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

堵截式澆注系統(tǒng)不僅充分發(fā)揮了傳統(tǒng)澆注系統(tǒng)的優(yōu)點(diǎn)，而且通過對(duì)上下層澆道進(jìn)鋼時(shí)機(jī)進(jìn)行有效控制，避免了傳統(tǒng)澆注系統(tǒng)溫度梯度倒置問題，實(shí)現(xiàn)了鑄件的順序凝固，提高了冒口補(bǔ)縮效率，保證了鑄件內(nèi)部質(zhì)量。我公司通過對(duì)采用堵截式澆注系統(tǒng)的齒圈、輪帶、磨輥體等大型鑄鋼件的跟蹤，并不斷改進(jìn)，使堵截式澆注技術(shù)最終取得圓滿成功，各工藝參數(shù)滿足生產(chǎn)需要，使用效果良好，達(dá)到了預(yù)期目的，有效解決了大型鑄鋼件澆口端的UT無損檢測(cè)合格率低的問題，提高了鑄件質(zhì)量和鋼液利用率，降低了生產(chǎn)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.

痊愈為NIHSS評(píng)分減少≥90%，腦電圖正常；顯效為90%＞NIHSS評(píng)分減少≥50%，腦電圖顯著改善；有效為49%＞NIHSS分恢復(fù)≥15%，腦電圖有所好轉(zhuǎn)；無效為以上指標(biāo)均未滿足。

Imaging examinations

江西茶葉出口企業(yè)應(yīng)該重視品牌的力量，加大品牌宣傳力度。企業(yè)要加強(qiáng)對(duì)品牌理論和實(shí)踐的研究，積極向外國(guó)學(xué)習(xí)創(chuàng)新的品牌營(yíng)銷模式，學(xué)習(xí)國(guó)外品牌發(fā)展的建設(shè)經(jīng)驗(yàn)，尤其是值得借鑒跨國(guó)公司成功的經(jīng)驗(yàn)。企業(yè)可以增強(qiáng)與國(guó)內(nèi)其他知名品牌（如黃山毛峰）之間的交流和合作，學(xué)習(xí)借鑒他們的品牌建設(shè)模式，強(qiáng)強(qiáng)聯(lián)合，共同推動(dòng)國(guó)茶走向世界。企業(yè)還可以聘請(qǐng)一些品牌營(yíng)銷和策劃的專家以及相關(guān)方面的人才進(jìn)行品牌的國(guó)際推廣，加強(qiáng)品牌的國(guó)際宣傳，提高國(guó)際市場(chǎng)的知名度。

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].

《鴇羽》是一首怨徭役的詩(shī)歌。 盡管由于怨徭役太多，誤了耕種，眼看要挨餓，但不是要反抗，而是發(fā)出要求安定的呼聲。 憂遠(yuǎn)，在這里得到生動(dòng)體現(xiàn)。

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）船員適任證書等級(jí)降低。由于航標(biāo)船舶作業(yè)特點(diǎn)的原因，目前我國(guó)大型航標(biāo)船總噸也不到2000噸（沿海二等船），而一般航海院校畢業(yè)的船舶輪駕人員至少持有沿海一等（3000總噸以上）船員適任證書，如果他們長(zhǎng)期在航標(biāo)船舶上工作，會(huì)導(dǎo)致任職資歷不符，最后被迫降低船員適任證書等級(jí)，這個(gè)也是相當(dāng)一部分外包船員的顧慮之一。

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

碳氧單鍵（C-O）的吸收峰在1300-1100cm-1，波羅的海琥珀的吸收峰為1260cm-1和1164cm-1雙吸收峰，并且1164cm-1吸收峰強(qiáng)于1260cm-1，1164cm-1為波羅的海的特有吸收峰，可以作為波羅的海琥珀產(chǎn)地鑒定的重要依據(jù)。而多米尼加琥珀在此區(qū)域內(nèi)存在多個(gè)吸收峰并在1240cm-1附近吸收最高，峰形獨(dú)立清晰；墨西哥琥珀吸收強(qiáng)度較弱，峰位相對(duì)于多米尼加琥珀吸收峰較平緩；而緬甸琥珀在此區(qū)域內(nèi)也是呈現(xiàn)“山”字吸收峰[8]，在1150cm-1附近處吸收峰為緬甸琥珀特征吸收峰。多米尼加和墨西哥琥珀缺失1164cm-1吸收峰。這是產(chǎn)生天然樹脂的不同樹種決定的。

Fan JR