The cellular pathways of liver fibrosis in non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is considered the advanced stage of non-alcoholic fatty liver disease (NAFLD). It is characterized by liver steatosis, inflammation and different degrees of fibrosis. Although the exact mechanisms by which fatty liver progresses to NASH are still not well understood, innate and adaptive immune responses seem to be essential key regulators in the establishment, progression, and chronicity of these disease. Diet-induced lipid overload of parenchymal and non-parenchymal liver cells is considered the first step for the development of fatty liver with the consequent organelle dysfunction, cellular stress and liver injury. These will generate the production of pro-inflammatory cytokines, chemokines and damage-associated molecular patterns (DAMPs) that will upregulate the activation of Kupffer cells (KCs) and monocyte-derived macrophages (MMs) favoring the polarization of the tolerogenic environment of the liver to an immunogenic phenotype with the resulting transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts developing fibrosis. In the long run, dendritic cells (DCs) will activate CD4+ T cells polarizing into the pro-inflammatory lymphocytes Th1 and Th17 worsening the liver damage and inflammation. Therefore, the objective of this review is to discuss in a systematic way the mechanisms known so far of the immune and non-proper immune liver cells in the development and progression of NASH.

Liver Recovery and Transplantation From Deceased Donors in the Metropolitan Area of the Valley of Mexico.

BACKGROUND: Evaluation of donation and transplantation activity allows for strategic planning. Liver donation and transplantation activity in the Metropolitan Area of the Valley of Mexico (MAVM) has never been published. The aim of this study was to analyze deceased liver donation and transplantation, liver use, and observed-to-expected (O:E) ratio in the MAVM. METHODS: Information from 2014 to 2018 was obtained from the National Center of Transplantation and adjusted per million persons. O:E ratio was analyzed and compared between regions. RESULTS: From all Mexican states, Mexico City (CDMX) had the highest liver donation and transplantation per million persons rates in the country. In contrast, when the MAVM was considered, the region was sixth in liver donation and first in transplantation, although the latter was not statistically different to Nuevo Leon (5.4 vs 4.3; P = .52). Liver use in Mexico State within the MAVM (37.8%) was not different from that of CDMX (15th in the nation, 35.2%, P = .78), while deceased donor liver use in the rest of the state was statistically higher (52.4%, P = .01; third in the nation). O:E ratio was higher in Mexico states outside the MAVM (CDMX 10.1, 2.1 vs 29.4, 26.5; P = .009). CONCLUSIONS: Analysis of deceased donation and transplantation of Mexican states without considering the metropolitan areas is insufficient. To consider CDMX as a region without acknowledging the MAVM leads to an inappropriately small denominator during efficiency analysis.

Living Donor Liver Transplantation for Perihilar Cholangiocarcinoma: Outcomes and Complications.

BACKGROUND: Neoadjuvant therapy and liver transplantation is an effective treatment for perihilar cholangiocarcinoma (pCCA). Living donor liver transplantation (LDLT) addresses the problem of organ shortage, but has higher risk of technical complication that can be aggravated by radiotherapy. We investigated the incidence of vascular and biliary complication in pCCA compared with non-pCCA patients and their impact on patient and graft survival. STUDY DESIGN: All consecutive LDLTs (n = 247) performed between 2000 and 2017 were reviewed, including demographics, donor variables, operative details, and postoperative outcomes. Logistic regression models were used to investigate the relationship between variables and outcomes. RESULTS: Seventy-four LDLTs (30.0%) were performed for pCCA and 173 for other indications. Forty-nine patients (66.2%) had primary sclerosing cholangitis-associated pCCA; the remainder had de novo pCCA. LDLT for pCCA was associated with nonstandard arterial (p = 0.001) or portal vein reconstruction (p < 0.001) and Roux-en-Y choledochojejunostomy (p < 0.001). The incidence of early hepatic artery thromboses was similar (5.4% vs 7.6%; p = 0.54). Late hepatic artery (18.9% vs 4.1%; p < 0.001) and portal vein (37.8% vs 8.7%; p < 0.001) complication was more common in the pCCA group. Anastomotic biliary complications occurred in 39.2% vs 54.1% (p = 0.032) of patients. Overall survival for pCCA at 1, 5, and 10 years was 84.9%, 66.5%, and 55.6%, respectively. Cancer recurred in 12.3%. Residual tumor on explant prognosticated inferior survival (hazard ratio 5.69; 95% CI, 1.97 to 16.35) and vascular and biliary complications did not. CONCLUSIONS: Late vascular complication is common after LDLT for pCCA, but do not adversely affect long-term survival. LDLT provides excellent survival, particularly for patients with no residual disease at the time of transplantation.

