Nonalcoholic Fatty Liver Disease 2020: The State of the Disease

While non-alcoholic fatty liver disease (NAFLD) is highly prevalent (15% to 45%) in modern societies, only 10% to 25% of cases develop hepatic fibrosis leading to cirrhosis, end-stage liver disease or hepatocellular carcinoma. Apart from pre-existing fibrosis, the strongest predictor of fibrotic progression in NAFLD is steatohepatitis or non-alcoholic steatohepatitis (NASH). The critical features other than steatosis are hepatocellular degeneration (ballooning, Mallory hyaline) and mixed infl ammatory cell infi ltration. While much is understood about the relationship of steatosis to metabolic factors (over-nutrition, insulin resistance, hyperglycemia, metabolic syndrome, hypoadiponectinemia), less is known about infl ammatory recruitment, despite its importance for the perpetuation of liver injury and fi brogenesis. In this review, we present evidence that liver infl ammation has prognostic signifi cance in NAFLD. We then consider the origins and components of liver infl ammation in NASH. Hepatocytes injured by toxic lipid molecules (lipotoxicity) play a central role in the recruitment of innate immunity involving Toll-like receptors (TLRs), Kupffer cells (KCs), lymphocytes and neutrophils and possibly infl ammasome. The key pro-infl ammatory signaling pathways in NASH are nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). The downstream effectors include adhesion molecules, chemokines, cytokines and the activation of cell death pathways leading to apoptosis. The upstream activators of NF-κB and JNK are more contentious and may depend on the experimental model used. TLRs are strong contenders. It remains possible that infl ammation in NASH originates outside the liver and in the gut microbiota that prime KC/TLR responses, infl amed adipose tissue and circulating infl ammatory cells. We briefl y review these mechanistic considerations and project their implications for the effective treatment of NASH. (Gut Liver 2012;6:149-171)

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NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22726

Ethnic differences in hepatic steatosis: an insulin resistance paradox?

Nonobese Fatty Liver Disease

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.27869

Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study

Background and Aim:  Recent data indicate that hepatic steatosis is associated with insulin resistance, dyslipidemia and obesity (especially central body fat distribution). There have been few studies on the correlation between biopsy-proven hepatic steatosis and the above factors in a disease-free population. The aim of the present study was to evaluate the relation between hepatic steatosis assessed by biopsy and clinical characteristics including regional fat distribution measured by computed tomography (CT) in living liver donors.



Methods:  Laboratory data, liver/spleen Hounsfield ratio (L/S ratio), regional fat distribution by CT and liver status by biopsy were evaluated retrospectively in a total of 177 living liver donors without a history of alcohol intake.



Results:  The unpaired t-test showed that age, triglycerides (TG), high density lipoprotein, total cholesterol, alanine aminotransferase, body mass index, L/S ratio, visceral adipose tissue area (VAT) and subcutaneous adipose tissue area (SAT) were associated with hepatic steatosis. In the multiple logistic regression analysis, VAT (odds ratio 1.031, 95% CI 1.013–1.048, P < 0.01) and TG (odds ratio 1.012, 95% CI 1.004–1.020, P < 0.01) were independent risk factors of hepatic steatosis. Subgroup analysis also showed that VAT was an independent risk factor in men (odds ratio 1.022, 95% CI 1.003–1.041, P < 0.05) and women (odds ratio 1.086, 95% CI 1.010–1.168, P < 0.05).



Conclusion:  Our results suggest that visceral abdominal adiposity is correlated with hepatic steatosis in healthy living liver donors.

Visceral adipose tissue area is an independent risk factor for hepatic steatosis

The thiopurine drugs, azathioprine (AZA), and 6-mercaptopurine (6-MP) are well-established drugs for the treatment of inflammatory bowel disease (IBD). Although leukopenia is a well-recognized side effect of AZA/6-MP treatment, its association with therapeutic effects has yet to be determined. We therefore evaluated the influences of thiopurine-induced leukopenia on the long-term prognosis of IBD. We included 196 IBD patients [45 with ulcerative colitis (UC), 68 with Crohn’s disease (CD), and 83 with intestinal Behcet’s disease (BD)] who were treated with AZA/6-MP and achieved remission between January 2006 and December 2012. We retrospectively analyzed patient characteristics, AZA/6-MP maintenance dose (mg/kg), the lowest white blood cell (WBC) count during AZA/6-MP treatment, duration of remission, and the occurrence of relapse. We compared the clinical variables between leukopenic (n = 120, WBC count <4,000/μL) and nonleukopenic (n = 76, WBC count ≥4,000/μL) patients. The two groups were well matched for baseline clinical characteristics. The cumulative relapse-free survival rate was higher in the leukopenic group than the nonleukopenic group by Kaplan–Meier survival analysis (log-rank test, P < 0.001). On multivariate analysis, age, duration of AZA/6-MP treatment, presence of macrocytosis, and the presence of leukopenia were negatively associated with relapse (odds ratios 0.975, 0.988, 0.563, and 0.390, respectively). On subgroup analysis, the cumulative relapse-free survival rate was significantly higher in the leukopenic group than in the nonleukopenic group for all types of IBDs, including UC, CD, and intestinal BD (log-rank test, P = 0.032, 0.047, and 0.002, respectively). Leukopenia during thiopurine maintenance therapy was associated with prolonged remission in patients with IBD and Behcet’s disease.

Leukopenia predicts remission in patients with inflammatory bowel disease and Behcet's disease on thiopurine maintenance.

