Association of interleukin-18 genotypes (-607C > A) and (-137 G > C) with the hepatitis B virus disease progression to hepatocellular carcinoma.

Chronic infection with HBV has been reported to be associated with the development of HCC. The inflammation mounted by cytokine-mediated immune system plays an important role in the pathogenesis of HBV-associated HCC. IL-18 is a pro-inflammatory cytokine whose role in the development of HBV-associated chronic to malignant disease state has not been much studied. The present study was conceived to determine the role of genetic polymorphisms in IL-18, serum levels of IL-18, and expression level of its signal transducers in the HBV disease progression. A total of 403 subjects were enrolled for this study including 102 healthy subjects and 301 patients with HBV infection in different diseased categories. Polymorphism was determined using PCR-RFLP. Genotypic distributions between the groups were compared using odd's ratio and 95% CI were calculated to express the relative risk. Circulating IL-18 levels were determined by ELISA. Expression levels of pSTAT-1 and pNFƙB was determined by western blotting. In case of IL-18(- 607C > A), the heterozygous genotype (CA) was found to be a protective factor while in case of IL-18(- 137G > C) the heterozygous genotype (GC) acted as a risk factor for disease progression from HBV to HCC. Moreover, serum IL-18 levels were significantly increased during HBV disease progression to HCC as compared to controls. Also the levels of activated signal transducers (pSTAT-1 and pNF-κB) of IL-18 in stimulated PBMCs were significantly increased during HBV to HCC disease progression. These findings suggest that IL-18 has the potential to act as a biomarker of HBV-related disease progression to HCC.

Adult onset hereditary hemochromatosis is associated with a novel recurrent Hemojuvelin (HJV) gene mutation in north Indians.

Hereditary hemochromatosis (HH) is a rare disorder in Indians and is not associated with the common mutation Cys282Tyr in HFE gene found in Caucasians. Non-HFE HH can be associated with mutations in HJV, HAMP, TFR2 and SLC40A1 genes. Nineteen unrelated north Indian HH patients were detected after screening 258 chronic liver disease patients on the basis of increased transferrin saturation, ferritin levels >1000 ng/L and siderosis by Perl's stain on liver biopsy wherever available. Automated DNA sequencing was performed for the promoters and entire coding exons for HFE, HJV, HAMP, TFR2 and SLC40A1. A novel homozygous mutation at position p.Gly336Ter (c.1006 G>T) in exon 4 in HJV was identified in four adult unrelated patients. We encountered compound heterozygosity for p.Thr217Ile (c.650C>T) and p.His63Asp (c.187C>G) mutation of HFE gene in one patient. Two patients were compound heterozygous for two novel polymorphisms at c.-358 (G>A) and c.-36 (G>A) in 5'UTR of HJV gene. Our study shows a novel HJV gene mutation p.Gly336Ter as a recurrent mutation associated with HH in north Indians. Low index of suspicion, underlying nutritional iron deficiency and protective effect of menstrual blood loss may account for the late clinical presentation of juvenile HH.

Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure.

