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1.  Clinical outcomes and resource utilisation in Medicare patients with chronic liver disease: a historical cohort study 
BMJ Open  2014;4(5):e004318.
The aim of this study is to assess recent trends in health resource utilisation and patient outcomes of Medicare beneficiaries with chronic liver disease (CLD).
Liver-related mortality is the 10th leading cause of death in the USA, and hepatitis C virus (HCV) and obesity-related non-alcoholic fatty liver disease are the major causes of CLD. As the US population ages and becomes more obese, the impact of CLD is expected to become more prominent for the Medicare population.
This is a retrospective cohort study of Medicare beneficiaries with a diagnosis of CLD based on inpatient (N=21 576; 14 977 unique patients) and outpatient (N=515 990; 244 196 patients) claims from 2005 to 2010.
Primary and secondary outcome measures
The study outcomes included hospital length of stay (LOS) and inpatient mortality as well as inpatient and outpatient inflation-adjusted payments.
Between 2005 and 2010, there was an annual decrease in LOS of 3.17% for CLD-related hospitalisations. Risk-adjusted in-hospital mortality decreased (OR 0.90, 95% CI 0.87 to 0.94), while short-term postdischarge mortality remained stable (1.00, 0.98 to 1.03). Inpatient per-claim payment increased from $11 769 in 2005 to $12 347 in 2010 (p=0.0006). Similarly, the average yearly payments for outpatient care increased from $366 to $404 (p<0.0001). This change in payment was observed together with a consistent decrease in the proportion of beneficiary-paid amount (25.4–20%, p<0.0001) as opposed to Medicare-paid amount (73.1–80%, p<0.0001). The major predictors of higher outpatient payments were younger age, Asian race or Hispanic ethnicity, living in California, and having more diagnoses and outpatient procedures per claim. The predictors of inpatient spending also included younger age, location and the number of inpatient procedures.
Length of inpatient stay and inpatient mortality among Medicare beneficiaries with CLD decreased, while inpatient and outpatient spending increased.
PMCID: PMC4025451  PMID: 24838722
Qualitative Research
2.  Validation of the chronic liver disease questionnaire in Serbian patients 
AIM: To translate into Serbian and to investigate the validity of the cross-culturally adapted the chronic liver disease questionnaire (CLDQ).
METHODS: The questionnaire was validated in 103 consecutive CLD patients treated between October 2009 and October 2010 at the Clinic for Gastroenterology, Clinical Centre of Serbia, Belgrade (Serbia). Exclusion criteria were: age < 18 years, psychiatric disorders, acute complications of CLD (acute liver failure, variceal bleeding, and spontaneous bacterial peritonitis), hepatic encephalopathy (grade > 2) ​​and liver transplantation. Evaluation of the CLDQ was done based on the following parameters: (1) acceptance is shown by the proportion of missing items; (2) internal reliabilities were assessed for multiple item scales by using Cronbach alpha coefficient; and (3) in order to assess whether the allocation of items in the domain corresponds to their distribution in the original questionnaire (construction validity), an exploratory factor analysis was conducted. Discriminatory validity was determined by comparing the corresponding CLDQ score/sub-score in patients with different severity of the diseases.
RESULTS: The Serbian version of CLDQ questionnaire completed 98% patients. Proportion of missing items was 0.06%. The total time needed to fill the questionnaire was ranged from 8 to 15 min. Assistance in completing the questionnaire required 4.8% patients, while 2.9% needed help in reading, and 1.9% involved writing assistance. The mean age of the selected patients was 53.8 ± 12.9 years and 54.4% were men. Average CLDQ score was 4.62 ± 1.11. Cronbach’s alpha for the whole scale was 0.93. Reliability for all domains was above 0.70, except for the domain “Activity” (0.49). The exploratory factor analysis model revealed 6 factors with eigenvalue of greater than 1, explaining 69.7% of cumulative variance. The majority of the items (66%) in the Serbian version of the CLDQ presented the highest loading weight in the domain assigned by the CLDQ developers: “Fatigue” (5/5), “Emotional function” (6/8), “Worry” (5/5), “Abdominal symptoms” (0/3), “Activity” (0/3), “Systemic symptoms” (3/5). The scales “Fatigue” and “Worry” fully corresponded to the original. The factor analysis also revealed that the factors “Activity” and “Abdominal symptoms” could not be replicated, and two new domains “Sleep” and “Nutrition” were established. Analysis of the CLDQ score/sub-score distribution according to disease severity demonstrated that patients without cirrhosis had lower total CLDQ score (4.86 ± 1.05) than those with cirrhosis Child’s C (4.31 ± 0.97). Statistically significant difference was detected for the domains “Abdominal symptoms” [F (3) = 5.818, P = 0.001] and “Fatigue” [F (3) = 3.39, P = 0.021]. Post hoc analysis revealed that patients with liver cirrhosis Child’s C had significantly lower sub-score “Abdominal symptoms” than patients without cirrhosis or liver cirrhosis Child’s A or B. For domain “Fatigue”, patients with cirrhosis Child’s C had significantly lower score, than non-cirrhotic patients.
