Low circulating levels of dehydroepiandrosterone in histologically advanced nonalcoholic fatty liver disease

The biological basis of variability in histological progression of nonalcoholic fatty liver disease (NAFLD) is unknown. Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone and has been shown to influence sensitivity to oxidative stress, insulin sensitivity, and expression of peroxisome proliferator-activated receptor alpha and procollagen messenger RNA. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA. Serum samples were obtained prospectively at the time of liver biopsy in 439 patients with NAFLD (78 in an initial and 361 in validation cohorts) and in controls with cholestatic liver disease (n = 44). NAFLD was characterized as mild [simple steatosis or nonalcoholic steatohepatitis (NASH) with fibrosis stage 0-2] or advanced (NASH with fibrosis stage 3-4). Serum levels of sulfated DHEA (DHEA-S) were measured by enzyme-linked immunosorbent assay. Patients with advanced NAFLD had lower plasma levels of DHEA-S than patients with mild NAFLD in both the initial (0.25 +/- 0.07 versus 1.1 +/- 0.09 microg/mL, P < 0.001) and validation cohorts (0.47 +/- 0.06 versus 0.99 +/- 0.04 microg/mL, P < 0.001). A "dose effect" of decreasing DHEA-S and incremental fibrosis stage was observed with a mean DHEA-S of 1.03 +/- 0.05, 0.96 +/- 0.07, 0.83 +/- 0.11, 0.66 +/- 0.11, and 0.35 +/- 0.06 microg/mL for fibrosis stages 0, 1, 2, 3, and 4, respectively. All patients in both cohorts in the advanced NAFLD group had low DHEA-S levels, with the majority in the hypoadrenal range. The association between DHEA-S and severity of NAFLD persisted after adjusting for age. A relationship between disease/fibrosis severity and DHEA-S levels was not seen in patients with cholestatic liver diseases. CONCLUSION: More advanced NAFLD, as indicated by the presence of NASH with advanced fibrosis stage, is strongly associated with low circulating DHEA-S. These data provide novel evidence for relative DHEA-S deficiency in patients with histologically advanced NASH.     

Open-label pilot study of folic acid in patients with nonalcoholic steatohepatitis.

BACKGROUND/AIMS: Folate deficiency disturbs hepatic methionine metabolism and promotes the development of steatohepatitis in animal models. Our aims were (1) to determine the safety and efficacy of folic acid treatment in patients with nonalcoholic steatohepatitis (NASH) on changes in liver biochemistries, and (2) to investigate the presence of subclinical folate deficiency in this population. METHODS: Patients with biopsy-proven NASH were treated with folic acid 1 mg/day for 6 months. Liver enzymes and adverse events were monitored every 3 months until completion. RESULTS: Ten patients (one male and nine females) with a median age of 54 years were enrolled in this study. At baseline, the median steatosis grade was 2 (range 1-3), the median necroinflammatory grade was 1 (1-3), and the median fibrosis stage was 2 (0-4). The median level of red cell folate was 526 ng/ml (range 99-708); the normal level was 268-616 ng/ml. One compensated cirrhotic patient had folate deficiency. No serious adverse events occurred. After 6 months of therapy, no significant reductions in serum aspartate and alanine aminotransferase levels (60+/-25 vs. 54+/-29, P=0.5 and 86+/-29 vs. 83+/-42, P=0.6, respectively), were observed. Serum levels of bilirubin, alkaline phosphatase, albumin, and prothrombin time remained in the normal range during treatment in all patients. CONCLUSION: Six months of therapy with folic acid at a dose of 1 mg/day, although safe and well tolerated, does not lead to a significant biochemical improvement in patients with NASH. In a small number of patients, folate deficiency was present in only a cirrhotic patient.     

Primary sclerosing cholangitis: overview and update

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disorder that most commonly affects middle-aged men. PSC is strongly associated with IBD, and in this setting the risk of colorectal cancer is markedly increased. Cholangiocarcinoma, and its devastating consequences, is another well-recognized complication of PSC. This condition tends to progress to end-stage liver disease, and patients with PSC have reduced survival rates compared with the general population. Despite significant research efforts in this field, the pathogenetic mechanisms of PSC are still incompletely understood, although growing evidence supports the role of genetic and immunologic factors. Effective medical therapy is lacking; liver transplantation is the only curative treatment modality, with excellent outcomes in this patient population.     

Light to moderate alcohol consumption is associated with lower frequency of hypertransaminasemia

OBJECTIVES: The effect of light to moderate alcohol consumption on the liver is controversial. To determine the association between light to moderate alcohol consumption and frequency of hypertransaminasemia, a cross-sectional and a subsequent longitudinal cohort study were conducted using annual health checkup data at a Japanese workplace. METHODS: We analyzed 1,177 male subjects (age 20-59) without HCV or HBV infection or other chronic liver diseases. To determine the association between alcohol consumption (none or minimal <70 g/wk, light > or =70 g and <140 g/wk, moderate > or =140 g and <280 g/wk, excessive > or =280 g/wk) and hypertransaminasemia, we performed multiple logistic regressions. We then followed 326 subjects without a history of fatty liver or hypertransaminasemia up to 5 years for incidental hypertransaminasemia and performed Cox proportional hazard regressions. RESULTS: Excess alcohol consumption was associated with increased odds of hypertransaminasemia (adjusted odds ratio [AOR]versus none or minimal consumption 1.4[1.1-1.93], P= 0.023). There was significant interaction between age group and alcohol consumption (P < 0.01). In the younger group, moderate consumption was associated with decreased odds (AOR 0.5 [0.3-0.9], P= 0.032), while in the older group, light consumption was associated with decreased odds (AOR 0.6 [0.4-1.0], P= 0.036) and excess consumption was associated with increased odds (AOR 1.6 [1.1-2.3], P= 0.014) of hypertransaminasemia. During follow-up, moderate consumption was associated with decreased incidence of hypertransaminasemia versus none or minimal consumption (adjusted hazard ratio 0.4 [0.1-0.9], P= 0.02). CONCLUSION: Light to moderate alcohol consumption may protect against the development of hypertransaminasemia among male subjects without other liver conditions. Further studies are required before recommending light to moderate alcohol consumption.     

