Mithun Sharma

The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.

Clinical utility of the Revised Atlanta Classification of acute pancreatitis in a prospective cohort: Have all loose ends been tied?

BACKGROUND AND AIM Revision of the Atlanta classification for acute pancreatitis (AP) was long awaited. The Revised Atlanta Classification has been recently proposed. In this study, we aim to prospectively evaluate and validate the clinical utility of the new definitions. PATIENT AND METHODS 163 consecutive patients with AP were followed till death/6 mths after discharge. AP was categorized as mild (MAP) (no local complication[LC] and organ failure[OF]), moderate (MSAP)(transient OF and/or local/systemic complication but no persistent OF) and severe (SAP) AP (persistent OF). LC included acute peripancreatic fluid collections, pseudocyst, acute necrotic collection, walled-off necrosis, gastric outlet dysfunction, splenic/portal vein thrombosis, and colonic necrosis. Baseline characteristics (age/gender/hematocrit/BUN/SIRS/BISAP) and outcomes (total hospital stay/need for ICU care/ICU days/primary infected (peri)pancreatic necrosis[IN]/in-hospital death) were compared. RESULTS 43 (26.4%) patients had ANP, 87 (53.4%) patients had MAP, 58 (35.6%) MSAP and 18 (11.04%) SAP. Among the baseline characteristics, BISAP score was significantly higher in MSAP compared to MAP [1.6 (1.5-2.01) vs 1.2 (1.9-2.4); p = 0.002]; and BUN was significantly higher in SAP compared to MSAP[64.9 (50.7-79.1) vs 24.9 (20.7-29.1); p < 0.0001]. All outcomes except mortality were significantly higher in MSAP compared to MAP. Need for ICU care (83.3%vs43.1%; p = 0.01), total ICU days[7.9 (4.8-10.9) vs 3.5 (2.7-5.1); p = 0.04] and mortality (38.9%vs1.7%; p = 0.0002) was significantly more in SAP compared to MSAP. 8/18 (44.4%) patients had POF within seven days of disease onset (early OF). This was associated with 37.5% of total in-hospital mortality. Patients with MSAP who had primary IN (n = 10) had similar outcomes as SAP. CONCLUSIONS This study prospectively validates the clinical utility of the Revised Atlanta definitions of AP. However, MSAP patients with primary infected necrosis may behave as SAP. Furthermore, patients with early severe acute pancreatitis (early OF) could represent a subgroup that needs to be dealt with separately in classification systems.

Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management.

Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day (diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease (NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individuals genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD.

Autologous mobilized peripheral blood CD34+ cell infusion in non-viral decompensated liver cirrhosis

AIM To study the effect of mobilized peripheral blood autologous CD34 positive (CD34(+)) cell infusion in patients with non-viral decompensated cirrhosis. METHODS Cirrhotic patients of non-viral etiology were divided into 2 groups based on their willingness to be listed for deceased donor liver transplant (DDLT) (control, n = 23) or to receive autologous CD34(+) cell infusion through the hepatic artery (study group, n = 22). Patients in the study group were admitted to hospital and received granulocyte colony stimulating factor injections 520 μg/d for 3 consecutive days to mobilize CD34(+) cells from the bone marrow. On day 4, leukapheresis was done and CD34(+) cells were isolated using CliniMAC magnetic cell sorter. The isolated CD34(+) cells were infused into the hepatic artery under radiological guidance. The patients were discharged within 48 h. The control group received standard of care treatment for liver cirrhosis and were worked up for DDLT as per protocol of the institute. Both groups were followed up every week for 4 wk and then every month for 3 mo. RESULTS In the control and the study group, the cause of cirrhosis was cryptogenic in 18 (78.2%) and 16 (72.72%) and alcohol related in 5 (21.7%) and 6 (27.27%), respectively. The mean day 3 cell count (cells/μL) was 27.00 ± 20.43 with a viability of 81.84 ± 11.99%. and purity of 80%-90%. Primary end point analysis revealed that at 4 wk, the mean serum albumin in the study group increased significantly (2.83 ± 0.36 vs 2.43 ± 0.42, P = 0.001) when compared with controls. This improvement in albumin was, however, not sustained at 3 mo. However, at the end of 3 mo there was a statistically significant improvement in serum creatinine in the study group (0.96 ± 0.33 vs 1.42 ± 0.70, P = 0.01) which translated into a significant improvement in the Model for End-Stage Liver Disease score (15.75 ± 5.13 vs 19.94 ± 6.68, P = 0.04). On statistical analysis of secondary end points, the transplant free survival at the end of 1 mo and 3 mo did not show any significant difference (P = 0.60) when compared to the control group. There was no improvement in aspartate transaminase, alanine transaminase, and bilirubin at any point in the study population. There was no mortality benefit in the study group. The procedure was safe with no procedural or treatment related complications. CONCLUSION Autologous CD 34(+) cell infusion is safe and effectively improves liver function in the short term and may serve as a bridge to liver transplantation.