CONCLUSION: The Serbian version of CLDQ is well accepted and represents a valid and reliable instrument in Serbian sample of CLD patients.
PMCID: PMC3740425  PMID: 23946600
Chronic liver disease; Quality of life; Questionnaire; Validation; Factor analysis
3.  Gene expression profiles associated with depression in patients with chronic hepatitis C (CH-C) 
Brain and Behavior  2012;2(5):525-531.
The standard treatment for CH-C, pegylated interferon-α and ribavirin (PEG-IFN + RBV), is associated with depression. Recent studies have proposed a new role for cytokines in the pathogenesis of depression. We aimed to assess differential gene expression related to depression in CH-C patients treated with PEG-IFN + RBV. We included 67 CH-C patients being treated with PEG-IFN+RBV. Of the entire study cohort, 22% had pre-existing depression, while another 37% developed new depression in course of the treatment. Pretreatment blood samples were collected into PAXgene™ RNA tubes, the RNAs extracted from peripheral blood mononuclear cells (PBMCs) were used for one step RT-PCR to profile 160 mRNAs. Differentially expressed genes were separated into up- and down-regulated genes according to presence or absence of depression at baseline (pre-existing depression) or following the initiation of treatment (treatment-related depression). The mRNA expression profile associated with any depression and with treatment-related depression included four and six genes, respectively. Our data demonstrate a significant down-regulation of TGF-β1 and the shift of Th1-Th2 cytokine balance in the depression associated with IFN-based treatment of HCV infection. We propose that TGF-β1 plays an important role in the imbalance of Th1/Th2 in patients with CH-C and depression. With further validation, TGF-β1 and other components of Th1/Th2 regulation pathway may provide a future marker for CH-C patients predisposed to depression.
PMCID: PMC3489805  PMID: 23139898
Depression; hepatitis C; interferon; ribavirin; TGFβ1; Th1/Th2 cytokines; treatment
4.  Expression of NALPs in adipose and the fibrotic progression of non-alcoholic fatty liver disease in obese subjects 
BMC Gastroenterology  2014;14(1):208.
Visceral obesity is often accompanied by non-alcoholic fatty liver disease (NAFLD). Activation of NACHT, LRR and PYD domains-containing proteins (NALPs) may contribute to the release of pro-inflammatory cytokines by adipose and the obesity-associated progression of NAFLD to non-alcoholic steatohepatitis (NASH).
We analyzed visceral adipose expression of various NALPs and its downstream effectors caspase-1, ASC (Apoptosis-associated speck-like protein containing a CARD), IL-18 (Interleukin-18) and IL-1β (Interleukin- 1Beta) in obese subjects (BMI ≥ 35) with biopsy proven NAFLD.
In adipose samples collected from NASH and pericellular fibrosis patients cohorts, expression levels of NALPs and IL-1β were lower than that in non-NASH patients. In portal fibrosis, the levels of mRNA encoding anti-inflammatory NALP6 were upregulated. The expression levels of all NALPs were significantly co-correlated. Circulating IL-18 levels were associated with increased liver injury markers AST and ALT and portal fibrosis.
Our observations point at a possible shift in inflammation and fibrotic response from adipose tissue to liver and a possible negative feedback regulation of tissue inflammation that may instigate NAFLD severity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-014-0208-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4279907  PMID: 25512222
Obesity; NAFLD; Inflammasomes; Cytokines; Fibrosis
5.  Expression of energy metabolism related genes in the gastric tissue of obese individuals with non-alcoholic fatty liver disease 
BMC Gastroenterology  2014;14:72.
Stomach is an integral part of the energy balance regulating circuit. Studies exploring the effects of cross-system changes in the energy homeostasis in stomach tissue are scarce. The proximity of the stomach to liver - the most common secondary target affected by obesity – suggests that these two organs are exposed to each other’s local secretion. Therefore, we aimed at expression profiling of energy metabolism associated genes in the gastric tissue of obese non-alcoholic fatty liver disease (NAFLD) patients.
A total of 24 patients with histologically-proven NAFLD were included. In the gastric tissue, gene expression profiling of 84 energy metabolism associated genes was carried out.
