Rethinking hyperbilirubinemia: Gilbert syndrome in children with cystic fibrosis, a case report

Abstract

Cystic Fibrosis leads to liver complications, including cystic fibrosis liver disease but hyperbilirubinemia in CF patients on CFTR modulators is less understood. This article describes two pediatric CF patients on Elexacaftor/Tezacaftor/Ivacaftor therapy with elevated bilirubin, ultimately diagnosed with Gilbert syndrome, highlighting the importance of fractionated bilirubin testing for early diagnosis and management.

1. Introduction

Cystic Fibrosis (CF) is an autosomal recessive genetic disorder with a prevalence of 1 in 3500 newborns. It is characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that expresses the CFTR membranous channel, leading to disruptions in the flow of chloride ions and water across the cell membrane. Complications of CF include chronic sinopulmonary infections, pancreatic insufficiency, diabetes and pancreatitis. The liver and biliary systems are not spare [1].

Reports describe that between 10 and 15 % of patients with CF (pwCF) demonstrate cystic fibrosis liver disease (CFLD) [2]. The affected cholangiocyte function causes alteration in the bile composition which can induce chronic damage to the biliary epithelium resulting in the development of hepatobiliary diseases such as periportal fibrosis, biliary obstruction, biliary cirrhosis, and portal hypertension [2]. Altered bile fluid can inspissate in the biliary ductules and progress to cholelithiasis/choledocholithiasis, obstructive cirrhosis, and post-hepatic hyperbilirubinemia. The prevalence of hyperbilirubinemia in pwCF is not well described in the literature [3].

Introduction of CFTR modulators has revolutionized the treatment and prognosis of pwCF. The introduction of Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy has resulted in tremendous improvements in the frequency of exacerbations and pulmonary symptoms [4]. However, the effect of CFTR modulators on CFLD has not been established and remains unclear [5]. CFTR modulators are associated with drug related hepatotoxicity. Elevations in serum aminotransferases occurred in 3–10 % and hyperbilirubinemia occurred in 3 % of pwCF treated with ETI [5].

Consensus recommendations to address the screening and surveillance of hepatobiliary disease have been recently published [6]. The Cystic Fibrosis Foundation (CFF) recommends that annual labs (total bilirubin, AST, ALT, alkaline phosphatase, GGT, and platelet count) should be performed in all pwCF. Patients with CFLD should be assessed every 6 months with elastography or annual liver fibrosis index calculation [5].

The most recently published guidelines do not address other potential abnormalities in bilirubin metabolism such as Gilbert syndrome. Gilbert syndrome is a benign genetic disorder, with an estimated prevalence of 2–20 %. This condition affects the liver's ability to conjugate bilirubin leading to indirect hyperbilirubinemia because of a mutation in the promoter region of uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1). Patients usually present with jaundice due to elevated unconjugated bilirubin in times of stress or illness [7].

In this article, we describe two pediatric pwCF on CFTR modulators presenting with hyperbilirubinemia requiring frequent lab monitoring due to the concern of CFTR modulator related liver toxicity. Fractioned Bilirubin, which is not part of the CF standard of care routine monitoring, revealed an isolated unconjugated hyperbilirubinemia which was not in line with the use of ETI. Further investigations eventually revealed genetic mutations consistent with the diagnosis of Gilbert syndrome.

2. Case summary 1

Patient 1 is an 11-year-old female born at term. CF (Homozygous F508del/F508del) was diagnosed via an abnormal newborn screen. She is pancreatic insufficient. ETI was initiated at the age of 6 years. Prior to starting ETI, serum aminotransferases and total bilirubin levels were normal. A bilirubin level was repeated 3 months after the initiation of ETI and continued to be within normal range. Elevation of total bilirubin (1.6 mg/dl) was noticed 6 months after ETI initiation; however, serum aminotransferases continued to be normal with routine monitoring every 6 months (Fig. 1).

Fig. 1.

Total Bilirubin over time with introduction of ETI.

Fluctuating levels of bilirubin were noted on repeated sampling over a period of 1 year. She was referred to gastroenterology for evaluation with liver elastography and liver ultrasound within normal limits. Liver enzymes continued to be normal. Further work up including screening for hepatitis A, B and C, and alpha-1 anti-trypsin deficiency was negative. Fractioned bilirubin revealed unconjugated hyperbilirubinemia with the differential diagnosis including Gilbert syndrome, hemolysis and thyroid dysfunction while ETI was less likely to be a culprit to the unconjugated hyperbilirubinemia. UGT1A1 testing was consistent with Gilbert syndrome with recommendation against frequent monitoring.

Trend of total bilirubin levels over time showing bilirubin changes before and after introduction ETI. An increase in total bilirubin is noticeable.

3. Case summary 2

Patient 2 is a 7-year-old male born at term with CF (F508del and 2789+2insA), diagnosed via an abnormal newborn screen and 2 positive sweat chloride tests. He is pancreatic sufficient. ETI was initiated at 6 years of age. He presented to the Duke Pediatric CF center with severe and generalized nocturnal pruritis in the absence of a skin rash. His physical examination was unremarkable. Specifically, he had no scleral icterus or hepatosplenomegaly. Laboratory testing revealed an isolated hyperbilirubinemia with a value of 1.5 mg/dl total bilirubin, for which he was referred to GI (Fig. 2).

Fig. 2.

