Prognostic, clinical, and therapeutic importance of RANTES-CCR5 axis in hepatitis A infection: A multiapproach study.

Fulminant hepatic failure (FHF) is a lethal manifestation of hepatitis A virus (HAV) infection, whose underlying mechanisms are poorly understood. We aimed to evaluate the importance of the modulation of the RANTES-chemokine receptor type 5 (CCR5) signaling axis and its immunomodulatory effects in directing hepatitis A disease pathogenesis using an in silico, in vitro and patient cohort-based approach. In silico interaction studies were performed using computation approaches with suitable software. Differential expression of relevant cytokines and immune cell markers were studied using real-time quantitative reverse transcription PCR (qRT-PCR), enzyme-linked immunosorbent assay, and flow-cytometry-based methods. In the HepG2 cell line, we studied inflammatory responses and susceptibility to HAV infection following RANTES stimulation and antibody blockade of CCR5. The HAV-VP3 region exhibited high interaction in CCR5: HAV complexes. RANTES levels were significantly increased in FHF cases. Reduced monocyte and T-cell activation were observed in FHF cases. RANTES expression inversely correlated with viremia but positively correlated with proinflammatory responses. Hyper Th1-biased immune responses, marked by high interleukin (IL)-12/IL-10 ratio were observed in FHF cases, which were also characterized by upregulated tumor necrosis factor-alpha (TNF-α) expression and reduced interferon-gamma expression. In vitro, RANTES was protective against HAV infection but resulted in upregulated TNF-α expression. Although viral load increased upon the regulation of inflammatory responses by CCR5 blocking, it was still significantly lower compared to control HAV-infected cells. Our study suggests the importance of RANTES-CCR5 signaling and linked-immunomodulation in HAV disease pathogenesis, as well as highlights the utility of CCR5 antagonists as a risk-reduction strategy in FHF patients. Our findings, therefore, have important implications for the management of high-risk HAV infections.

Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure.

Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.

Indian National Association for the Study of the Liver Consensus Statement on Acute Liver Failure (Part 1): Epidemiology, Pathogenesis, Presentation and Prognosis.

Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.

2019 Update of Indian National Association for Study of the Liver Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri II Recommendations.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality, and healthcare expenditure in patients with chronic liver disease in India. The Indian National Association for Study of the Liver (INASL) had published its first guidelines on diagnosis and management of HCC (The Puri Recommendations) in 2014, and these guidelines were very well received by the healthcare community involved in diagnosis and management of HCC in India and neighboring countries. However, since 2014, many new developments have taken place in the field of HCC diagnosis and management, hence INASL endeavored to update its 2014 consensus guidelines. A new Task Force on HCC was constituted that reviewed the previous guidelines as well as the recent developments in various aspects of HCC that needed to be incorporated in the new guidelines. A 2-day round table discussion was held on 5th and 6th May 2018 at Puri, Odisha, to discuss, debate, and finalize the revised consensus statements. Each statement of the guideline was graded according to the Grading of Recommendations Assessment Development and Evaluation system with minor modifications. We present here the 2019 Update of INASL Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri-2 Recommendations.

Reduced glutathione in hepatitis E infection and pregnancy outcome.

AIM: To study reduced glutathione (GSH) as a marker of oxidative stress in hepatitis E virus (HEV) infection during pregnancy, and to clarify its association with pregnancy outcome. METHODS: A total of 30 pregnant and 30 non-pregnant women with HEV infection were enrolled in the present study, along with 30 age- and gestation-matched healthy pregnant controls. Serum GSH was measured using commercially available enzyme-linked immunoassay kit. RESULTS: Significantly lower GSH was observed in HEV-infected pregnant women than in healthy pregnant controls (10.44 ng/mL vs 19.77 ng/mL; P < 0.01). No significant association was observed between GSH and pregnant women and non-pregnant women with HEV infection (P = 0.54). Serum GSH ≤10.88 ng/mL was more likely to be associated with HEV infection during pregnancy, with sensitivity and specificity of 73.3%. Lower GSH was observed in pregnant women with HEV infection having preterm delivery and low birthweight newborns compared with healthy pregnant women (P < 0.01 and P < 0.05, respectively). Serum GSH was lower in pregnant women with HEV infection who had stillbirth compared with those having live births (7.21 ng/mL vs 6.12 ng/mL, P = 0.60). CONCLUSION: Oxidative stress is present in HEV infection during pregnancy, as shown by low GSH, and is associated with adverse pregnancy outcomes. Serum GSH ≤10.88 ng/mL during pregnancy can be used for risk stratification for HEV infection.

Frequency of nucleotide sequence variations in the internal ribosome entry site region of hepatitis C virus RNA isolated from responding and non-responding patients with hepatitis C virus genotype 3 infection.

