The spectrum of hepatobiliary disorders in cystic fibrosis (CF) includes specific alterations from the underlying genetic defect and lesions of iatrogenic origin or that reflect the effects of a disease process occurring outside the liver (1). In general, CF-related liver disease is presently classified among genetic cholangiopathies and results from lack or dysfunction of the cystic fibrosis transmembrane regulator (CFTR) at the apical membrane of bile duct cells (1). Although hepatic steatosis is a common liver complication in CF, it does necessarily progress to fibrotic liver disease (2), which is the accepted consensus of the majority of experts caring for patients. With increasing life expectancy, liver complications of CF are being recognized more frequently as a result of an older-age distribution (3). Liver disease has been found to be an independent risk factor for mortality in CF (4).
There have been significant advancements in the treatment of CF, which has assisted in extending the life expectancy into adulthood. One innovation was the development of ivacaftor therapy, which corrects the gating defect of the CFTR channel (5). The genetic mutation with the most research completed using ivacaftor is G551D. We present a case of an adolescent patient with CF who had significant improvement in hepatic steatosis with ivacaftor.
A 17-year-old girl with CF (ΔF508/G551D genotype) had 2 previous liver biopsies with mild fatty metamorphosis of the parenchyma in 1997 with progression to macrovesicular steatosis and mild portal inflammation and fibrosis in 2006. Noncontrast computed tomography (CT) of the abdomen before the biopsy in 2006 demonstrated an abnormal appearance of the hepatic parenchyma with uniformly diminished radiodensity consistent with steatosis with an average radiodensity of the liver measuring only 14 Hounsfield units (HU), with reference splenic radiodensity measuring 50 HU (Fig. 1A). Moreover, alanine aminotransferase and aspartate aminotransferase levels were 81 U/L (normal <40) and 59 U/L (normal 15–50), respectively. Subsequently, ursodiol was started with alanine aminotransferase and aspartate aminotransferase consistently <30 U/L thereafter.
She started ivacaftor therapy in 2010 and 2 years later a noncontrast CT of the abdomen performed because of acute abdominal pain. This showed normal appearance of the hepatic parenchyma without the evidence of steatosis with an average radiodensity of the liver measuring 51 HU with reference splenic radiodensity measuring 48 HU (Fig. 1B).
An important indicator of response to ivacaftor is the sweat chloride level, and this patient had a significant reduction from 124 to 24 mmol/L. Pulmonary function also improved: forced vital capacity 3.24 L (95% predicted) to 3.49 L (100% predicted) and forced expiratory volume in 1 second 2.69 L (89% predicted) to 2.91 L (94% predicted). Her overall nutritional status improved as well based on an increase in body mass index from 21.4 to 22.4 kg/m2. Although fat-soluble vitamin levels were within the normal range before ivacaftor therapy, her vitamin A, E, and D-25-OH levels increased to higher normal levels on the treatment. There was no significant change in her hepatic function testing.
In conclusion, significant improvement in hepatic steatosis in an adolescent patient with CF occurred with ivacaftor therapy based on CT imaging. A repeat biopsy is not indicated, so we cannot definitely say that the histopathology alterations have improved, but the radiographic images clearly show positive changes. We speculate that a potential mechanism of action leading to this the clinical improvement is improved CFTR function, resulting in enhanced fat metabolism and less fat accumulation in the liver. Improved body mass index and higher fat-soluble vitamin levels would support this theory as well. Based on our experiences with this patient, the clinical benefits of ivacaftor in CF continue to evolve. To enhance our understanding of the benefits of this drug, future research should include alterations in liver function and parenchymal changes because of its important role in the health of patients with CF.
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