Transient elastographic evaluation in adult subjects without overt liver disease: influence of alanine aminotransferase levels

Background and Aim: Studies on normal values of liver stiffness (LS) in subjects at “low risk” for liver disease are scant. The aim of the present study was to assess liver stiffness values in the subjects without overt liver disease with normal alanine aminotransferases (ALT) and to determine potential factors, which may influence these values with special reference to newly suggested updated upper limits of normal for ALT. Methods: Liver stiffness measurements were performed in 445 subjects without overt liver disease (mean age, 41.1 ± 13.6; male, 73.5%) and normal liver enzymes. Results: Mean LS value was 5.10 ± 1.19 kPa. LS values were higher in men than in women (5.18 ± 1.67 vs 4.86 ± 1.24 kPa, respectively, P = 0.008); in subjects with higher body mass index (BMI) category (Normal, overweight and obese subjects; 4.10 ± 0.75, 5.08 ± 0.66, and 6.05 ± 1.28 kPa, respectively; P < 0.001); in subjects with metabolic syndrome than in those without (5.63 ± 1.37 vs 5.01 ± 1.14 kPa, P = 0.001); and in subjects with ALT levels more than updated limits of normal compared to subjects with ALT levels less than updated limits of normal (5.68 ± 1.21 vs 4.77 ± 1.05 kPa, P < 0.001). On multiple linear regression, BMI and ALT was found to be significant predictor of LS. Conclusions: Liver stiffness values in subjects without overt liver disease with normal ALT are influenced by BMI and ALT levels. Subjects with ALT levels less than updated limits of normal have lower LS values as compared to those with higher levels.     

Effects of nonalcoholic fatty liver disease on the development of metabolic disorders

Background and Aim: Nonalcoholic fatty liver disease (NAFLD) is considered to be the liver component of metabolic syndrome. However, the impact of NAFLD on metabolic syndrome is unclear. The aim of this study was to explore the influence of NAFLD on the development of metabolic disorders. Methods: Patients with NAFLD and an age, sex, and occupation‐matched control group were recruited from employees of Bao‐Steel Group (Shanghai, China) who had received medical check‐ups biennially between 1995 and 2002. Anthropometric and laboratory data, and incidence of metabolic disorders were assessed at baseline and at follow‐up of at least 4 years. SPSS 11.5 was used for statistical analysis. Results: The study consisted of 358 patients (326 men and 32 women) and 788 matched controls (711 men and 77 women) with a similar mean age of 39.0 years and median follow‐up of 6 years. At the end of follow‐up, incidence of obesity (47.6% vs 19.5%), hypertension (69.6% vs 16.3%), hypertriglyceridemia (39.1% vs 16.3%), hypercholesterolemia (24.5% vs 17.3%), impaired fasting glucose (IFG) (25.1% vs 11.6%), diabetes mellitus (20.3% vs 5.2%) and multiple metabolic disorders (MMD) (56.3% vs 16.3%) were significantly higher in the fatty liver group than the control group. Interestingly, the mean alanine aminotransferase (ALT) level in patients with fatty liver significantly decreased at follow‐up compared with baseline (28.56 ± 18.86 vs 31.51 ± 18.34 U/L, P < 0.05). To separate the effects of obesity from fatty liver, the subjects were re‐classified according to the presence of obesity and fatty liver at baseline. The incidence of hypertension (61.1% vs 41.3%), hypertriglyceridemia (38.1% vs 15.0%), hypercholesterolemia (29.9% vs 16.6%), IFG (21.3% vs 10.0%) and diabetes (11.1% vs 4.3%) were significantly higher in the fatty liver group without obesity (n = 84) than in the group with without fatty liver or obesity (n = 614). In addition, the incidence of hypertension (72.9% vs 57.4%), hypertriglyceridemia (39.4% vs 22.7%) and diabetes (23.2% vs 8.4%) was higher in the group with fatty liver and obesity (n = 274) than in the group with obesity alone (n = 174). Conclusions: The presence of NAFLD might predict the development of metabolic disorders due to insulin resistance, rather than obesity itself. ALT levels decreased over time in patients with fatty liver.     

What are ‘true normal’ liver stiffness values using FibroScan®?: a prospective study in healthy living liver and kidney donors in South Korea

Aims: To identify the normal range of liver stiffness (LS) values by recruiting healthy living liver and kidney donors in South Korea. Methods: Liver stiffness measurement (LSM) was performed in 69 healthy living liver and kidney donors who were admitted for transplantation. None of the subjects suffered from diabetes mellitus, hypertension, hepatitis B virus infection, hepatitis C virus infection, heart dysfunction, liver dysfunction or metabolic syndrome. Results: LSM failure rate was 2.7%. Among 12 liver donors (17.4%) with available liver histology, eight showed normal liver histology and four showed liver steatosis of <5% of the hepatocytes. The mean age of our study population was 38.9 ± 11.9 years (35 men and 34 women), with a mean LS value of 4.6 ± 0.5 kPa (range 3.3–5.6 kPa). LS values were not significantly different between men (4.6 ± 0.6 kPa) and women (4.5 ± 0.5 kPa, P=0.636), nor were they significantly different according to age (P=0.851). Using the fifth and 95th percentiles, we determined the normal range of LS values to be 3.9–5.3 kPa. Conclusions: We identified the normal range of LS values and found that LS values were not significantly influenced by age and gender.     

