New therapeutic strategy with extracorporeal membrane oxygenation for refractory hepatopulmonary syndrome after liver transplant: A case report

BACKGROUND Due to the lack of published literature about treatment of refractory hepatopulmonary syndrome(HPS)after liver transplant(LT),this case adds information and experience on this issue along with a treatment with positive outcomes.HPS is a complication of end-stage liver disease,with a 10%-30%incidence in cirrhotic patients.LT can reverse the physiopathology of this process and restore normal oxygenation.However,in some cases,refractory hypoxemia persists,and extracorporeal membrane oxygenation(ECMO)can be used as a rescue therapy with good results.CASE SUMMARY A 59-year-old patient with alcohol-related liver cirrhosis and portal hypertension was included in the LT waiting list for HPS.He had good liver function(Model for End-Stage Liver Disease score 12,Child-Pugh class B7).He had pulmonary fibrosis and a mild restrictive respiratory pattern with a basal oxygen saturation of 82%.The macroaggregated albumin test result was>30.Spirometry demonstrated a forced expiratory volume in one second(FEV1)of 78%,forced vital capacity(FVC)of 74%,FEV1/FVC ratio of 81%,diffusion capacity for carbon monoxide of 42%,and carbon monoxide transfer coefficient of 57%.He required domiciliary oxygen at 2 L/min(16 h/d).The patient was admitted to the intensive care unit(ICU)and extubated in the first 24 h,needing high-flow therapy and non-invasive ventilation and inhaled nitric oxide afterwards.Reintubation was needed after 72 h.Due to the non-response to supportive therapies,installation of ECMO was decided with progressive recovery after 9 d.Extubation was possible on the tenth day,maintaining a high-flow nasal cannula and de-escalating to conventional oxygen therapy after 48 h.He was discharged from ICU on postoperative day(POD)20 with a 90%-92%oxygen saturation.Steroid recycling was needed twice for acute rejection.The patient was discharged from hospital on POD 27 with no symptoms,with an 89%-90%oxygen saturation.CONCLUSION Due to the favorable results observed,ECMO could become the central axis of treatment of HPS and refractory hypoxemia after LT.

Progress in investigating the pathogenesis of hepatopulmonary syndrome

BACKGROUND: The pathogenesis of hepatopulmonary syndrome is complicated and remains unknown. This review aims to provide an updated knowledge about the pathogenesis of the syndrome. DATA SOURCES: Five medical databases, MEDLINE, Science-Direct, OVID, Springer Link, and Wiley Inter Science were searched for articles on 'hepatopulmonary syndrome', 'cirrhosis', 'angiogenesis', 'intestinal endotoxemia', 'nitric oxide', 'carbon monoxide', and other related subjects. RESULTS: Currently, imbalance between vasodilation and vasoconstriction, intestinal bacterial translocation, intestinal endotoxemia, and activation of the lung monocyte/macrophage system may play important roles in the pathogenesis of hepatopulmonary syndrome. Recent studies found that angiogenesis is also an important factor in the pathogenesis of experimental hepatopulmonary syndrome. CONCLUSION: Angiogenesis inhibition may be a potential approach for the treatment of hepatopulmonary syndrome in the future.

Growth hormone cocktail improves hepatopulmonary syndrome secondary to hypopituitarism:A case report

BACKGROUND Metabolic associated fatty liver disease frequently occurs in patients with hypopituitarism and growth hormone(GH)deficiency.Some patients may develop to hepatopulmonary syndrome(HPS).HPS has a poor prognosis and liver transplantation is regarded as the only approach to cure it.CASE SUMMARY A 29-year-old man presented with progressive dyspnea for 1 mo.At the age of 10 years,he was diagnosed with panhypopituitarism associated with pituitary stalk interruption syndrome.Levothyroxine and hydrocortisone were given since then.To achieve ideal height,he received GH treatment for 5 years.The patient had an oxygen saturation of 78%and a partial pressure of arterial oxygen of 37 mmHg with an alveolar–arterial oxygen gradient of 70.2 mmHg.Abdominal ultrasonography showed liver cirrhosis and an enlarged spleen.Perfusion lung scan demonstrated intrapulmonary arteriovenous right-to-left shunt.HPS(very severe)was our primary consideration.His hormonal evaluation revealed GH deficiency and hypogonadotropic hypogonadism when thyroid hormone,cortisol,and desmopressin were administrated.After adding with long-acting recombinant human GH and testosterone for 14 mo,his liver function and hypoxemia were improved and his progressive liver fibrosis was stabilized.He was off the waiting list of liver transplantation.CONCLUSION Clinicians should screen HPS patients'anterior pituitary function as early as possible and treat them primarily with GH cocktail accordingly.

