Severity Of Hepatic Injury Research Articles

EVALUATION OF LIVER FIBROSIS IN LIVER BIOPSY OF ALCOHOLIC LIVER DISEASE CASES, WITH RETICULIN STAIN AND CD31 IMMUNOSTAIN

Background: Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality world - wide. Liver biopsy is the gold standard method to assess the presence of liver fibrosis , and is useful in determining the staging and severity of hepatic injury. To interpret Liver fibrosis in liver biopsies, Reticulin stain, and CD31,an immunohistochemical marker, which plays an important role in determining the degree of fibrosis in Alcoholic liver disease, were used in the evaluation of it. Methods: 50 Alcoholic Liver Disease patients, were evaluated for Liver fibrosis, with H&E stain and Reticulin stain, and were correlated with the staging of Liver fibrosis with CD 31 immunostaining expression by statistical analysis. Results: Strong positive correlation with CD31 and Reticulin staining was seen among 34 cases (68%), moderate positive correlation in 8 cases (16%), mild positive correlation in 2 cases (4%), negative correlation in 6 cases (12%). Conclusion: The existence of strong correlation, between CD31 immunostaining and fibrosis seen with Reticulin stain, revealed that the immunohistochemical methods are very much applicable in assessing prognostic and therapeutic strategies.

Old-fashioned and newly discovered biomarkers: the future of NAFLD-related HCC screening and monitoring

Nonalcoholic fatty liver disease (NAFLD) is the major contributor to the global burden of chronic liver diseases and ranges from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may progress into cirrhosis and hepatocellular carcinoma (HCC). HCC represents the most common liver cancer, and it is a leading cause of death worldwide with an increasing trend for the future. Due to late diagnosis, non-responsiveness to systemic therapy, and high cancer heterogeneity, the treatment of this malignancy is challenging. To date, liver biopsy and ultrasound (US) are the gold standard procedures for HCC diagnosis and surveillance, although they are not suitable for mass screening. Therefore, it is impelling to find new, less invasive diagnostic strategies able to detect HCC at an early stage as well as monitor tumor progression and recurrence. Common and rare inherited variations that boost the switching from NASH to liver cancer may help to predict tumor onset. Furthermore, epigenetic changes which reflect intertumoral heterogeneity occur early in tumorigenesis and are highly stable under pathologic conditions. The severity of hepatic injuries can be detected through the analysis of cell circulating tumor DNAs (ctDNAs), microRNAs (miRNAs), and noncoding RNAs (ncRNAs), which are involved in several pathological processes that feature cancer, including cell growth, survival, and differentiation, thus representing appealing biomarkers for HCC. Therefore, this review discusses the current options for HCC surveillance, focusing on the role of genetic and epigenetic biomarkers as new strategies to refine HCC management.

S2707 A Case of Fatal Immune Checkpoint Inhibitor Mediated Hepatitis

Introduction: Immune checkpoint inhibitors (ICPI) have become mainstays of therapy for advanced malignancies including melanoma, lung cancer, and renal cell carcinoma. Although they have shown promising mortality benefit, their risk of serious immune-related toxicities, including hepatitis, is increasingly documented in the literature. Case Description/Methods: A 27-year-old man with stage IV renal cell carcinoma on nivolumab/ipilimumab was transferred from state prison for acute transaminitis and hyperbilirubinemia. Prison records showed AST 3267, ALT 2236, and total bilirubin 5.9, increased from AST 113 and ALT 156 two weeks prior. On presentation the patient endorsed generalized abdominal pain and fatigue. Sclera were icteric and the abdomen was diffusely tender to palpation without organomegaly. Abdominal ultrasound revealed mild hepatomegaly, elevated hepatic artery velocity, and numerous gallstones. Broad work up to exclude other etiologies of liver failure was negative. Treatment included high-dose solumedrol, mycophenolate mofetil, n-acetylcysteine, and ursodiol. Transaminases improved but bilirubin worsened to >34. Repeat abdominal ultrasounds showed no biliary obstruction. An MRCP was non-diagnostic due to procedural intolerance. Hospital course was complicated by encephalopathy, septic shock from bacteremia, renal failure and disseminated intravascular coagulation. The patient was not a transplant candidate due to metastatic malignancy. He transitioned to comfort-oriented measures and expired within 24 hours. Discussion: ICPI mediated hepatitis is typically asymptomatic and occurs 6-14 weeks following treatment initiation, as was the case in our patient. Treatment is guided by the severity of hepatic injury as represented by transaminase and bilirubin levels (Grades 1-4) and typically involves medication discontinuation and steroid administration. Severe disease is also treated with mycophenolate mofetil. Acute hepatitis occurs in less than 5-10% of patients receiving a single ICPI, with 1-2% experiencing grade 3-4 hepatitis. However, grade 3-4 hepatitis has been observed in approximately 20% of patients receiving ipilimumab + nivolumab, consistent with previous findings that combination CTLA-4 and PD-1 blockade is associated with more frequent and more severe immune-related toxicities. This case illustrates a rare but important complication of dual ICPI therapy that, if not promptly diagnosed and treated, can be fatal.Figure 1.: Mechanisms of Action of Ipilimumab and Nivolumab.

