Sanjiv Saigal

End-stage nonalcoholic fatty liver disease: evaluation of pathomorphologic features and relationship to cryptogenic cirrhosis from study of explant livers in a living donor liver transplant program

In a proportion of liver cirrhosis, the etiology continues to remain elusive. It is uncertain whether and to what extent cirrhosis evolving from nonalcoholic fatty liver disease contributes to this group of cryptogenic cirrhosis because the clinicopathologic features of nonalcoholic fatty liver disease cirrhosis are largely unknown. We explored these facets by examining the explant livers and clinical data in living donor liver transplant recipients. Among 103 adult liver transplant recipients with different types of chronic liver disease, 30 had a pre-liver transplant diagnosis of cryptogenic cirrhosis. A final categorization of the native liver disease was attempted in these cases on the basis of detail pathomorphological findings in adequately sampled explant liver correlated with careful review of pre-liver transplant clinical data. Of the 30 cryptogenic cirrhosis cases, 19 (63.3%) finally labeled as nonalcoholic fatty liver disease cirrhosis showed histologic features in several respects different from those reported for the early and established phases of nonalcoholic fatty liver disease. Steatosis was infrequent and focal or even absent, whereas variable grades of Mallory hyaline and inflammation were consistently present. Ductular proliferation and hydropic change of hepatocytes were also frequent. Only 9 (47%) of the 19 cases had nonalcoholic fatty liver disease associated risk factors like diabetes and obesity. It was concluded that appreciation of quantitative and qualitative differences in hepatic morphology between the cirrhotic and the early/established stage of nonalcoholic fatty liver disease will help in making a correct diagnosis of nonalcoholic fatty liver disease cirrhosis in the proper clinical setting. When appropriate criteria are used, nonalcoholic fatty liver disease appears to account for close to two thirds of cases currently labeled as cryptogenic cirrhosis.

Evolution of a reliable biliary reconstructive technique in 400 consecutive living donor liver transplants.

BACKGROUND Biliary complications (BCs) are a major cause of morbidity and mortality after living donor liver transplantation (LDLT). They occur because the graft hepatic ducts are often small, thin walled, multiple, and may become ischemic during transection. STUDY DESIGN Of the 460 LDLTs done at our center before November 2009, the first 402 partial liver grafts had at least 3 months of follow-up. In the first 158, conventional hepatic duct isolation was used in the donor (group C). In the last 244 cases, the complete hilar plate and Glissonian sheath approach (HPGS) was used (group H). We compared the incidence and outcomes of BCs in the 2 groups. RESULTS The rate of BC was significantly lower in group H (5.3%) than in group C (15.8%, p = 0.000). The incidence of early (within 3 months of transplant) BCs was similarly significantly lower in group H (3.3%) than in group C (13.2%, P=0.000). The incidence of late BCs in the 145 patients in group H who had completed at least 12 months of follow-up was 2.8%.The proportion of BCs needing surgical correction was much higher in group C (44%) than in group H (7.7%, p = 0.022). CONCLUSIONS By providing a graft with a well-vascularized hepatic duct or ducts with a sheath of supporting tissue that holds sutures well, the HPGS approach minimizes the incidence and severity of BCs in LDLT.

Consensus Statement of HCV Task Force of the Indian National Association for Study of the Liver (INASL). Part I: Status Report of HCV Infection in India

Globally, around 150 million people are infected with hepatitis C virus (HCV). India contributes a large proportion of this HCV burden. The prevalence of HCV infection in India is estimated at between 0.5% and 1.5%. It is higher in the northeastern part, tribal populations and Punjab, areas which may represent HCV hotspots, and is lower in western and eastern parts of the country. The predominant modes of HCV transmission in India are blood transfusion and unsafe therapeutic injections. There is a need for large field studies to better understand HCV epidemiology and identify high-prevalence areas, and to identify and spread awareness about the modes of transmission of this infection in an attempt to prevent disease transmission.

Hepatocellular carcinoma in nonalcoholic fatty liver cirrhosis and alcoholic cirrhosis: risk factor analysis in liver transplant recipients.

Background Cirrhosis and hepatocellular carcinoma (HCC) evolving from nonalcoholic fatty liver disease (NAFLD) are being increasingly documented. However, clinicopathologic studies to support this are inadequate. Also, the pathogenesis of HCC in alcoholic cirrhosis (ALC) in which the pathologic and clinical features are very similar to those of nonalcoholic fatty liver cirrhosis (NAFLC) is unknown. Methods A clinicomorphologic study on 47 confirmed NAFLC cases, with HCC in eight of them and 75 confirmed ALC cases with HCC in five from among orthotopic liver transplant recipients, was performed. Results Patients with NAFLC were older by about 9 years than those with ALC. HCC in NAFLC occurred almost exclusively in men. The presence of NAFLD risk factors, obesity and diabetes both together, was significantly higher in NAFLC than in ALC cases and within the latter, in those with HCC than in those without HCC, whereas in the NAFLC group, this was no different between those with and without the tumor. The steatohepatitic variant of HCC, consistently accompanied by similar histologic changes in the nontumor part of liver, which is a histologic hallmark of association with NAFLC risk factors, was much more frequent in the NAFLC group compared with the ALC group. Conclusion Hepatic alterations induced by risk factors of NAFLD not only have cirrhogenic but also, very likely, a carcinogenic effect. The incidence of HCC in NAFLC seems higher than in ALC. These findings and their bases need to be established by further studies.