Growth hormone ameliorates hepatopulmonary syndrome and nonalcoholic steatohepatitis secondary to hypopituitarism in a child:A case report

BACKGROUND Craniopharyngioma is a benign tumor that usually develops in children;however,it is located in the center and close to sensitive structures,such as the pituitary gland and hypothalamus.As the hypothalamus plays a crucial role in the homeostasis of anterior pituitary hormone synthesis,damage to the hypothalamus leads to multiple pituitary hormone deficiencies and non-alcoholic fatty liver disease,including hepatopulmonary syndrome(HPS).HPS has limited treatment and poor prognosis.CASE SUMMARY A girl aged 13 years and 6 mo underwent surgery for craniopharyngioma 6 years prior.Right craniotomy was performed with total resection via the corpus callosum approach,and the tumor at the base was approximately 3.5 cm×3.5 cm×4.0 cm.At 1 year postoperatively,she exhibited abdominal distension and weakness,and the laboratory tests revealed fatty liver disease.Thereafter,she had not visited the outpatient clinic for 2 years.Two years ago,she developed decreased activity endurance,severe cyanosis,chest tightness,wheezing,and intermittent and recurrent low fever after mild physical labor.Hepatobiliary ultrasonography,liver biopsy,and contrast echocardiography of the right heart showed cirrhosis and multiple pituitary hormone deficiencies,indicating HPS.After 1 year of treatment with recombinant human growth hormone,the liver function and oxygenation improved;she did not undergo liver transplantation.CONCLUSION Craniopharyngioma surgery can easily cause hypopituitarism,which can lead to nonalcoholic steatohepatitis and HPS in children.Early growth hormone therapy is important to improve the prognosis of these diseases.

Hepatopulmonary syndrome: An update

Hepatopulmonary syndrome(HPS)is characterized by defects in oxygenation caused by intra-pulmonary vasodilation occurring because of chronic liver disease,portal hypertension,or congenital portosystemic shunts.Clinical implications of portal hypertension are very well-known,however,awareness of its effect on multiple organs such as the lungs are less known.The presence of HPS in chronic liver disease is associated with increased mortality.Medical therapies available for HPS have not been proven effective and definitive treatment for HPS is mainly liver transplantation(LT).LT improves mortality for patients with HPS drastically.This article provides a review on the definition,clinical presentation,diagnosis,and management of HPS.

Clinical Significance of a Myeloperoxidase Gene Polymorphism and Inducible Nitric Oxide Synthase Expression in Cirrhotic Patients with Hepatopulmonary Syndrome

The clinical significance of a myeloperoxidase (MPO) gene polymorphism and inducible nitric oxide synthase (iNOS) expression in cirrhotic patients with hepatopulmonary syndrome (HPS) was explored. Enrolled subjects were divided into three groups according to their disease/health conditions: the HPS group (cirrhotic patients with HPS; n=63), the non-HPS group (cirrhotic patients without HPS; n=182), and the control group (healthy subjects without liver disease; n=35). The distribution of the MPO–463 G/A genotype and its relationship with iNOS expression in a typical cell block from ascitic fluid were detected by immunohistochemistry and polymerase chain reaction-restricted fragment length polymorphism analysis (PCR-RFLP). In the HPS group, the partial pressure of oxygen in blood and ascitic fluid was significantly decreased (8.95±1.58 kPa and 6.81±0.95 kPa, respectively; both P<0.01), while the partial pressure of carbon dioxide significantly increased (4.62±0.20 kPa and 5.92±0.45 kPa, respectively; P<0.01). MPO and iNOS levels were significantly increased in the HPS group as compared with the non-HPS group. These increases were even more remarkable in ascitic fluid (41.36±11.62 and 13.23±4.81 μg/L; 10.27± 3.20 and 4.95±1.12 μg/L) than in blood (16.66±5.24 and 4.87±1.73 μg/L; 5.79±2.31 and 2.35±0.84 μg/L). The distribution of the MPO genotypes GG, GA, and AA were 76.2%, 22.2% and 1.6% in the HPS group, and 57.7%, 37.9% and 4.4% in the non-HPS group (P<0.05). The expression of iNOS was significantly higher in patients with the G alleles (G/G and G/A) (61.54%, 48/78) than in patients with A alleles (G/A and A/A) (38.46%, 30/78) (P<0.01). It was suggested that the expression levels of iNOS and MPO were correlated with HPS-induced hypoxemia. The MPO-463 G/A mutation might be a protective factor that prevents the development of HPS. The MPO might be involved in the regulation of iNOS expression. In humans, MPO pathways, the iNOS/NO system, and their interaction might have an impact on the occurrence and development of HPS.