Liver Transplant for Cholangiocarcinoma.

Liver transplant (LT) for perihilar cholangiocarcinoma (CCA) offers an opportunity for survival among patients with early-stage but anatomically unresectable disease. The 5-year survival rate after LT is 65% to 70%, higher among patients with primary sclerosing cholangitis, who are often diagnosed earlier, and lower among patients with de novo CCA. The results of LT for hilar CCA, along with recent limited data suggesting favorable survival among patients with very early intrahepatic CCA (ICC), have reignited interest in the subject. This article discusses LT following neoadjuvant therapy for CCA and the early data on LT alone for ICC.

Long-term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy.

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. The aim of this study was to analyze the long-term outcomes for obese patients undergoing LT, including a noninvasive weight loss program and combined LT and sleeve gastrectomy (SG). Since 2006, all patients referred for LT with a body mass index (BMI) ≥35 kg/m2 were enrolled. Patients who achieved weight loss (BMI <35) underwent LT alone, and those who did not underwent simultaneous LT + SG. Analysis of long-term outcomes for patients ≥3 years posttransplant was performed. Since 2006, there were 36 in the weight loss intervention (LT cohort) and 13 in the LT + SG cohort with >3 years of follow-up, whereas overall, a total of 29 patients underwent LT + SG. Patients in the LT cohort had less severe obesity at enrollment (40.0 ± 2.7 vs. LT + SG cohort 46.0 ± 4.5; P < 0.001). In the LT cohort, 83.3% (30 of 36) achieved >10% loss in total body weight (TBW) pre-LT. Three years posttransplant, 29.4% of patients in the LT cohort maintained >10% loss in TBW, whereas 100% of the LT + SG patients did (P < 0.001). Patients who underwent LT + SG maintained a significantly higher percentage of total body weight loss after 3 years of follow-up (LT cohort 3.9 ± 13.3% vs. LT + S G cohort 34.8 ± 17.3%; P < 0.001). Patients in the LT + SG also had a lower prevalence of hypertension, insulin resistance, and hepatic steatosis and required fewer antihypertensive medications and lipid agents at last follow-up. CONCLUSION: Whereas weight loss before transplantation was achieved by obese patients, weight regain was common in the LT cohort. Combined LT + SG resulted in more effective and more durable weight loss, as well as fewer metabolic complications at last follow-up. (Hepatology 2018).

Surgical Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. In select patients, surgical treatment in the form of either resection or transplantation offers a curative option. The aims of this review are to (1) review the current American Association for the Study of Liver Diseases/European Association for the Study of the Liver guidelines on the surgical management of HCC and (2) review the proposed changes to these guidelines and analyze the strength of evidence underlying these proposals. Three authors identified the most relevant publications in the literature on liver resection and transplantation for HCC and analyzed the strength of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. In the United States, the liver allocation system provides priority for liver transplantation to patients with HCC within the Milan criteria. Current evidence suggests that liver transplantation may also be indicated in certain patient groups beyond Milan criteria, such as pediatric patients with large tumor burden or adult patients who are successfully downstaged. Patients with no underlying liver disease may also benefit from liver transplantation if the HCC is unresectable. In patients with no or minimal (compensated) liver disease and solitary HCC ≥2 cm, liver resection is warranted. If liver transplantation is not available or contraindicated, liver resection can be offered to patients with multinodular HCC, provided that the underlying liver disease is not decompensated. Many patients may benefit from surgical strategies adapted to local resources and policies (hepatitis B prevalence, organ availability, etc). Although current low-quality evidence shows better overall survival with aggressive surgical strategies, this approach is limited to select patients. Larger and well-designed prospective studies are needed to better define the benefits and limits of such approach.

Fighting Mortality in the Waiting List: Liver Transplantation in North America, Europe, and Asia.

Liver disease is a major cause of mortality worldwide. Liver transplantation (LT) is the most effective treatment for end stage liver disease. Available resources and social circumstances have led to different ways of implementing LT around the world. The experience with pediatric LT corroborates the hypothesis that a combination of surgical strategies can be beneficial. The goal of this manuscript is to describe the strategies used by LT centers in North America, Europe and Asia and how these strategies can be applied to reduce waitlist mortality and increase access to LT.

Quality of life in bile duct injury: 1-, 5-, and 10-year outcomes after surgical repair.