Thyroid dysfunction in primary biliary cirrhosis,primary sclerosing cholangitis and non‐alcoholic fatty liver disease

Background/Aims: Primary biliary cirrhosis (PBC) is frequently associated with autoimmune diseases, including thyroid disease, although it is uncertain that this association is higher than in other liver diseases. Methods: We compared the prevalence and incidence of thyroid dysfunction (TD) in a series of patients with PBC (n=67) with patients with primary sclerosing cholangitis (PSC) (n=79) and non‐alcoholic fatty liver disease (NAFLD) (n=97) seen in a tertiary referral centre who had previously participated in clinical trials. Results: At initial evaluation, prevalence of TD in PBC was 13% compared with 11% in PSC (P=0.71) and 25% in NAFLD (P=0.08). Incidence of TD was 2.9 patients per 100 person‐years in PBC compared with 2.1 patients per 100 person‐years in PSC (P=0.57) and 1.8 patients per 100 person‐years in non‐alcoholic liver disease (P=0.45). Older age, female gender, biochemical abnormalities and concurrent autoimmune disorders were not predictive of the development of TD. Conclusions: TD was unexpectedly as common in patients with PBC as in patients with PSC and NAFLD, yet significantly more common than expected in the general population. Further investigation of thyroid disease in PSC and NAFLD is warranted.     

Quality of life and everyday activities in patients with primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is generally a slowly progressive disease that may lead to cirrhosis and liver failure. However, patients with PBC often suffer from a variety of symptoms long before the development of cirrhosis that include issues of daily living that have an impact on their work environment and their individual quality of life. We therefore examined multiple parameters by taking advantage of the database of our cohort of 1032 patients with PBC and 1041 matched controls. The data were obtained from patients from 23 tertiary referral centers throughout the United States and from rigorously matched controls by age, sex, ethnicity, and random-digit dialing. The data showed that patients with PBC were more likely than controls to have significant articular symptoms, a reduced ability to perform household chores, and the need for help with routine activities. Patients with PBC rated their overall activity similar or superior to that of controls; however, more of them reported limitations in their ability to carry out activities at work or at home and difficulties in everyday activities. PBC cases also more frequently reported limitations in participating in certain sports or exercises and pursuing various hobbies; however, they did not report significant limitations in social activities. In a multivariable analysis, household income, a diagnosis of systemic lupus erythematosus, limitations in work activities, a reduction in work secondary to disability, and church attendance were independently increased in PBC cases with respect to controls. CONCLUSION: Our data indicate that the quality of life of patients with PBC in the United States is generally well preserved. Nevertheless, patients with PBC suffer significantly more than controls from a variety of symptoms that are beyond the immediate impact of liver failure and affect their lifestyle, personal relationships, and work activities.     

Moexipril for Treatment of Primary Biliary Cirrhosis in Patients with an Incomplete Response to Ursodeoxycholic Acid

Blockade of angiotensin II synthesis attenuates hepatic fibrosis in different experimental models of chronic liver injury. We evaluated the safety and efficacy of moexipril, an angiotensin-converting enzyme inhibitor, in patients with primary biliary cirrhosis (PBC) who have had a suboptimal response to ursodeoxycholic acid (UDCA). Twenty PBC patients on UDCA (13–15 mg/kg/day) therapy with an elevation of serum alkaline phosphatase at least twice the upper limit of normal were treated with oral moexipril 15 mg/day for one year. No significant changes in serum alkaline phosphatase (379 ± 32 vs. 379 ± 51), bilirubin (0.8 ± 0.1 vs. 0.9 ± 0.1), aspartate aminotransferase (60 ± 8 vs. 63 ± 9), and Mayo risk score (3.55 ± 0.2 vs. 3.62 ± 0.2) was associated with the treatment. Fatigue and health-related quality of life scores during treatment demonstrated a trend toward improvement. Moexipril was not clinically beneficial to PBC patients responding suboptimally to UDCA.     

因5q15-q22染色体缺失导致家族性腺瘤性息肉病与智力发育迟缓的病例报道

由于位于染色体5q21上的腺瘤性大肠息肉病基因突变所引起的家族性腺瘤性息肉病，是以结肠、直肠息肉病及几乎100％进展为结肠直肠癌为特点的常染色体显性症候群。该报道了1例因5q15-q22染色体缺失导致家族性腺瘤性息肉病及智力发育迟缓病例。染色体分析用来对智力发育迟缓的患儿进行部分评估。应用高分辨染色体分析染色体组型有助于对大的染色体缺失特征进行描述，其中包括一些已知的肿瘤抑制基因。由家族性腺瘤性息肉病可因腺瘤样息肉基因位点相关新的染色体缺失而引起，因此有5q21染色体缺失的个体应高度考虑患家族性腺瘤性息肉病的风险，这可在10—12岁间应用可屈性乙状结肠镜进行标准筛查。