Department of Neonatology, University Children's Hospital, Faculty of Medicine, Eberhard-Karls-University, Calwer Straße 7, 72076, Tübingen, Germany.
Eur J Nutr. 2021 Jun;60(4):1737-1759. doi: 10.1007/s00394-020-02358-2. Epub 2020 Aug 14.
Cystic Fibrosis (CF) is an autosomal recessive disorder with life-threatening organ manifestations. 87% of CF patients develop exocrine pancreas insufficiency, frequently starting in utero and requiring lifelong pancreatic enzyme substitution. 99% develop progressive lung disease, and 20-60% CF-related liver disease, from mild steatosis to cirrhosis. Characteristically, pancreas, liver and lung are linked by choline metabolism, a critical nutrient in CF. Choline is a tightly regulated tissue component in the form of phosphatidylcholine (Ptd'Cho) and sphingomyelin (SPH) in all membranes and many secretions, particularly of liver (bile, lipoproteins) and lung (surfactant, lipoproteins). Via its downstream metabolites, betaine, dimethylglycine and sarcosine, choline is the major one-carbon donor for methionine regeneration from homocysteine. Methionine is primarily used for essential methylation processes via S-adenosyl-methionine.
CF patients with exocrine pancreas insufficiency frequently develop choline deficiency, due to loss of bile Ptd'Cho via feces. ~ 50% (11-12 g) of hepatic Ptd'Cho is daily secreted into the duodenum. Its re-uptake requires cleavage to lyso-Ptd'Cho by pancreatic and small intestinal phospholipases requiring alkaline environment. Impaired CFTR-dependent bicarbonate secretion, however, results in low duodenal pH, impaired phospholipase activity, fecal Ptd'Cho loss and choline deficiency. Low plasma choline causes decreased availability for parenchymal Ptd'Cho metabolism, impacting on organ functions. Choline deficiency results in hepatic choline/Ptd'Cho accretion from lung tissue via high density lipoproteins, explaining the link between choline deficiency and lung function. Hepatic Ptd'Cho synthesis from phosphatidylethanolamine by phosphatidylethanolamine-N-methyltransferase (PEMT) partly compensates for choline deficiency, but frequent single nucleotide polymorphisms enhance choline requirement. Additionally, small intestinal bacterial overgrowth (SIBO) frequently causes intraluminal choline degradation in CF patients prior to its absorption. As adequate choline supplementation was clinically effective and adult as well as pediatric CF patients suffer from choline deficiency, choline supplementation in CF patients of all ages should be evaluated.
囊性纤维化（CF）是一种常染色体隐性遗传病，可导致危及生命的器官病变。87%的 CF 患者会出现外分泌胰腺功能不全，这种情况通常在子宫内开始，并需要终生补充胰腺酶。99%的患者会出现进行性肺部疾病，20-60%的 CF 相关肝病，从轻度脂肪变性到肝硬化。胰腺、肝脏和肺部的特征是通过胆碱代谢联系在一起的，胆碱是 CF 中的一种关键营养物质。胆碱以磷脂酰胆碱（Ptd'Cho）和神经鞘磷脂（SPH）的形式作为紧密调节的组织成分存在于所有膜和许多分泌物中，尤其是肝脏（胆汁、脂蛋白）和肺部（表面活性剂、脂蛋白）。通过其下游代谢物甜菜碱、二甲基甘氨酸和肌氨酸，胆碱是从同型半胱氨酸再生蛋氨酸的主要一碳供体。蛋氨酸主要通过 S-腺苷甲硫氨酸用于必需的甲基化过程。
患有外分泌胰腺功能不全的 CF 患者经常会出现胆碱缺乏，因为胆汁中的 Ptd'Cho 通过粪便丢失。每天约有 50%（11-12 克）的肝脏 Ptd'Cho 分泌到十二指肠。其再摄取需要由胰腺和小肠磷脂酶将其裂解为溶酶体 Ptd'Cho，这需要碱性环境。然而，CFTR 依赖性碳酸氢盐分泌受损会导致十二指肠 pH 值降低，磷脂酶活性受损，粪便 Ptd'Cho 丢失和胆碱缺乏。低血浆胆碱会导致实质 Ptd'Cho 代谢的可用性降低，从而影响器官功能。胆碱缺乏会导致通过高密度脂蛋白从肺部组织摄取肝脏中的胆碱/Ptd'Cho，这解释了胆碱缺乏与肺功能之间的联系。通过磷酸乙醇胺-N-甲基转移酶（PEMT）从磷脂酰乙醇胺合成肝 Ptd'Cho 部分补偿了胆碱缺乏，但频繁的单核苷酸多态性增加了胆碱的需求。此外，小肠细菌过度生长（SIBO）经常导致 CF 患者在吸收前在肠道内降解胆碱。由于适当的胆碱补充在临床上是有效的，并且成年和儿科 CF 患者都患有胆碱缺乏症，因此应评估所有年龄段 CF 患者的胆碱补充。