The accumulation of the fat in the liver parenchyma is accompanied by downregulation of genes encoding for carboxypeptidase E (CPE) and Interleukin 1B (IL1B) in the gastric mucosa of same patient. In patients with high grade hepatic steatosis, Interleukin 1 beta encoding gene with anorexigenic function, IL1B was downregulated. The levels expression of 21 genes, including ADRA2B, CNR1 and LEP were significantly altered in the gastric tissue of NAFLD patients with hepatic inflammation. There were also indications of an increase in the opioid signaling within gastric mucosa that may results in a shift to proinflammatory environment within this organ and contribute to systemic inflammation and the pathogenic processes in hepatic parenchyma.
We have shown differential expression of energy metabolism associated genes in the gastric tissue of obese NAFLD patients. Importantly, these gene expression profiles are associated with changes in the hepatic parenchyma as reflected in increased scores for hepatic steatosis, inflammation, fibrosis and NASH. This study suggests the complex interplay of multiple organs in the pathogenesis of obesity-related complications such as NAFLD and provides further evidence supporting an important role for gastric tissue in promoting obesity-related complications.
PMCID: PMC4021272  PMID: 24716593
6.  Molecular signature of adipose tissue in patients with both Non-Alcoholic Fatty Liver Disease (NAFLD) and Polycystic Ovarian Syndrome (PCOS) 
Polycystic ovarian syndrome (PCOS) is one of the most common reproductive disorders with strong association with both insulin resistance and non-alcoholic fatty liver disease (NAFLD). To untangle the complex relationship between PCOS and NAFLD, we analyzed serum biomarkers of apoptosis, some adipokines and mRNA profiles in the visceral adipose tissue of obese patients with NAFLD who were also diagnosed with PCOS and compared to a group with NAFLD only.
We included patients with biopsy-proven NAFLD and PCOS (N = 12) and BMI-matched biopsy-proven NAFLD patients without PCOS (N = 12). Expression levels of individual mRNAs and soluble serum biomarkers were compared by non-parametric Mann–Whitney test. The analysis also included Spearman rank correlation tests and multiple regression analysis. For co-correlated genes, the factor analysis was performed.
The total serum levels of apoptotic biomarker M30 were significantly elevated in PCOS patients with liver steatosis as compared to non-PCOS NAFLD controls (P < 0.02), pointing that androgen-dependent proapoptotic PCOS environment that may directly contribute to NAFLD progression in these patients. Similarly, hyperandrogenism may explain the observed PCOS-specific decrease (P < 0.04) in adipose LDLR mRNA expression that may be connected to the proneness of PCOS patients to NAFLD. The levels of mRNA encoding angiogenesis-associated GSK-3B interacting protein ninein were also significantly increased in the adipose tissue of NAFLD patients with PCOS (P < 0.007). Furthermore, the levels of resistin positively correlated with expression levels of LDLR and prothrombin time (PT).
An androgen-dependent proapoptotic PCOS environment may directly contribute to NAFLD progression in these patients. Hyperandrogenism may explain an observed decrease in adipose LDLR mRNA expression. An inflammation-associated increase in the release of resistin into circulation might contribute to the prothrombotic state observed under conditions associated with insulin resistance, including PCOS. The studies of larger cohorts of NAFLD with and without PCOS patients are needed to further assess these potential interactions.
PMCID: PMC3681627  PMID: 23721173
NAFLD; PCOS; LDLR; M30; Apoptosis; Ninein; Resistin
7.  The impact of IL28B genotype on the gene expression profile of patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin 
Recent studies of CH-C patients have demonstrated a strong association between IL28B CC genotype and sustained virologic response (SVR) after PEG-IFN/RBV treatment. We aimed to assess whether IL28B alleles rs12979860 genotype influences gene expression in response to PEG-IFN/RBV in CH-C patients.
Clinical data and gene expression data were available for 56 patients treated with PEG-IFN/RBV. Whole blood was used to determine IL28B genotypes. Differential expression of 153 human genes was assessed for each treatment time point (Days: 0, 1, 7, 28, 56) and was correlated with IL28B genotype (IL28B C/C or non-C/C) over the course of the PEG-IFN/RBV treatment. Genes with statistically significant changes in their expression at each time point were used as an input for pathway analysis using KEGG Pathway Painter (KPP). Pathways were ranked based on number of gene involved separately per each study cohort.
The most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype.
IL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.
PMCID: PMC3296607  PMID: 22313623
HCV; Gene Expression; Pathway Analysis; IL28B; SOCS1; IRF2; chronic hepatitis C; HCV treatment
8.  Non-Invasive markers for hepatic fibrosis 
BMC Gastroenterology  2011;11:91.