BACKGROUND AND AIM: There is limited data on predictors of acute kidney injury in acute on chronic liver failure. We developed a PIRO model (Predisposition, Injury, Response, Organ failure) for predicting acute kidney injury in a multicentric cohort of acute on chronic liver failure patients. PATIENTS AND METHODS: Data of 2360 patients from APASL-ACLF Research Consortium (AARC) was analysed. Multivariate logistic regression model (PIRO score) was developed from a derivation cohort (n=1363) which was validated in another prospective multicentric cohort of acute on chronic liver failure patients (n=997). RESULTS: Factors significant for P component were serum creatinine[(≥2 mg/dL)OR 4.52, 95% CI (3.67-5.30)], bilirubin [(<12 mg/dL,OR 1) vs (12-30 mg/dL,OR 1.45, 95% 1.1-2.63) vs (≥30 mg/dL,OR 2.6, 95% CI 1.3-5.2)], serum potassium [(<3 mmol/LOR-1) vs (3-4.9 mmol/L,OR 2.7, 95% CI 1.05-1.97) vs (≥5 mmol/L,OR 4.34, 95% CI 1.67-11.3)] and blood urea (OR 3.73, 95% CI 2.5-5.5); for I component nephrotoxic medications (OR-9.86, 95% CI 3.2-30.8); for R component,Systemic Inflammatory Response Syndrome,(OR-2.14, 95% CI 1.4-3.3); for O component, Circulatory failure (OR-3.5, 95% CI 2.2-5.5). The PIRO score predicted acute kidney injury with C-index of 0.95 and 0.96 in the derivation and validation cohort. The increasing PIRO score was also associated with mortality (P<.001) in both the derivation and validation cohorts. CONCLUSIONS: The PIRO model identifies and stratifies acute on chronic liver failure patients at risk of developing acute kidney injury. It reliably predicts mortality in these patients, underscoring the prognostic significance of acute kidney injury in patients with acute on chronic liver failure.

Acute Liver Failure Due to Etodolac, a Selective Cycloxygenase- 2 (COX -2) Inhibitor Non-Steroidal Anti-Inflammatory Drug Established by RUCAM-Based Causality Assessment.

Drug induced liver injury is a common cause of acute liver failure (ALF). While most of these cases are due to dose dependent hepatotoxicity with acetaminophen, idiosyncratic drug-induced liver injury (DILI) is responsible for about 15% cases of ALF. Antibiotics are the most common cause of idiosyncratic DILI as well as DILI induced ALF. Etodolac is a selective cycloxygenase- 2 (COX -2) inhibitor non-steroidal anti-inflammatory drug used as an analgesic and anti-inflammatory in musculoskeletal diseases. Severe liver impairment is extremely rare. Till date, only 3 cases of ALF related to etodolac have been reported in the literature. Here we report two cases with a unique presentation of ALF occurring due to DILI caused by etodolac, as diagnosed by Roussel Uclaf Causality Assessment Method (RUCAM).

IFN-γ (+874) and not TNF-α (-308) is associated with HBV-HCC risk in India.

Tumor necrosis factor (TNF)-α and interferon (IFN)-γ, the pro-inflammatory Th1 cytokines are the indispensable coordinators of the inflammatory responses involved in hepatitis B virus (HBV) pathogenesis. This study attempted to evaluate any possible association among TNF-α (-308G>A) and IFN-γ (+874T/A) genotypes, the spontaneous blood and mRNA levels and expression of their major signal transducers, namely STAT1 and NF-кB with hepatitis B virus-induced hepatocellular carcinoma (HCC) susceptibility in India. For this, 398 subjects (146 controls, 68 inactive-HBV-carriers, 64 chronic-active HBV patients, 61 HBV-cirrhotics, and 59 HBV-HCC subjects) were enrolled. Polymerase chain reaction-restriction fragment length polymorphism, allele-specific PCR, enzyme-linked immunosorbent assay, reverse transcriptase-PCR, and Western blot analysis were done for assessing polymorphism, blood levels, mRNA expression, and protein expression of signal transducers, respectively, of TNF-α and IFN-γ. The study revealed no significant association of TNF-α (-308) GA genotype, while a significant negative association of IFN-γ (+874) TA and AA genotypes, in HBV-HCC risk. Moreover, blood levels of TNF-α were significantly elevated as disease progresses to HCC, while IFN-γ levels were raised in HCC patients only. Besides, IFN-γ mRNA levels were significantly elevated in cirrhotics, with no change observed in TNF-α transcript levels. Moreover, NF-кB expression also consistently increased during HCC progression. These observations suggest a vital negative association of IFN-γ (+874) with HBV-HCC risk, with no significant association evident in TNF-α (-308). However, the TNF-α and IFN-γ levels markedly increased in HCC development.