Steatohepatitic Hepatocellular Carcinoma, a Morphologic Indicator of Associated Metabolic Risk Factors: A Study From India

CONTEXT The common risk factors for hepatocellular carcinoma (HCC) include persistent viral infection with either hepatitis B or C virus, alcohol abuse, hemochromatosis, and metabolic syndrome. Steatohepatitic (SH) HCC has been recently recognized as a special morphologic variant of HCC associated with metabolic risk factors. OBJECTIVE To assess the SH pattern in HCC cases of various etiologies in Indian patients and to further correlate this morphology with the presence of metabolic risk factors. DESIGN A total of 101 cases of HCC with various etiologies in explanted livers from adults were included in the study. Morphologic examination was performed to identify SH lesions within the tumor and in the nontumorous liver parenchyma. Correlation of nontumor and tumor SH morphology with clinically identifiable metabolic risk factors and with non-SH type of HCC was performed. RESULTS The SH variant of HCC was identified in 19 livers (18.8%). Most SH-HCC cases were associated with metabolic risk factors such as obesity, diabetes, hypertension, and hyperlipidemias. Comparison of SH-HCC with non-SH-HCC was statistically significant in terms of presence of metabolic risk factors. CONCLUSIONS Steatohepatitic morphology in HCC is frequent in nonalcoholic fatty liver disease-associated cirrhosis (P = .009) and is significantly associated with metabolic risk factors (P = .03). By recognizing SH pattern, one may predict associated metabolic diseases and determine the prognosis both in pretransplant and posttransplant patients.

Etiologic types of end-stage chronic liver disease in adults: analysis of prevalence and their temporal changes from a study on native liver explants.

Background Whole native livers from orthotopic liver transplant (LT) recipients provide an ideal resource material for the proper identification and etiologic evaluation of end-stage liver diseases in these patients. This study determined the etiologic types of chronic liver disease (CLD) in adults of our geographic region receiving living donor LT and projected approximate estimates of their current prevalence and temporal changes in these in the general population. Materials and methods The final etiologic categorization of CLD in 372 adult LT recipients was made only after correlating the morphologic findings on explanted whole native livers with all pre-LT data and diagnosis. Results The final etiologic categorizations of end-stage CLD in the majority (88.4%) of explanted livers in our series were as follows: hepatitis virus related – 48.6% [hepatitis C virus (HCV) – 31.1%, hepatitis B virus (HBV) – 15.9%, HCV and HBV – 1.6%]; alcohol related – 23.1%; and NALD related – 16.7%. Of 84 cases clinically considered as cryptogenic cirrhosis, 57 and nine were finally categorized as nonalcoholic fatty liver disease (NAFLD) cirrhosis and noncirrhotic portal fibrosis, respectively. Hepatocellular carcinoma (HCC) was found in 20.7% of all livers, 81.8% of these tumors developing in HBV-related and/or HCV-related CLD and 9.1% each in alcohol-related and NAFLD-related CLD. Conclusion The etiology of end-stage CLD in adults of our region has changed over time. HCV, more than HBV, is now the major cause of both CLD and HCC; alcohol-related CLD has increased significantly and several cases of cirrhosis clinically considered as cryptogenic, some of them with HCC, evolve from NAFLD. A proportion of cryptogenic cirrhosis cases that require LT are constituted by the noncirrhotic disease noncirrhotic portal fibrosis.

Consensus Statement of HCV Task Force of the Indian National Association for Study of the Liver (INASL). Part II: INASL Recommendations for Management of HCV in India.

The estimated prevalence of hepatitis C virus (HCV) infection in India is between 0.5 and 1.5% with hotspots showing much higher prevalence in some areas of northeast India, in some tribal populations and in certain parts of Punjab. Genotype 3 is the most prevalent type of infection. Recent years have seen development of a large number of new molecules that are revolutionizing the treatment of hepatitis C. Some of the new directly acting agents (DAAs) like sofosbuvir have been called game-changers because they offer the prospect of interferon-free regimens for the treatment of HCV infection. These new drugs have not yet been approved in India and their cost and availability is uncertain at present. Till these drugs become available at an affordable cost, the treatment that was standard of care for the whole world before these newer drugs were approved should continue to be recommended. For India, cheaper options, which are as effective as the standard-of-care (SOC) in carefully selected patients, are also explored to bring treatment within reach of poorer patients. It may be prudent to withhold treatment at present for selected patients with genotype 1 or 4 infection and low levels of fibrosis (F1 or F2), and for patients who are non-responders to initial therapy, interferon intolerant, those with decompensated liver disease, and patients in special populations such as stable patients after liver and kidney transplantation, HIV co-infected patients and those with cirrhosis of liver.

