Multidisciplinary Care for Cystic Fibrosis Liver Disease: Where Does the Adult Hepatologist Fit In?

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Abbreviations

CF

cystic fibrosis

CFLD

cystic fibrosis–related liver disease

CFTR

cystic fibrosis transmembrane conductance regulator

FEV₁

forced expiratory volume in 1 second

FVC

forced vital capacity

UDCA

ursodeoxycholic acid

Cystic fibrosis (CF) is the most common inherited genetic disorder in Caucasians and is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF is a multisystem disease, and an estimated 9.5% of patients with CF have hepatobiliary complications. Improved care for the pulmonary manifestations of the disease has improved life expectancy dramatically from a median predicted survival age of 30 years in 1986 to 46.2 years in 2017.1 In light of this increasing life span, cystic fibrosis–related liver disease (CFLD) is increasingly recognized and is now the third most common cause of mortality in this patient population. Even though CFLD most commonly presents in childhood and progresses into adulthood, adult‐onset CFLD has recently been described.2 Multidisciplinary team–based care for patients with CF at dedicated CF centers is considered standard of care.3 CF centers are directed by a physician with considerable CF experience supported by dedicated CF nurses, psychologists, social workers, pharmacists, and dieticians. It is also recommended that CF centers have close links to other consultants, including those specializing in gastroenterology and hepatology. Taking this one step further, European CF guidelines recommend annual screening and evaluation for CFLD by a gastroenterologist.4 In the United States, the Cystic Fibrosis Foundation has recognized the growing demand for physicians focusing on the gastrointestinal and hepatobiliary manifestations of the disease, and has created the Developing Innovative Gastroenterology Specialty Training program to encourage specialty training and research in the field.5 Although a number of CF centers include a gastroenterologist and/or hepatologist among their multidisciplinary staff, data assessing the effects of a combined pulmonology/hepatology clinic in the care of adult patients with CF are scarce. In this article, we provide a brief overview of CFLD, propose a role for the adult hepatologist with a focus on CFLD, and describe our institutional experience with multidisciplinary care through a combined pulmonology/hepatology clinic for adult patients with CF.

CF Liver Disease

Definition and spectrum of disease

Hepatobiliary involvement in patients with CF is phenotypically heterogenous. Several CFTR‐related hepatobiliary manifestations have been described, including neonatal cholestasis, focal biliary cirrhosis, multilobular biliary cirrhosis, portal hypertension, microgallbladder, and cholelithiasis. The most advanced stage of CFLD, biliary cirrhosis with portal hypertension, has an overall prevalence rate of 3% and most often presents in the first 10 years of life.1, 6 Hepatic steatosis and drug‐related hepatotoxicity are also commonly encountered but have not been directly attributed to the underlying CFTR defect7, 8 (Table 1). Classically, many of the hepatobiliary manifestations of CF have been thought to be caused by small bile duct obstruction, leading to focal biliary cirrhosis and subsequent cirrhosis with portal hypertension. More recently, however, noncirrhotic portal hypertension with focal nodular hyperplasia has also been described in adults, suggesting alternative underlying pathophysiological mechanisms.9

Table 1.

Hepatobiliary Manifestations in CF

Type of Lesion	Clinical Manifestation	Frequency (%)
Manifestations related to CFTR defect	Focal biliary cirrhosis	20‐30
	Microgallbladder	30
	Cholelithiasis	15
	Multilobular biliary cirrhosis	10
	Portal hypertension	2‐5
	Neonatal cholestasis	<10
Manifestations of unknown etiology	Hepatic steatosis	25‐60
	Drug hepatotoxicity	undefined

Adapted with permission from Journal of Cystic Fibrosis.4 Copyright 2011, European Cystic Fibrosis Society and Elsevier.

The wide spectrum of hepatobiliary involvement in CF has created an inherent difficulty in achieving a consensus definition of CFLD. The most widely adopted definition of CFLD was described by Debray et al.4 and suggests the diagnosis of CFLD be considered if other causes of liver disease are excluded and two of the following variables are present: abnormal physical examination (hepatomegaly or splenomegaly confirmed by ultrasound), abnormal liver function tests on three occasions (alanine aminotransferase, aspartate aminotransferase, gamma‐glutamyltransferase), or abnormal findings on liver ultrasonography (increased or heterogenous echogenicity, irregular margins, signs of portal hypertension). The role of liver biopsy is more limited compared with other chronic liver diseases because of the nonuniform nature of liver involvement in CFLD, increasing the risk for sampling errors.10

Epidemiology

CFLD most frequently presents in childhood and progresses into adulthood; a recent large French cohort study involving 3328 patients with CF found the cumulative incidence rate of CFLD increases by 1% yearly, reaching 32.2% by age 25 years, with the cumulative incidence rate of severe CFLD reaching 10% by age 30 years.11 Adult‐onset CFLD has also recently been described; a natural history study by Koh et al.2 identified a second spike in CFLD incidence around a median age of 35 years. Remarkably, none of the patients had evidence of liver disease at the time of enrollment during childhood.

Management

The natural bile acid, ursodeoxycholic acid (UDCA), is the only medical therapy currently in use for CFLD. Although UDCA has been found to result in short‐term improvements in liver chemistries and is thought to prevent progression of the disease,12 no long‐term trials comparing UDCA with placebo have been conducted, and a Cochrane systematic review found insufficient evidence to justify routine use of UDCA in patients with CF.13 However, given its favorable safety profile, consensus guidelines recommend initiation of UDCA as soon as the diagnosis of CFLD is made with the goal of delaying the progression of disease.4 Newer medications targeting dysfunctional CFTR proteins such as ivacaftor and lumacaftor have been found to significantly improve the pulmonary manifestations of the disease but have not been primarily investigated for their effects on CFLD. With progression of CFLD and development of cirrhosis, management focuses on preventing the complications of cirrhosis and portal hypertension. Referral to a transplant center is indicated for end‐stage disease; however, indications for liver transplantation in CFLD differ from those for other chronic liver diseases and incorporate extrahepatic variables including the rapidity of deterioration of nutritional and pulmonary status (Table 2).4

Table 2.

