Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis.

OBJECTIVES: Non-invasive fibrosis scores are widely used to identify/exclude advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). However, these scores were principally developed and validated in patients aged between 35 and 65 years of age. The objective of this study was to assess the effect of age on the performance of non-invasive fibrosis tests in NAFLD. METHODS: Patients were recruited from European specialist hepatology clinics. The cohort was divided into five age-based groups: ≤35 (n=74), 36-45 (n=96), 46-55 (n=197), 56-64 (n=191), and ≥65 years (n=76), and the performance of the aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio, fibrosis 4 (FIB-4), and NAFLD fibrosis score (NFS) for advanced fibrosis (stage F3-F4) for each group was assessed using liver biopsy as the standard. RESULTS: Six hundred and thirty-four patients were included. The diagnostic accuracy of the AST/ALT ratio was lower than NFS and FIB-4 in all the age groups. The AST/ALT ratio, NFS, and FIB-4 score performed poorly for a diagnosis of advanced fibrosis in those aged ≤35 years (area under the receiver operating characteristic curves (AUROCs 0.52, 0.52, and 0.60, respectively). For all groups >35 years, AUROCs for advanced fibrosis were similar for the NFS and FIB-4 score (range 0.77-0.84). However, the specificity for advanced fibrosis using the FIB-4 and NFS declined with age, becoming unacceptably low in those aged ≥65 years (35% for FIB-4 and 20% for NFS). New cutoffs were derived (and validated) for those aged ≥65 years, which improved specificity to 70% without adversely affecting sensitivity (FIB-4 2.0, sensitivity 77%; NFS 0.12, sensitivity 80%). CONCLUSIONS: The NFS and FIB-4 scores have similar accuracy for advanced fibrosis in patients aged >35 years. However, the specificity for advanced fibrosis is unacceptably low in patients aged ≥65 years, resulting in a high false positive rate. New thresholds for use in patients aged ≥65 years are proposed to address this issue.

Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management.

BACKGROUND AND AIMS: There remains uncertainty about the natural history of non-alcoholic fatty liver disease (NAFLD). The spectrum of NAFLD includes non-alcoholic fatty liver (NAFL; steatosis without hepatocellular injury) and steatohepatitis (NASH; steatosis with hepatocyte ballooning degeneration±fibrosis). Our aim was to assess the histological severity of NAFLD in a cohort with serial biopsy data, and determine factors predicting progression. METHODS: Patients with two liver biopsies more than a year apart were identified. Clinical and laboratory data were collected from the time of liver biopsy. RESULTS: 108 patients had serial biopsies (median interval 6.6years, range 1.3-22.6). 81 (75%) patients had NASH and 27 had NAFL. Overall, 45 (42%) patients had fibrosis progression, 43 (40%) had no change in fibrosis, while 20 (18%) had fibrosis regression. Importantly, no significant difference in the proportion exhibiting fibrosis progression was found between those with NAFL or NASH at index biopsy (37% vs. 43%, p=0.65). Progression to NASH was seen in 44% of patients with baseline NAFL. Of 10 patients with NAFL who had fibrosis progression, 3 progressed by 1 stage, 5 by 2 stages and 2 by 3 stages; all had NASH on follow-up biopsy. Of concern, 6 of 27 (22%) patients with baseline NAFL, reached stage 3 fibrosis at follow-up biopsy. Among the patients with NAFL, 80% of those having fibrosis progression were diabetic at the follow-up liver biopsy compared with 25% of non-progressors (p=0.005). CONCLUSIONS: Contrary to current dogma, this study suggests that steatosis can progress to NASH and clinically significant fibrosis.

Differential effects of exercise intensity and tolerable duration on exercise-induced diaphragm and expiratory muscle fatigue.

We investigated the effect of exercise intensity and tolerable duration on the development of exercise-induced diaphragm and expiratory muscle fatigue. Ten healthy adults (25 ± 5 yr; 2 females) cycled to intolerance on three separate occasions: 1) 5% below critical power ( 0.05). In conclusion, the magnitude of exercise-induced diaphragm fatigue was greater after longer-duration severe exercise than after shorter-duration severe and heavy exercise. By contrast, the magnitude of exercise-induced expiratory muscle fatigue was unaffected by exercise intensity and tolerable duration.NEW & NOTEWORTHY Exercise-induced respiratory muscle fatigue contributes to limiting exercise tolerance. Accordingly, better understanding the exercise conditions under which respiratory muscle fatigue occurs is warranted. Although heavy-intensity as well as short- and long-duration severe-intensity exercise performed to intolerance elicit diaphragm and expiratory muscle fatigue, we find, for the first time, that the relationship between exercise intensity, exercise duration, and the magnitude of exercise-induced fatigue is different for the diaphragm compared with the expiratory muscles.

The Effect of Preexercise Expiratory Muscle Loading on Exercise Tolerance in Healthy Men.