Paroxysmal Nocturnal Hemoglobinuria is rare cause for thrombosis of the intra-abdominal veins in the ethnic Indian population - results from FLAER-based flowcytometry screening.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) may present as cytopenia, hemolysis, or thrombosis at unusual sites including splanchnic vessels. Thrombosis of the portal veins and hepatic veins are associated with thrombophilic risk factors: deficiencies of protein C, protein S, and antithrombin, positivity for antiphospholipid antibodies, and factor V Leiden mutation. There is limited information regarding PNH presenting primarily as a thrombotic event. We prospectively screened 142 consecutive patients with intrabdominal thrombosis and 106 controls with fluorescently labeled inactive toxin aerolysin (FLAER)-based flowcytometry to assess the frequency of PNH as a thrombophilic risk factor in patients with intra-abdominal thrombosis. METHODS: Granulocytes of patients and controls were screened with CD 24 and FLAER and monocytes with CD 14 and FLAER. Dual negativity of >1% events in both lineages was interpreted as a positive PNH clone. Screening for thrombophilia risk factors was carried out. RESULTS: Two (1.4%) cases had large PNH clones. RBC also demonstrated the PNH defect. Thrombophilia risk factors were as follows: deficiency of protein S, protein C, and antithrombin in 13.4%, 4.9%, and 2.1%, respectively, and positivity for anti-beta-2 glycoprotein 1, anticardiolipin antibodies, and lupus anticoagulant in 9.2%, 1.4%, and 0.7%, respectively. Factor V Leiden mutation was seen in 1.4% patients. CONCLUSION: PNH was uncommon in patients with intra-abdominal thrombosis in the ethnic Indian population. Despite low positivity, screening by flowcytometry for PNH is of value in this group of patients because it provides an opportunity to rapidly establish the diagnosis of this treatable disorder, which might otherwise be missed if the initial presentation is only thrombotic.

IL-6(-572/-597) polymorphism and expression in HBV disease chronicity in an Indian population.

OBJECTIVES: This study evaluated the association among IL-6(-572) and IL-6(-597) genotypes, haplotypes, mRNA, and protein levels with hepatitis B virus (HBV)-Hepatocellular carcinoma (HCC) risk in India. METHODS: For this, 403 participants (153 controls, 61 inactive HBV-carriers, 65 chronic-active HBV patients, 63 HBV-cirrhotics, and 61 HBV-HCC participants) were enrolled in the study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), ELISA, and RT-PCR methods were used for assessing polymorphism, protein, and the mRNA levels, respectively, of IL-6. RESULTS: The study revealed that the IL-6(-572) GC genotype shared a positive association with hepatitis among controls, and a negative association with cirrhosis and consequent HCC development among carriers. However, the CC genotype shared a significant negative association with cirrhosis among controls and carriers. The IL-6(-597G>A), GA genotype acted as a potential protective factor for hepatitis, cirrhosis, and subsequent HCC development among carriers. The GA and CG haplotypes acted as a vital risk factor for HCC among controls and carriers. On the contrary, the CA haplotype was found to be a potential protective factor for HCC among carriers. Besides, the IL-6 levels significantly increased with cirrhosis development, as compared to carriers and hepatitis subjects. CONCLUSIONS: These preliminary findings indicate a potential role of IL-6(-572/-597) genotypes in HBV disease pathogenesis in an Indian population.

Association of interleukin-10 with hepatitis B virus (HBV) mediated disease progression in Indian population.

