[Effect of growth hormone supplementation on liver and lung function in patients with hypopituitarism].

To analyze the clinical features of patients with anterior hypopituitarism (HP) complicated with cirrhosis, and to explore the effects of growth hormone supplementation on liver and lung function. A total of 11 patients with HP complicated with cirrhosis admitted to Peking Union Medical College Hospital from January 2016 to December 2022 were included in the study, including 8 males and 3 females, aged [M(Q1, Q3)]31 (20, 37) years. There were 6 patients with pituitary stalk interruption syndrome, 4 patients after craniopharyngioma resection, and 1 patient after germinal cell tumor chemoradiotherapy. Cirrhosis appeared at [M(Q1, Q3)]7 (1, 16) years after the diagnosis of HP. There were 7 cases complicated with hepatopulmonary syndrome (HPS). The liver and lung function of 5 patients were improved significantly after the addition of growth hormone, and the arterial partial pressure of oxygen increased from (47±11) mmHg(1 mmHg=0.133 kPa) to (84±12) mmHg. Timely supplementation of growth hormone can improve the symptoms of fatty liver, cirrhosis and HPS, and postpone or even avoid the transplantation of liver and other organs.

Physiologic changes in the hepatopulmonary syndrome before and after liver transplant: A longitudinal and predictor analysis.

BACKGROUND AND AIMS: Hepatopulmonary syndrome (HPS) is a common complication of liver disease defined by abnormal oxygenation and intrapulmonary vascular dilatation, treated with liver transplantation. Little is known about changes in HPS physiological parameters over time. We sought to describe baseline clinical and physiological characteristics in HPS and their relationships, temporal changes in physiological parameters before and after transplant, and predictors of changes in oxygenation. APPROACH AND RESULTS: This was a retrospective cohort study in the Canadian HPS Program (n = 132). Rates of change after diagnosis were: -3.7 (-6.4, -0.96) mm Hg/year for partial pressure of arterial oxygen (PaO 2 ); -26 (-96, 44) m/year for 6-minute walk distance, and 3.3% (-6.6, -0.011) predicted/year for diffusion capacity. Noninvasive shunt of ≥ 20% predicted a slower PaO 2 decline by 0.88 (0.36, 1.4) mm Hg/month. We identified 2 PaO 2 deterioration classes-"very severe disease, slow decliners" (PaO 2 45.0 mm Hg; -1.0 mm Hg/year); and "moderate disease, steady decliners" (PaO 2 65.5 mm Hg; -2.5 mm Hg/year). PaO 2 increased by 6.5 (5.3, 7.7) mm Hg/month in the first year after transplant. The median time to normalization was 149 (116, 184) days. Posttransplant improvement in PaO 2 was 2.5 (0.1, 4.9) mm Hg/month faster for every 10 mm Hg greater pretransplant orthodeoxia. CONCLUSIONS: We present a large and long longitudinal data analysis in HPS. In addition to rates of physiological decline and improvement before and after liver transplantation, we present novel predictors of PaO 2 decline and improvement rates. Our findings enhance our understanding of the natural history of HPS and provide pathophysiologic clues. Importantly, they may assist providers in prognostication and prioritization before and after transplant.

[Budd-Chiari syndrome with hepatopulmonary syndrome: a case report and literature review].