Hepatic Injury in Patients With COVID-19.

Coronavirus disease 2019 (COVID-19) has infected over 2 million people worldwide over the course of just several months. Various studies have highlighted that patients infected with COVID-19 may develop various degrees of liver injury. Here, we discuss the impact of underlying liver disease and manifestations of hepatic injury with COVID-19. We also review mechanisms of hepatic injury. We searched the database PubMed for all studies focused on hepatic injury in COVID-19. We identified 13 studies that assessed the impact of underlying liver disease in patients infected with COVID-19 (N=3046). Underlying liver disease was one of the most common known comorbid categories in patients infected with COVID-19. Overall, 25% of the patients identified from the 13 studies had hepatic injury. Twenty-one percent and 24% had elevated alanine transaminase and aspartate transaminase values, respectively. Nine percent of the patients had elevated total bilirubin values. Ten of the 13 studies assessed COVID-19 acuity with severity of hepatic injury. In 9 of the 10 studies, clinical outcomes were worse with hepatic injury. Liver injury is highly prevalent in patients that present with COVID-19. Since the liver is one of the most affected organs outside of the respiratory system in COVID-19, more intensive surveillance is warranted for severe cases, particularly among those with pre-existing advanced liver disease.

Adipose tissue remodelling in obese subjects is a determinant of presence and severity of fatty liver disease.

Experimental data suggest that visceral adipose tissue (VAT) dysfunction contributes to non-alcoholic fatty liver disease (NAFLD) development in obesity, however, data on humans are limited. Aims of this study were to investigate the relationship between NAFLD and VAT morphofunctional impairment and to determine whether the extent of VAT remodelling is associated with liver damage and metabolic alterations in obesity. We analysed data from 40 obese individuals candidate to bariatric surgery in whom paired intraoperative liver and omental biopsies were performed for diagnosing NAFLD and VAT inflammation by immunohistochemistry and mRNA expression studies. Within our study population, NAFLD was significantly associated with greater VAT CD68+ macrophages infiltration (P = .04), fibrosis (P = .04) and impaired microvascular density (P = .03) as well as increased expression of markers of local hypoxia, apoptosis and inflammation (UNC5B, CASP7, HIF1-α, IL-8, MIP2, WISP-1, all P < .01). The degree of VAT inflammation correlated with the severity of hepatic injury (steatosis, inflammation, fibrosis; all P < .01) and impaired gluco-metabolic profile. In obese patients, NAFLD is associated in a dose-dependent manner with signs of VAT remodelling, which reflect more severe clinical metabolic impairment. Our study depicts morphological alterations and novel mediators of VAT dysfunction, adding knowledge for future therapeutic approaches to NAFLD and its metabolic complications.

Dexmedetomidine activates the PI3K/Akt pathway to inhibit hepatocyte apoptosis in rats with obstructive jaundice.

Obstructive jaundice (OJ) is a common disease in clinical surgery. The present study aimed to determine the effects of dexmedetomidine (Dex) on hepatocyte apoptosis in rats with OJ and also to explore the underlying mechanism. A total of 30 adult male Sprague Dawley rats were randomly divided into 3 groups: Sham group, bile duct ligation (BDL) group, and BDL+Dex group. The serum liver function index, expression levels of serum inflammatory factor interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and the liver pathological changes were compared amongst groups. The serum liver function index and expression levels of inflammatory factors in the BDL group and BDL+Dex group were higher compared with the sham group. The serum liver function index and expression levels of inflammatory factors were lower in the BDL+Dex group compared with the BDL group. The severity of hepatic injury was diminished in the BDL+Dex group compared with the BDL group. Compared with the sham group, the hepatocyte apoptosis rate increased significantly in the BDL group and BDL+Dex group. The present findings suggested that Dex improved the liver function of rats with OJ, reduced the production of inflammatory factors and inhibited the apoptosis of hepatocytes. Dex demonstrated a protective effect on liver damage potentially via activation of the phosphoinositide 3-kinase/protein kinase B signaling pathway.