Rectal neuroendocrine tumors (NETs) have been increasing in incidence. However, the recommendations for disease surveillance after tumor resection have not been well established. We evaluated the long-term outcomes of rectal NETs and surveillance strategies according to recurrence risk stratification. From January 2000 to July 2011, 188 patients diagnosed with rectal NETs were included in this study. Patient characteristics, treatment methods, recurrence rates, risk factors of recurrence, and surveillance schedules were analyzed. The male-to-female ratio was 1.29:1 and the mean age at diagnosis was 50.6 years. The mean tumor size was 6.5 (range 1–30) mm. A total of 144 patients (76.6 %) were treated with endoscopic resection, and 44 patients (23.4 %) were treated with surgical resection as the initial treatment. During the follow-up period, ten patients (5.3 %) had disease recurrence, including one case of local recurrence and nine cases of recurrence at a distant site. Tumor size of >10 mm, invasion of the muscularis propria, increased mitotic index, lymphovascular invasion, and regional lymph node metastases were statistically significant predictors of recurrence by univariate analysis. Among the 152 patients without risk factors of recurrence, only one patient who underwent transanal resection had a local recurrence at 15 months after surgery. Our patients with rectal NETs showed favorable clinical outcomes and had a low rate of recurrence. Intensive surveillance with endoscopy or imaging study may not be required in patients without risk factors for recurrence.

Surveillance strategy for rectal neuroendocrine tumors according to recurrence risk stratification.

Objective To compare the long-term outcomes of acute noise-induced tinnitus (ANT) and acute idiopathic tinnitus (AIT) to intratympanic dexamethasone (ITD) therapy. Materials and methods Patients treated for tinnitus occurring immediately after noise exposure comprised the ANT group (n=20) and patients treated for idiopathic tinnitus comprised the AIT group (n=39). All patients were treated with ITD within 3 months of the onset of tinnitus. Quantitative assessment of the improvement in tinnitus using questionnaires and changes in hearing thresholds were compared between the two groups. Results Mean follow-up durations were 75.90±69.83 weeks in the ANT group and 93.41±101.43 weeks in the AIT group. Patients with ANT were younger in age than those with AIT (38.30±18.28 vs. 53.56±14.08, p=0.00) and were predominately male (Male: Female, M:F 13:7 vs. 13:26, p=0.02, respectively). The subjective tinnitus loudness, time of tinnitus awareness, and Tinnitus Handicap Inventory score improved in both groups, although the changes in these parameters were not significantly different between the groups. The cure and overall improvement rates of the ANT group were and 10.00% and 25.00%, respectively. The cure and overall improvement rates of the AIT groups were 25.64% and 35.90%, respectively and there were no significant differences between the two groups in terms of the cure and overall improvement rates (p=0.19 and 0.40, respectively). Conclusion The long-term outcome in terms of control of tinnitus with ITD in the ANT group was similar to that in the AIT group. Thus, ITD injection may be a useful treatment option for acute tinnitus caused by noise trauma.

Comparison of Long-Term Outcome of Intratympanic Dexamethasone Therapy between Acute Noise-Induced Tinnitus and Acute Idiopathic Tinnitus.

The subacute toxicities (10 male and 10 female rats at each dose) and the toxicokinetics (5 male rats at each dose) of DA-8159, a new phosphodiesterase type V (PDE V) inhibitor, were evaluated after single (at day 1) and 4-week (at day 28) oral administration of the drug at doses of 0 (to serve as a control), 20, 80 and 320 mg/kg/day to rats. DA-8159 showed a decrease in body weight gain, clinical signs such as chromodacryohaemorrhoea, ptosis and decreased locomotor activity, an increase in WBC number, changes in parameters related to RBCs, an increase in organ weight of the liver, spleen and lung, and finally microscopic lesions such as cholangiofibrosis and inflammatory cell infiltration in the liver, alveolar macrophage accumulation, and inflammatory cell infiltration in the lung, an increase in bone marrow density and extrahaematopoiesis in the spleen. These changes were observed mainly at a dose of 80 mg/kg or above. While some changes were observed at a dose of 20 mg/kg, these changes were non-specific and transient since this were also observed in control rats. In addition, there was no dose-dependency in these changes. Based on these results, the NOAEL (No-Observed-Adverse-Effect-Level) for DA-8159 in rats was estimated to be 20 mg/kg/day, and the target organs were determined to be liver, bone marrow, spleen, lung and blood cells. After a 4-week oral administration, accumulation of DA-8159 was evident at a dose of 20 mg/kg/day, but was not considerable at toxic doses (80 and 320 mg/kg/day). After a single oral administration, the dose-normalized area under the plasma concentration–time curve from time zero to the last measured time, 24 h, in plasma (AUC0−24 h) was significantly different among the three doses (the AUC0–24 h based on 20 mg/kg/day was 2.33, 7.00 and 4.19 μg h/ml for 20, 80 and 320 mg/kg/day, respectively). Similar results were also obtained from DA-8164, a metabolite of DA-8159; the AUC0–24 h of DA-8164 after dose-normalized to 20 mg/kg/day of DA-8159 were 2.74, 5.00 and 1.68 μg h/ml, respectively. Copyright © 2003 John Wiley & Sons, Ltd.

Subacute toxicities and toxicokinetics of DA-8159, a new phosphodiesterase type V inhibitor, after single and 4-week repeated oral administration in rats.

Dong Hyun Kim

Papers

Visceral adipose tissue area is an independent risk factor for hepatic steatosis

Leukopenia predicts remission in patients with inflammatory bowel disease and Behcet's disease on thiopurine maintenance.

Surveillance strategy for rectal neuroendocrine tumors according to recurrence risk stratification.

Comparison of Long-Term Outcome of Intratympanic Dexamethasone Therapy between Acute Noise-Induced Tinnitus and Acute Idiopathic Tinnitus.

Subacute toxicities and toxicokinetics of DA-8159, a new phosphodiesterase type V inhibitor, after single and 4-week repeated oral administration in rats.