Objective: To summarize the clinical features and prognosis of Budd-Chiari syndrome with hepatopulmonary syndrome (HPS) in children. Methods: The clinical data of a child who had Budd-Chiari syndrome with HPS treated at the Department of Pediatrics of the First Affiliated Hospital of Zhengzhou University in December 2016 was analyzed retrospectively. Taking "Budd-Chiari syndrome" and "hepatopulmonary syndrome" in Chinese or English as the keywords, literature was searched at CNKI, Wanfang, China Biomedical Literature Database and PubMed up to July 2023. Combined with this case, the clinical characteristics, diagnosis, treatment and prognosis of Budd-Chiari syndrome with HPS in children under the age of 18 were summarized. Results: A 13-year-old boy, presented with cyanosis and chest tightness after activities for 6 months, and yellow staining of the skin for 1 week. Physical examination at admission not only found mild yellow staining of the skin and sclera, but also found cyanosis of the lips, periocular skin, and extremities. Laboratory examination showed abnormal liver function with total bilirubin 53 µmol/L, direct bilirubin 14 µmol/L, and indirect bilirubin 39 µmol/L, and abnormal blood gas analysis with the partial pressure of oxygen of 54 mmHg (1 mmHg=0.133 kPa), the partial pressure of carbon dioxide of 31 mmHg, and the alveolar-arterial oxygen gradient of 57 mmHg. Hepatic vein-type Budd-Chiari syndrome, cirrhosis, and portal hypertension were indicated by abdominal CT venography. Contrast-enhanced transthoracic echocardiography (CE-TTE) was positive. After symptomatic and supportive treatment, this patient was discharged and received oxygen therapy outside the hospital. At follow-up until March 2023, there was no significant improvement in hypoxemia, accompanied by limited daily activities. Based on the literature, there were 3 reports in English while none in Chinese, 3 cases were reported. Among a total of 4 children, the chief complaints were dyspnea, cyanosis, or hypoxemia in 3 cases, and unknown in 1 case. There were 2 cases diagnosed with Budd-Chiari syndrome with HPS at the same time due to respiratory symptoms, and 2 cases developed HPS 1.5 years and 8.0 years after the diagnosis of Budd-Chiari syndrome respectively. CE-TTE was positive in 2 cases and pulmonary perfusion imaging was positive in 2 cases. Liver transplantation was performed in 2 cases and their respiratory function recovered well; 1 case received oxygen therapy, with no improvement in hypoxemia; 1 case was waiting for liver transplantation. Conclusions: The onset of Budd-Chiari syndrome with HPS is insidious. The most common clinical manifestations are dyspnea and cyanosis. It can reduce misdiagnosis to confirm intrapulmonary vascular dilatations with CE-TTE at an early stage. Liver transplantation is helpful in improving the prognosis.

[Pulmonary Complications in Patients with Liver Cirrhosis].

Portal hypertension is a clinical syndrome defined by an increased portal venous pressure. The most frequent cause of portal hypertension is liver cirrhosis, and many of the complications of cirrhosis, such as ascites and gastroesophageal variceal bleeding, are related to portal hypertension. Portal hypertension is a pathological condition caused by the accumulation of blood flow in the portal system. This blood flow retention reduces the effective circulation volume. To compensate for these changes, neurotransmitter hormone changes and metabolic abnormalities occur, which cause complications in organs other than the liver. A hepatic hydrothorax is fluid accumulation in the pleural space resulting from increased portal pressure. Hepatopulmonary syndrome and portopulmonary hypertension are the pulmonary complications in cirrhosis by deforming the vascular structure. Symptoms, such as dyspnea and hypoxia, affect the survival and the quality of life of patients. These lung complications are usually underestimated in the management of cirrhosis. This review briefly introduces the type of lung complications of cirrhosis.

Macitentan treatment of portopulmonary hypertension with hepatopulmonary syndrome: a case report and literature review.

Pulmonary arterial hypertension-targeted therapies in portopulmonary hypertension (PoPH) are scarce, let alone for patients with chronic liver failure (CLF) and hepatopulmonary syndrome (HPS). A 48-year male was admitted to the hospital because of cirrhosis for 18 years, systemic oedema, and chest distress after exercise for 1 week. He was diagnosed with CLF, PoPH, and HPS. After 7 weeks of macitentan treatment, the patient's activity tolerance, pulmonary artery systolic pressure, arterial partial pressure of oxygen (PaO2 ), cTNI, and NT-proBNP changes indicated gradual recovery, without hepatic safety concerns. This case indicated that administering macitentan in patients diagnosed as PoPH (with CLF and HPS) may be efficient and safe enough in a clinical setting.