Non-cirrhotic portal fibrosis: one disease with many names? An analysis from morphological study of native explant livers with end stage chronic liver disease

Background A group of non-cirrhotic chronic liver diseases, all with sustained portal hypertension and clinically mistaken as cirrhosis, have been described under various names, apparently because of differences in pathological features. The pathogenesis is uncertain and they were believed to have a good prognosis until it was recently shown, from study of explant livers, that they had progressed to end stage disease, needing liver transplantation. Aims To describe detailed morphological features of such end stage non-cirrhotic disease and examine whether the diseases bearing various names are different or represent variable morphological expressions of one entity. Methods Morphological features of 10 native explant livers from patients with pre-transplant diagnosis of end stage cirrhosis but finally categorised as non-cirrhotic portal fibrosis were analysed along with the relevant clinical information. Results Besides absence of criteria for cirrhosis, variable grades of obliterative changes in portal vein branches and portal fibrosis were consistently seen in all livers. Fibrous intimal thickening with luminal compromise in some medium and large sized portal veins was randomly distributed but appeared characteristic of this disease, very likely representing organised mural thrombi. Areas of closely placed nodular hyperplastic parenchyma separated by compressed hepatocytes, megasinusoids and peliotic changes were seen only in a proportion of cases. Conclusion Non-cirrhotic portal fibrosis is a justifiable name for this disease that can progress to end stage liver disease. It represents a single entity that has been considered as different diseases and given various names on the basis of the dominant element in its heterogeneous morphological manifestation.

Current Status of Immunosuppression in Liver Transplantation

With advancements in immunosuppressive strategies and availability of better immunosuppressive agents, survival rate following liver transplantation has improved significantly in the recent times. Besides improvements in surgical techniques, the most important factor that has contributed to this better outcome is the progress made in the field of immunosuppression. Over the last several years, the trend has changed to tailored immunosuppression with the aim of achieving optimal graft function while avoiding its undesirable side effects. Induction agents are no longer used routinely and the aim is to provide minimal immunosuppression in the maintenance phase. The present review discusses the various types of immunosuppressive agents, their mechanism of action, clinical utility, advantages and disadvantages, and their side effects in short and long-term. It also discusses about tailoring immunosuppression in presence of various situations such as renal dysfunction, metabolic syndrome, hepatitis C recurrence, cytomegalovirus infections and so on. The issue of chronic kidney disease and the available renal sparing immunosuppressive strategies has been particularly stressed upon. Finally, it discusses about the practical aspects of various immunosuppression regimens including drug monitoring.

Innovative approach using an intragastric balloon for weight loss in a morbidly obese patient undergoing liver transplantation

Morbid obesity is associated with poor outcomes after liver transplantation. Bariatric surgery or weight loss by lifestyle modification is often not possible because of the presence of decompensated cirrhosis. A 61-year-old male presented with decompensated alcoholic cirrhosis (jaundice, low albumin level, high international normalized ratio, and mild ascites). His comorbidities included diabetes mellitus and morbid obesity (body mass index 1⁄4 48.3 kg/m). He had residual esophageal varices (after endoscopic variceal ligation) but no fundal varices. He was listed for deceased donor liver transplantation, and a BioEnterics intragastric balloon was placed endoscopically to promote weight loss. He lost 24 kg over 6 months (body mass index at transplantation 1⁄4 39.2 kg/m), and his diabetic control improved significantly (with his hemoglobin A1c level decreasing from 9.2 to 5.4 g/dl). He underwent deceased donor liver transplantation 3 months later; the balloon was removed endoscopically just before surgery in order to facilitate a better operative field. His postoperative recovery was uneventful, and he was doing well 3 months after deceased donor liver transplantation without any rebound weight gain. Patients with decompensated cirrhosis have a significant risk of perioperative mortality after bariatric surgery in comparison with patients with compensated cirrhosis (16.3% versus 0.9%). Intragastric balloon placement is a nonsurgical approach, and it has been shown to improve parameters of insulin resistance, obesity-related complications, and quality of life for obese patients. A metaanalysis including 3608 patients has shown that an intragastric balloon is more effective than a placebo for weight loss, with nausea and vomiting being the most common side effects (8.6%). We could not find any reports regarding the use of intragastric balloons to promote liver transplantation in morbidly obese patients. Although long-term weight loss has not been described with the use of balloons, improved diabetic control and a lower body mass index decrease the perioperative complications of liver transplantation. In conclusion, in a decompensated patient with cirrhosis who is morbidly obese and does not have significant gastroesophageal varices, the placement of an intragastric balloon is a useful and innovative modality for promoting short-term weight loss and thereby making the patient fit for surgery and reducing perioperative morbidity andmortality.