The Effect of 30-minute Ischemia on the Levels of IL6, TNFα, NO, Glutathione and Lactic Acid in the Hepatic Tissue of Rats with Hepatic Steatosis

Fatty liver disease (FLD) is becoming increasingly common. Ischemia-reperfusion injury (IRI) is the main pathogenic factor determining morbidity and mortality after major hepatic surgery. This experimental study investigated changes in the levels of interleukin 6 (IL6), tumor necrosis factor α (TNFα), nitric oxide (NO), glutathione (GSH) and lactic acid (LA) in hepatic tissue, in normal rats and rats with severe hepatic steatosis, after 30-minute hepatic ischemia and reperfusion. The aim was to evaluate the ability of the severely steatotic liver to sustain ischemia. The study was conducted on 96 male Wistar rats aged 12–14 weeks, in 48 of which severe hepatic steatosis was induced by administration of a choline-free diet for 12–14 weeks. The other 48 rats received standard laboratory diet for the same period. The effect of 30-minute hepatic ischemia and reperfusion was examined in 24 steatotic and 24 lean livers, which were subjected to hepatic ischemia-reperfusion injury. After 6 and 24 hours of reperfusion, the levels of IL6, TNFα, NO, LA and GSH in the liver tissue of all the rats were measured. The serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) were measured to determine the severity of hepatic injury, and the survival of the rats after surgery was assessed. Rats with steatotic livers subjected to 30-minute hepatic ischemia and reperfusion showed significantly higher liver values of TNFα and LA and significantly lower liver values of IL6, GSH and NO than lean rats. The serum levels of AST and ALT were higher in rats with severely steatotic livers than in those with lean livers, after 30-minute hepatic ischemia and reperfusion, and no rat with a steatotic liver survived surgery. Rats with steatotic livers undergoing 30-minute ischemia and reperfusion show significant elevation of TNFα and LA and reduction in IL6, GSH and NO in liver tissue, with poor survival after surgery, compared to non-steatotic rats. These findings suggest that steatotic livers are more susceptible to ischemia-reperfusion injury than lean livers.

Transarterial Embolization Affects Recovery in Nonoperative Management of Severe Blunt Hepatic Injuries: A Retrospective Study

Introduction: Transarterial embolization (TAE) has been used as an essential technique in the nonoperative management (NOM) of severe blunt hepatic injuries (BHI) but has a possible risk of tissue ischemia and necrosis, which may affect hepatic recovery. The injured liver tissue gets encapsulated and absorbed by intact liver tissue; therefore, the healing process requires the formation of a wall surrounding the injured tissue. In this study, we determined the impact of TAE on the hepatic healing process.Patients and methods: We reviewed hemodynamically stable patients (n=35; males, 23; females, 12; mean age, 32 years), admitted to our hospitals over a 10-year period, who underwent NOM of severe BHI (American Association for the Surgery of Trauma Organ Injury Scale, grades IV and V). Data collected included demographic information, serial CT findings, severity of hepatic injuries showing lacerations (Couinaud's liver segment classification), TAE performed for active hepatic bleeding, and the amount of hemoperitoneum. Extrahepatic factors were evaluated using the Abbreviated Injury Scale for injuries to the head, face, thorax, and extremities. Time taken by injured segments to encapsulate was individually obtained from serial CTs. Cox regression and Kaplan-Meier analyses were used to identify risk factors associated with delayed healing among the hepatic and extrahepatic factors mentioned above.Results: Risk factors were independently and significantly associated with TAE (odds ratio, 2.45; 95% confidence interval, 1.01-5.92; p=0.047). Multivariate analysis indicated that patients who underwent TAE took 2.45-times longer time to attain liver encapsulation than those who did not undergo TAE and that extrahepatic factors did not correlate with the time to encapsulation.Conclusion: TAE for active liver hemorrhage resulted in a delayed recovery from BHI, regardless of extrahepatic factors.

Relationship between liver injury and serum cytokeratin 18 levels in asymptomatic hepatitis B virus carriers and in patients with chronic hepatitis B infection