Correlation between Pulmonary Endothelin Receptors and Alveolar-arterial Oxygen Gradient in Rats with Hepatopulmonary Syndrome

The correlation between pulmonary endothelin receptors and alveolar-arterial oxygen gradient （A aDO2） in rats with hepatopulmonary syndrome was investigated. Animals were divided into 2 groups： Sham operated （Sham） group and common bile duct ligation （CBDL） group. Arterial blood gas was evaluated by a blood gas analyzer. The concentrations of ET-1 in blood and lung tissue sample were evaluated by radioimmunoassay. The distribution and expression of two kinds of subtype receptor of ET-1, ETRA and ETRB were examined by in situ hybridization. The results showed that the level of A aDO2, was higher in CBDI. group than that in Sham group （P〈0.05）. The levels of plasma and pulmonary ET-1 in CBDL group were both higher than in Sham group （P〈0.05 ）. There was no significant difference in average A of ETRA between two groups by imaging analysis （0.21±0.06 vs 0.22±0.08, P〉0.05）, while that of ETRB was higher in CBDI. group than in Sham group （0.58±0.16 vs 0.28±0.07, P〈0.05）. The expression of ETRBinlung was positively correlated with A aDO2（P〈0.05）. It was concluded that the widened A-aDO2 may be related with enhancement of the expression of ETRB in lung.

Serum Soluble Vascular Endothelial Growth Factor Receptor 1 as a Potential Biomarker of Hepatopulmonary Syndrome

Background and Aims:The results of basic research implicate the vascular endothelial growth factor(VEGF)family as a potential target of hepatopulmonary syndrome(HPS).However,the negative results of anti-angiogenetic therapy in clinical studies have highlighted the need for markers for HPS.Therefore,we aimed to determine whether VEGF family members and their receptors can be potential biomarkers for HPS through clinical and experimental studies.Methods:Clinically,patients with chronic liver disease from two medical centers were enrolled and examined for HPS.Patients were divided into HPS,intrapulmonary vascular dilation[positive contrast-enhanced echocardiography(CEE)and normal oxygenation]and CEE-negative groups.Baseline information and perioperative clinical data were compared between HPS and non-HPS patients.Serum levels of VEGF family members and their receptors were measured.In parallel,HPS rats were established by common bile duct ligation.Liver,lung and serum samples were collected for the evaluation of pathophysiologic changes,as well as the expression levels of the above factors.Results:In HPS rats,all VEGF family members and their receptors underwent significant changes;however,only soluble VEGFR1(sFlt-1)and the sFlt-1/placental growth factor(PLGF)ratio were changed in almost the same manner as those in HPS patients.Furthermore,through feature selection and internal and external validation,sFlt-1 and the sFlt-1/PLGF ratio were identified as the most important variables to distinguish HPS from non-HPS patients.Conclusions:Our results from animal and human studies indicate that sFlt-1 and the sFlt-1/PLGF ratio in serum are potential markers for HPS.

Clinical characteristics of hepatopulmonary syndrome and hepatorenal syndrome and associated therapeutic potential of transjugular intrahepatic portosystemic shunt

Hepatorenal syndrome(HRS)and hepatopulmonary syndrome(HPS)are two serious complications of liver disease,causing damage not only to the liver but also to the kidneys,lungs,and heart.HRS and HPS affect the patient's circulatory and respiratory systems,with poor prognosis and high mortality in clinical practice.There is a lack of effective treatment other than liver transplantation.Transjugular intrahepatic portosystemic shunt(TIPS)is an effective tool to prolong the survival of patients with advanced liver disease and is mainly used to treat portal hypertension and ascites because it can effectively reduce portal pressure.Studies on the treatment of both of these complications with TIPS are limited and deserve further study because the therapeutic effects of TIPS have the potential to improve the prognosis of severe liver disease.This article reviews the clinical features of HRS and HPS,the consequences of these syndromes,and the potential mechanistic effects after TIPS intervention.

