Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 2.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality. In many countries, there is a lack of comprehensive epidemiological data that are crucial in implementing disease control measures as new treatment options become available. Published literature, unpublished data and expert consensus were used to determine key parameters, including prevalence, viremia, genotype and the number of patients diagnosed and treated. In this study of 15 countries, viremic prevalence ranged from 0.13% in the Netherlands to 2.91% in Russia. The largest viremic populations were in India (8 666 000 cases) and Russia (4 162 000 cases). In most countries, males had a higher rate of infections, likely due to higher rates of injection drug use (IDU). Estimates characterizing the infected population are critical to focus screening and treatment efforts as new therapeutic options become available.

Strategies to manage hepatitis C virus (HCV) infection disease burden - volume 2.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries, and the relative impact of two scenarios was considered: (i) increased treatment efficacy while holding the treated population constant and (ii) increased treatment efficacy and increased annual treated population. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. In most countries, the annual treated population had to increase several fold to achieve the largest reductions in HCV-related morbidity and mortality. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. In most of the studied countries, the majority of patients were born between 1945 and 1985.

The present and future disease burden of hepatitis C virus (HCV) infections with today's treatment paradigm - volume 2.

Morbidity and mortality attributable to chronic hepatitis C virus (HCV) infection are increasing in many countries as the infected population ages. Models were developed for 15 countries to quantify and characterize the viremic population, as well as estimate the number of new infections and HCV related deaths from 2013 to 2030. Expert consensus was used to determine current treatment levels and outcomes in each country. In most countries, viremic prevalence has already peaked. In every country studied, prevalence begins to decline before 2030, when current treatment levels were held constant. In contrast, cases of advanced liver disease and liver related deaths will continue to increase through 2030 in most countries. The current treatment paradigm is inadequate if large reductions in HCV related morbidity and mortality are to be achieved.

Association of interleukin-10 polymorphisms with chronic hepatitis C virus infection in a case-control study and its effect on the response to combined pegylated interferon/ribavirin therapy.

We conducted a case-control study involving 150 genotype 3 chronic hepatitis C virus (HCV) patients and 150 healthy controls to investigate the association of polymorphisms in the interleukin-10 (IL-10) gene with chronic HCV infection and the association of these polymorphic variants with the combination of pegylated interferon (Peg-IFN) and ribavirin therapy response. Our data revealed that the GG genotype of IL-10 -1082A/G exhibited significant association with genotype 3 chronic HCV infection compared to controls. Treatment response data also showed a significant increase in risk for the GG genotype of IL-10 -1082A/G in response-relapse patients or non-responder patients compared to sustained virological response patients. Further, a significant increase in risk was also revealed for the CC genotype of IL-10 -592A/C in response-relapse patients or non-responder patients compared to sustained virological response patients, suggesting a role of the GG genotype of IL-10 -1082A/G and CC genotype of IL-10 -592A/C in the treatment outcome of combined Peg-IFN/ribavirin therapy.

Randomized clinical trial: efficacy and safety of telbivudine and lamivudine in treatment-naïve patients with HBV-related decompensated cirrhosis.

Patients with decompensated cirrhosis owing to chronic hepatitis B viral (HBV) infection have a high morbidity/mortality rate, and the treatment remains a challenge. We studied the safety and efficacy of telbivudine and lamivudine in such patients. This noninferiority, double-blind trial randomized 232 treatment-naive patients with decompensated HBV (1:1) in 80 academic hospitals to receive once-daily telbivudine 600 mg or lamivudine 100 mg for 104 weeks. Primary composite endpoint was proportion of patients with HBV DNA <10 000 copies/mL, normal alanine aminotransferase (ALT) and Child-Turcotte-Pugh score improvement/stabilization at week 52. Response rates using a post hoc modified endpoint (HBV DNA <300 copies/mL [57 IU/mL] and ALT normalization) in intent-to-treat analysis (missing = failure) were 56.3%vs 38.0% after 76 weeks (P = 0.018) and 45.6%vs 32.9% after 104 weeks (P = 0.093) for telbivudine vs lamivudine. Telbivudine treatment was an independent predictive factor for HBV DNA <300 copies/mL and ALT normalization (P = 0.037). Response rates with protocol-defined composite endpoint in intent-to-treat analysis (M = F) were 56.2 vs 54.0% (noninferiority not achieved) and 39.1%vs 36.4% (noninferiority achieved) in telbivudine and lamivudine groups at 52 and 104 weeks. Telbivudine treatment was associated with a significant improvement in glomerular filtration rate compared to lamivudine treatment and was also associated with a trend for improvement in survival (87%vs 79%). No cases of lactic acidosis were reported. Telbivudine compared to lamivudine was associated with a higher rate of patients with both viral suppression and ALT normalization, a trend towards a higher rate of survival and significant improvement in glomerular filtration.