Prophylaxis of hepatic encephalopathy in acute variceal bleed: a randomized controlled trial of lactulose versus no lactulose

Background and Aims: Acute variceal bleed (AVB) is an important precipitating factor for development of hepatic encephalopathy (HE). However, there is paucity of data on the role of lactulose for prevention of HE after AVB. We evaluated the role of lactulose for prophylaxis of HE after AVB. Methods: Consecutive patients of cirrhosis with AVB enrolled. Patients included if >18 years old and had no HE at the time of presentation. Patients were randomized to receive lactulose (Group‐L) or no lactulose (Group‐P) along with standard treatment of AVB as per Baveno 4 guidelines. Primary endpoint was development of overt HE as per West Haven criteria within 120 h of randomization. Results: Seventy patients were randomized into group‐L (Gp‐L, n = 35) and group‐P (Gp‐P, n = 35). There was no significant difference in baseline characteristics between the two groups. Characteristics of variceal bleed were also similar (Gp‐L vs Gp‐P [mean arterial pressure 81.0 ± 10.5 vs 79.5 ± 9.9 mmHg], Hb [8.4 ± 1.5 vs 9.3 ± 2.3 g/dL], blood transfusion requirement [1.6 ± 1.1 vs 1.3 ± 0.9 units], time to endoscopy [6.3 ± 2.8 vs 7.0 ± 3.1 h], and esophageal source of bleed [92% vs 88%]). Nineteen (27%) patients developed HE; five patients (14%) in Gp‐L and 14 patients (40%) in Gp‐P, P = 0.03. The median grade of HE was 2 (range 2–4) and median time interval of development of HE after randomization was 2 days (range 1–4). Nine patients (13%) died; three (8.5%) patients in Gp‐L and six (17%) patients in Gp‐P, P = 0.23. Patients who developed HE had significantly higher baseline Child‐Turcotte‐Pugh score score (10.2 ± 1.2 vs 9.4 ± 1.4 P = 0.04), model for end stage liver disease score (18.2 ± 3.9 vs 15.4 ± 4.5 P = 0.02), arterial ammonia level (112.2 ± 22.7 vs 94.8 ± 17.6 umol/L, P = 0.001), baseline total leukocyte count (10 505.2 ± 8911.9 vs 5784.3 ± 3387.0 P = 0.002), total bilirubin (3.4 ± 1.3 vs 2.1 ± 1.8 mg%, P = 0.008) as compared to patients who did not develop HE. On multivariate analysis only baseline arterial ammonia, blood requirement during hospital stay and lactulose therapy were predictors of development of HE. Conclusions: Lactulose is effective in prevention of HE in patients with cirrhosis and acute variceal bleed.     

Significant changes in liver stiffness measurements in patients with chronic hepatitis B: 3-year follow-up study

Summary. For patients with chronic hepatitis B (CHB) infection, changes in liver stiffness measurement (LSM) over time are not known. We examined changes longitudinally in a cohort of patients. Four hundred and twenty‐six patients with CHB underwent transient elastography. Patients were followed regularly, and repeat elastography was performed at 3 years. Hepatitis serology, viral load and routine liver biochemistry were monitored. Of the 426 patients, 38 (9%) were hepatitis B e‐antigen (HBeAg)‐positive, 293 (69%) were HBeAg‐negative and 95 (22%) were patients with prior hepatitis B surface antigen (HBsAg) seroclearance. A total of 110 patients received oral antiviral therapy. There was a significant decline of LSMs at the follow‐up measurement compared to baseline (6.1 vs 7.8 kPa respectively, P = 0.002) in treated patients who had elevated alanine aminotransferase (ALT) at baseline and subsequent normalization after 3 years (normal ALT limit being 30 U/L for males and 19 U/L for females). In nontreated patients, only the patients with persistently normal ALT at both time points had significantly lower LSMs at the follow‐up measurement compared to baseline: 4.9 vs 5.3 kPa, respectively, in patients who remained positive for HBsAg (P = 0.005) and 5.1 vs 5.4 kPa, respectively, in patients who had HBsAg seroclearance (P = 0.026). In patients who remained positive for HBsAg, independent factors associated with a significant decline in LSM of ≥1 kPa included antiviral therapy (P = 0.011) and the ALT levels at the follow‐up time point (P = 0.024). Thus, in patients with CHB, a significant decline in LSM after 3 years was observed in treated patients with ALT normalization and in untreated patients who had persistently normal ALT. Antiviral therapy and follow‐up ALT levels were independent significant factors associated with a decline in LSM.     

