are tested for the presence of HPS. This can be done through arterial blood gas analysis, contrast-enhanced echocardiography or pulse oximetry, the latter being proposed more frequently as the option of choice[1,42,91,101]. In patients with oxygen saturation lower than 96%, the most effective way of confirming the existence of HPS is through an arterial blood gas analysis, followed by a contrast echocardiography, or vice versa[42,91]. These screening models are based on the detection through pulse oximetry of HPS patients with significant hypoxemia, due to existing implications in prioritization and post-transplantation survival of these patients. As we have already mentioned, the findings of new studies could question this form of screening[86,95].
In terms of mortality rates for those on the active transplantation list, in a prospective study, no differences were observed between patients who had HPS and those who did not. In the study, the majority of cases were mild or moderate and MELD scores were not taken into account. This means that the survival of HPS patients was evaluated without the “distorting” effect associated with the inclusion of these scores. Other retrospective studies, which include large samples, have found that mortality rates for HPS patients on the list are lower than those for patients without HPS, a situation which is explained by the addition of MELD points to severe or very severe cases of HPS, thereby favoring transplantations in these patients as opposed to those who do not have HPS[86,95].
Hypoxemia can worsen in HPS patients who are on the active transplantation list, with a median decrease in pO2 of 5.2 mmHg per year. It has been suggested that an arterial blood gas analysis should be carried out every 6 mo, although there are no studies which have evaluated the method for carrying out this follow-up process (arterial blood gas analysis vs pulse oximetry) nor how frequently it should be carried out[42,91] (Figure 2).
Figure 2 Hepatopulmonary syndrome screening model and diagnosis in liver transplantation candidates.
AaO2: Alveolar-arterial oxygen gradient; HPS: Hepatopulmonary syndrome; LT: Liver transplantation; pO2: Partial oxygen pressure; Sat O2: Arterial oxygen saturation; 99mTc-MAA: Macroaggregated albumin lung perfusion scan.
Anesthetics and post LT intensive care: There are very few studies concerning the influence of HPS in anesthetic procedures or in the intensive care unit immediately following a LT and those that do exist are based on very small samples. It would appear that inhaled general anesthetics have a worse immediate effect on hypoxemia than intravenous anesthetics, but after an hour there is no apparent difference. Inhaled nitric oxide, methylene blue, extracorporeal membrane oxygenation and non-invasive ventilation have all been suggested as ways of improving oxygenation in immediate post-surgery[141-143]. More studies are required in order to increase our understanding of HPS in terms of both anesthetics and immediate post-surgery so as to improve patient care.
Post LT survival: Ten years survival after LT in HPS patients stands at 64%. The majority of published studies analyze gross mortality rate of transplanted HPS patients retrospectively. Post LT mortality rates obtained in these studies range between 7.7% and 33%. Retrospective and later prospective studies show that hypoxemia ≤ 50 mmHg and cerebral uptake on 99mTc-MAA ≥ 20% are predictors of post operative mortality, but patient sample figures have been small[66,67,79,83]. Since 2007, in the United States, as a result of these findings, and due to the progression of hypoxemia on the transplantation list, it has been recommended to assign a 22 MELD score to HPS patients with pO2 < 60 mmHg, with increases every 3 mo. Nevertheless, later studies have failed to confirm these findings[86,145].
Recently, a number of comparative studies have been carried out comparing survival rates for patients who have HPS and those who do not. In the majority of retrospective studies there were no statistically significant differences[65,69,146] and this was also true in a prospective study. Finally, two prospective studies analyzing transplantation data of the UNOS, and therefore a larger sample of HPS patients, showed a better rate of survival in HPS patients, probably due to lower waiting list mortality and a similar level of post-transplantation mortality, influenced by the MELD score, as a previous study suggested[86,95,147]. Another finding from one of the studies was greater mortality when pO2 is ≤ 44 mmHg, but this was not the case in lower levels of hypoxemia to which MELD scores are currently being applied in an exceptional manner. These recent findings have opened a debate concerning the suitability of the MELD scoring system as applied to HPS, which prioritizes patients for LT, and there could well be changes to this policy in the near future.
Reversibility after LT: The improvement in the parameters which define HPS after LT has mainly been evaluated in retrospective studies which have shown total reversibility figures ranging from 52% to 100% over a 6 to 12 mo period. The definition of reversibility has used a range of different criteria[58,67-70,145,148,149].
There is a prospective study which analyzes HPS reversibility at 6, 9 and 12 mo after LT based on the different criteria used to define the syndrome. It shows that full reversibility of HPS can be seen after 12 mo and that the process is rapid, since even after 6 mo, in mainly mild and moderate cases there is a 95.8% reversal. In terms of the evolution of the characteristic parameters of HPS, pO2 and AaO2 levels improve more quickly than in intrapulmonary shunt demonstrated by means of a contrast echocardiography.
It has also been observed that there is a post transplantation improvement in DLCO, although not in all patients. Previously, the reversibility of this parameter was not described. It should be noted that the sample in both studies was small.