Total Bilirubin over time with introduction of ETI.

Upon further evaluation by GI, he had normal liver transaminases (ALT of 25U/L and AST of 43U/L), normal albumin (4.5 mg/dl), an elevated total bilirubin (2.3 mg/dl) with conjugated bilirubin 0.4 mg/dl, and a normal INR of 1. Genetic testing noted decreased UGT1A1 activity consistent with the diagnosis of Gilbert syndrome. Abdominal US Elastography revealed mild hepatic fibrosis.

Trend of total bilirubin levels over time showing bilirubin changes before and after introduction ETI. An increase in total bilirubin is noticeable.

4. Case discussion

CFLD is a disorder of cholangiocyte transport protein defect causing reduced bile flow caused by dysfunction of CFTR [8]. The gallbladder and biliary tree have high concentrations of CFTR expression [4]. The CFTR protein maintains the fluid and electrolyte homeostasis of bile. It initiates the exchange of chloride for bicarbonate and the passive flow of water, leading to the alkalinization and hydration of bile. Altered hydration of bile in CF can lead to the accumulation of toxic bile salts which can induce infection, inflammation and cytotoxic injury. The prevalence of CFLD ranges between 5 and 68 % [8]. Liver involvement can range from asymptomatic elevation of aminotransferases, to cholelithiasis, cirrhosis, and liver decompensation [8].

ETI is a CFTR corrector/potentiator triple combination therapy approved by the United States Federal Drug Administration in October 2019 [4]. The introduction of ETI has revolutionized the treatment of pwCF. It is recommended for patients 2 years and older with CF carrying at least one F508del variant. ETI therapy has demonstrated safety; however, elevated aminotransferases have been observed in 10.9 % of ETI-treated patients [9].

Gilbert syndrome is a prevalent, benign genetic disorder of bilirubin glucuronidation characterized by elevated total and unconjugated bilirubin with an estimated prevalence of 2–20 % [7]. It is caused by mutations in the promotor region of the UGT1A1 gene which leads to decreased activity of the UDP glucuronosyltransferase (UGT) enzyme and subsequently elevated unconjugated and total bilirubin with normal transaminase levels. Patients are asymptomatic but can present with jaundice, scleral icterus, and abdominal pain during times of stress, illness, and fasting. Elevated bilirubin in Gilbert syndrome is benign for patients when controlled for triggers [[9], [10], [11]].

It has been reported that 59.6 % of pwCF carry the A(TA)7TAA allele - either heterozygous or homozygous – of the UGT1A1 gene. Furthermore, the UGT1A1 promoter is a lithogenic risk factor in pwCF [11] such that pwCF and gallstones were significantly more likely to carry at least one Gilbert-associated UGT1A1 allele and have higher levels of unconjugated bilirubin [10]. Another mechanism of the hyperbilirubinemia in pwCF diagnosed with Gilbert syndrome receiving ETI is the inhibition of the uptake of bilirubin transporters in the liver. Elexacaftor inhibits the uptake of bilirubin by OATP1B3 and OATP1B1 which are polypeptides and organic anion transporters expressed in the liver (OATPs) with a role in eliminating bilirubin by facilitating its uptake into the liver [12]. This may be worsened with comorbid Gilbert Syndrome [9]. These polypeptides are considered to be of particular importance for hepatic drug elimination and drug pharmacokinetics. To our knowledge, the elimination of CFTR modulators being primarily through the liver in patients with CF and Gilbert syndrome has not been described [13].

Genetic testing is the gold standard to diagnose Gilbert syndrome. Further investigations are not warranted unless there is elevation in aminotransferases. In our cases, both patients had normal aminotransferases levels and no intervention was recommended [7].

5. Conclusion

Our report describes two pediatric pwCF presenting with hyperbilirubinemia following initiation of ETI therapy. Total bilirubin levels are screened annually in pwCF and every 3 months with the initiation/change of a CFTR modulator – i.e., ETI. That being said, fractioned bilirubin is not routinely measured or recommended. Uncoupling Gilbert syndrome from CFLD may be challenging in patients with elevated transaminases, hence, the value of fractioned bilirubin measurement is heightened in these cases especially in cases of cholelithiasis. Early recognition of Gilbert syndrome may reduce the need for frequent sampling and follow up. Additionally, early diagnosis may alleviate the provider and family stress associated with side effects related to CFTR modulators and possible need to discontinue therapy. Adding the fractioned bilirubin panel to the recommended annual CF screening tests would serve as a first step to this diagnosis.

Gilbert syndrome is described with an increased risk of gallstones, which is described at a significant increased risk in pwCF where earlier identification of this added risk factor may lead to earlier diagnosis of gallstones prior to development of complications. The pharmacokinetics of CFTR modulators and their hepatic elimination in pwCF and Gilbert syndrome is an area of further investigation.

CRediT authorship contribution statement

Yara Salameh: Writing – original draft. John Lyles: Writing – review & editing. Shatha Yousef: Writing – review & editing.

Statement of informed consent

I hereby confirm that informed consent has been obtained from both patient's parents included in the case reports. Parents have been provided with comprehensive information regarding the purpose, nature, and potential use of their medical information for this report. They have given their voluntary consent.

Ethical approval statement

IRB approval was not required according to our institutional policy at Duke University, as this case report includes only two cases. IRB approval is necessary for three or more cases, as specified by our policy.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.