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

lNTRODUCTlON

Nonalcoholic steatohepatitis and hepatopulmonary syndrome (HPS) are rare in children with secondary pituitary insufficiency after surgery for craniopharyngioma. Craniopharyngioma and treatment sequelae may lead to polypituitary insufficiency, which further affects the hormone secretion in the body. Endocrine diseases also cause nonalcoholic fatty liver disease (NAFLD)[1]. This report aims to further elucidate the clinical characteristics of nonalcoholic steatohepatitis (NASH) and HPS caused by hypothalamic-pituitary dysfunction after surgery for craniopharyngioma and the improvement of this disease after hormone replacement therapy, which has great significance in the clinical prognosis.

CASE PRESENTATlON

Chief complaints

The chief complaints were liver enlargement for 4 years, activity loss for 2 years, and cyanosis for more than 1 year.

History of present illness

A female patient aged 13 years and 6 mo was diagnosed with craniopharyngioma 6 years prior and underwent surgical resection without postoperative hormone replacement therapy. She had weakness after the surgery, and multiple laboratory tests revealed hypernatremia and hyperchloremia. The maximum serum sodium level was 176 mmol/L, which was improved by infusion of glucose, and the lowest sodium level was reduced to approximately 155 mmol/L. Four years ago, abdominal distension due to liver enlargement was noted, and B-ultrasound examination suggested fatty liver disease. The patient had severe cyanosis, chest tightness, wheezing, intermittent fever, and progressive exacerbation after mild physical labor for more than 1 year. Oxygen saturation fluctuated around 85% under highflow oxygen inhalation. Hepatobiliary ultrasonography, liver biopsy, and contrast echocardiography of the right heart revealed cirrhosis and HPS.

History of past illness

堵截式浇注系统不仅充分发挥了传统浇注系统的优点，而且通过对上下层浇道进钢时机进行有效控制，避免了传统浇注系统温度梯度倒置问题，实现了铸件的顺序凝固，提高了冒口补缩效率，保证了铸件内部质量。我公司通过对采用堵截式浇注系统的齿圈、轮带、磨辊体等大型铸钢件的跟踪，并不断改进，使堵截式浇注技术最终取得圆满成功，各工艺参数满足生产需要，使用效果良好，达到了预期目的，有效解决了大型铸钢件浇口端的UT无损检测合格率低的问题，提高了铸件质量和钢液利用率，降低了生产成本。

Personal and family history

The patient was born to a G1P1 mother at full term. The patient’s parents are alive, healthy, and divorced. The patient does not have siblings.

Physical examination

Under atmospheric inhalation, oxygen saturation (SpO) mostly fluctuated at around 70%. Cyanosis of the face and lips was noted. The heart rate was 124 beats/min, respiration was 26 breaths/min, blood pressure was 96/46 mmHg, height was 141.5 cm (-2.5 SD), and weight was 41.85 kg (-0.5 SD). The skin sclera did not have obvious yellow staining, and acanthosis nigricans was noted around the neck and axillae. No abnormality was found during cardiopulmonary auscultation, and the abdomen was soft but enlarged with palpable spleen and liver. Examination of the nervous system was negative, double breasts were in stage B1, pubic hair was in stage PH1, and no axillary hair was found.

Echocardiography of the right heart revealed a diffuse arteriovenous shunt in the lung (grade III ＞100/frame), which was consistent with HPS (Figure 1A). Abdominal ultrasonography revealed bile duct dilatation, cirrhosis, and splenomegaly (Figure 1B). Biopsy of the liver parenchyma showed loss of lobular structure, formation of regenerated nodules, swelling of the hepatocytes, mild steatosis (20%),fibroseptal bile duct hyperplasia, and fibrous tissue hyperplasia. The diagnostic view showed nodular cirrhosis (considering the origin of NASH) (Figure 2). The liver vasculature of computed tomography angiography revealed cirrhotic hepatosplenomegaly and portal hypertension, spongiform changes in the left portal artery, mild varicose veins in the lower esophagus, and splenic-renal shunt. Magnetic resonance cholangiopancreatography did not show abnormal changes in the pancreatic duct. The pituitary magnetic resonance imaging that included the conventional plain scan and dynamic contrastenhanced scan showed postoperative changes in craniopharyngioma.

Laboratory examinations

The patient exhibited hypernatremia (serum sodium level, 167 mmol/L; normal range, 135-145 mmol/L), mild liver function abnormality (alanine aminotransferase level, 67 U/L, normal range, 7-40 U/L; aspartate aminotransferase level, 93 U/L, normal range, 13-40 U/L; γ-glutamyltranspeptidase, 107 U/L, normal range, 7-45 U/L; total bilirubin level, 45.1 μmol/L, normal range, 0.0-21 μmol/L; total biliary acid level, 22.3 μmol/L, normal range, 0.0-10.0 μmol/L; indirect bilirubin level, 33.6 μmol/L,normal range, 3-14 μmol/L; triglyceride level, 2.53 mmol/L, normal range, 0.3-1.7 mmol/L), abnormal renal function (creatinine level, 79 μmol/L; normal range, 15-77 μmol/L), and high blood ammonia level (94 μmol/L; normal range, 10-47 μmol/L). The patient had hypopituitarism and multiple pituitary hormone deficiencies (Table 1). However, the coagulation function, immune function, and Epstein-Barr virus and cytomegalovirus levels were normal. The hepatitis series, including hepatitis A virus,hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus, were normal.