Cardiac index and hepatopulmonary syndrome in liver transplantation candidates: The pulmonary vascular complications of liver disease study.

BACKGROUND AND AIMS: Hepatopulmonary syndrome (HPS) and a hyperdynamic circulation are common complications of advanced liver disease, but the relationship between HPS and cardiac index (CI) is poorly understood. We sought to compare CI in patients with and without HPS and to assess the relationship between CI and symptoms, quality of life, gas exchange, and exercise capacity among liver transplantation (LT) candidates. We performed a cross-sectional analysis within the Pulmonary Vascular Complications of Liver Disease 2 study, a multicenter prospective cohort study of patients being evaluated for LT. We excluded patients with obstructive or restrictive lung disease, intracardiac shunting, and portopulmonary hypertension. We included 214 patients (81 with HPS and 133 controls without HPS). Compared with controls, patients with HPS had a higher CI (least square mean 3.2 L/min/m 2 , 95% CI 3.1-3.4 vs. 2.8 L/min/m 2 , 95% CI 2.7-3.0, p < 0.001) after adjustment for age, sex, Model for End-stage Liver Disease-Sodium (MELD-Na) score and beta-blocker use, and a lower systemic vascular resistance. Among all LT candidates, CI was correlated with oxygenation (Alveolar-arterial oxygen gradient r =0.27, p < 0.001), intrapulmonary vasodilatation severity ( p < 0.001), and biomarkers of angiogenesis. Higher CI was independently associated with dyspnea and worse functional class and physical quality of life after adjusting for age, sex, MELD-Na, beta-blocker use, and HPS status. HPS was associated with a higher CI among LT candidates. Independent of HPS, higher CI was associated with increased dyspnea and worse functional class, quality of life, and arterial oxygenation.

Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease exception policy and outcomes in pediatric patients with hepatopulmonary syndrome requiring liver transplantation.

Hepatopulmonary syndrome (HPS) is associated with increased waitlist mortality in liver transplantation (LT) candidates. Children with HPS are granted Model for End-Stage Liver Disease (MELD)/Pediatric End-Stage Liver Disease (PELD) exception points for waitlist prioritization in the United States based on criterion developed for adults. In this study, the impact of this MELD/PELD exception policy on post-LT survival in children was examined. A retrospective cohort of patients aged younger than 18 years with a MELD/PELD exception request who underwent LT between 2007 and 2018 were identified in the Scientific Registry of Transplant Recipients. Patients were stratified by waitlist partial pressure of arterial oxygen (PaO 2 ) to assess risk factors for waitlist mortality and post-LT survival. Among 3082 pediatric LT recipients included in the study, 124 patients (4%) received MELD/PELD exception points for HPS. Patients with HPS were a median age of 9 years (interquartile range: 6, 12 years), 54.8% were girls, and 54% were White. Most patients (87.9%) were listed with laboratory MELD/PELD scores <15. Waitlist mortality for patients with HPS exception points was rare and not different from patients without HPS. When stratified by pre-LT PaO 2 , hypoxemia severity was not associated with differences in 1-, 3-, or 5-year survival rates after LT ( p = 0.13). However, patients with HPS showed a slightly lower survival rate at 5 years compared with patients without HPS (88.7% vs. 93.4%; p = 0.04). MELD/PELD exceptions for children with HPS mitigated waitlist mortality, and recipients with HPS experienced excellent 5-year survival after LT, although slightly lower than in patients without HPS. Unlike adults with HPS, the severity of pre-LT hypoxemia in children does not impact post-LT survival. These data suggest that adult criteria for granting MELD/PELD exception points may not appropriately capture HPS severity in pediatric patients. Further prospective multicenter studies to examine the risk factors predicting negative survival outcomes in children with HPS are warranted.

Hypoxemia and if it is the liver? Hepatopulmonary syndrome : about a case.