Association of 5, 10- methylenetetrahydrofolate reductase C677T polymorphism in susceptibility to tropical chronic pancreatitis in north Indian population.

MTHFR is a key enzyme in folate metabolism that catalyzes the conversion of 5, 10—methlenetetrahydrofolate (5, 10— methylene THF) to 5—methyltetrahydrofolate (5—methyl THF), a predominant circulatory form of folate and methyl donor for the remethylation of homocysteine to methionine. Some studies have shown that C667T polymorphism increases the risk of pancreatic cancer. Since MTHFR is involved in methylation, inflammation and protection against oxidative stress, the processes especially important for pancreatic homeostasis. The altered enzyme activity could play a role in pancreatic injury. The role of MTHFR C677T polymorphism in chronic pancreatitis has been explored by conducting a hospital based; case—control study involving 100 patients radiologically confirmed chronic pancreatitis and 329 healthy controls. All samples were analyzed for MTHFR C677T polymorphism using PCR—RFLP method. Restriction enzyme Hinf I was used to digest the 198 bp amplified product. The frequency of the MTHFR was 57.3%, 34.1% and 8.5% among cases compared with 87.2%,11.2% and 1.5% of controls for CC, CT and TT genotypes, respectively. The T Allele frequency was found significantly higher in patients than in controls. A significant association with T allele was observed with p—value (< 0.0001) odds ratio 4.475 and (95% CI=2.961—7.046). It could be predisposing to the traditional risk factors such as diabetes, dietary, alcohal and smoking habit that are known to be associated with chronic pancreatitis. Additionally it was observed that smoking increases the risk of chronic pancreatitis by 4.1 times. The T allele frequency of MTHFR (C667T) was found to be a significant risk factor for chronic pancreatitis playing a crucial role in altered folate metabolsim.

Frequency and factors associated with small intestinal bacterial overgrowth in patients with cirrhosis of the liver and extra hepatic portal venous obstruction.

Spontaneous bacterial peritonitis (SBP), a common complication of cirrhosis of liver, might result from translocation of bacteria from the small bowel. However, there is scanty data on frequency of small intestinal bacterial overgrowth (SIBO) in patients with cirrhosis of the liver. There are no data on SIBO in patients with extra-hepatic portal venous obstruction (EHPVO) in the literature. A total of 174 patients with cirrhosis of the liver, 28 with EHPVO and 51 healthy controls were studied for SIBO using glucose hydrogen breath test (GHBT). Persistent rise in breath hydrogen 12 ppm above basal (at least two readings) was considered diagnostic of SIBO. Of 174 patients (age 47.2 +/- 11.9 years, 80.5% male) with cirrhosis due to various causes, 67 (38.5%) were in Child's class A, 70 (40.2%) class B and 37 (21.7%) class C. Of the 174 patients with cirrhosis, 42 (24.14%) had SIBO as compared to 1 of 51 (1.9%) healthy controls (P < 0.0001). Patients with EHPVO had similar frequency of SIBO compared to healthy controls [2/28 (7.14%) vs 1/51 (1.97%), P = ns]. Frequency of SIBO in Child's A, B and C was comparable [13 (18.6%) vs 16 (23.9%) and 13 (35.1%), respectively; P = ns]. Presence of SIBO were not related to ascites, etiology of cirrhosis, and degree of liver dysfunction. SIBO is common in patients with cirrhosis of the liver. Patients with EHPVO do not have higher frequency of SIBO than healthy subjects. SIBO in cirrhosis is not related to the degree of derangement in liver function or of portal hypertension.

