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The patient is a 14-year-old woman with cystic fibrosis (CF) with mild lung disease (FEV1 111%) and pancreatic insufficiency who presented with abdominal and low back pain.
The patient reported three weeks of intermittent, crampy, progressively worsening lower abdominal pain that radiated to the back. The pain was exacerbated by eating and movement, and improved with over-the-counter pain medications. Associated symptoms included decreased appetite and activity level, nausea, vomiting, bloating, and weight loss. She was having large, infrequent bowel movements with occasional streaks of blood. She had regular menstrual cycles with rare dysmenorrhea. The patient denied abdominal trauma, fevers, diarrhea, dysuria, urinary urgency or frequency, hematuria, or flank pain.
The patient was referred to our center after an abdominal CT with intravenous contrast demonstrated a right hemorrhagic ovarian cyst and complete replacement of the pancreas by innumerable cysts of varying sizes. Additionally, mild intrahepatic biliary ductal dilatation was noted and was greater in the left hepatic lobe. Her exam was significant only for tenderness in the bilateral lower abdominal quadrants. Laboratory evaluation included normal electrolytes, transaminases, bilirubin, gGTP, lipase/amylase, and white blood cell count. Her albumin and hemoglobin were low at 2.8 g/dL (NL 3.8-5.4) and 11.1 g/dL (NL 12-16), respectively, and platelets were elevated at 789 109/L (NL 156-369). She was admitted for further evaluation of her abdominal pain and the cystic mass. A bowel regimen was started, her abdominal pain improved, and she was subsequently discharged to her home. As an outpatient, she was started on oral contraceptive pills for management of her ovarian cysts.
Figure 1: Abdominal Imaging and Liver Histology: (A) Liver core biopsy showing representative portal tract with edema and a mixed inflammatory infiltrate that contains numerous neutrophils and occasional eosinophils. Bile ducts show evidence of mild damage (arrows) (HE, 200X). Other areas showed mild pericentral cholestasis and mild portal and central fibrotic changes (not shown).
(B) Axial CT image of complete replacement of pancreas with cysts.
During outpatient follow-up, the patient continued to have intermittent abdominal pain. Celiac serologies and stool calprotectin were normal. A hepatic function panel checked in the interim remained normal, and abdominal ultrasounds showed stable pancreatic cysts and biliary tree dilatation. Ten months after her initial hospitalization, she was admitted for a pulmonary exacerbation. During this stay, she acutely developed scleral icterus, jaundice, and pruritus. Labs were significant for a direct hyperbilirubinemia (total bilirubin 6.9 mg/dL, direct 5.8 mg/dL), and elevated gGTP, AST, and ALT (335 U/L, 510 U/L, 382 U/L, respectively).
An abdominal ultrasound demonstrated increased biliary ductal dilatation and gallbladder sludge. A magnetic resonance cholangiopancreatography (MRCP) showed irregular dilatation of the intrahepatic biliary ducts, dilatation of the common bile duct, and persistence of the pancreatic cysts. Ursodiol was started, and her oral contraceptive was discontinued. Her transaminases improved and she was discharged.
Shortly after her discharge, a percutaneous liver biopsy showed evidence of mild cholestasis and a biliary obstructive pattern of injury with mild fibrotic changes. Her bilirubin normalized, but her transaminases and gGTP continued to rise. Five months later, she redeveloped scleral icterus and pruritus and had a repeat MRCP concerning for “sclerosing cholangitis” with beaded, dilated intrahepatic bile ducts (Figure 1).
Abnormal pancreatic imaging is common in patients with CF, with several patterns of radiographic findings noted that include normal pancreas, partial or complete fibrofatty replacement, and pancreatic atrophy.1 Pancreatic cystosis, however, is a rare entity characterized by complete replacement of the pancreas with epithelial-lined macrocysts of varying sizes. The pathophysiology of pancreatic cystosis is postulated to be defective bicarbonate secretion inherent to CF. The bicarbonate transport defect leads to inspissated secretions, increased fluid pressure proximal to the obstruction, expansion of the pancreatic ducts, and eventually transformation into cysts of various sizes.2 Pancreatic cystosis is typically discovered incidentally with ultrasound (US) or magnetic resonance imaging (MRI) during evaluation of abdominal pain. While some advocate that MRI is the most accurate imaging method for evaluating the cysts and surrounding structures,3 others have noted that MRI may not contribute additional information beyond US.1
The differential diagnosis for pancreatic cystosis includes polycystic kidney disease, von Hippel-Lindau disease with pancreatic involvement, microcystic adenoma, mucinous cystic neoplasm, and lymphangioma.2 In general, a confirmatory biopsy is considered unnecessary among patients with pancreatic cystosis in the CF population.1,3 Most patients with pancreatic cystosis are asymptomatic.