痊愈为NIHSS评分减少≥90%，脑电图正常；显效为90%＞NIHSS评分减少≥50%，脑电图显著改善；有效为49%＞NIHSS分恢复≥15%，脑电图有所好转；无效为以上指标均未满足。

Imaging examinations

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FlNAL DlAGNOSlS

Recent studies have demonstrated an increased prevalence of NASH in adult patients with GH deficiency and improvement in liver function impairment after GH replacement therapy. Although it is unclear whether GH replacement therapy directly or indirectly reduces oxidative stress in the liver, GH has antioxidant stress effects. GH can directly reduce adipogenesis in liver cells and simultaneously regulate the production of IGF1, which can induce cell senescence and inactivate hepatic stellate cells, thus improving liver fibrosis[25].

TREATMENT

NAFLD is a chronic liver disease worldwide, and its incidence is increasing with the prevalence of obesity, diabetes, and metabolic syndrome. Statistically, the global incidence is 25%[6]. NAFLD is histologically classified into NAFLD and NASH, cirrhosis, and hepatocellular carcinoma. NAFLD and NASH are associated with hypothalamic hypopituitarism, but their pathogeneses remain unclear, and an increasing number of studies have found that the development of NASH is closely related to endocrine hormone abnormalities[7]. In children, it is caused by craniopharyngioma or pituitary adenoma and sequelae of treatment, leading to hypothyroidism, adrenal insufficiency, hypogonadotropism, and GH deficiency[8]. Adams[9] reported 21 cases of NAFLD, among which 15 were secondary after brain tumor surgery (approximately 71%), suggesting that brain tumor near the pituitary hypothalamus is an important cause of NAFLD. More than 50% (eight cases) of these tumors were craniopharyngiomas, suggesting the importance of careful diagnosis and exclusion of this type of tumor in the presence of clinically unexplained NAFLD[9]. Jung[10] reported the case of a 19-yearold girl diagnosed with craniopharyngioma who developed hypothalamic obesity, NAFLD, and progression to HPS after tumor resection[10]. Recently, studies on patients with hypothalamic-pituitary involvement after craniopharyngioma have found that the prevalence of NAFLD in children is approximately 3%-10%, while the incidence of NAFLD caused by hypothalamic-pituitary damage after craniopharyngioma has increased to approximately 50%[11,12]. Previously, it was generally believed that the risk factors for NAFLD were excessive fructose intake, insulin resistance, and metabolic syndrome,followed by oxidative stress injury and endoplasmic reticulum stress, adipocytokine, mitochondrial dysfunction, and bisphenol A intake[13,14].

《鸨羽》是一首怨徭役的诗歌。 尽管由于怨徭役太多，误了耕种，眼看要挨饿，但不是要反抗，而是发出要求安定的呼声。 忧远，在这里得到生动体现。

OUTCOME AND FOLLOW-UP

Craniopharyngioma is a rare primary brain tumor that originates from ectopic embryonic remnants of the craniopharyngeal duct or squamous epithelial cells. Its incidence is 0.5-2 casesmillion personsyear, with peaks in childhood/adolescence (8 years) and adulthood (40-50 years)[2,3]. Although histologically defined as a benign tumor, craniopharyngioma often compresses nearby key structures,such as the optic neurohypophysis or hypothalamus[4,5]. Postoperative complications of craniopharyngioma, especially endocrine dysfunction, have a high incidence and mainly manifest asintractable diabetes insipidus hypothalamic-pituitary insufficiency, severe electrolyte disorder, and neuropsychological defects, which seriously affect the quality of life of children.

The patient had no history of hypertension, diabetes, or heart disease. She had undergone surgery for craniopharyngioma 6 years ago.

DlSCUSSlON

Oxygen saturation improved significantly after 1 mo of GH treatment and currently fluctuated at around 92% for low-flow nasal catheter oxygen. Liver function was reduced to the normal range,hypernatremia improved, and total bilirubin, indirect bilirubin, total bile acid, and lipid levels were significantly improved. During regular follow-up, it was found that liver transplantation was not required.

The patient received multiple hormone replacement and desmopressin therapies: Growth hormone(GH) (4 IU qn), thyroid hormone (levothyroxine sodium hydrate, 50 μg/d), corticosteroid(hydrocortisone, 15 mg/d), and desmopressin (Minirin, 0.05 mg/d). Moreover, the patient received symptomatic oxygen inhalation and calcium and potassium supplementation.

In a retrospective study that reported the association between hypopituitarism, hypothalamic dysfunction, and NAFLD, NAFLD was found in 2.3% of patients with hypopituitarism and hypothalamic obesity[15]. Moreover, a recent analysis of long-term outcomes after childhood-onset craniopharyngioma found that 1 of 32 patients (3%) died of cirrhosis[16].