BACKGROUND & OBJECTIVES: Interleukin (IL)-10, an anti-inflammatory Th2 cytokine, is one of the key coordinators of the inflammatory responses involved. The present study was designed to evaluate the impact of IL-10 (-819/-592) genotypes, haplotypes, mRNA and the protein levels with risk for hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) development in India. METHODS: A total of 390 subjects (145 controls, 62 inactive HBV-carriers, 64 chronic-active HBV patients, 60 HBV related cirrhotics and 59 HBV- HCC subjects) were enrolled in the study. Allele specific (AS)-PCR, ELISA and RT-PCR methods were used for assessing polymorphism, spontaneous blood levels and the mRNA expression, respectively of IL-10. RESULTS: The study revealed that the CC/TA genotype acted as a risk factor for cirrhosis (OR a =2.02; P<0.05) and the subsequent HCC development (OR a =2.20; P<0.05), with controls as reference. However, no significant association was found between the two haplotypes (CC and TA) observed and HCC risk. Moreover, the IL-10 protein and mRNA levels in peripheral blood mono nuclear cells (PBMCs) showed a significant elevation as the disease progressed to cirrhosis. But, no variation was observed in the IL-10 levels in subjects with different IL-10 genotypes. INTERPRETATION & CONCLUSIONS: These preliminary results suggest a strong association of IL10 (-819/-592) with the HBV infection mediated disease progression, from inactive carrier state to malignancy, in Indian population.

Serum levels of angiogenic and anti-angiogenic factors: their prognostic relevance in locally advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prototype tumor wherein angiogenesis plays a vital role in its progression. The role of VEGF, a major angiogenic factor in HCC is known; however, the role of anti-angiogenic factors simultaneously with the angiogenic factors has not been studied before. Hence, in this study, the serum levels of major angiogenic [Vascular Endothelial Growth Factor (VEGF), angiopoietin-2 (Ang-2)] and anti-angiogenic (endostatin, angiostatin) factors were analyzed and correlated with clinico-radiological features and with outcome. A total of 150 patients (50 HCC, 50 cirrhosis and 50 chronic hepatitis) and 50 healthy controls were enrolled in this study. Serum levels of VEGF, Ang-2, endostatin, and angiostatin were estimated by enzyme-linked immunosorbent assay. HCC shows significantly elevated serum levels of angiogenic factors VEGF and Ang-2 and of anti-angiogenic factors endostatin and angiostatin. ROC curve analysis for serum VEGF yielded an optimal cut-off value of 225.14 pg/ml, with a sensitivity of 78 % and specificity of 84.7 % for a diagnosis of HCC and its distinction from other group. Using this value, the univariate and multivariate analysis revealed significantly poor outcome in patients with higher levels of serum VEGF (p = 0.009). Combinatorial analysis revealed that patients with higher levels of both angiogenic and anti-angiogenic factors showed poor outcome. Serum VEGF correlates with poor survival of HCC patients and, therefore, serves as a non-invasive biomarker of poor prognosis. Moreover, elevated levels of anti-angiogenic factors occur endogenously in HCC patients.

Angiogenic and anti-angiogenic factor gene transcript level quantitation by quantitative real time PCR in patients with hepatocellular carcinoma.

Tumor angiogenesis, a major requirement for tumor growth and metastasis, is regulated by pro- and anti-angiogenic factors. The aim of this study was to quantify the expression of angiogenic (VEGF, HIF-1α, Angiopiotein-2) and anti-angiogenic (endostatin, angiostatin and Thrombospondin-1) factors and to discern their clinical relevance. A total 90 patients (67 HCC, 9 cirrhosis and 14 chronic hepatitis) were enrolled in the study. Tissue transcript levels of angiogenic (VEGF, HIF-1α, Ang-2) and anti-angiogenic (endostatin, angiostatin and TSP-1) factors were analyzed by quantitative real time-polymerase chain reaction (qRT-PCR) in the tissue samples. The tissue transcript levels of VEGF, HIF-1α and endostatin were found to be significantly higher in HCC in comparison to cirrhosis and chronic hepatitis. Although Ang-2, angiostatin and TSP-1 tissue transcript levels were higher in HCC group than the others groups but the difference was not statistically significant. In univariate analysis both VEGF and HIF-1α were found to be associated with poor survival of HCC patients. Multivariate analysis by the cox proportional hazard model revealed only VEGF as an independent factor predicting poor survival of the HCC patients. Angiogenic and anti-angiogenic factors are all highly expressed in HCC patients. Upregulation of tissue anti-angiogenic factors indicates the urgency for the alternative of anti-angiogenic therapies.