Single-nucleotide polymorphisms of DNA repair genes OGG1 and XRCC1: association with gallbladder cancer in North Indian population.

BACKGROUND: DNA damage by endogenous or exogenous source of reactive oxygen species (ROS) plays an important role in induction and progression of various cancers. Physiologically, gallbladder is likely to be exposed to various ROS which leads to extensive DNA damage. Cells overcome the DNA damage by repair mechanisms. Genetic variants of OGG1 and XRCC1, important enzymes participating in base excision repair pathway, may confer interindividual variations in susceptibility to gallbladder cancer (GBC). This study was aimed to examine the role of OGG1 Ser326Cys (rs1052133) and XRCC1 Arg194Trp (C > T) (rs25487) and Arg399Gln (G > A) (rs1799782) polymorphisms in GBC susceptibility. METHODS: The study included 173 GBC patients and 204 controls. Genotyping was done by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Differences in the frequencies were estimated by chi-square test and risk was estimated by using unconditional logistic regression after adjusting for age and gender. RESULTS: OGG1 Cys/Cys genotype frequency was significantly higher in GBC patients [odds ratio (OR) = 2.93; 95% confidence interval (CI) = 1.14-7.51]. The increased risk was more pronounced in female GBC patients (OR = 5.92; 95%CI = 1.20-29.13), patients with gallstone (OR = 5.50; 95%CI = 1.99-15.16), female gender, and late onset of disease (OR = 4.72, 95%CI = 1.43-15.53). In XRCC1 Arg399Gln polymorphism, significant differences in frequencies of Gln/Gln and Arg/Gln genotypes conferred significantly low risk for GBC (OR = 0.62; 95%CI = 0.39-0.97 and OR = 0.37; 95%CI = 0.19-0.71 respectively). However, XRCC1 Arg194Trp polymorphism was not associated with GBC. The carriers of Arg-Gln haplotype consisting of 194Arg and 399Gln alleles of XRCC1 were also at significant low risk for GBC (OR = 0.59, 95%CI = 0.42-0.82). Interaction of genotypes and tobacco usage did not modulate the risk. CONCLUSION: Results suggest that Cys/Cys genotype of OGG1 Ser326Cys polymorphism is associated with increased risk of GBC. However, Arg399Gln polymorphism and Arg-Gln haplotype comprising XRCC1 Arg194Trp and Arg399Gln polymorphisms conferred low risk for GBC susceptibility.

CCR5 Delta32 polymorphism: associated with gallbladder cancer susceptibility.

Inflammation of gallbladder is an established risk factor for gallbladder cancer (GBC) pathogenesis. Chemokine receptors play crucial role in antitumour immunity and are involved in inflammation and pathogenesis of cancers. Present study was aimed to examine the role of CCR5 Delta32 polymorphism in conferring genetic susceptibility to GBC. Present case-control study included 144 proven GBC patients and 210 healthy controls. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Statistically significant difference was observed in distribution of CCR5+/Delta32 genotype (P = 0.028) [odds ratio (OR) = 2.850; 95% confidence interval (CI) = 1.1-7.2] and CCR5 Delta32 allele (P = 0.012) (OR = 3.145, 95% CI = 1.2-7.7) in GBC patients which was conferring high risk. Stratification of GBC patients showed significant association of CCR5+/Delta32 genotype and CCR5 Delta32 allele with GBC patients with and without gallstones. Analysis based on age of onset and gender suggested significant association of CCR5 Delta32 allele with early onset (<50 years) of the disease but only marginal influence of gender in CCR5 Delta32-mediated risk of cancer. Risk was further modulated by tobacco usage and significantly increased risk was observed in tobacco users with CCR5+/Delta32 genotype. In conclusion, CCR5+/Delta32 genotype and CCR5 Delta32 allele confer significant risk for GBC particularly in patients with early onset and tobacco usage. Role of CCR5+/Delta32 polymorphism in GBC susceptibility is independent of gallstone formation.

Association of APOE-C1 gene cluster polymorphisms with gallstone disease.