The risk of progression from childhood simple fatty liver to adult cirrhosis and liver failure is low,and the natural course of NAFLD in patients with hypothalamic and pituitary dysfunction may be more aggressive than that in the general population. Therefore, children with craniopharyngioma should be closely followed postoperatively, especially for liver function and pituitary hormone levels. Some scholars have reported NASH 4 years after pituitary tumor resection, accompanied by dyspnea and hypoxemia, which eventually developed into HPS[17]. HPS is a serious complication of chronic liver disease, which includes three main characteristics: Abnormal liver function, pulmonary telangiectasia(shunt), and hypoxemia[18]. It is a progressive disease that is a complication of cirrhosis or portal hypertension. The main clinical manifestations are dyspnea and cyanosis. At this point, the exact pathogenesis of HPS is still unclear, and is most likely thought to occur due to vasodilatation caused by nitric oxide[19], which increases pulmonary blood flow and cardiac output, leading to pulmonary ventilation-perfusion mismatch and arteriovenous shallows, ultimately making it difficult for oxygen molecules to bind with hemoglobin, and resulting in hypoxemia[20,21]. Currently, liver transplantation is the accepted treatment. Despite successful liver transplantation, NAFLD has a high recurrence rate.Therefore, the prospects for the treatment of NAFLD and HPS secondary to craniopharyngioma are not optimistic, and the need for liver transplantation should be carefully considered. We present the case of a 13-year-old girl with hypopituitarism following surgery for craniopharyngioma; particularly, GH deficiency resulted in slow-progressive NASH, which progressed to cirrhosis, and HPS was eventually diagnosed. After GH replacement therapy, liver biochemical indexes and hypoxemia were significantly improved. Therefore, it is speculated that GH may provide a new approach for the treatment of HPS in the future. An 11-year-old boy from Japan was reported to have developed hypopituitarism after surgical resection of a pituitary tumor and subsequently progressed to NASH and HPS. He underwent living-donor liver transplantation at 15 years of age and developed NAFLD again 1 year after transplantation; GH replacement therapy improved liver function, which stabilized to the normal range during 10 years of follow-up[17]. Kodama[22] and Torii[23] reported that GH replacement therapy improved NASH and HPS[22,23]. A 29-year-old man with pituitary stalk interruption syndrome progressed slowly to HPS, and after 14 mo of treatment with recombinant human GH, the liver function and hypoxemia improved, and liver fibrosis did not progress[24].

The final diagnoses were liver cirrhosis, HPS, hypopituitarism, and electrolyte imbalance.

CONCLUSlON

Craniopharyngioma in children likely damages the pituitary gland and leads to hypopituitarism,regardless of its unique location or treatment with surgery or radiotherapy. Hypopituitarism in children is likely to develop into NASH, cirrhosis, and even HPS. In this study, GH replacement therapy significantly improved liver function, metabolic status, and hypoxemia, providing new clinical support for the early diagnosis and treatment of NASH and HPS in children with hypopituitarism.

FOOTNOTES

Zhang XY and Wang CL conceived and designed the study; Zhang XY and Yuan K provided clinical research; Zhang XY wrote the paper; Zhang XY, Yuan K, Fang YL, and Wang CL reviewed and edited the manuscript; all authors read and approved the manuscript.

Informed written consent was obtained from the patient for the publication of this report and any accompanying images.

The authors declare that they have no conflicts of interest related to this manuscript.

（3）船员适任证书等级降低。由于航标船舶作业特点的原因，目前我国大型航标船总吨也不到2000吨（沿海二等船），而一般航海院校毕业的船舶轮驾人员至少持有沿海一等（3000总吨以上）船员适任证书，如果他们长期在航标船舶上工作，会导致任职资历不符，最后被迫降低船员适任证书等级，这个也是相当一部分外包船员的顾虑之一。

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

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China

Xiao-Yuan Zhang 0000-0003-1607-2490; Ke Yuan 0000-0002-0458-3683; Yan-Lan Fang 0000-0001-6579-417X; Chun-Lin Wang 0000-0002-4273-1341.

Fan JR

Wang TQ

碳氧单键（C-O）的吸收峰在1300-1100cm-1，波罗的海琥珀的吸收峰为1260cm-1和1164cm-1双吸收峰，并且1164cm-1吸收峰强于1260cm-1，1164cm-1为波罗的海的特有吸收峰，可以作为波罗的海琥珀产地鉴定的重要依据。而多米尼加琥珀在此区域内存在多个吸收峰并在1240cm-1附近吸收最高，峰形独立清晰；墨西哥琥珀吸收强度较弱，峰位相对于多米尼加琥珀吸收峰较平缓；而缅甸琥珀在此区域内也是呈现“山”字吸收峰[8]，在1150cm-1附近处吸收峰为缅甸琥珀特征吸收峰。多米尼加和墨西哥琥珀缺失1164cm-1吸收峰。这是产生天然树脂的不同树种决定的。

Fan JR