Located within 5' untranslated region of HCV RNA is internal ribosome entry site (IRES) which directs cap-independent translation of viral polyprotein. Mutations in IRES sequence have been shown to cause changes in efficiency of protein translation in vitro in few instances. No study has been done to investigate association between frequency of nucleotide sequence variations in IRES region of HCV-3 RNA and response to pegylated interferon-α plus ribavirin therapy. Hence, this study was planned to analyze relationship between frequency of nucleotide sequence variations of HCV-3 IRES region and response to therapy. Twenty-seven HCV-3 patients were studied, of whom 19 responded to therapy and 8 did not. Alanine aminotransferase and aspartate aminotransferase levels were significantly lower in responders compared to non-responders. HCV RNA detection and genotyping was performed by nested-PCR and RFLP respectively. Viral load quantification in pre and post therapy samples was done by real time PCR. The viral load was significantly lower in the patients after treatment as compared to before treatment. HCV IRES region from pre-treatment sera of 27 HCV-3 infected patients was amplified by nested PCR and sequenced. Secondary structure of IRES region of HCV-3 was predicted using the M fold Web Server. Mutational analysis revealed hot spot of mutations in HCV-3 IRES region from 40-80 and 210-280 nucleotides. Though more mutations were found in non-responders as compared to responders, this difference was statistically insignificant. Therefore, in addition to IRES region of HCV-3, some other host and viral factors may contribute to therapy outcome.

The Indian National Association for Study of the Liver (INASL) Consensus on Prevention, Diagnosis and Management of Hepatocellular Carcinoma in India: The Puri Recommendations.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.

GSTM1 and GSTT1 polymorphism and susceptibility to esophageal cancer in high- and low-risk regions of India.

Glutathione transferases, a super family of dimeric phase II metabolic enzymes play a vital role in biotransformation of many substances. This study evaluates the influence of genetic polymorphism of GSTM1 and GSTT1 gene loci on esophageal cancer risk in Assam and Delhi from India. DNA from blood samples of esophageal cancer cases (203,112) and controls (286,150) from Assam and Delhi, respectively, were extracted. GSTM1 and GSTT1 polymorphisms were analyzed by multiplex PCR procedure. Differences in proportions were tested using Pearson's chi-square test with odds ratio (OR) and 95 % confidence interval (CI). Risk of esophageal cancer was approximately twice in individuals having homozygous GSTM1 (OR-2.1, 95 % CI, 1.44-3.13) and GSTT1 null genotypes (OR-1.7,95 % CI, 0.99-2.77) in Assam, and around three times in GSTT1 null genotype (OR-2.9, 95 % CI, 1.56-5.27) in Delhi population. GSTM1 null genotype seems to play a protective role (OR-0.7, 95 % CI, 0.39-1.27) in Delhi. A significant association of GSTM1 null genotype with esophageal cancer was observed in a younger age group in Assam (OR-2.7, 95 % CI, 1.48-5.01), and in Delhi population association was observed in smokers with GSTT1 null genotype (OR-2.5, 95 % CI, 1.04-6.07), and alcoholics having GSTM1 null genotype (OR-2.6, 95 % CI, 0.99-6.77). Significant association of GSTM1 null genotype in Assam was observed between cancer cases and controls in fermented betel nut chewers only (OR-2.8, 95 % CI, 1.19-6.72), whereas, smoking and alcohol failed to show any correlation with GSTM1/GSTT1 genotypes. Cancer development is not only due to exogenous or endogenous carcinogens but depends on their interaction with genes that are involved in the detoxification of these carcinogens.

Waldenstrom macroglobulinemia presenting with pancreatic mass: a case report and review of literature.

CONTEXT: Waldenstrom macroglobulinemia is a rare lymphoplasmacytic lymphoma characterized by a wide range of clinical presentations related to direct tumor infiltration and the production of IgM. Most commonly it presents with cytopenia, hepatosplenomegaly, lymphadenopathy, constitutional symptoms, and hyperviscosity syndrome. CASE REPORT: We report a case of Waldenstrom macroglobulinemia in an 60-year-old female who initially presented with intermittent abdominal pain. The patient had no peripheral lymphadenopathy. On extensive investigation she was found to have pancreatic mass. The diagnosis of Waldenstrom macroglobulinemia was established after cytomorphology and immunohistochemical analysis of the patient's bone marrow revealed the presence of a lymphoid/lymphoplasmacytoid-like bone marrow infiltrate along with an elevated serum IgM level. The patient responded both clinically and serologically to chemotherapy. This case is unusual because the patient lacked all common clinical features of Waldenstrom macroglobulinemia with exception of anemia. CONCLUSION: To our knowledge this is the first report of a patient with Waldenstrom macroglobulinemia presenting with a pancreatic mass adding to the spectrum of clinical presentations seen in this disease. This adds to the wide variety of gastrointestinal related clinical presentations of Waldenstrom macroglobulinemia and points to the need for considering Waldenstrom macroglobulinemia along with other lymphoid neoplasms in the differential diagnosis of pancreatic lesions.