BACKGROUND: Quality of life after bile duct injury is a relevant health issue besides physician-oriented outcomes. A prospective study was performed to explore short- and long-term outcomes after surgical repair. METHOD: We studied a cohort of patients with Strasberg E injuries who underwent Roux-en-Y jejunal anastomosis from 1990 to 2008. The Short Form Health Survey (SF-36) was selected as the appropriate quality of life assessment instrument. Two groups were comprised: Group I included patients with 10-year follow-up after surgery. Group II included patients operated during 2008 with preoperative 1- and 5-year questionnaires. RESULTS: Group I patients (N = 41) were operated from 1990 to 2003 and Group II (N = 44) during 2008. There is a significant improvement in quality of life after the first year of repair in all domains. Readmissions (48 vs 25 %; p < 0.01), colangitis (46 vs 14 %; p < 0.001), and hepatojejunal redo (26 vs. 4 %; p < 0.0001) were less frequent in Group II. No differences in quality of life summary scores were found between Group I and II. CONCLUSIONS: Quality of life improves significantly after the first year of surgical repair, reaching a plateau at 5 years. No correlation exists with physician-centered outcomes.

Glisson's capsule blistering after hyperthermic intraperitoneal chemotherapy.

Hypertermic intraperitoneal chemotherapy is a treatment option after cytorreduction of certain types of malignancies with peritoneal spread. Blistering of the Glisson's capsule has not been previously reported as a consequence of this treatment modality. Patient do not experiment any associated morbidity.

Arcuate ligament compression as a cause of early-onset thrombosis of the hepatic artery after liver transplantation.

BACKGROUND: Early hepatic artery thrombosis (HAT) is a potentially lethal complication after orthotopic liver transplantation (OLT) requiring immediate intervention. AIM: To report an infrequent cause of HAT after OLT and by itself a controversial clinical entity, the median arcuate ligament celiac artery compression. CASE REPORT: A 59-year-old female with hepatitis C virus-induced cirrhosis, Child B, MELD 15, underwent cadaveric-donor OLT with complete vena cava exclusion. Type 1 hepatic artery anatomy was found both in the donor and the recipient, the gastroduodenal artery was ligated. During the first eight postoperative days, clinical and analytical evolution was satisfactory and Doppler ultrasound showed no abnormalities. On the ninth postoperative day, the patient developed hypovolemic shock due to bleeding at the hepatic artery anastomosis, surgical reconstruction was performed. Postoperative color Doppler showed absent hepatic artery flow and an angiography suggested celiac artery compression. The patient was explored again the same day, liberating the celiac artery from the median arcuate ligament and performing thrombectomy and reconstruction of the hepatic artery anastomosis. The patient made a satisfactory recovery and color Doppler showed adequate flow in the hepatic artery. She is alive, free of biliary complications and enjoying a good quality of life 12 months after transplantation. CONCLUSION: Median arcuate ligament celiac artery compression is an infrequent anatomical variant that should be intentionally evaluated in the recipient at the time of arterial reconstruction in OLT and specifically be considered in early HAT to allow recognition and effective correction.

Liver failure after an uncovered TIPS procedure associated with hepatic infarction.

Transjugular intrahepatic portosystemic shunt (TIPS) is a safe and effective procedure for the treatment of complications of liver cirrhosis, such as refractory ascites, hepatic hydrothorax and refractory variceal bleeding. The aim of this paper is to describe a rare case of liver failure after a TIPS procedure. A 38-year-old diabetic male with Child-Pugh C liver cirrhosis due to chronic hepatitis C infection who had developed refractory ascites was scheduled for a TIPS procedure. Within 24 h following TIPS placement, the patient developed distributive shock, jaundice, persistentgrade 3 hepatic encephalopathy, severe coagulopathy and acute renal failure. He was treated with lactulose enemas, broad-spectrum antibiotics and blood-derived products. Laboratory data revealed a 100-fold increase in aminotransferases and a non-enhanced computed tomography showed an irregular hypodense area in the right posterior segment of the liver. Despite being initially being in a stable condition, the patient developed progressive liver failure and died 2 mo later. Hepatic infarction is an uncommon phenomenon after a TIPS procedure; however, it can greatly complicate the course of a disease in a patient with an already compromised liver function.

Hepatic expression of ghrelin and adiponectin and their receptors in patients with nonalcoholic fatty liver disease.