With great advancements in the therapeutic modalities used for the treatment of chronic liver diseases, the accurate assessment of liver fibrosis is a vital need for successful individualized management of disease activity in patients. The lack of accurate, reproducible and easily applied methods for fibrosis assessment has been the major limitation in both the clinical management and for research in liver diseases. However, the problem of the development of biomarkers capable of non-invasive staging of fibrosis in the liver is difficult due to the fact that the process of fibrogenesis is a component of the normal healing response to injury, invasion by pathogens, and many other etiologic factors. Current non-invasive methods range from serum biomarker assays to advanced imaging techniques such as transient elastography and magnetic resonance imaging (MRI). Among non-invasive methods that gain strongest clinical foothold are FibroScan elastometry and serum-based APRI and FibroTest. There are many other tests that are not yet widely validated, but are none the less, promising. The rate of adoption of non-invasive diagnostic tests for liver fibrosis differs from country to country, but remains limited. At the present time, use of non-invasive procedures could be recommended as pre-screening that may allow physicians to narrow down the patients' population before definitive testing of liver fibrosis by biopsy of the liver. This review provides a systematic overview of these techniques, as well as both direct and indirect biomarkers based approaches used to stage fibrosis and covers recent developments in this rapidly advancing area.
PMCID: PMC3176189  PMID: 21849046
9.  Treatment options for nonalcoholic fatty liver disease 
Nonalcoholic fatty liver disease (NAFLD) has become increasingly recognized as the most common cause of abnormal liver enzymes in the last few decades and is among the most common forms of chronic liver disease in the Western world and across the globe. With the growing epidemic of obesity and diabetes, NAFLD is estimated to affect about one-quarter of the US population. Although most patients with NAFLD have nonprogressive bland steatosis, a minority of patients develop the histological subtype of nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, hepatocellular carcinoma, and liver-related death. This is especially true when NASH patients have type 2 diabetes. Treatment of NAFLD should therefore be directed towards patients with established NASH. Sustained weight loss seems to improve insulin resistance and associated NASH. In fact, weight loss with bariatric surgery leads to biochemical and histological improvement in morbidly obese patients with NASH. Several pharmacologic agents have been studied in an effort to improve insulin resistance and pro-inflammatory mediators potentially responsible for the development and progression of NASH. While some studies have shown initial promise, none has established long-term efficacy using randomized clinical trials. This paper briefly reviews the epidemiology, natural history, and pathophysiology of NAFLD and NASH and then focuses on the clinical trials of various therapeutic modalities for NAFLD. These include weight loss agents, bariatric surgery, insulin-sensitizing agents, lipid-lowering agents, antioxidants, probiotics, anti-tumor necrosis factor agents, cytoprotective and other novel agents.
PMCID: PMC3002571  PMID: 21180596
NAFLD; NASH; treatment
10.  Suspected Nonalcoholic Fatty Liver Disease and Mortality Risk in a Population-based Cohort Study 
Case series suggest that Nonalcoholic Fatty Liver Disease (NAFLD) is associated with increased all-cause and cardiovascular mortality. The current study compared the survival of subjects with and without suspected NAFLD in a population-based cohort, and placed the finding in the context of previously published case series.
Primary analysis assessed mortality for NHANES-III participants with and without suspected NAFLD using the National Death Index. Suspected NAFLD was based upon unexplained ALT elevation. The Olmsted County and Cleveland Clinic case series were also used for comparison. Survivals were compared using Proportional Hazards Model and direct age standardization.
The NHANES cohort included 980 with and 6594 subjects without suspected NAFLD. Over a mean of 8.7 years, suspected NAFLD had a hazards ratio of 1.37 (95%CI 0.98–1.91) for all-cause mortality. In the 45–54 age group, suspected NAFLD had significantly higher all-cause (4.40 95%CI 1.27–13.23) and cardiovascular mortality (8.15 , 95%CI 2.00–33.20) after adjusting for conventional cardiovascular risk factors. The age-standardized rate per 10,000 per year was 129 (95%CI 118–140) for the NHANES non-NAFLD cohort, 154 (95%CI 116–198) for the NHANES suspected NAFLD cohort, 214 (95%CI 157–279) for the Olmsted County series, and 426 (95%CI 298–573) for the Cleveland Clinic series.
The magnitude of mortality risk in NAFLD depends on the setting and method of ascertainment. Suspected NAFLD in the 45–54 age group is a strong independent risk factor for cardiovascular death and warrants further cardiovascular risk management guidelines.
PMCID: PMC2574666  PMID: 18684196

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