Normal liver stiffness: a study in living donors with normal liver histology

AIM: To define the normal range of liver stiffness(LS) values using transient elastography in living-related liver transplantation candidate donors with normal liver histology. METHODS: LS was measured using Fibroscan in 50(16 women, 34 men) healthy potential donors(mean age 28.4 ± 5.9 years) who were being evaluated for liver donation for their relatives at the National Liver Institute, Menoufeya University, Egypt. All potential donors had normal liver tests and were negative for hepatitis B or C virus infection. Abdominal ultrasounds showed normal findings. None of the subjects had diabetes, hypertension, renal impairment, heart disease, or body mass index 30 kg/m2. All subjects had normal liver histology upon liver biopsy. They all donated the right lobe of their liver with successful outcomes.RESULTS: The mean LS was 4.3 ± 1.2 k Pa(range: 1.8-7.1 k Pa). The 5th and 95 th percentiles of normal LS were 2.6 k Pa and 6.8 k Pa, respectively, with a median of 4 k Pa; the interquartile range was 0.6 ± 0.4. LS measurements were not significantly different between men and women(4.4 ± 1.1 k Pa vs 3.9 ± 1.3 k Pa) and did not correlate with age. However, stiffness values were significantly lower in subjects with a body mass index 26 kg/m2 compared to those with an index ≥ 26 kg/m2(4.0 ± 1.1 k Pa vs 4.6 ± 1.2 k Pa; P 0.05). There were no differences in hospital stay or postoperative bilirubin, albumin,alanine and aspartate transaminases, or creatinine levels(at discharge) between donors with livers stiffness ≤ 4 k Pa and those with stiffness 4 k Pa. CONCLUSION: Healthy donors with normal liver histology have a median LS of 4 k Pa. Stiffness values are elevated relative to increase in body mass index.     

Normal liver elasticity values using acoustic radiation force impulse imaging: a prospective study in healthy living liver and kidney donors

Background and Aim: Although several studies have investigated the normal range of liver elasticity using acoustic radiation force impulse (ARFI) elastography in healthy volunteers, they could not strictly exclude the morphological and functional liver abnormalities. The aim of this study was to identify the normal range of ARFI velocity by recruiting healthy living liver and kidney donors who passed the full laboratory tests and imaging studies. Methods: The study prospectively enrolled 108 healthy living liver (n = 42) and kidney donors (n = 66) who were admitted for transplantation between July 2010 to April 2011. None of the subjects had abnormal liver function test and imaging findings including conventional ultrasonography, computed tomography or magnetic resonance imaging. Results: The mean age of the study population (58 men and 50 women) was 35.5 years, and the mean ARFI velocity was 1.07 ± 0.11 m/s (range: 0.79–1.27). ARFI velocity was not significantly different between subjects with body mass index (BMI) < 23.5 kg/m² and those with BMI ≥ 23.5 kg/m² (1.05 ± 0.12 m/s vs 1.07 ± 0.10 m/s, P = 0.518), nor was it significantly different according to age (P = 0.067) and gender (1.08 ± 0.12 m/s for men vs 1.05 ± 0.11 m/s for women, P = 0.085). Using the 5^th and 95^th percentiles, we determined the normal range and mean of ARFI velocity to be 0.85–1.25 m/s and 1.07 ± 0.11 m/s. Conclusions: We identified the normal range of ARFI velocity as 0.85–1.25 m/s and found that it was not significantly influenced by BMI, gender, and age.     

Coinfection with hepatitis C virus,oxidative stress and antioxidant status in HIV‐positive drug users in Miami*

Background

The pathogenesis of HIV/hepatitis C virus (HCV) coinfection is poorly understood. We examined markers of oxidative stress, plasma antioxidants and liver disease in HIV/HCV‐coinfected and HIV‐monoinfected adults.

Methods

Demographics, medical history, and proof of infection with HIV, hepatitis A virus (HAV), hepatitis B virus (HBV) and HCV were obtained. HIV viral load, CD4 cell count, complete blood count (CBC), complete metabolic panel, lipid profile, and plasma concentrations of zinc, selenium, and vitamins A and E were determined. Malondialdehyde (MDA) and glutathione peroxidase concentrations were obtained as measures of oxidative stress. Aminotransferase to platelet ratio index (APRI) and fibrosis index (FIB‐4) markers were calculated.