Prospective evaluation of postoperative outcome after liver transplantation in hepatopulmonary syndrome patients

Background Only a few reviews of small case series and individual case reports including a relatively small number of adult patients undergoing liver transplantation for hepatopulmonary syndrome （HPS） are available, and there has been no prospective evaluation of the long-term outcome of HPS patients after orthotopic liver transplantation （OLT）. The aim of this study was to determine the frequency of HPS in OLT patients with chronic end-stage liver-disease, and the short-term and long-term postoperative outcome of HPS patients after OLT. Methods This prospective study included 31 HPS and 30 control, non-HPS patients. The preoperative conditions were similar between the two groups. Twenty-six of 31 HPS patients and all of the non-HPS patients underwent OLT. Standardized methods, such as arterial blood gas at room air and ^99m-technetium macroaggregated albumin （^99mTc MAA） lung and brain perfusion scanning were performed for the diagnosis of HPS. Patients were followed after OLT. Results The incidence of HPS in OLT patients was 9.3% [26/279]. Hypoxemia in HPS was obviously improved with a normalized shunt of ^99mTC MAA in the lungs after OLT. The immediate postoperative survival rate [within 28 days after OLT） of HPS was 76.9% （20/26）. The one year survival was 61.5% （16/26） and four-year survival was 57.7% （15/26）; much higher than HPS patients without OLT （0）. But high postoperative morbidity and mortality were observed in HPS patients whose death occurred within 3 months of OLT due to complications summarized in this study. Conclusions Liver transplantation was an effective treatment for HPS. But the postoperative mortality rate following OLT in HPS patients was still much higher than that of patients without HPS.

Hepatopulmonary Syndrome and Liver Transplantation:A Recent Review of the Literature

A severe and common pulmonary vascular complication of liver disease is hepatopulmonary syndrome (HPS).It is a triad of liver dysfunction and/or portal hypertension,intrapulmonary vascular dilatations,and increased alveolar-arterial oxygen gradient.Prevalence varies according to various study groups from 4%-47%.While the most common presenting symptom of HPS is dyspnea,it is usually asymptomatic,and thus all liver transplant candidates should be screened for its presence.Pulse oximetry is a useful screening method,but arterial blood gas examination is the gold standard.If there is an abnormal P (A-a)O2 gradient,microbubble transthoracic echocardiography should be done for diagnosis.Outcome is unpredictable,and there is currently no effective medical therapy.The only effective therapy is considered to be liver transplantation.Complete resolution of HPS after liver transplantation is seen within a year in most HPS patients.

Prevalence and prognostic impact of hepatopulmonary syndrome in patients with unresectable hepatocellular carcinoma undergoing transarterial chemoembolization: a prospective cohort study

Background::To determine the prevalence and prognostic impact of hepatopulmonary syndrome(HPS)in patients with unresectable hepatocellular carcinoma(HCC)undergoing transarterial chemoembolization(TACE).Methods::Fifty-four patients with unresectable HCC undergoing TACE between December 2014 and December 2015 were prospectively screened for HPS and were followed up for a maximum of 2 years or until the end of this prospective study.Results::Nineteen of the 54(35.2%)patients were considered to have HPS,including one(5.3%)with severe HPS,nine(47.4%)with moderate HPS,and nine(47.4%)with mild HPS.The median overall survival(OS)was 10.1(95%confidence interval[CI],3.9–16.3)months for patients with HPS and 15.1(95%CI,7.3–22.9)months for patients without HPS,which is not a significant difference(P=0.100).The median progression-free survival was also not significantly different between patients with and without HPS(5.2[95%CI,0–12.8]vs.8.4[95%CI,3.6–13.1]months;P=0.537).In the multivariable Cox regression analyses,carbon monoxide diffusing capacity(hazard ratio[HR]=1.033[95%CI,1.003–1.064];P=0.028)and Child-Pugh class(HR=1.815[95%CI,1.011–3.260];P=0.046)were identified to be the independent prognostic factors of OS.Conclusion::Mild or moderate HPS is common in patients with unresectable HCC undergoing TACE,but it does not seem to have a significant prognostic impact.

Cardiac Syndromes in Liver Disease:A Clinical Conundrum

Understanding the interaction between the heart and liver is pivotal for managing patients in whom both organs are affected.Studies have shown that cardio-hepatic interactions are bidirectional and that their identification,assessment,and treatment remain challenging.Congestive hepatopathy is a condition that develops in the setting of long-standing systemic venous congestion.If left untreated,congestive hepatopathy may lead to hepatic fibrosis.Acute cardiogenic liver injury develops as a combination of venous stasis and sudden arterial hypoperfusion due to cardiac,circulatory,or pulmonary failure.The treatment of both conditions should be directed toward optimizing the cardiac substrate.Hyperdynamic syndrome may develop in patients with advanced liver disease and lead to multiorgan failure.Cirrhotic cardiomyopathy or abnormalities in pulmonary vasculature,such as hepatopulmonary syndrome and portopulmonary hypertension may also develop.Each complication has unique treatment challenges and implications for liver transplantation.The presence of atrial fibrillation and atherosclerosis in liver disease brings another layer of complexity,particularly in terms of anticoagulation and statin use.This article provides an overview of cardiac syndromes in liver disease,focusing on current treatment options and future perspectives.