The hepatopulmonary syndrome is defined as the triad of liver disease, pulmonary gas exchange abnormalities leading to arterial deoxygenation and widespread pulmonary vascular dilatation. It is one of the not infrequently cases of dyspnea within patients with liver disease. We report the case of a 32-year-old woman with cirrohsis and portal hypertention who presented with dyspnea worsning progressively. The blood gas revealed a deep hypoxemia with a PaO2 rate 42mmHg but clinically well tolerated. Pulmonary embolism and pneumonia were rapidly excluded by a CT pulmonary angiography. An echocadiography done in order to find any heart disease suspected a patent foramen ovale. A transthoracic contrast echocardiography showed an important pulmonary vascular dilatation.The association of cirrohsis, pulmonary vascular dilatation and hypoxemia made the diagnos of hepatopulmonary syndrome.

Shortness of breath due to portopulmonary hypertension and hepatopulmonary syndrome: diagnostic challenges and complex management approach in frail patients.

A 60-year-old woman with a background of frailty, non-alcoholic fatty liver disease (NAFLD), cirrhosis and type 2 diabetes mellitus (T2DM), presented with worsening shortness of breath and a drop in oxygen saturation on sitting and standing up. Her chest X-ray demonstrated evidence of upper lobe venous diversion. Given the hypoxia, she had a computed tomography pulmonary angiography (CTPA) to rule out a pulmonary embolism. The only finding from the CTPA was pulmonary hypertension in the absence of any clots in the lungs. An ultrasound of the abdomen confirmed portal hypertension with splenomegaly and a cirrhotic liver, therefore, an initial diagnosis of portopulmonary hypertension and hepatopulmonary syndrome was made.The patient declined an agitated saline contrast echocardiography. Based on frailty she was not deemed to be a suitable candidate for a liver transplant and was discharged with a package of care alongside home oxygen therapy with periodic review in the gastroenterology clinic. She was assessed as stable with no new concerns while on home oxygen and diuretics.This case highlights challenges in diagnosing and managing patients with cirrhosis, portopulmonary hypertension and hepatopulmonary syndrome with a background of complex comorbidities and frailty.

[Improve the understanding of hepatic disease related pulmonary vascular disease].

Hepatic disease-related pulmonary vascular disease refers to the changes in the structure or function of pulmonary circulation caused by liver parenchymal or hepatic vascular diseases, mainly including hepatopulmonary syndrome characterized by hypoxemia, portopulmonary hypertension characterized by pulmonary hypertension, and hepatic vascular shunt characterized by increased cardiac output and pulmonary hypertension. Early diagnosis and treatment of liver disease and early evaluation of liver transplantation may significantly improve the prognosis for patients with hepatic disease-related pulmonary vascular disease. Moreover, it is necessary to improve clinicians' understanding of this disease and strengthen multidisciplinary cooperation, improve the level of diagnosis and treatment.

Pulmonary vascular disease and exercise hemodynamics in chronic liver disease.