Results

Significant differences were found between HIV/HCV‐coinfected and HIV‐monoinfected participants in levels of alanine aminotransferase (ALT) (mean±standard deviation: 51.4±50.6 vs. 31.9±43.1 U/L, respectively; P=0.014), aspartate aminotransferase (AST) (56.2±40.9 vs. 34.4±30.2 U/L; P<0.001), APRI (0.52±0.37 vs. 0.255±0.145; P=0.0001), FIB‐4 (1.64±.0.91 vs. 1.03±0.11; P=0.0015) and plasma albumin (3.74±0.65 vs. 3.94±0.52 g/dL; P=0.038). There were no significant differences in CD4 cell count, HIV viral load or antiretroviral therapy (ART) between groups. Mean MDA was significantly higher (1.897±0.835 vs. 1.344± 0.223 nmol/mL, respectively; P=0.006) and plasma antioxidant concentrations were significantly lower [vitamin A, 39.5 ± 14.1 vs. 52.4±16.2 μg/dL, respectively (P=0.0004); vitamin E, 8.29±2.1 vs. 9.89±4.5 μg/mL (P=0.043); zinc, 0.61±0.14 vs. 0.67±0.15 mg/L (P=0.016)] in the HIV/HCV‐coinfected participants than in the HIV‐monoinfected participants, and these differences remained significant after adjusting for age, gender, CD4 cell count, HIV viral load, injecting drug use and race. There were no significant differences in glutathione peroxidase concentration, selenium concentration, body mass index (BMI), alcohol use or tobacco use between groups. Glutathione peroxidase concentration significantly increased as liver disease advanced, as measured by APRI (β=0.00118; P=0.0082) and FIB‐4 (β=0.0029; P=0.0177). Vitamin A concentration significantly decreased (β=?0.00581; P=0.0417) as APRI increased.

Conclusion

HIV/HCV coinfection is associated with increased oxidative stress and decreased plasma antioxidant concentrations compared with HIV monoinfection. Research is needed to determine whether antioxidant supplementation delays liver disease in HIV/HCV coinfection.

     

Discriminant value of serum HBV DNA levels as predictors of liver fibrosis in chronic hepatitis B

Summary. Current guidelines recommend antiviral therapy in chronic hepatitis B (HBV) patients with significant histological disease. We aimed to compare histological fibrosis (METAVIR, ≥F2) in patients with HBV DNA ≥20 000 IU/mL vs≥2000 IU/mL and identify predictors of fibrosis. We performed prospective liver biopsies on 203 HBeAg‐negative patients in four groups: Group I (n = 55): HBV DNA ≥20 000 IU/mL and persistently elevated alanine aminotransferase (ALT) levels (PEALT; >40 U/L); Group II (n = 34): HBV DNA ≥20 000 IU/mL and persistently normal ALT (PNALT); Group III (n = 40): HBV DNA <20 000 IU/mL and PEALT; and Group IV (n = 74): HBV DNA <20 000 IU/mL, and PNALT. We reanalysed all groups in relation to updated cut‐off for treatable viremia (2000 IU/mL). Genotype D was detected in 86% of patients. Hepatic fibrosis ≥F2 was detected in 72.7%, 52.9%, 57.5% and 18.9% in Groups I–IV, respectively (P < 0.0001). Except in Group II with a trend for lower ≥F2 fibrosis (P = 0.067), there was no significant difference by using HBV DNA cut‐off 20 000 vs 2000 IU/mL. Multivariate logistic regression analysis identified study Group IV (OR, 0.0276; CI: 0.088–0.868; P = 0.0276) and milder (A0–1) necroinflammatory grade (OR, 0.135; CI: 0.063–0.287; P < 0.0001) as independent predictors of ≥F2 fibrosis. The specificity, positive and negative predictive values for PEALT in detection of ≥F2 fibrosis for viremia ≥2000 IU/mL (80%, 69% and 65%, respectively) or ≥20 000 IU/mL (86%, 73% and 63%, respectively) were similar, with a marginal gain in sensitivity (51%vs 42%, respectively). Significant fibrosis is prevalent in a large proportion of HBeAg‐negative patients with high viremia and persistently normal ALT. Lower HBV DNA cut‐offs could be adopted with marginal gains in fibrosis detection and without loss of diagnostic accuracy.     