BACKGROUND: Genetic polymorphisms in apolipoprotein genes may be associated with alteration in lipid profile and susceptibility to gallstone disease. AIM: To find out the association of APOE HhaI and APOC1 HpaI polymorphisms with gallstone disease. SUBJECTS: HhaI polymorphism of APOE and HpaI polymorphism of APOC1 were analysed in DNA samples of 214 gallstone patients and 322 age- and sex-matched healthy controls. METHODS: For genotyping DNA samples of all study subjects were amplified using polymerase chain reaction, followed by restriction digestion. All statistical analyses were done using SPSS v11.5 and ARLEQUIN v2.0 softwares. RESULT: APOC1 HpaI polymorphism was found to be significantly associated with gallstone disease. Frequency of H2H2 was significantly higher (P = 0.017) in patients than in controls and it was imposing very high risk (OR 9.416, 95% CI 1.125-78.786) for gallstone disease. When data were stratified in male and female, H2H2 was associated (P = 0.011) with disease in females only. Analysis at allele level revealed no association. APOE HhaI polymorphism and APOE-C1 haplotypes showed no association with gallstone disease. CONCLUSION: APOC1 HpaI polymorphism is associated with gallstone disease and shows gender-specific differences. APOE HhaI polymorphism may not be associated with gallstone disease.

Exocrine pancreatic and beta-cell function in malnutrition-related diabetes among north Indians.

OBJECTIVE: To compare the pancreatic exocrine and beta-cell function in the two variants of malnutrition-related diabetes mellitus (MRDM): fibrocalculous pancreatic diabetes (FCPD) and protein-deficient pancreatic diabetes (PDPD). RESEARCH DESIGN AND METHODS: Fecal chymotrypsin (FCT) and fasting C-peptide levels were measured in 20 consecutive patients with FCPD and 19 with PDPD. FCPD was diagnosed by pancreatic calcification on ultrasonography, while the diagnosis of PDPD was made on the basis of low body mass index, severe diabetes requiring insulin therapy, and ketosis resistance on interruption of insulin. Twenty patients with type I diabetes and 32 healthy subjects served as control subjects. RESULTS: Both FCPD and PDPD patients had diminished levels of FCT when compared with those of control subjects and patients with type I diabetes. However, FCT levels were significantly lower in subjects with FCPD (median 0.4 U/g, range 0-8.9 U/g), in comparison with those with PDPD (4.7 U/g, 0.6-40.5 U/g; P < 0.001). Of the FCPD patients, 13 of 20 (65%) had severe exocrine pancreatic deficiency (FCT < 1 U/g) vs. 3 of 19 (15.8%) PDPD subjects (P < 0.01). In comparison with control subjects, fasting serum C-peptide levels were significantly diminished in both MRDM groups. However, C-peptide levels in subjects with FCPD (mean +/- SE, 0.22 +/- 0.04 nmol/l) and PDPD (0.26 +/- 0.04 nmol/l) were comparable. CONCLUSIONS: Among the two variants of MRDM, subjects with FCPD have severe pancreatic exocrine deficiency in comparison with those with PDPD, even though their C-peptide levels are comparably diminished. This suggests that the pathogenesis of these two entities may differ or that the genetic and/or environmental factors leading to exocrine damage are different.

Beta-cell function and insulin sensitivity in tropical calcific pancreatitis from north India.

Tropical calcific pancreatitis (TCP) is a variant of chronic pancreatitis, occurring only in developing countries. It frequently leads to diabetes at a young age. To determine the pathogenesis of glucose intolerance, beta-cell function and insulin sensitivity were measured in 11 TCP patients with normal glucose tolerance (TCP-NGT), six TCP patients with mild hyperglycemia [TCP-DM] median fasting plasma glucose, 6.1 mmol/L), and 16 healthy control subjects. The technique of continuous infusion of glucose with model assessment (CIGMA) was used to calculate beta-cell function (%B) and insulin sensitivity (%S), based on plasma glucose and insulin levels achieved after an intravenous infusion of glucose. %S was similar in both groups of TCP patients and controls. In contrast, %B was significantly lower in TCP-DM patients (median, 53; interquartile range, 41 to 62) compared with controls (90; 65 to 143; P < .01) and with TCP-NGT patients (119; 91 to 159; P < .01). TCP-NGT and control subjects had similar beta-cell function. Among patients with TCP, %B negatively correlated with the duration of pancreatitis (r = -.63, P < .05). Our results suggest that patients with TCP develop diabetes due to a diminution in beta-cell function, and that insulin resistance does not play a significant role in its pathogenesis.

