Adult-onset cystic fibrosis liver disease: Diagnosis and characterization of an underappreciated entity.

Cystic fibrosis (CF) liver disease (CFLD), a leading cause of death in CF, is mostly described in pediatric populations. Adult-onset CFLD lacks sufficient characterization and diagnostic tools. A cohort of CF patients without CFLD during childhood were followed for up to 38 years with serologic testing, imaging, and noninvasive fibrosis markers. Historical CFLD diagnostic criteria were compared with newly proposed CFLD criteria. Thirty-six CF patients were followed for a median of 24.5 years (interquartile range 15.6-32.9). By the last follow-up, 11 (31%) had died. With conventional criteria, 8 (22%) patients had CFLD; and by the new criteria, 17 (47%) had CFLD at a median age of 36.6 years (interquartile range 26.5-43.2). By the new criteria, those with CFLD had higher median alanine aminotransferase (42 versus 27, P = 0.005), aspartate aminotransferase (AST; 26 versus 21, P = 0.01), direct bilirubin (0.13 versus 0.1, P = 0.01), prothrombin time (14.4 versus 12.4, P = 0.002), and AST-to-platelet ratio index (0.31 versus 0.23, P = 0.003) over the last 2 years of follow-up. Subjects with a FibroScan >6.8 kPa had higher alanine aminotransferase (42 versus 28U/L, P = 0.02), AST (35 versus 25U/L, P = 0.02), AST-to-platelet ratio index (0.77 versus 0.25, P = 0.0004), and Fibrosis-4 index (2.14 versus 0.74, P = 0.0003) and lower platelet counts (205 versus 293, P = 0.02). One CFLD patient had nodular regenerative hyperplasia. Longitudinally, mean platelet counts significantly declined in the CFLD group (from 310 to 230 U/L, P = 0.0005). Deceased CFLD patients had lower platelet counts than those alive with CFLD (143 versus 258 U/L, P = 0.004) or those deceased with no CFLD (143 versus 327U/L, P = 0.006). CONCLUSION: Adult-onset CFLD may be more prevalent than previously described, which suggests a later wave of CFLD that impacts morbidity; routine liver tests, radiologic imaging, noninvasive fibrosis markers, and FibroScan can be used algorithmically to identify adult CFLD; and further evaluation in other CF cohorts should be performed for validation. (Hepatology 2017;66:591-601).

Lack of association between excretion of sorafenib in sweat and hand-foot skin reaction.

STUDY OBJECTIVE: To determine if excretion of sorafenib in sweat is associated with hand-foot skin reaction in patients receiving sorafenib. DESIGN: Prospective pilot study. SETTING: Outpatient clinic of a cancer research institution. PATIENTS: Two patients who were receiving sorafenib and developed a hand-foot skin reaction of at least grade 1 and two healthy subjects (controls). INTERVENTION: Sweat production was stimulated in both the patients with hand-foot skin reaction and the healthy subjects by means of pilocarpine iontophoresis. MEASUREMENTS AND MAIN RESULTS: Sweat samples were collected from the patients with hand-foot skin reaction and from the healthy subjects. Using liquid chromatography-tandem mass spectrometry, sorafenib concentrations were measured in the sweat samples. Sweat samples from the healthy subjects were spiked with known concentrations of sorafenib to determine the lower limit of quantification of the assay, which was determined to be 5 ng/ml. Sorafenib concentrations in the samples from the patients with hand-foot skin reaction were undetectable based on the assay's sensitivity. CONCLUSION: Our results suggest that hand-foot skin reaction in patients receiving sorafenib is not associated with excretion of sorafenib in sweat. Further studies are needed to understand the mechanism of hand-foot skin reaction, a treatment-limiting adverse effect of multikinase inhibitors.

Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome.

RATIONALE: Pulmonary nontuberculous mycobacterial (PNTM) disease is increasing, but predisposing features have been elusive. OBJECTIVES: To prospectively determine the morphotype, immunophenotype, and cystic fibrosis transmembrane conductance regulator genotype in a large cohort with PNTM. METHODS: We prospectively enrolled 63 patients with PNTM infection, each of whom had computerized tomography, echocardiogram, pulmonary function, and flow cytometry of peripheral blood. In vitro cytokine production in response to mitogen, LPS, and cytokines was performed. Anthropometric measurements were compared with National Health and Nutrition Examination Survey (NHANES) age- and ethnicity-matched female control subjects extracted from the NHANES 2001-2002 dataset. MEASUREMENTS AND MAIN RESULTS: Patients were 59.9 (+/-9.8 yr [SD]) old, and 5.4 (+/-7.9 yr) from diagnosis to enrollment. Patients were 95% female, 91% white, and 68% lifetime nonsmokers. A total of 46 were infected with Mycobacterium avium complex, M. xenopi, or M. kansasii; 17 were infected with rapidly growing mycobacteria. Female patients were significantly taller (164.7 vs. 161.0 cm; P < 0.001) and thinner (body mass index, 21.1 vs. 28.2; P < 0.001) than matched NHANES control subjects, and thinner (body mass index, 21.1 vs. 26.8; P = 0.002) than patients with disseminated nontuberculous mycobacterial infection. A total of 51% of patients had scoliosis, 11% pectus excavatum, and 9% mitral valve prolapse, all significantly more than reference populations. Stimulated cytokine production was similar to that of healthy control subjects, including the IFN-gamma/IL-12 pathway. CD4(+), CD8(+), B, and natural killer cell numbers were normal. A total of 36% of patients had mutations in the cystic fibrosis transmembrane conductance regulator gene. CONCLUSIONS: Patients with PNTM infection are taller and leaner than control subjects, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis transmembrane conductance regulator mutations, but without recognized immune defects.