Sex differences in essential hypertension

Abstract. A group of 41-year-old hypertensive men (n = 35, blood pressure (BP) 149.9 ± 2.1/ 98.9 ± 1.1 mmHg, mean ± SEM) who had never received treatment for their condition were compared with hypertensive women of the same age (n = 18, BP 155.9 ± 4.3/ 98.1 ± 1.6 mmHg) with comparable body mass index (BMI. 25.9 ± 0.5 vs. 24.9 ± 4.5 kg m^?2) who, also, had never received treatment. The lipid profile was more atherogenic in the men, with lower HDL cholesterol (1.21 ± 0.04 vs. 1.38 ± 0.06 mmol l^?1 P = 0.04), higher total cholesterol (6.04 ± 0.14 vs. 5.54 ± 0.18 mmol l^?1. P = 0.04) and triglycerides (1.80 ± 0.16 vs. 0.96 ± 0.10 mmol l^?1, P < 0.001). The hypertensive men had higher haemoglobin (P < 0.001) and haematocrit. Plasma catecholamines were inversely related to BMI in the women only (r = ?0.52, P < 0.05 for both noradrenaline and adrenaline). Women with BMI above 25 kg m^?2 had significantly lower arterial plasma adrenaline and noradrenaline than those with BMI below 25 kg m^?2 (28 ± 5 vs. 78 ± 16 pg ml^?1, P < 0.01 and 101 ± 17 vs. 206 ± 33 pg ml^?1, P < 0.01 respectively). A negative curvelinear relationship appeared between arterial adrenaline and insulin (r = 0.49, P= 0.05). These results suggest a male propensity for athero-thrombogenic risk factors in otherwise comparable hypertensive subjects. A close relationship between metabolic risk factors within the normal range seems to exist even in hypertensive women. The decreased sympathetic activity at rest in the obese hypertensive women indicates different pathophysiological mechanism for hypertension in lean and obese. Decreased sympathetic activity and thus reduced energy expenditure, promotes a risk for weight gain, and could explain the inverse relationship between insulin and adrenaline.     

Human RBP4 adipose tissue expression is gender specific and influenced by leptin

Objective The role of retinol‐binding protein‐4 (RBP4) in human insulin resistance remains controversial, which may in part be explained by a gender‐specific secretion of RBP4 in adipose tissue (AT). The aim of the study was to determine gender‐specific depot expression of RBP4 and to identify metabolic parameters and cytokines/adipokines associated with RBP4. Research Design and Methods The study is an ex ‐ vivo prospective analysis of paired AT‐samples from 22 men and 26 women of similar age [men: 43·4 ± 13 (mean ± SD)years, women: 44·1 ± 12 years], BMI (men: 41·9 ± 18kg/m², women: 38·4 ± 11kg/m²) and homeostasis model assessment of insulin resistance taken during elective surgery and ex‐vivo culture using visceral‐AT (VAT)‐explants (n = 10). Plasma RBP4 and cytokines were measured by ELISA and mRNA expression in AT by real‐time PCR. VAT‐explants were cultured with recombinant leptin and insulin and RBP4 determined by western blot analyses. Results Overall subcutaneous AT (SCAT)‐RBP4 mRNA expression was higher than VAT‐expression [3·1 ± 0·26 signal units (SU; mean ± SE) vs 1·79 ± 0·18 SU, n = 48, P < 0·0001], but neither correlated with circulating RBP4. SCAT‐RBP4 expression was higher in women and correlated with BMI (r = ?0·5, P = 0·009) and fat mass (r = ?0·5, P = 0·002). VAT‐RBP4 correlated positively with GLUT‐4 expression and adiponectin in men only (r = 0·54, P = 0·03 and r = 0·64, P < 0·002, respectively) when correcting for age and fat mass. Multiple regression determined leptin AT‐expression as a positive predictor of AT‐RBP4 in women (SCAT: β = 0·50, P = 0·002; VAT: β = 0·58, P = 0·003) and adiponectin for VAT‐RBP4 in men (β = 0·69; P = 0·001). AT‐RBP4 mRNA expression showed no relation with insulin resistance. Leptin stimulated RBP‐4 secretion ex‐vivo, whilst insulin did not affect RBP4. Conclusion AT‐derived RBP4‐mRNA expression is gender specific and regulated by leptin. Circulating RBP4 levels appear to be independent of AT‐RBP4 secretion.     

Liver fibrosis in patients with chronic hepatitis C and persistently normal liver enzymes: influence of HIV infection