Complex ruptured amebic liver abscesses: the role of percutaneous catheter drainage.

The failure of medical therapy for amebic liver abscess may be followed by its perforation, a complication associated with high mortality. We assessed the role of percutaneous catheter drainage in management of the sequelae of ruptured amebic abscesses in 13 critically ill patients; 22 intrahepatic lesions, three of which were multiloculated, were drained. Catheters were also placed in 17 extrahepatic collections: pleural space (n = 5), subphrenic (n = 7), perihepatic/subhepatic (n = 3), greater sac of peritoneum (n = 2). No attempt at percutaneous drainage failed. Prompt resolution of clinical features following drainage was a uniform feature. Successful resolution of the abscesses occurred within 20 days in 11 patients. In the remaining two, catheters needed to be retained in situ for 35 and 50 days. The mean hospital stay was 15 days (range 10-20 days). 100% patient survival was achieved, without a single morbid episode. Our results suggest that patients with ruptured amebic abscesses can be effectively and safely managed by percutaneous catheter drainage irrespective of the extent of extrahepatic contamination.

Percutaneous catheter drainage of amebic liver abscesses with and without intrahepatic biliary communication: a comparative study.

Influence of communication with the intrahepatic biliary system on the clinical picture of amebic liver abscesses in 33 consecutive patients resistant to medical therapy, and their response to percutaneous catheter drainage was evaluated. Abscess-biliary communication was found in 27% of the sample. Patients with abscesses communicating with the biliary tree presented more frequently with jaundice (67% vs. 0%, P < 0.005), with a longer duration of illness (median 20 vs. 12 days, P < 0.001), had larger lesions (median 600 vs. 320 ml, P < 0.001) and required catheter drainage for longer periods (median 17 vs. 6.5 days, P < 0.000001). However the presence of a biliary communication did not materially affect the cure rate with catheter drainage (89% vs 100%, P > or = 0.05). In conclusion, an abscess-biliary communication is not uncommon in refractory amebic liver abscesses, and can be clinically detected by the presence of jaundice. Though a prolonged period of drainage may be necessary in the presence of this complication, catheter drainage can be expected to result in cure.

Endosonographic evaluation of the venous anatomy around the gastro-esophageal junction in patients with portal hypertension.

BACKGROUND/AIMS: Para-esophageal venous collaterals and perforating veins have recently been suspected to play an important role in the development of esophageal varices and their recurrence after initial obliteration in patients with portal hypertension. We undertook this study to look at the cross-sectional venous anatomy around the gastro-esophageal junction, with special attention to those venous structures, using the Endoscopic Ultrasound (EUS) in patients with different grades of esophageal varices. MATERIAL AND METHODS: EUS examination was performed on the upper stomach, GE junction, and lower esophagus in 50 patients with liver cirrhosis, 20 of whom had small (grades 1 & 2) and 30 had large (grades 3 & 4) esophageal varices. RESULTS: Esophageal varices could be detected in all the 30 (100%) patients with large, but in 9 (45%) of patients with small varices. Gastric Varices were detected significantly more often by EUS (33; 66%) compared with endoscopy (17; 34%, p < 0.005). The mean number (2.8 +/- 1.4 and 4.7 +/- 1.78, p < 0.0005) and size 3.41 +/- 0.57 and 5.98 +/- 1.66, p < 0.00001) of paraesophageal veins were higher in patients with large varices compared with those with small varices. When the lower 5 cm of the esophagus was scanned in patients with small and large varices, perforating veins connecting the para-esophageal and the submucosal veins (varices) could be identified in 3 (15%) and 21 (70%, p < 0.0005) of patients, respectively. CONCLUSION: Perforating veins connecting the paraesophageal with the submucosal veins (varices) in the lower esophagus, demonstrated for the first time by EUS, may have an important role in the development of varices and in their recurrence after sclerotherapy.