BACKGROUND & AIMS: Portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS) are severe pulmonary vascular complications of chronic liver disease and strongly associated with morbidity and mortality. The prevalence of these complications is relatively high in patients evaluated for liver transplantation, however it is virtually unknown in patients with stable chronic liver disease. METHODS: We assessed the pulmonary hypertension (PH) and HPS prevalence in a prospective registry study of our liver out-patient clinic in a tertiary center. Between 2011 and 2016, consecutive patients with cirrhosis or non-cirrhotic portal hypertension were prospectively enrolled after written informed consent. We excluded patients with acute decompensation of liver disease and other causes of PH like severe chronic heart or lung diseases and chronic thromboembolic PH. HPS was diagnosed using contrast enhanced echocardiography and blood gas analysis. Patients were screened for PH using an algorithm implementing severity of dyspnea, echocardiography, cardiopulmonary exercise testing and exercise echocardiography employing a threshold of systolic pulmonary arterial pressure (SPAP) = 50 mmHg at peak exercise. If the algorithm indicated an increased PH risk, patients were invited for invasive investigations by means of right heart and hepatic vein catheter. We defined POPH as resting mPAP≥21 mmHg and PVR>3WU and PAWP<15 mmHg, mild PH as resting mPAP = 21-24 mmHg, and exercise PH as mPAP>30 mmHg and TPR >3 WU at peak exercise. RESULTS: Two-hundred-five patients were enrolled (male 75%; cirrhosis 96%; median age 57 yrs). Sixty-seven patients (33%) fulfilled HPS criteria but only two (1.0%) for severe (PaO2:50-60 mmHg) or very severe HPS (PaO2<50 mmHg). In 18/77 patients (23%) undergoing exercise echocardiography, SPAP at peak exercise exceeded 50 mmHg. Finally, n = 3 (1.5%) patients were invasively diagnosed with POPH, n = 4 (2.9%) with mild PH and n = 2 with exercise PH. CONCLUSION: In chronic liver disease, excluding acute decompensation and other causes of PH, POPH and severe HPS are rare findings while mild to moderate HPS and mild PH or exercise PH are more frequent.

A novel mutation in TRMT5 associated with idiopathic non-cirrhotic portal hypertension and hepatopulmonary syndrome: Case report of two siblings.

Non-cirrhotic portal hypertension (NCPH) is a rare clinical entity in children. Familial clusters of idiopathic non-cirrhotic portal hypertension (INCPH) were previously reported in cases with deoxyguanosine kinase (DGOUK) and potassium calcium-activated channel subfamily N member 3 (KCNN3) mutations. Herein, we report two siblings who had a novel mutation in mitochondrial tRNA methyltransferase 5 (TRMT5) gene and presented with hepatopulmonary syndrome and later diagnosed as INCPH. Autosomal recessive inheritance of this mutation may suggest a role of TRMT5 mutations in the development of NCPH. Screening of TRMT5 mutations could be considered when familial INCPH is suspected.

[Hepatopulmonary syndrome: Prevalence, pathophysiology and clinical implications]. / Syndrome hépatopulmonaire : prévalence, physiopathologie et implications cliniques.

Hepatopulmonary syndrome (HPS) is a pulmonary vascular disease induced by portal hypertension that is characterized by dilation of the pulmonary capillaries and right-to-left shunting, leading to gas exchange abnormalities. While dysregulation of several endothelial cell (EC)-derived angiocrine factors and the development of HPS have been associated, the field is currently lacking in mechanistic understanding on how they contribute to disease initiation, perpetuation, and worsening. Although substantial progress has been made in the description of clinical characteristics and outcomes, no specific targeting therapy has been shown to have a long-term effect on the evolution of HPS; only liver transplantation can lead full or partial reversibility of the syndrome. This article aims to provide a comprehensive review of the clinical and epidemiological definitions of HPS and to describe its experimental models as well as recent advances in understanding the pathophysiology of the disease, with specific focus on BMP-9 and its signaling pathway.

Severe hepatopulmonary syndrome with hypoxemia refractory to liver transplant: Recovery after 67 days of ECMO support.

Hepatopulmonary syndrome (HPS) is a complication of end stage liver disease (ESLD) and is manifested by severe hypoxemia, which usually responds to liver transplantation (LT). As compared to patients undergoing LT for other etiologies, patients with HPS present an increased risk of postoperative morbidity and mortality. There is no effective treatment for patients whose hypoxemia does not respond to LT. This subset of patients is at a highly increased risk of death. There are very few reports on the use of extracorporeal membrane oxygenation (ECMO) in this setting with rapid response. However, there is no prior report of ECMO utilization for longer than 4 weeks. We present the case of a 17 year-old male patient who underwent LT for ESLD secondary to chronic portal vein thrombosis and HPS. He received a liver from a deceased donor and presented with severe HPS after LT, requiring ECMO support for 67 days. The patient was discharged home and is breathing in ambient air. He is currently asymptomatic and has a normal liver function.