Summary. Liver fibrosis progress slowly in patients with chronic hepatitis C and persistently normal alanine aminotransferase (PNALT) compared to subjects with elevated aminotransferases. Differences in liver fibrosis according to human immunodeficiency virus (HIV) status in this population have not been examined. All patients with serum hepatitis C virus (HCV)‐RNA and PNALT who underwent liver fibrosis assessment using elastometry since 2004 at three different European hospitals were evaluated. Patients previously treated with interferon were excluded. PNALT was defined as ALT below the upper limit of normality in at least three consecutive determinations within the last 12 months. Fibrosis stage was defined as mild (Metavir F0–F1) if stiffness ≤7.1 kPa; moderate (F2) if 7.2–9.4 kPa; severe (F3) if 9.5–14 kPa, and cirrhosis (F4) if >14 kPa. A total of 449 HIV‐negative and 133 HIV‐positive patients were evaluated. HIV‐negative patients were older (mean age 51.8 vs 43.5 years) and more frequently females (63%vs 37%) than the HIV counterparts. Mean serum HCV‐RNA was similar in both the groups (5.9 vs 5.8 log IU/mL). Overall, 78.8% of the HIV patients were on HAART and their mean CD4 count was 525 (±278) cells/μL. In HIV‐negatives, liver fibrosis was mild in 84.6%; moderate in 8.7%, severe in 3.3% and cirrhosis was found in 3.3%. In HIV patients, these figures were 70.7%, 18.8%, 6%, and 4.5%, respectively. In the multivariate logistic regression analysis, older age (odds ratio or OR: 1.04; 95% confidence interval or CI: 1.02–1.07; P < 0.001) and being HIV+ (OR: 2.6; 95% CI: 1.21–5.85; P < 0.01) were associated with severe liver fibrosis or cirrhosis (F3–F4). Thus, severe liver fibrosis and cirrhosis are seen in 6.6% of the HCV‐monoinfected and in 10.5% of HCV‐HIV co‐infected patients with PNALT. Some degree of liver fibrosis that justifies treatment is seen in 15% of the HCV‐monoinfected but doubles to nearly 30% in HIV‐HCV co‐infected patients with PNALT.     

Altered thyrotropic and lactotropic axes regulation in Huntington’s disease

Background Recently, a loss of hypothalamic dopamine D₂ receptors was demonstrated in Huntington’s disease (HD). Activation of dopamine D₂ receptors is known to inhibit the function of both thyrotropic and lactotropic axes. Objective To assess whether the activity of the thyrotropic and lactotropic axes is disturbed in patients with HD, contributing to symptoms such as unintended weight loss. Participants and methods In nine medication‐free patients with early‐stage HD (six men, three women) and nine age‐, sex‐ and body mass index‐matched controls, we measured serum levels of thyroid‐stimulating hormone (TSH) and prolactin (men only) every 10 min for 24 h. Multiparameter auto‐deconvolution and approximate entropy analysis were applied to quantify basal, pulsatile and total TSH and prolactin secretion rates as well as the regularity of hormone release. Results Compared with controls, TSH and prolactin secretion tended to be slightly, but not significantly, higher in patients with HD (TSH: 1·13 ±0·14 vs 0·91 ± 0·19 mU/l, P = 0·40; prolactin: 213 ± 18 vs 209 ± 11 pmol/l, P = 0·87). However, in patients with HD, total T₃ levels were significantly higher (1·60 ± 0·05 vs 1·35 ± 0·09, P = 0·045), while T₄ levels tended to be higher as well (91·9 ± 3·9 vs 81·3 ± 3·1, P = 0·085). Prolactin secretion was significantly more irregular in patients with HD (Approximate entropy (ApEn): 1·06 ± 0·08 vs 0·80 ± 0·09, P = 0·037). Total T₃ levels were negatively associated with motor impairment (r = ?0·72, P = 0·030), whereas increasing free T₄ levels were associated with a larger mutant cytosine‐adenine‐guanine (CAG) repeat size (r = +0·68, P = 0·044). Conclusion: Our findings indicate a mild hyperactivity of the thyrotropic axis and a disturbed regulation of the lactotropic axis in patients with early‐stage HD.     

Chronic hepatitis C infection and sex hormone levels: effect of disease severity and recombinant interferon-alpha therapy

Background: We aimed to investigate the associations between androgen status and markers of liver disease severity and to determine the effect of interferon‐α (IFN‐α) treatment on sex hormone levels in the context of hepatitis C infection. Methods: We audited liver biopsy and sex hormone data from 35 men with chronic hepatitis C and a separate group of 11 men with hepatitis C who received IFN‐α treatment at Fremantle Hospital. Results: We found that men with low fibrosis scores (0–2) on the modified Knodell histological activity index were more likely to have lower sex hormone–binding globulin (SHBG) levels (38.2 ± 13.2 vs 66.6 ± 43.3 nmol/L, P < 0.001) and higher free testosterone levels (380.4 ± 102.0 vs 255.9 ±83.0 pmol/L, P = 0.01) than those with higher fibrosis scores (3–6). SHBG directly correlated with fibrosis scores (r = 0.37, P = 0.032). Free testosterone levels inversely correlated with liver fibrosis scores (r = ?0.43, P = 0.011). A transient reduction in total testosterone of 5.7 ± 4.2 nmol/L (P = 0.014) occurred within the first 6 months of IFN‐α therapy although free testosterone was unaffected. Conclusion: More severe liver disease was associated with lower free testosterone and higher SHBG. IFN‐α therapy reduced total testosterone but not to hypogonadal levels, with no decline in free testosterone. These data suggest that liver disease in hepatitis C infection modulates androgen status indirectly via increased SHBG. Screening for androgen deficiency in the context of hepatitis C infection should selectively target men with more severe liver disease or documented higher grade fibrosis.     