The clinical spectrum of fibrocalculous pancreatic diabetes in north India.

BACKGROUND: Fibrocalculous pancreatic diabetes (FCPD) is a secondary form of diabetes, unique to tropical countries. In earlier reports, patients with FCPD had severe insulin-requiring diabetes, malnutrition and a dismal prognosis. With Improvements in nutrition and medical care, the presentation and prognosis of FCPD may have changed. We report on the clinical profile and prognosis of a cohort of FCPD patients from north India and compare our findings with earlier reports. METHODS: Eighty consecutive FCPD patients who presented to the Diabetes, Gastroenterology and Surgical Gastroenterology services were evaluated for their nutritional status, clinical presentation, beta-cell function (fasting C-peptide) and exocrine function (faecal chymotrypsin). All patients diagnosed between 1994 and 2000 (n = 32) were followed prospectively for weight gain and glycaemic control. RESULTS: Only 55% of FCPD patients had a low body mass index (< 18 kg/m2). At the time of diagnosis of diabetes, only 26 (33%) patients presented with severe insulin-requiring diabetes; these patients were younger [23.7 (8.3) years v. 28.7 (10.6) years, p = 0.04], and had higher haemoglobin A1c [9.7 (3.8)% v. 7.3 (2.6)%, p = 0.005] than those requiring diet control or oral hypoglycaemic agents. FCPD patients had a wide range of fasting serum C-peptide (0.03-0.76 nmol/L). C-peptide was negatively associated with increasing duration of diabetes (r = -0.48, p = 0.001), but there was no correlation with faecal chymotrypsin. On prospective follow up (mean 2.3 years), there was significant improvement in body mass index [19.4 (2.9) kg/m2 v. 17.0 (3.7) kg/m2, p < 0.01] and haemoglobin A,c [6.4 (1.6)% v. 8.0 (3.0)%, p < 0.001]. CONCLUSION: FCPD patients differed from those described in earlier reports in many respects, Including improved nutritional status, a wide range of 3cell function and a more favourable prognosis.

Role of trace elements in hepatic encephalopathy: zinc and manganese.

Apart from increased blood ammonia, alterations in various other substances have been implicated in the pathogenesis of hepatic encephalopathy (HE). The role of trace elements like zinc and manganese has been described recently. Zinc is an essential trace element and functions as an antioxidant. Low zinc concentrations have been reported in patients with cirrhosis of the liver, particularly those with HE. Patients with fulminant hepatic failure and subacute hepatic failure have also been shown to have low serum zinc levels. In animal experiments, zinc supplementation leads to a reduction in blood ammonia. Zinc deficiency also leads to alteration of neurotransmitters like gamma aminobutyric acid and norepinephrine. Zinc supplementation has been tried in HE. It may have a role in mild chronic HE, though further trials are necessary. Increased serum manganese levels have been shown in acute and chronic hepatitis, cirrhosis and congenital disorders like Alagille's syndrome. High manganese content has been reported in the globus pallidus in animals as well as brain tissues of patients dying of HE. Miners with chronic manganese exposure have encephalopathy and extra-pyramidal features similar to HE. It has been postulated that manganese impairs neuronal oxidative metabolism. The role of manganese in the pathogenesis of HE and the possibility of its chelation as treatment need further study.

Extra-anatomic stenting of the biliary system.

Tumor necrosis interfered with conventional methods of stenting in a patient with hilar cholangiocarcinoma. Therefore, a hepaticoduodenal fistula was percutaneously catheterized and dilated, and a large caliber endoprosthesis inserted to drain the right hepatic ductal system.

Association of digital clubbing with corrosive stricture of esophagus.

We report a young woman who developed digital clubbing following corrosive esophageal injury. The clubbing regressed with effective dilatation of the esophageal stricture.

Periampullary carcinoma in a young female with situs inversus.

Periampullary carcinoma in a young female with situs inversus viscerum is reported. Endoscopy was difficult because of the altered anatomy.