Tongue hyperpigmentation resulting from peginterferon alfa-2b and ribavirin treatment in a patient with chronic hepatitis C.

Hepatitis C virus (HCV) infection has been associated with several cutaneous diseases such as lichen planus, porphyria cutanea tarda, chronic pruritus, and cutaneous necrotizing vasculitis (Doutre, Arch Dermatol 135:1401-1403, 1999). The antiviral treatment for chronic HCV with interferon alfa (INF) or peginterferon alfa (PEG-INF) combined with rivabirin also leads to many skin side effects including injection site reaction, generalized skin rashes, pruritus, dry skin, alopecia, and exacerbation of autoimmune processes, particularly psoriasis, lichen planus or vitiligo (Dalekos et al., Eur J Gastroenterol Hepatol 10:933-939, 1998; Sookoian et al., Arch Dermatol 135:1000-1000, 1999). There are case reports of tongue hyperpigmentation during combination therapy of PEG IFN and RBV in chronic hepatitis C both in dark-skined as well as Caucasian. We report the first case of tongue hyperpigmentation associated with PEG-INF-2b plus ribavirin administration in a non-Caucasian patient with genotype 4.

Impact of compensated cirrhosis on survival in patients with acute-on-chronic liver failure.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is considered a main prognostic event in patients with chronic liver disease (CLD). We analyzed the 28-day and 90-day mortality in ACLF patients with or without underlying cirrhosis enrolled in the ACLF Research Consortium (AARC) database. METHODS: A total of 1,621 patients were prospectively enrolled and 637 (39.3%) of these patients had cirrhosis. Baseline characteristics, complications and mortality were compared between patients with and without cirrhosis. RESULTS: Alcohol consumption was more common in cirrhosis than non-cirrhosis (66.4% vs. 44.2%, p < 0.0001), while non-alcoholic fatty liver disease/cryptogenic CLD (10.9% vs 5.8%, p < 0.0001) and chronic HBV reactivation (18.8% vs 11.8%, p < 0.0001) were more common in non-cirrhosis. Only 0.8% of patients underwent liver transplantation. Overall, 28-day and 90-day mortality rates were 39.3% and 49.9%, respectively. Patients with cirrhosis had a greater chance of survival compared to those without cirrhosis both at 28-day (HR = 0.48; 95% CI 0.36-0.63, p < 0.0001) and 90-day (HR = 0.56; 95% CI 0.43-0.72, p < 0.0001), respectively. In alcohol CLD, non-cirrhosis patients had a higher 28-day (49.9% vs. 23.6%, p < 0.001) and 90-day (58.4% vs. 35.2%, p < 0.001) mortality rate than cirrhosis patients. ACLF patients with cirrhosis had longer mean survival than non-cirrhosis patients (25.5 vs. 18.8 days at 28-day and 65.2 vs. 41.2 days at 90-day). Exaggerated systemic inflammation might be the reason why non-cirrhosis patients had a poorer prognosis than those with cirrhosis after ACLF had occurred. CONCLUSIONS: The 28-day and 90-day mortality rates of ACLF patients without cirrhosis were significantly higher than those with cirrhosis in alcoholic CLD. The presence of cirrhosis and its stage should be evaluated at baseline to guide for management. Thai Clinical Trials Registry, TCTR20191226002.

Extra hepatic portal vein obstruction and pregnancy outcome: largest reported experience.