Efficacy of ursodeoxycholic acid in the treatment of patients with chronic hepatitis C

A case-control study was conducted to evaluate the efficacy of ursodeoxycholic acid (UDCA) in the treatment of Chinese patients with chronic hepatitis C. Patients who failed to have sustained responses to interferon (IFN) therapy, refused to take IFN or were unsuitable for IFN treatment were enrolled into this study. The treatment group had 15 patients and they received UDCA 600 mg orally per day for 6 months. Another 15 patients with matched sex, age and initial serum alanine aminotransferase (ALT) levels were chosen as the control group. Three parameters (i.e. serum ALT levels, serum hepatitis C virus (HCV) RNA and serum cytokines) were measured before and after UDCA treatment. After the treatment period, the mean serum ALT levels in both groups were not significantly different (153.8 ± 111.0 U/L vs 112.1 ± 53.8 U/L, P > 0.05) and mean serum ALT level in the UDCA-treated group did not decrease after the treatment (pre-treatment vs post-treatment value: 139.1 ± 73.1 U/L vs 153.8 ± 111.0 U/L, P > 0.05). In addition, all of the patients with positive HCV RNA before treatment still had active HCV viraemia after the UDCA treatment. Also, the serum levels of interleukin-6 (IL-6) and the tumour necrosis factor-α (TNF-α) were not significantly different between the two groups before and after the treatment period. In conclusion, a regimen of UDCA as prescribed in the present study did not show obvious benefits in the treatment of Chinese patients with chronic hepatitis C.     

Liver stiffness measured by transient elastography correlates with fibrosis area in liver biopsy in patients with chronic hepatitis C

Aim: Liver stiffness (LS) measured by transient elastography (TE) has been reported to correlate with liver fibrosis, which is usually semiquantitatively assessed. In the present study, the fibrosis area was measured by image analysis software in liver biopsy specimens and its correlation with LS was assessed. Methods: LS was measured by TE in all 165 patients with chronic hepatitis C virus (HCV) infection who underwent liver biopsy consecutively in Fujita Health University Hospital from July 2004 to September 2007. Results: Fibrosis area was significantly correlated with fibrosis stage as assessed by the Metavir score (ρ = 0.733, P < 0.0001). The optimal cut‐off value of fibrosis area was 1.6% for F > or = 2, 3.1% for F > or = 3, and 3.8–6.4% for F4. LS was significantly correlated with fibrosis stage (ρ = 0.734, P < 0.0001). The optimal cut‐off value of LS was 7.1 kPa for F > or = 2, 9.6 kPa for F > or = 3 and 11.6–16.9 kPa for F4. Multiple linear regression analysis selected fibrosis area (P = 0.0002), alanine aminotransferase (ALT) (P = 0.0237), γ‐glutamyltransferase (γ‐GTP) (P = 0.0114), prothrombin time (P = 0.0114) and hyaluronic acid (P < 0.0001) as factors correlating with LS. Conclusion: The correlation between LS and liver fibrosis was confirmed by the objective measurement of fibrosis area. ALT was significantly correlated with LS, suggesting that inflammatory activity also affects LS values. Despite some limitation, LS measurement is a useful method for the diagnosis of liver fibrosis.     

Extended-release naltrexone/bupropion and liver health: Pooled,post hoc analysis from four randomized controlled trials

Sustained weight loss improves liver histology in non-alcoholic fatty liver disease. This post hoc analysis of four phase III, 56-week, randomized controlled trials investigated if extended-release naltrexone and bupropion (NB) affects alanine aminotransferase (ALT) and Fibrosis-4 (FIB-4) index in adults with overweight or obesity. Two thousand and seventy-three subjects (NB = 1310; placebo = 763; 79.0% female; 81.6% Caucasian) had baseline mean weight 101 kg, body mass index 36.2 kg/m², ALT 26.9 IU/L and FIB-4 0.79. At 56 weeks, NB-treated subjects experienced more weight loss than placebo (8.7 vs. 3.2 kg, respectively, P < .0001). Weight loss, independent of treatment, was associated with improved ALT and FIB-4 (P < .0001). There was a significant independent effect of NB on change from baseline for FIB-4 (P < .0001), but not for ALT (P = .54). Categorical ALT response (from above to within normal ranges: 10-40 IU/L for men; 7-35 IU/L for women) and achievement of 25% and 50% reduction in ALT were greater for NB versus placebo, and independently affected by weight loss (P < .0001), but not treatment. NB-associated weight loss may improve liver health by normalizing ALT values for those with high baseline levels.     

