Hepatopulmonary syndrome (HPS) is a rare complication of metabolic associated fatty liver disease (MAFLD) which can occur after the surgical resection of hypothalamic or pituitary tumors. Characterized by arterial oxygenation defects due to intrapulmonary vasodilatations (1), HPS presents significant diagnostic and therapeutic challenges. Currently, liver transplantation (LT) is the only established effective treatment, with no medical therapies proven useful to date (2, 3). Since patients in the early phase of HPS can be frequently asymptomatic, the disease is often under-recognized, resulting in delayed diagnosis (4). However, considering its significant morbidity and mortality, prompt diagnosis and management are necessary.

Patients with hypopituitarism may be susceptible to developing HPS (5). This may be attributed to the dysfunction of the hypothalamus or pituitary gland, leading to the development of MAFLD and non-alcoholic steatohepatitis (NASH) (6), a predisposing factor for HPS. Craniopharyngioma, the most common suprasellar tumor in children, can induce hypothalamic injury and hormonal dysregulation and is thus often associated with hypothalamic obesity and development of MAFLD (7). Although few cases of HPS associated with hypopituitarism secondary to craniopharyngioma resection have been reported (5, 8, 9), treatment courses in this population have rarely been investigated.

In this comprehensive review, we analyzed previous reports of pediatric HPS cases following neurosurgical procedures for pituitary or hypothalamic lesions, along with a detailed case report of HPS children successfully treated with growth hormone replacement therapy. The aim of this review and case report is to provide clinicians and surgeons with information regarding the extended clinical course of pediatric patients undergoing pituitary surgery and suggest non-surgical alternatives for the management of HPS.

In this pediatric case of HPS secondary to hypopituitarism following craniopharyngioma resection, we successfully treated the patient with GH therapy, eliminating the need for LT, which is the only therapeutic option for HPS.

Initially described by Kennedy and Knudson in 1977 (12), HPS primarily manifests as hypoxemia due to impaired gas exchange resulting from alterations in the pulmonary microvasculature (1). The vasodilatation of pulmonary vessels and the formation of direct arterio-venous shunts contribute to ventilation-perfusion mismatch, while alveolar dysfunction by impaired alveolar integrity further worsens gas exchange (1, 13). HPS has been reported to be associated with hypothalamic dysfunction or hypopituitarism ( Table 2 ) (2–6, 8–11), with some cases linked to the resection of tumors located in the hypothalamus or sellar lesion (2–4, 8, 9) including craniopharyngioma.

Craniopharyngioma is a benign epithelial tumor of dysembryogenic origin arising suprasellar area and often involving the hypothalamus (14). Resection of the tumor frequently leads to hypopituitarism, which results in various endocrine disorders accompanied with hormonal imbalances due to surrounding tissue injuries following surgery. Particularly, the development of insulin resistance and hypothalamic obesity can increase intrahepatic fat accumulation. Additionally, GH deficiency can also lead to significant fat accumulation in the viscera and liver, contributing to the development of NASH and MAFLD, along with metabolic syndrome.

In addition to GH deficiency, impaired appetite regulation and compromised energy expenditure may contribute to MAFLD development in patients with hypothalamic dysfunction (14). Leptin, a cytokine produced exclusively in adipose tissue, functions in the hypothalamus to reduce food intake and increase energy expenditure (15). Therefore, damage to the hypothalamus during cranial tumor surgery may likely disrupt the function of leptin, resulting in hyperphagia and reduced metabolic rate. Moreover, leptin levels are significantly increased in patients with hypopituitarism, indicating a “leptin resistance” state (15, 16). Leptin acts as a fibrogenic cytokine and plays a key regulatory role in the progression of fibrosis and inflammation in chronic liver disease, including MAFLD and NASH (15).

Although LT remains the primary treatment for HPS, some researchers have reported improvements in respiratory symptoms (2, 6, 10) with rHGH therapy, which has enabled the patients to avoid LT. GH has also been reported as effective in reducing hepatic fat content in patients with MAFLD (17, 18). This can be explained by the role of GH in directly inhibiting lipogenesis and indirectly activating hormone-sensitive lipase, which reduces adipose deposition in the liver (19). Additionally, insulin-like growth factor-1 alleviates liver cirrhosis by inducing cell senescence and inactivating hepatic stellate cells (20). Altogether, the GH/insulin-like growth factor-1 axis plays an essential role in preventing hepatic steatosis aggravation in fatty liver disease, which may ameliorate the respiratory symptoms in HPS (19, 21).

To date, investigational medical therapies have been used to treat HPS; however, no significant advantages have been established over LT. Vasodilators, such as pentoxifylline, inhaled nitric oxide (NO), and iloprost, as well as inhibitors of angiogenesis including octreotide or sorafenib, have demonstrated no definite evidence of improving oxygenation in HPS (13). The use of NO synthase inhibitors and pulmonary vasoconstrictors has also been attempted, but no obvious benefits have been demonstrated (22). Although the favorable effect of GH in improving oxygenation in HPS has only been observed in those secondary to hypopituitarism (2, 3, 5, 6, 10), it is worthwhile to explore the potential effectiveness of GH in patients with HPS of alternative etiologies, considering recent reports indicating that GH replacement therapy may have a positive impact on non-alcoholic fatty liver disease (21). Not only pediatric hypopituitarism patients but also adult patients with hypopituitarism, GH deficiency, obesity, and MAFLD are reported to have positive effects from GH replacement therapy (21). Furthermore, in patients with decompensated cirrhosis, GH treatment in conjunction with standard medical therapy has shown beneficial effects across various parameters, including skeletal muscle index, liver frailty index, and Child-Turcotte-Pugh score for end-stage liver disease (23). While GH may not be universally beneficial in all patients with liver damage, it appears promising as a therapeutic option for those with hepatic impairment.

Craniopharyngioma is historically benign but locally aggressive and prone to frequent recurrence (14). In our case, the patient only received 2 months of rHGH therapy before being diagnosed with HPS owing to tumor recurrence. Likewise, Mazerkina et al. (24) reported a case of hypopituitarism subsequent to craniopharyngioma resection in a patient who had never received rHGH treatment before or after HPS diagnosis because of concerns regarding recurrence, ultimately resulting in death. In HPS, the symptoms may not be severe in the initial phase, often leading to a delayed diagnosis. The severity of liver disease and the degree of hypoxemia do not necessarily correlate (25). While MAFLD occurs in 50% of patients with craniopharyngioma (15), HPS can occur in 4–30% of patients with chronic liver disease (1). Therefore, carefully monitoring patients who have had craniopharyngioma resection surgery for HPS occurrence and actively considering GH treatment in this population is important.

In our study, rHGH replacement therapy was effective in improving HPS, consistent with similar findings in some studies reported previously. However, due to limited number of cases, the absence of randomized controlled trials, and the retrospective nature of the analysis, generalizing these results to all HPS patients may be challenging. The efficacy of rHGH replacement therapy may vary depending on factors such as the age at onset of hypopituitarism, duration of hormonal replacement treatment before onset of HPS, comorbidities, and the patient’s general condition at the time of diagnosis. Therefore, caution is warranted when applying this study results to patients with HPS.

HPS may develop in patients who have undergone resection for tumors in the hypothalamus or pituitary gland, particularly in those not currently receiving GH treatment. While evidence from the literature is limited, rHGH replacement therapy emerges as a promising treatment modality for HPS secondary to hypopituitarism, demonstrating successful improvements in oxygenation and normalization of intrapulmonary shunt. However, further investigations are required to determine the effectiveness of GH in patients with HPS in other underlying etiologies.