Monitoringwith ultrasound or MRI every six to 12 months has been suggested3 although no uniform recommendations exist for management of symptomatic patients. Endoscopic drainage of large cysts and surgical resection have been described.3 Regarding prognosis, no cases of malignant transformation within pancreatic cystosis have been reported.
CF-related liver disease (CFLD) occurs in about a third of patients with CF and can carry significant morbidity and mortality. Absence of the normal biliary epithelial CF transmembrane regulator (CFTR) protein function is thought to lead to cholestasis, biliary obstruction, periductal inflammation and proliferation, and fibrosis. Phenotypically, patients present most commonly with focal biliary cirrhosis, though steatosis, gallbladder involvement, multilobular cirrhosis, and a biliopathy with a sclerosing cholangitis-type picture also can occur.4,5 From an imaging standpoint, CFLD is most commonly evaluated with ultrasound, though for suspected biliary abnormalities, MRCP is the preferred modality.
Concurrent with the diagnosis of pancreatic cystosis, our patient had imaging findings of CF-associated biliopathy. Initially, dilatation of intrahepatic bile ducts was noted with normal serological markers. More recently, an MRCP showed irregular dilatation and beading of intrahepatic bile ducts and dilatation of the common bile duct in the setting of elevated bilirubin, transaminases, and gGTP. In a small study of adults with CF, 38 percent had sclerosing cholangitis-type lesions on imaging.5 Prevalence in the pediatric population is unknown. Our patient’s liver disease is most likely multifactorial, both from obstruction of bile flow due to her pancreatic cystosis and intrinsic liver disease in the form of a sclerosing cholangitis phenotype.
At this point, the optimal strategy to manage and slow the progression of her liver disease in the setting of her large pancreatic cysts is unknown. Ideally, therapeutic endoscopic retrograde cholangiopancreatography (ERCP) could be used to improve bile flow and slow liver injury, but it could be technically difficult and high-risk for complications given her pancreatic pathology. Pancreatectomy is also considered to be an option. She has not had evidence of decompensated liver disease or portal hypertension to suggest need for liver transplant. A multidisciplinary approach involving hepatology, pulmonology, gastroenterology, and abdominal transplant teams is required for care of these complicated patients.
Pancreatic cystosis is a rare finding in patients with CF and should be considered in the differential diagnosis of those with gastrointestinal symptoms. It is often an incidental finding in the work-up of abdominal pain, so multiple gastrointestinal and non-gastrointestinal etiologies should also be considered. An intrahepatic CF-associated biliopathy is recognized in adults with CFLD, but pediatric data is lacking. Co-existent biliopathy, recurrent episodes of cholestasis, and pancreatic cystosis has not been previously described and present a unique management challenge requiring a thoughtful team approach.
1 Berrocal T, Pajares MP, Zubillaga AF. Pancreatic Cystosis in Children and Young Adults With Cystic Fibrosis: Sonographic, CT, and MRI Findings. Am J Roentgenol. 2005; 184(4): 1305-1309.
2 Freeman AJ, Ooi CY. Pancreatitis and Pancreatic Cystosis in Cystic Fibrosis. J Cystic Fibrosis. 2017; 16 Suppl 2: S79-s86.
3 Hatziagorou E, Kampouras A, Sidiropoulou M, Markou A, Anastasiou A, Tsanakas J. Pancreatic Cystosis in Two Adolescents with Cystic Fibrosis. Case Reports in Pediatrics. 2016; 2016: 5321785.
4 Leung DH, Narkewicz MR. Cystic Fibrosis-related Cirrhosis. J Cystic Fibrosis. 2017; 16 Suppl 2: S50-s61.
5 Durieu I, Pellet O, Simonot L, et al. Sclerosing Cholangitis in Adults With Cystic Fibrosis: A Magnetic Resonance Cholangiographic Prospective Study. J Hepatology. 1999; 30(6): 1052-1056.