Hepatopulmonary Syndrome and Portopulmonary Hypertension: Pulmonary Vascular Complications of Liver Disease.

Pulmonary vascular disease is a frequent complication of chronic liver disease and portal hypertension, affecting up to 30% of patients. There are two distinct pulmonary vascular complications of liver disease: hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). HPS affects 25% of patients with chronic liver disease and is characterized by intrapulmonary vasodilatation and abnormal arterial oxygenation. HPS negatively impacts quality of life and is associated with a 2-fold increased risk of death compared to controls with liver disease without HPS. Angiogenesis, endothelin-1 mediated endothelial dysfunction, monocyte influx, and alveolar type 2 cell dysfunction seem to play important roles in disease pathogenesis but there are currently no effective medical therapies. Fortunately, HPS resolves following liver transplant (LT) with improvements in hypoxemia. POPH is a subtype of pulmonary arterial hypertension (PAH) characterized by an elevated mean pulmonary arterial pressure and pulmonary vascular resistance in the setting of normal left-sided filling pressures. POPH affects 5% to 6% of patients with chronic liver disease. Although the pathogenesis has not been fully elucidated, endothelial dysfunction, inflammation, and estrogen signaling have been identified as key pathways involved in disease pathogenesis. POPH is typically treated with PAH targeted therapy and may also improve with liver transplantation in selected patients. This article highlights what is currently known regarding the diagnosis, management, pathobiology, and outcomes of HPS and POPH. Ongoing research is needed to improve understanding of the pathophysiology and outcomes of these distinct and often misunderstood pulmonary vascular complications of liver disease. © 2021 American Physiological Society. Compr Physiol 11:1-22, 2021.

Supine vs upright exercise in patients with hepatopulmonary syndrome and orthodeoxia: study protocol for a randomized controlled crossover trial.

BACKGROUND: The hepatopulmonary syndrome (HPS) is a pulmonary complication of liver disease found in 10 to 32% of patients with cirrhosis and is characterized by intrapulmonary vascular dilatations and abnormal oxygenation. Liver transplantation is the only effective therapy for this disease. Patients with HPS have significant exercise limitations, impacting their quality of life and associated with poor liver transplant outcomes. Many patients with HPS exhibit orthodeoxia-an improvement in oxygenation in the supine compared to the upright position. We hypothesize that exercise capacity will be superior in the supine compared to the upright position in such patients. METHODS: We propose a randomized controlled crossover trial in patients with moderate HPS (PaO2 < 80 mmHg) and orthodeoxia (supine to upright PaO2 decrease > 4 mmHg) comparing the effect of supine vs upright position on exercise. Patients with pulmonary hypertension, FEV1/FVC ratio < 0.65, significant coronary artery disease, disorders preventing or contraindicating use of a cycle ergometer, and/or moderate or severe ascites will be excluded. Participants will be randomized to cycle ergometry in either the supine or upright position. After a short washout period (a minimum of 1 day to a maximum of 4 weeks), participants will crossover and perform an exercise in the alternate position. Exercise will be performed at a constant work rate of 70-85% of the predicted peak work rate until the "stopping time" is reached, defined by exhaustion, profound desaturation, or safety concerns (drop in systolic blood pressure or life-threatening arrhythmia). The primary outcome will be the difference in the stopping time between exercise positions, compared with a repeated measures analysis of variance method with a mixed effects model approach. The model will be adjusted for period effects. P < 0.05 will be considered statistically significant. DISCUSSION: HPS patients have hypoxemia leading to significant exercise limitations. If our study is positive, a supine exercise regimen could become a routine prescription for patients with HPS and orthodeoxia, enabling them to exercise more effectively. Future studies could explore the corresponding effects of a supine exercise training regimen on physiologic variables such as long-term exercise capacity, quality of life, dyspnea, and liver transplantation outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration and Results System (PRS) NCT04004104 . Registered on 1 July 2019.