Sweet's syndrome in a patient with infective endocarditis: a rare clinical entity.

Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, has been associated with malignancy, autoimmune disease and collagen vascular disease. The association of infective endocarditis and Sweet's syndrome is rare. The authors report a case of Sweet's syndrome in a patient with infective endocarditis. Infective endocarditis should be excluded in patients of rheumatic heart disease presenting with Sweet's syndrome. Alternatively, Sweet's syndrome should be considered as a differential diagnosis when a patient with infective endocarditis develops skin lesions.

Polymorphism of tumor necrosis factor-α and interleukin-10 gene promoter region in chronic hepatitis C virus patients and their effect on pegylated interferon-α therapy response.

The development and resolution of an inflammatory process is regulated by a complex interplay among cytokines that have pro- and anti-inflammatory effects. Regulatory mechanisms that control the production of cytokines include genetic polymorphism in particular promoter/leader region. Polymorphisms may directly or indirectly affect the binding of transcriptional factors, consequently increasing or decreasing the production of mRNA, thus regulating cytokine production. A total of 70 hepatitis C virus (HCV) RNA-positive patients and 70 healthy control subjects were included in the present study, who were attending the medical outpatient department (OPD) and wards of a tertiary care hospital in New Delhi during 2006-2008. This study was designed to determine the polymorphism of tumor necrosis factor-α and interleukin-10 genes in patients with chronic HCV infection patients and their effect on pegylated interferon-α therapy response. Polymorphism in the tumor necrosis factor-α G/G, G/A, and A/A genotype was significant between HCV patients and healthy controls. Interleukin-10 variants (G/G, G/A) were nonsignificant among HCV patients compared with healthy controls. As this is a preliminary study on small sample size, we believe that our findings may stimulate further studies on larger number of patients from this geographic region.

Mediastinal mass-a rare presentation of desmoplastic small round cell tumour.

Primary mediastinal desmoplastic small round cell cancer is an uncommon tumour usually located in the abdomen and pelvis. Here the authors report an extremely rare case of a young male with a primary desmoplastic small round cell tumour in the anterior and middle mediastinum. The patient had non-specific complaints but an abnormal shadow was seen in a routine chest x-ray. He was diagnosed as having mediastinal mass with few lung parenchymal deposits on CT. Mediastinoscopy and guided biopsy revealed desmoplastic small round cell tumour. Desmoplastic small round cell tumour is a rare and aggressive tumour which rarely involves the mediastinum as a primary site. The nature of the lesion and its prognosis were explained to the patient. He was offered chemotherapy and radiotherapy for the tumour management. He refused treatment and left against medical advice.

Percutaneous liver biopsy.

Percutaneous liver biopsy has been performed for more than 120 years, and remains an important diagnostic procedure for the management of hepatobiliary disorders. Modern biochemical, immunologic, and radiographic techniques have facilitated the diagnosis and management of liver diseases but have not made liver biopsy obsolete. This comprehensive review article will discuss the history of development of percutaneous liver biopsy, its indications, contraindications, complications and the various aspects of the biopsy procedure in detail.

Chronic pancreatitis. A prospective nationwide study of 1,086 subjects from India.

CONTEXT: Chronic pancreatitis is common in India. However, its risk factors are not clear. There is sparse data on the current prevalence of tropical pancreatitis in India. OBJECTIVE: To undertake a prospective nationwide study of the risk factors and clinical profile of chronic pancreatitis. SETTING: Thirty-two major centers from different regions of India contributed data on 1,086 patients to a common online website (www.ipans.org). MAIN OUTCOME MEASURES: Risk factors, clinical features complications and treatment of chronic pancreatitis. RESULTS: Of the 1,086 subjects, complete data on risk factors were available for 1,033 subjects. Idiopathic pancreatitis was the most common form of pancreatitis (n=622; 60.2%) and alcoholic chronic pancreatitis accounted for about a third of the cases (n=400; 38.7%); the rest (n=11; 1.1%) had rare risk factors. Smoking and cassava intake were documented in 292 (28.3%) and 189 (18.3%) subjects, respectively. Using well-defined criteria, only 39 (3.8%)cases could be labeled as 'tropical pancreatitis'. Pain occurred in 971 patients (94.0%). Four hundred and eighteen (40.5%) subjects had diabetes mellitus. Of alcohol consumers, alcoholism and female gender were independent risk factors for diabetes in subjects with chronic pancreatitis (OR=1.48, P=0.003; and OR=1.75, P<0.001, respectively). The most common complications were pseudocysts (15.8%) and biliary obstruction (8.2%). Pancreatic cancer occurred in 42 subjects (4.1%). Ultrasound detected calculi in 69.7%, ductal dilatation in 63.4% and atrophy in 27.3%. The majority of patients were on medical therapy (n=849; 82.2%); endotherapy and surgery accounted for the rest. About 50% percent of the patients with diabetes required insulin (198/418). CONCLUSIONS: In this first nationwide prospective survey of chronic pancreatitis in India, idiopathic pancreatitis was the most common form, followed by alcoholic pancreatitis. The classical form of tropical chronic pancreatitis is becoming less common.