PURPOSE: Acute nonfatiguing inspiratory muscle loading transiently increases diaphragm excitability and global inspiratory muscle strength and may improve subsequent exercise performance. We investigated the effect of acute expiratory muscle loading on expiratory muscle function and exercise tolerance in healthy men. METHODS: Ten males cycled at 90% of peak power output to the limit of tolerance (TLIM) after 1) 2 × 30 expiratory efforts against a pressure-threshold load of 40% maximal expiratory gastric pressure (PgaMAX) (EML-EX) and 2) 2 × 30 expiratory efforts against a pressure-threshold load of 10% PgaMAX (SHAM-EX). Changes in expiratory muscle function were assessed by measuring the mouth pressure (PEMAX) and PgaMAX responses to maximal expulsive efforts and magnetically evoked (1 Hz) gastric twitch pressure (Pgatw). RESULTS: Expiratory loading at 40% of PgaMAX increased PEMAX (10% ± 5%, P = 0.001) and PgaMAX (9% ± 5%, P = 0.004). Conversely, there was no change in PEMAX (166 ± 40 vs 165 ± 35 cm H2O, P = 1.000) or PgaMAX (196 ± 38 vs 192 ± 39 cm H2O, P = 0.215) from before to after expiratory loading at 10% of PgaMAX. Exercise time was not different in EML-EX versus SHAM-EX (7.91 ± 1.96 vs 8.09 ± 1.77 min, 95% CI = -1.02 to 0.67, P = 0.651). Similarly, exercise-induced expiratory muscle fatigue was not different in EML-EX versus SHAM-EX (-28% ± 12% vs -26% ± 7% reduction in Pgatw amplitude, P = 0.280). Perceptual ratings of dyspnea and leg discomfort were not different during EML-EX versus SHAM-EX. CONCLUSION: Acute expiratory muscle loading enhances expiratory muscle function but does not improve subsequent severe-intensity exercise tolerance in healthy men.

The cardiovascular consequences of fatiguing expiratory muscle work in otherwise resting healthy humans.

In 11 healthy adults (25 ± 4 yr; 2 female, 9 male subjects), we investigated the effect of expiratory resistive loaded breathing [65% maximal expiratory mouth pressure (MEP), 15 breaths·min-1, duty cycle 0.5; ERLPm] on mean arterial pressure (MAP), leg vascular resistance (LVR), and leg blood flow ([Formula: see text]). On a separate day, a subset of five male subjects performed ERL targeting 65% of maximal expiratory gastric pressure (ERLPga). ERL-induced expiratory muscle fatigue was confirmed by a 17 ± 5% reduction in MEP (P < 0.05) and a 16 ± 12% reduction in the gastric twitch pressure response to magnetic nerve stimulation (P = 0.09) from before to after ERLPm and ERLPga, respectively. From rest to task failure in ERLPm and ERLPga, MAP increased (ERLPm = 31 ± 10 mmHg, ERLPga = 18 ± 9 mmHg, both P < 0.05), but group mean LVR and [Formula: see text] were unchanged (ERLPm: LVR = 0.78 ± 0.21 vs. 0.97 ± 0.36 mmHg·mL-1·min, [Formula: see text] = 133 ± 34 vs. 152 ± 74 mL·min-1; ERLPga: LVR = 0.70 ± 0.21 vs. 0.84 ± 0.33 mmHg·mL-1·min, [Formula: see text] = 160 ± 48 vs. 179 ± 110 mL·min-1) (all P ≥ 0.05). Interestingly, [Formula: see text] during ERLPga oscillated within each breath, increasing (∼66%) and decreasing (∼50%) relative to resting values during resisted expirations and unresisted inspirations, respectively. In conclusion, fatiguing expiratory muscle work did not affect group mean LVR or [Formula: see text] in otherwise resting humans. We speculate that any sympathetically mediated peripheral vasoconstriction was counteracted by transient mechanical effects of high intra-abdominal pressures during ERL.NEW & NOTEWORTHY Fatiguing expiratory muscle work in otherwise resting humans elicits an increase in sympathetic motor outflow; whether limb blood flow ([Formula: see text]) and leg vascular resistance (LVR) are affected remains unknown. We found that fatiguing expiratory resistive loaded breathing (ERL) did not affect group mean [Formula: see text] or LVR. However, within-breath oscillations in [Formula: see text] may reflect a sympathetically mediated vasoconstriction that was counteracted by transient increases in [Formula: see text] due to the mechanical effects of high intra-abdominal pressure during ERL.

The syringe potentiometer: a low-cost device for pneumotachograph calibration.

The purpose of this report was to 1) detail the construction of a low-cost device that provides a "reference" flow waveform for pneumotachograph (PNT) calibration, i.e., the "syringe potentiometer" (SP), and to compare the 2) accuracy and 3) practical performance of "calibration curves" obtained with the SP device to other more established methods of PNT calibration, i.e., the weighted averaging (WA) and polynomial least-squares (PolyLS) methods. Volume and flow waveforms obtained via the SP device were validated against a motion capture system and were deemed accurate surrogates of actual syringe volume and flows. The SP device was used to construct a calibration curve of a PNT by dividing the flow waveform of the SP by the analog output of the PNT amplifier. A total of 187 inspiratory and 187 expiratory strokes were collected. When the entire data set of expiratory strokes was used, the SP, WA, and PolyLS methods together demonstrated acceptable volume and flow errors as per American Thoracic Society/European Respiratory Society recommendations (less than ±3.5% and less than ±5.0% errors, respectively). The "practical" performance of each method was assessed with a nested subsampling procedure, whereby volume and flow errors were evaluated as the number of strokes was increased (in blocks of 5 strokes). To this end, the SP method demonstrated practical performance superior to that of the WA and PolyLS approaches, whereby acceptable volume and flow errors were achieved after only 5 calibration strokes; the WA and PolyLS methods required 15 and 20 strokes, respectively, to achieve the same level of volume and flow accuracy.NEW & NOTEWORTHY This report describes the construction and validation of a low-cost device for the purposes of pneumotachograph (PNT) calibration: the "syringe potentiometer" (SP). Calibration of a PNT with the SP device yielded acceptable volume and flow errors (<3.5% and 5%, respectively) across a wide range of flows (<0.5 to 15 L/s). The SP device offered superior "practical performance" over other established PNT calibration methods, whereby acceptable volume and flow errors were achieved after only five calibration strokes.