AIM: Evaluate pregnancy outcome in women with extra hepatic portal vein obstruction (EHPVO). MATERIAL & METHODS: A total of 26 pregnancies in 14 women with EHPVO were evaluated for maternal and perinatal outcomes in a tertiary centre of Northern India. Fourteen pregnancies were evaluated prospectively while the details of 12 previous pregnancies in the same women were studied retrospectively. RESULTS: Mean age of pregnant women with EHPVO was 24.5 years and approximately one-third were primigravidae. Only one patient was diagnosed as EHPVO in the index pregnancy. The presenting event was hematemesis in 71% of the patients; others presented with thrombosis, pain abdomen and jaundice or incidental splenomegaly. The incidence of abortion, preterm deliveries and still births was 20%, 15.4% and 7.7%, respectively. Underlying hypercoagulable and prothrombotic state was diagnosed in around one-fifth of the patients. Half of these women required platelet transfusion in the intrapartum period due to hypersplenism resulting in thrombocytopenia. Anemia was seen in 40% of the patients; however, no other major complications were seen as a result of EHPVO. The vaginal delivery rate and obstetrical outcome were similar as in general population. CONCLUSION: Pregnancy outcome is expected to be successful in women with EHPVO if disease is adequately controlled prior to pregnancy.

Phylogenetic analysis and subtyping of acute and fulminant strains of hepatitis E virus isolates of North India with reference to disease severity.

Hepatitis E is endemic to the Indian subcontinent, with a seroprevalence of 4-20%, and more than 25% of acute viral hepatitis is due to HEV. The northern parts of India have been experiencing outbreaks and sporadic cases of HEV since 1955. In a total of sixteen HEV sequences, ten acute viral hepatitis and 6 fulminant hepatic failure cases were analysed. Subtypes 1a and 1c of HEV are prevalent in North India, with the subtype-1c showing a trend towards fulminancy.

Clinical significance of genotypes and precore/basal core promoter mutations in HBV related chronic liver disease patients in North India.

PURPOSE: Data on genotypes, basal core promoter (BCP) and precore mutants of hepatitis B virus and their association with different HBV related liver disease have been studied inadequately and are controversial. Thus, the aim of this study was to determine the incidence of BCP and precore HBV mutants and their relationship with HBV genotype and different stages of HBV related liver disease in North Indian patients. METHODS: A total 273 patients with different stages of HBV related liver diseases were enrolled. Nested polymerase chain reaction (PCR) was used to amplify the BCP/PC regions. RFLP and direct sequencing were performed to validate the mutations identified in these regions. HBV genotyping was accomplished by multiplex PCR. RESULTS: Genotype D was the predominant genotype found in each of the various HBV related liver diseases. The BCP mutation was found significantly more often in inactive carriers and compensated cirrhosis as compared to the other groups. The BCP mutation was present in 29.1% of patients with genotype D versus 17.1% with genotype A (P = 0.001). The precore mutation was also more frequently observed with genotype D compared with genotype A (36.9 vs. 4.8%, P = 0.0007). CONCLUSION: Genotype D is predominant in North Indian patients. The BCP and precore mutations occur in one-third of HBV positive patients in association with the genotype D. We did not find any correlation with severity of liver disease with genotypes and mutations.

Comparison of 7 staging systems in north Indian cohort of hepatocellular carcinoma.

BACKGROUND & AIM: Many liver staging systems have been proposed for patients with hepatocellular carcinoma (HCC); however it is still controversial which staging system is best. The aim of this study was to compare the ability of 7 different staging systems in predicting survival in an Indian cohort of patients with HCC. METHODS: In this prospective study, 101 HCC patients were diagnosed and stratified according to 7 different staging systems; along with analysis of independent predictors of survival and their correlation with it (Kaplan-Meier analysis). RESULTS: CLIP, Tokyo score and BCLC staging system showed a significant difference in the probability of survival. All other staging systems failed to show a significant difference in survival. Age, portal vein thrombosis, serum bilirubin, MELD score showed a significant difference with survival in univariate analysis. However, serum bilirubin was the independent predictor of survival with a hazard ratio of 1.609 (95% CI 1.015-2.553, p = 0.043). CONCLUSION: The CLIP, Tokyo score and BCLC are the most useful staging systems in an Indian cohort.

Pancreatic cysts causing biliary obstruction in von Hippel Lindau syndrome.