Inflammatory pseudotumour of the liver: a diagnostic dilemma.

Inflammatory pseudotumour is a rare, focal, benign inflammatory lesion of the liver parenchyma. It is largely a self-limiting entity and has favorable prognosis; it is thus important to preoperatively distinguish this lesion from malignancy, which it closely imitates. Inflammatory pseudotumour may present variously. We present the case of a 54-year old gentleman who presented with a three-month history of low-grade intermittent fever. Ultrasonography and computed tomography revealed a mass in the left lobe of the liver and the erythrocyte sedimentation rate was raised with coincident hypergammaglobulinaemia. A diagnostic laparotomy with left lateral hepatectomy was performed and histopathological evaluation of the specimen along with special staining and tissue culture revealed an inflammatory pseudotumour. On the second day post-operative the fever subsided and following an uneventful five days the patient was discharged and remains well at one-year follow up with no recurrence or relapse.

A case of primary rectal non-Hodgkin's lymphoma treated with chemotherapy.

Primary rectal non-Hodgkin's lymphoma is a rare disease. Surgery has been proposed as the primary treatment modality for colorectal lymphomas. We report a case of rectal non-Hodgkin's lymphoma (B cell large cell type, Ann Arbor Stage 1E) who responded completely to systemic chemotherapy.

p53 gene mutation and human papillomavirus (HPV) infection in esophageal carcinoma from three different endemic geographic regions of India.

Infection of high-risk human papillomaviruses (HPVs), particularly the HPV types 16 and 18 and mutation or aberrant expression of the p53 tumour suppressor gene, has strongly been implicated in human esophageal carcinoma, which shows a great variation in geographic distribution. Neither the reason(s) for such a variation nor the etiopathogenesis of the disease is clearly understood. The present study has been carried out to determine prevalence of high-risk HPV types 16 and 18 and the p53 gene mutation in patients from three distinctly different endemic geographic regions of India, viz. Kashmir, Dibrugarh, and New Delhi where esophageal cancer is most prevalent. The people from each of these regions differ considerably in their food, drinking, smoking and chewing habits (tobacco and betel nut) and ethnic background. While PCR was employed to detect high-risk HPV types 16 and 18 DNA sequences, PCR-SSCP and direct nucleotide sequencing was used for analysis of p53 mutation. Out of a total of 101 biopsy specimens of carcinoma esophagus analysed, the frequency of HPV was found to be the highest 14/32 (44%) in Dibrugarh followed by 33% (11/33) in Kashmir, but, interestingly, no high-risk HPV could be detected in New Delhi patients who showed the highest frequency (30.6%) of p53 mutation as against only 12.5% in Dibrugarh and 6.1% in Kashmir. The difference in the frequency of p53 mutation between the three regions was statistically highly significant (0.018). Out of a total of 21 nucleotide alterations observed, 12 missense, five frameshift and four were silent changes. The p53 exon 7 appears to be the 'hot-spot' for esophageal cancer as it alone was responsible for more than 76% (13/17) of mutations and more than 95% (20/21) of the patients with p53 mutation were smokers. The results demonstrate differential distribution of HPV infection and p53 mutation in esophageal cancer from different geographic regions of India and this could be due to variation in diet, drinking, and tobacco habit, including ethnic, socio-cultural and genetic variation.

Non-familial juvenile polyposis with histological evidence of adenomatous transformation.

A 14-year-old male presented with abdominal pain, diarrhoea and a sensation of something prolapsing through the anus during defecation, and was found to have diffuse colonic polyposis. There was no evidence of mucocutaneous hyperpigmentation and family history was negative, suggesting a diagnosis of non-familial juvenile polyposis. Histological analysis of multiple endoscopic biopsies showed features typical of juvenile or retention type (hamartomatous) lesions: dilated cystic glands lined by mucocus-secreting epithelium and prominent, inflamed and congested lamina propria. However, admixed with these features, focal areas of atypical adenomatous changes were recognized. Even the intervening normal-looking colonic mucosa showed some dysplastic changes. These findings indicate that hamartomatous and atypical adenomatous epithelial changes can co exist in non-familial juvenile polyposis and the latter may confer a risk of malignant transformation in this otherwise non-neoplastic disease.