BACKGROUND & AIM: Adiponectin and ghrelin are hormones that participate in hepatic lipid metabolism, and their expression in liver tissue could have important implications for nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the hepatic expression of ghrelin, adiponectin, AdipoR, and IL-6 in patients with NAFLD and normal liver. METHODS: We studied patients with clinical-pathological diagnosis of NAFLD or a normal liver. Patients were classified according to their diagnosis into three groups: normal liver, nonalcoholic hepatic steatosis, and nonalcoholic steatohepatitis (NASH). Adiponectin, AdipoR1, AdipoR2, IL-6, and ghrelin mRNA levels were assessed in biopsies by reverse transcriptase-polymerase chain reaction. RESULTS: Of the 21 patients, three had a normal liver biopsy, 14 had nonalcoholic steatosis, and four had NASH. Patients with NAFLD exhibited significantly higher HOMA-IR and triglyceride concentration (both P<0.05). There was a nonsignificant trend towards higher ghrelin expression in patients with NASH > nonalcoholic steatosis > normal liver. Patients with NASH had significantly higher mRNA adiponectin levels and lower IL-6 levels than did those with a normal liver (P<0.05). AdipoR expression did not differ significantly between groups. CONCLUSION: Adiponectin overexpression was observed in patients with NASH. The role of hepatic ghrelin in NAFLD requires further research.

Sorafenib, a systemic therapy for hepatocellular carcinoma.

Hepatocellular carcinoma is a lethal disease that requires a multidisciplinary approach and management. Surgical therapy offers long-term survival; however, few patients are candidates. There has been no accepted systemic therapy for this disease until recently. This article briefly discusses the role of RAS/RAF/MEK/ERK signaling pathway in the pathogenesis of the disease and the promising role of sorafenib for advanced disease.

Importance of iron and iron metabolism in nonalcoholic fatty liver disease.

Iron homeostasis disturbances are associated with liver disease. Non-alcoholic steatohepatitis is part of the spectrum of non-alcoholic fatty liver disease, which can progress to hepatic cirrhosis and end-stage liver disease. Increasing information supports that multiple factors underlie the development and progression of nonalcoholic steatohepatitis. However, the relation between non-alcoholic steatohepatitis and iron metabolism/ overload is still controversial. We review the recent literature, both basic and clinical, regarding iron homeostasis as it pertains to the pathogenesis of nonalcoholic fatty liver disease.

Gallstones are associated with carotid atherosclerosis.

BACKGROUND/AIMS: Gallstone disease (GD) and cardiovascular disease (CD) are common diseases worldwide with considerable economical impact and they are strongly associated. Carotid atherosclerosis is an excellent marker of risk for CD like stroke and myocardial infarction. The aim of this study was to assess the association between gallstones and carotid atherosclerosis. METHODS: A cross-sectional study was conducted. We evaluated subjects with ultrasonographical evidence of GD and asymptomatic subjects without such evidence. Anthropometric, clinical and biochemical variables were collected. The Metabolic syndrome was evaluated using adult treatment panel III criteria. Carotid artery intima-media thickness (CIMT) was determined by a standard ultrasound protocol. Insulin-like growth factor-1 (IGF-1) serum levels were measured in all subjects. RESULTS: We studied 191 subjects: 62 subjects with GD (53.2% males) and 129 asymptomatic subjects without GD (65.9% males). Subjects with GD exhibited a higher body mass index, body fat percent, insulin serum levels and CIMT (P<0.05 for all). The prevalence of GD was higher in subjects with a CIMT>0.75 independently of other factors [odds ratio (OR) 2.12, 95% confidence interval (CI) 1.04-4.34; P=0.039], and for every 0.1 mm increase in CIMT the independent probability to be a case of GD increased by a factor of 1.25 (95% CI 1.02-1.53; P=0.027). IGF-1 levels did not differ among groups. CONCLUSIONS: Subjects with GD exhibit greater carotid atherosclerosis, and therefore have a higher risk for stroke and myocardial infarction.

Paclitaxel coated-stent for early-onset thrombosis after liver transplantation.

Hepatic artery thrombosis (HAT) is the most common vascular complication of orthotopic liver transplantation (OLT) and constitutes a potential emergency during the postoperative period. Surgical revascularization and retransplantation are the treatments of choice for this condition. The aim of this report is to present long-term follow-up on survival and graft function of three patients with paclitaxel-coated hepatic artery stents placed percutaneously after earlyonset HAT. Three patients developed early onset HAT after cadaveric-donor OLT in a tertiary care center in Mexico. These patients were treated percutaneously with balloon angioplasty and paclitaxel-coated stents. After 24 months or more of follow-up, 2 patients present total occlusion of the stent and one patient, intra-stent stenosis; interestingly, all patients have normal graft function and excellent quality of life. In conclusion, although balloon angioplasty and stent placement may be a therapeutic option for suitable patients with early-onset HAT after OLT, longterm patency is unlikely even with the use of paclitaxel- coated materials.