Background & Aims-Progressive familial intrahepatic cholestasis (PFIC) with normal serum levels of gamma-glutamyltranspeptidase can result from mutations in ATP8B1 (encoding familial intrahepatic cholestasis 1 [FIC1]) or ABCB11 (encoding bile salt export pump [BSEP]). We evaluated clinical and laboratory features of disease in patients diagnosed with PFIC, who carried mutations in ATP8B1 (FIC1 deficiency) or ABCB11 (BSEP deficiency). Our goal was to identify features that distinguish presentation and course of these 2 disorders, thus facilitating diagnosis and elucidating the differing consequences of ATP8B1 and ABCB11 mutations.

Gastroesophageal reflux (GER) is defined as the involuntary retrograde passage of gastric contents into the esophagus with or without regurgitation or vomiting. It is a frequently experienced physiologic condition occurring several times a day, mostly postprandial and causes no symptoms. These infants are also called 'happy spitters'. GER disease (GERD) occurs when reflux of the gastric contents causes symptoms that affect the quality of life or pathologic complications, such as failure to thrive, feeding or sleeping problems, chronic respiratory disorders, esophagitis, hematemesis, apnea, and apparent life-threatening events. About 70-85 % of infants have regurgitation within the first 2 months of life, and this resolves without intervention in 95 % of infants by 1 year of age. The predominant mechanism causing GERD is transient lower esophageal sphincter (LES) relaxation, which is defined as an abrupt decrease in LES pressure to the level of intragastric pressure, unrelated to swallowing and of relatively longer duration than the relaxation triggered by a swallow. Regurgitation and vomiting are the most common symptoms of infant reflux. A thorough history and physical examination with attention to warning signals suggesting other causes is generally sufficient to establish a clinical diagnosis of uncomplicated infant GER. Choking, gagging, coughing with feedings or significant irritability can be warning signs for GERD or other diagnoses. If there is forceful vomiting, laboratory and radiographic investigation (upper gastrointestinal series) are warranted to exclude other causes of vomiting. Irritability coupled with back arching in infants is thought to be a non-verbal equivalent of heartburn in older children. Other causes of irritability, including cow's milk protein allergy, neurologic disorders, constipation and infection, should be ruled out. The presentation of cow's milk protein allergy overlaps with GERD, and both conditions may co-exist in 42-58 % of infants. In these infants, symptoms decrease significantly within 2-4 weeks after elimination of cow's milk protein from the diet. For non-complicated reflux, no intervention is required for most infants. Effective parental reassurance and education regarding regurgitation and lifestyle changes are usually sufficient to manage infant reflux. Sandifer syndrome, apnea and apparent life-threatening events are the extraesophageal manifestations of GERD in infants. Pharmacotherapeutic agents used to treat GERD encompass antisecretory agents, antacids, surface barrier agents and prokinetics. Currently, North American Society for Pediatric Gasroenterology, Hepatology and Nutrition (NASPGHAN) and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) practice guidelines concluded that there is insufficient evidence to justify the routine use of prokinetic agents. Esomeprazole (Nexium) is now approved in the US for short-term treatment of GERD with erosive esophagitis in infants aged from 1 to 12 months. Although Nissen fundoplication...

Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma‐glutamyl transpeptidase levels can result from mutations in the ATP8B1 gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the ABCB11 gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). For surgeries performed prior to transplantation, BSEP patients were divided into two groups, BSEP‐common (bearing common missense mutations D482G or E297G, with likely residual function) and BSEP‐other. We evaluated clinical and biochemical outcomes in these patients. Overall, diversion improved biochemical parameters, pruritus, and growth, with substantial variation in individual response. BSEP‐common or FIC1 patients survived longer after diversion without developing cirrhosis, being listed for or undergoing liver transplantation, or dying, compared to BSEP‐other patients. Transplantation resolved cholestasis in all groups. However, FIC1 patients commonly developed hepatic steatosis, diarrhea, and/or pancreatic disease after transplant accompanied by biochemical abnormalities and often had continued poor growth. In BSEP patients with impaired growth, this generally improved after transplantation. Conclusion: Diversion can improve clinical and biochemical status in FIC1 and BSEP deficiencies, but outcomes differ depending on genetic etiology. For many patients, particularly BSEP‐other, diversion is not a permanent solution and transplantation is required. Although transplantation resolves cholestasis in patients with FIC1 and BSEP deficiencies, the overall outcome remains unsatisfactory in many FIC1 patients; this is mainly due to extrahepatic manifestations. (Hepatology Communications 2018;2:515‐528)

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