Endoscopic Retrograde Cholangiopancreatography as a Risk Factor for Pancreatic Panniculitis in a Post-Liver Transplant Patient

Post endoscopic retrograde cholangiopancreatography (ERCP) pancreatic panniculitis is a rare condition caused by fat necrosis following release of pancreatic enzymes into the bloodstream. No previous reports of pancreatic panniculitis have been reported in post-liver transplant subjects undergoing ERCP. We present a 63-year-old cryptogenic cirrhotic female post-cadaveric liver transplant who underwent ERCP for suspected biliary stricture and subsequently developed pancreatic panniculitis.

Refractory Hypoglycemia Presenting as First Manifestation of Advanced Hepatocellular Carcinoma

Hypoglycemia is a well-established paraneoplastic manifestation of hepatocellular carcinoma (HCC). However, hypoglycemia presenting as the primary presentation of HCC is extremely rare. Most cases are resistant to glucose infusion and may lead to severe complications such as hypoglycemic seizures. We present a patient who had hypoglycemia as first manifestation of HCC and was managed conservatively.

Hemophagocytic Lymphohistiocytosis Masquerading as Acute Liver Failure: A Single Center Experience

BACKGROUND/AIM Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening disorder of extreme inflammation and unregulated immune response which require prompt recognition and early introduction of definitive therapy. HLH can present with wide range of hepatic dysfunction ranging from mild elevation of transaminases to liver failure. This study is carried out to describe the clinical and laboratory presentation of HLH. METHODS Patients who were diagnosed with HLH between January 2013 and December 2015 were retrospectively included in this study. RESULTS Six patients were diagnosed as secondary HLH with median age of 28.5 years at diagnosis. All patients were presented with history of deep jaundice and high grade fever with pancytopenia and splenomegaly. Underlying diagnosis was viral infections in 4 and probable viral infection in remaining two. Bone marrow hemophagocytosis was present in 3 cases. Three patients were treated with corticosteroids only and one each with corticosteroids with cyclosporine or intravenous immunoglobulin (IVIG) and HLH treatment protocol. One patient died due to acute respiratory distress syndrome (ARDS); another patient died in follow-up due to respiratory failure due to pneumonia. CONCLUSIONS HLH is rare and potentially life-threatening cause of prolonged fever, jaundice and pancytopenia. Early diagnosis and initiation of specific therapy can improve clinical outcome.

Primary Ectopic Mediastinal Goiter in a Patient With Crohn’s Disease Presenting as Myasthenia Gravis

Mediastinum is an uncommon location for ectopic goiter. Primary ectopic mediastinal goiter has been reported to present mostly with compressive symptoms. We report a case of a 62-year-old man with history of Crohns disease, who presented with symptoms of myasthenia gravis and was found to have an anterior mediastinal mass. The mass was resected completely with successful outcome. On histopathologic examination this mass turned out to be colloid goiter. This is an extremely rare presentation of a primary ectopic mediastinal goiter.

Regional differences in genetic susceptibility to non-alcoholic liver disease in two distinct Indian ethnicities

AIM To validate the association of variants in PNPLA3 (rs2281135) and TM6SF2 (rs58542926) genes with ultrasound detected non-alcoholic fatty liver disease (NAFLD). METHODS A total of 503 individuals with and without fatty infiltration were recruited. Fatty infiltration was confirmed based on ultrasound findings. Anthropometric data and blood samples were collected from the study group. DNA was isolated from peripheral blood, quality and quantity was assessed by gel electrophoresis and spectrophotometer respectively. Genotyping of the variants in PNPLA3 and TM6SF2 genes was carried out by employing taqman probes (C_15875080_10 for PNPLA3 and C_8946351_10 for TM6SF2 SNP) on real time PCR (Stepone-Lifetechnologies). Genotype data was tested for deviations from Hardy-Weinberg equilibrium. χ2 test was used to analyze the statistical significance of the difference in genotype distribution of the studied variants in patients and controls and the strength of association was expressed as odds ratio (95%CI). A two-tailed P value of ≤ 0.05 was considered statistically significant. RESULTS The study group comprised of 503 individuals of which 256 had fatty infiltration and 247 without fatty infiltration and thus formed the patient and control groups respectively. As the patient group could be divided in to two distinct ethnicities (ancestral South Indians-ASI and North-East Indians-NEI), further recruitment of control cohort and association analyses was carried out based on ethnicities. Of the 256 with fatty infiltration 93 were ASI and 163 were NEI and of the 247 controls 138 were ASI and 109 were NEI. As expected, there were significant differences in the anthropometric and other clinical data between the control and the patient groups. However significant differences within the ethnicities were also noted. While rs2281135 in PNPLA3 gene was significantly associated (P = 0.03) with higher risk (odds 1.9, 95%CI: 1.5-3.14, P = 0.03) of NAFLD in NEI ethnicity, rs58542926 in TM6SF2 gene was significantly associated with NAFLD with a 2.7 fold higher risk (odds 2.7, 95%CI: 1.37-5.3, P = 0.0004) of the disease. There were significantly higher proportions of individuals with variants in both the genes in the patient group in both ASI (patients - 14/93 and controls - 7/138; P = 0.009) and NEI ethnicities (patients - 17/163 and controls - 7/109; P = 0.01). CONCLUSION Although the study identified distinct genetic susceptibility in the two ethnicities, transheterozygosity of the variants suggests higher risk of NAFLD in individuals with both the variants.