Pruritus of unknown origin and elevated total serum bile acid levels in patients without clinically apparent liver disease

Background and Aim: Generalized pruritus of unknown origin (PUO) is a highly distressing condition that is unrelated to any underlying dermatologic or systemic disorder (e.g. cholestasis). Little is known about the potential contribution of elevated total serum bile acid (TSBA) levels to PUO. Our aim in the present study was to investigate the role of elevated TSBA levels in patients with PUO and the efficacy of ursodeoxycholic acid (UDCA) and cholestyramine therapy. Methods: Retrospective study comprising 117 patients with chronic pruritic conditions (PUO, atopic disease, asteatotic eczema, latent cholestasis, etc.); 99 patients with available TSBA levels were included and compared with healthy controls. Results: Elevated TSBA levels were detected more frequently in patients with chronic pruritic diseases than in the control population (28.28% vs 6%; P < 0.001) with significantly higher pathological absolute levels (mean 17.45 ± 34.46 µmol/L vs 6.02 ± 4.73 µmol/L; P = 0.001). Patients with PUO (n = 18) showed the second‐highest prevalence of pathological bile acid level elevation (83.3%; control population 6%; P < 0.001), after patients with subclinical cholestasis and presented with particularly high TSBA serum values (mean 37.79 ± 53.38 µmol/L; P < 0.001). Cholestyramine (n = 9) and UDCA (n = 8) therapy were both effective in lowering TSBA levels and lead to substantial improvement of pruritus in patients with elevated TSBA levels. Conclusions: Total serum bile acid levels are elevated in a high proportion of patients with PUO. These results provide evidence of a potential involvement of subclinical cholestasis in the pathogenesis of PUO. We suggest that evaluation of TSBA levels should be included in the diagnostic work‐up of patients with chronic unexplained pruritus.     

Effect of sex difference in clinical presentation (stable coronary artery disease vs unstable angina pectoris or non‐ST‐elevation myocardial infarction vs ST‐elevation myocardial infarction) on 2‐year outcomes in patients undergoing percutaneous coronary intervention

Objective

To determine whether there is a difference in 2‐year prognosis among patients across the spectrum of coronary artery disease undergoing percutaneous coronary intervention (PCI).

Methods

We analyzed all consecutive patients undergoing PCI at a single center from 1/1‐12/31/2013. Clinical presentations were compared between sexes according to baseline clinical, angiographic, and procedural characteristics and 2‐year (mean 730 ± 30‐day) outcomes.

Results

We grouped 10 724 consecutive patients based on sex and clinical presentation. Among patients with ST‐elevation myocardial infarction (STEMI), rates of all‐cause death (6.7% vs 1.4%) and cardiac death (3.8% vs 1.1%) were significantly higher in women than in men (P < 0.05), but these rates did not differ between men and women with stable coronary artery disease (SCAD) and non‐ST‐elevation acute coronary syndrome ((NSTE‐ACS). Incidence of major bleeding was greater than in men only in those women presenting with ACS. After multivariable adjustment, female sex was not an independent predictor of outcomes in STEMI (hazard ratio [HR] for all‐cause death: 1.33, 95% confidence interval [CI]:0.52‐3.38; P = 0.55; HR for cardiac death: 0.69, 95%CI: 0.23‐2.09, P = 0.51], but was still an independent predictor of bleeding in STEMI (HR: 3.53, 95%CI: 1.26‐9.91, P = 0.017).

Conclusion

Among STEMI patients, women had worse 2‐year mortality after PCI therapy, but female sex was not an independent predictor of mortality after adjustment for baseline characteristics. In STEMI patients, women were at higher bleeding risk than men after PCI, even after multivariable adjustment.     

Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight,liver fat and liver function in obese patients with non‐alcoholic fatty liver disease: A pilot randomized trial

We compared the effects of weight loss induced by the glucagon‐like peptide 1‐agonist liraglutide with a structured lifestyle intervention in obese adults with non‐alcoholic fatty liver disease (NAFLD). Obese (body mass index ≥30 kg/m², mean weight 96.0 ± 16.3 kg) non‐diabetic Asian adults, with NAFLD diagnosed by liver fat fraction (LFF) ≥ 5.5% on magnetic resonance imaging without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/d) plus moderate‐intensity aerobic exercise (~200 min/wk; DE group, n = 12), or liraglutide at the 3 mg daily dose approved for weight loss (LI group, n = 12), for 26 weeks. Both DE and LI groups had significant (P < .01) and similar reductions in weight (?3.5 ± 3.3 vs ?3.5 ± 2.1 kg, respectively, P = .72), LFF (?8.9 ± 13.4 vs ?7.2% ± 7.1%, P = .70), serum alanine aminotransferase (?42 ± 46 vs ?34 ± 27 U/L, P = .52) and aspartate aminotransferase (?23 ± 24 vs ?18 ± 15 U/L, P = .53). In this first randomized study comparing the 2 weight‐loss modalities for improving NAFLD, liraglutide was as effective as structured lifestyle modification.