CONTEXT: Extrahepatic biliary obstruction secondary to pancreatic cysts is rare in patients with von Hippel Lindau syndrome. We describe a patient with von Hippel Lindau syndrome who had biliary obstruction due to pancreatic cysts who was initially managed endoscopically and then surgically. CASE REPORT: A female patient with von Hippel Lindau syndrome which had been diagnosed ten years earlier based on the presence of pancreatic and renal cysts with retinal hemangiomas, presented with cholestatic jaundice of two months duration. On investigation, she was found to have lower end biliary obstruction caused by pancreatic cysts. The patient was initially managed with endoscopic retrograde cholangiography and a 7 French/10F/12F biliary plastic stent placement. Her cholestatic symptoms improved but required frequent stent exchange due to stent block; she finally underwent a hepaticojejunostomy and is doing well on follow-up. CONCLUSION: This case highlights the fact that pancreatic involvement leading to biliary obstruction, although uncommon, can occur in patients with von Hippel Lindau syndrome. Endoscopic biliary stent placement and surgery are helpful in these patients.

Cost of Intensive Care Treatment for Liver Disorders at Tertiary Care Level in India.

BACKGROUND: Liver diseases contribute significantly to the health and economic burden globally. We undertook this study to assess the health system costs, out-of-pocket (OOP) expenditure and extent of financial risk protection associated with treatment of liver disorders in a tertiary care public sector hospital in India. METHODOLOGY: The present study was undertaken in an intensive care unit (ICU) of a tertiary care hospital in North India. It comprised an ICU and an HDU (high dependency unit). Bottom-up micro-costing was undertaken to assess the health system costs. Data on OOP expenditure and indirect costs were collected for 150 liver disorder patients admitted to the ICU or HDU from December 2013 to October 2014. Per-patient and per-bed-day costs of treatment were estimated from both health system and patient perspectives. Financial risk protection was assessed by computing prevalence of catastrophic health expenditure as a result of OOP expenditure. RESULTS: In 2013-2014, health system costs per patient treated in the ICU and HDU were US$2728 [Indian National Rupee (INR) 1,63,664] and US$1966 (INR 1,17,985), respectively. The mean OOP expenditures for treatment in the ICU and HDU were US$2372 (INR 1,42,297) and US$1752 (INR 1,05,093), respectively. Indirect costs of hospitalization in ICU and HDU patients were US$166 (INR 9952) and US$182 (INR 10,903), respectively. CONCLUSION: Treatment of chronic liver disorders poses an economic challenge for both the health system and patients. There is a need to focus on prevention of liver disorders, and finding ways to treat patients without exposing their households to the catastrophic effect of OOP expenditure.

Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions.

BACKGROUND: Insulin resistance plays an important role in the pathogenesis of NAFLD. Pharmacological treatment of patients with NAFLD is still evolving. Insulin sensitizing drugs like metformin may be effective in these patients. Twenty five adult patients with NAFLD who did not achieve normalization of alanine transaminases (ALT) after 6 months of lifestyle interventions and UDCA were treated with metformin 500mg tid for 6 months. Insulin resistance was determined by HOMA- IR. Liver function tests were done monthly and patients were defined having no response, partial response or complete biochemical response depending on the change in ALT. Results were compared with 25 patients with NAFLD from the same cohort treated only with lifestyle interventions (disease controls). RESULTS: Thirteen (52%) patients had class III (n = 5) or class IV (n = 8) disease amounting to histological NASH. Of these 13 patients none had severe inflammation and none had stage 4 fibrosis (cirrhosis). All 25 patients with NAFLD had insulin resistance in comparison to healthy controls. In comparison to disease controls (127.5 +/- 41.8 vs. 118 +/- 21.6 p = NS), all patients treated with metformin had partial biochemical response (mean ALT 122.2 +/- 26.8 vs 74.3 +/- 4.2 p < 0.01) and 14 (56%) of them achieved complete normalization of ALT. CONCLUSIONS: Metformin is effective to achieve biochemical response in patients with NAFLD who do not respond to lifestyle interventions and UDCA.