Indications for Liver Transplantation in CFLD

Progressive hepatic dysfunction as indicated by: Decreasing albumin <3 g/dL Increasing coagulopathy not corrected by vitamin K

Development of ascites and jaundice

Intractable variceal bleeding

Hepatopulmonary and portopulmonary syndromes

Severe malnutrition, unresponsive to intensive nutritional support

Deteriorating quality of life related to liver disease

Deteriorating pulmonary function (FEV1/FVC < 50%)

Adapted with permission from Journal of Cystic Fibrosis.4 Copyright 2011, European Cystic Fibrosis Society and Elsevier.

Expanding Role of the Adult Hepatologist

With the increasing recognition of CFLD as a cause of significant morbidity and mortality in patients with CF, adult hepatologists with a CFLD focus are expected to play a growing and multifaceted role within the context of the multidisciplinary adult CF clinic. First, they represent the initial point of contact for patients with CFLD in the crucial transition from pediatric to adult CF care, where the adult hepatologist has an essential role in facilitating the most appropriate and smoothest transition of care. Although the most optimal pediatric‐to‐adult transition pathway for patients with CFLD remains undetermined, there is increasing awareness and calls for research in this particular area.14 Second, adult hepatologists play an important role in educating patients with CF about the hepatobiliary aspects of the disease. As many as 30% of adult patients with CF do not recognize that liver involvement can occur within the context of their disease.15 Third, adult hepatologists with a CFLD focus are best equipped to navigate and implement best practice guidelines in this rapidly evolving field. For example, the use of vibration‐controlled transient elastography and noninvasive biomarkers has recently been proposed to allow earlier identification and treatment of CFLD in adults, yet optimal cutoffs for patients with CF have yet to be established.2 Fourth, hepatologists are often the first to recognize the need for referral to a liver transplant center. Hepatologists with a CFLD focus practicing at liver transplant centers also play a crucial role in facilitating discussions at transplant medical review boards, where other members may be less familiar with the implications of CFLD within the larger context of pulmonary manifestations of the disease.4 Finally, the adult hepatologist is well positioned to apply the general gastroenterology aspects of his or her practice to identify and manage other hepatobiliary and gastrointestinal manifestations of CF (such as pancreatic insufficiency, small‐bowel bacterial overgrowth, gastroesophageal reflux disease, higher incidence of gastrointestinal cancers, and others) and initiate referral to other subspecialists when indicated.

Our Institutional Experience

In 2016, we initiated a combined hepatology/pulmonology multidisciplinary clinic at the University of Florida Adult Cystic Fibrosis Center. At this clinic, adult patients with CF are evaluated simultaneously by a CF pulmonologist (C.T.‐A. or J.L.) and a transplant hepatologist with a CFLD focus (G.M.) at their annual clinic visit. This is in addition to the standard care provided by other members of the multidisciplinary adult CF team including pharmacy, nutrition, social work, and psychology. Clinic workflow for new patients includes: (1) preclinic multidisciplinary case review jointly by the hepatologist, pulmonologist, and other members of the care team; (2) patient evaluation separately by both the pulmonologist and hepatologist within the same clinic session; and (3) implementation of a final coordinated plan of care. For patients presenting in follow‐up, the plan of care is discussed in a preclinic multidisciplinary setting, and based on the most appropriate plan of care, the patient is seen by either the hepatologist, pulmonologist, or both.

In a review of care prior to initiation of the combined clinic, we found that about 81% of our CF patient population had known gastrointestinal and hepatobiliary pathology, yet only 39% of patients with advanced gastrointestinal and hepatobiliary issues were referred to a gastroenterologist/hepatologist in the year prior to their index clinic visit. Those referred had a protracted wait time of many weeks between referral and their gastroenterology/hepatology appointment. At 1 year after initiation of the combined clinic, we were able to evaluate all patients with known underlying gastrointestinal/hepatobiliary disease and screen those who do not have established disease. Assessment by the CFLD‐focused hepatologist led to a substantial number of patients requiring additional diagnostic studies and workup that led to a change in management of underlying hepatobiliary disease. Notably, an additional 10% of evaluated patients were diagnosed with CFLD that was previously unrecognized. Following initiation of the clinic, wait time for assessment by a gastroenterologist/hepatologist when indicated decreased significantly. Patients enrolled in the combined clinic also demonstrated increased compliance with a notable decrease in the number of missed appointments compared with the year prior to initiation of the combined clinic. Finally, in our annual patient engagement survey, 96% of those responding to the survey indicated that they found the ability to see both a hepatologist and pulmonologist at the same visit helpful.

Conclusions and Future Directions

The improving life expectancy of patients with CF has led to a significant increase in the number of adults presenting with and suffering from complications of CFLD. The adult hepatologist is expected to play an increasingly important role in the care of adults with CF both within and outside the context of multidisciplinary CF centers. Our institutional experience with a combined pulmonology/hepatology adult CF clinic was positive and well received by our adult patients with CF. Our experience may serve as a positive example for other centers implementing adult hepatologists into multidisciplinary CF clinics.