Effects of heme oxygenase-1 on pulmonary function and structure in rats with liver cirrhosis

Background The hepatopulmonary syndrome （HPS） is a severe vascular complication in lungs resulting in systemic hypoxemia in patients with cirrhosis and portal hypertension. The underlying structural change in HPS is intrapulmonary vasodilation, which can lead to impaired oxygenation of pulmonary venous blood. It has been demonstrated that the heme oxygenase-1/carbon monoxide （HO-1/CO） system plays an important role in the control of vascular tone. The aim of this study was to further investigate the role of HO-1 in the pathogenesis of HPS in animal model.Methods Totally 35 rats were divided into liver cirrhosis, zinc protoporphyrin Ⅸ （ZnPP）, cobalt protoporphyrin （CoPP）and sham groups. Biliary cirrhosis was established in the first three groups by bile duct ligation. Rats in the ZnPP and CoPP groups received once intraperitoneal injection of ZnPP and CoPP, respectively, 24 hours before sample collection.Expression of HO-1 mRNA in lung was detected by reverse-transcription polymerase chain reaction, while protein expression was determined by immunohistochemical analysis. Hematoxylin and eosin staining was performed to confirm the presence of liver cirrhosis and intrapulmonary vasodilation. Arterial blood gases, mean arterial pressure and portal vein pressure were also measured. Analysis of variance or Wilcoxon statistical methods were used to determine statistical significance.Results Compared with the sham group, the cirrhotic group demonstrated increased expression of pulmonary HO-1 mRNA and protein （P〈0.01）. The level of arterial carboxyhemoglobin （COHb）, alveolar-arterial oxygen gradient （A-aPO2）,mean arterial pressure, portal vein pressure （P〈0.05, respectively）, and intrapulmonary vasodilation were also significantly increased. Compared with the cirrhotic group, CoPP treatment increased pulmonary HO-1 mRNA and protein expression, the level of A-aPO2 （P 〈0.05 respectively）, COHb （P 〈0.01）, and intrapulmonary vasodilation, while ZnPP treatment decreased pulmonary HO-1 mRNA and protein expression, the level of COHb （P 〈0.05 respectively）,and intrapulmonary vasodilation, without obvious alteration of mean arterial pressure and portal vein pressure.Conclusion Increased pulmonary HO-1 expression is an important contributor to the development of experimental HPS.

A Simple and Quick Screening Method for Intrapulmonary Vascular Dilation in Cirrhotic Patients Based on Machine Learning

Background and Aims:Screening for hepatopulmonary syndrome in cirrhotic patients is limited due to the need to perform contrast enhanced echocardiography(CEE)and arterial blood gas(ABG)analysis.We aimed to develop a simple and quick method to screen for the presence of intrapulmonary vascular dilation(IPVD)using noninvasive and easily available variables with machine learning(ML)algorithms.Methods:Cirrhotic patients were enrolled from our hospital.All eligible patients underwent CEE,ABG analysis and physical examination.We developed a twostep model based on three ML algorithms,namely,adaptive boosting(termed AdaBoost),gradient boosting decision tree(termed GBDT)and eXtreme gradient boosting(termed Xgboost).Noninvasive variables were input in the first step(the NI model),and for the second step(the NIBG model),a combination of noninvasive variables and ABG results were used.Model performance was determined by the area under the curve of receiver operating characteristics(AUCROCs),precision,recall,F1-score and accuracy.Results:A total of 193 cirrhotic patients were ultimately analyzed.The AUCROCs of the NI and NIBG models were 0.850(0.738–0.962)and 0.867(0.760–0.973),respectively,and both had an accuracy of 87.2%.For both negative and positive cases,the recall values of the NI and NIBG models were both 0.867(0.760–0.973)and 0.875(0.771–0.979),respectively,and the precisions were 0.813(0.690–0.935)and 0.913(0.825–1.000),respectively.Conclusions:We developed a two-step model based on ML using noninvasive variables and ABG results to screen for the presence of IPVD in cirrhotic patients.This model may partly solve the problem of limited access to CEE and ABG by a large numbers of cirrhotic patients.