Background and study aimsApoptosis represents a well-known mechanism of cell death involved in most chronic liver injuries. Our aim was to investigate the serum fragment level of cytokeratin 18 (CK18), M30, in asymptomatic hepatitis B virus (HBV) carriers and patients with chronic hepatitis B (CHB) and to evaluate the relationship between serum M30 levels and the severity of hepatic injury. Patients and methodsAsymptomatic HBV carriers (n=169), patients with CHB (n=100), and healthy control subjects (n=43) were enrolled in the study. Serum CK18 (M30) levels were analysed in all subjects. Liver biopsy for histopathological assessment was performed in asymptomatic HBV carriers and in patients with CHB infection. ResultsSerum CK18 (M30) levels were significantly higher in asymptomatic HBV carriers (198.77±77.62U/L) than in healthy control subjects (146.92±40.18U/L). Patients with CHB (283.02±147.45U/L) had significantly higher CK18 (M30) levels than asymptomatic HBV carriers (p=0.001). The diagnostic efficacy of CK18 (M30) levels in distinguishing patients with HBeAg-negative CHB from asymptomatic HBV carriers was found to be moderate (c-statistics: 0.695), and the diagnostic cut-off value of CK18 (M30) was 262U/L (specificity: 85%, sensitivity: 48%, positive likelihood ratio: 3.35, and negative likelihood ratio: 0.60). There was a positive correlation between serum CK18 (M30) levels and histological activity index scores in asymptomatic HBV carriers and patients with CHB. ConclusionsSerum CK18 (M30) levels may be a valuable indicator in distinguishing asymptomatic HBV carriers from patients with HBeAg-negative CHB when considered together with ALT and HBV-DNA levels.

Lipid profile in acute viral hepatitis: A study from north eastern India

Background: Acute viral hepatitis is associated with significant hepatic dysfunction including lipid metabolism. Variations in the serum lipid fractions in acute viral hepatitis due to hepatic injury may serve as prognostic marker for severity of hepatic injury. Methods: Hospital-based prospective study on acute viral hepatitis. Fifty cases of acute viral hepatitis and 50 age and sex matched controls, (>18 years) were studied. Routine biochemical investigation, hepatotropic viral serology and fasting serum lipid fractions were analysed for changes in patients with acute viral hepatitis. Chi-square test was used for comparing variables. A ‘p value’ 0.05). Jaundice (100%) and high coloured urine (100%) were the commonest presentations. Hepatitis A virus (52%) and Hepatitis E virus (30%) were commonest aetiological agents. Serum cholesterol, triglycerides, low density lipoprotein (LDL) were significantly higher (p 0.05). Complications were seen in 7 (14%) cases with hepatic encephalopathy being the commonest (6%). Serum cholesterol, triglycerides, LDL were significantly higher and HDL was significantly lower in hepatitis with complications compared to uncomplicated hepatitis (p<0.01). Conclusion: Acute viral hepatitis leads to significant alterations of serum lipid fractions which may serve as an indicator of severity of liver damage and be helpful in assessing the prognosis of patients with acute viral hepatitis.

Hepatitis C Virus Infection Is Positively Associated with Gallstones in Liver Cirrhosis

Aim: To elucidate the prevalence and risk factors of gallstone disease (GD) among patients with liver disease and explore their association with the aetiology and severity of hepatic injury. Methods: We analysed 4,832 subjects of hepatic injury induced by one of the following aetiologies: hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, excessive alcohol consumption. The risk factors significantly associated with GD were analysed using stepwise logistic regression analysis, the influence of aetiology and severity of liver disease on the prevalence of GD were assessed by multiple logistic regression analysis adjusting for confounding factors. Results: Three thousand forty eight patients were of positive HBV surface antigen alone with a prevalence of GD of 18.6%, 526 were tested as positive Anti-HCV alone with a prevalence of GD of 22.4%, and 1,258 were identified with excessive alcohol consumption patterns with a prevalence of GD of 13.5%. In each aetiological category, the prevalence of GD increased by age. Stepwise logistic regression analysis showed that age, female, low-density lipoprotein-cholesterol (LDL-Cho), family history of GD, HBV infection, HCV infection, chronic hepatitis and cirrhosis were independent associated with HCV-related cirrhosis in both genders, HBV-related cirrhosis in males and alcohol-related cirrhosis in females compared with patients with less severe liver disease. After adjusting for gender, age, LDL-Cho and family history of GD, patients with HCV-related cirrhosis (OR 2.66, 95% CI 1.49-3.84) but not HBV-related cirrhosis (OR 1.52, 95% CI 0.73-1.82) were more likely to have GD compared with alcohol-related cirrhosis. Conclusion: HCV infection is positively associated with gallstone formation especially in those with cirrhosis patients.

Role of elevated liver transaminase enzymes in diagnosis of liver injury in cases after abdominal trauma

Background: Major liver trauma in polytraumatic patients accounts for significant morbidity and mortality. Delayed diagnosis of patients with severe liver injuries is associated with an adverse outcome. Diagnostic modalities include serial abdominal examination, focused abdominal sonography for trauma, computed tomography scanning, diagnostic peritoneal lavage. The objective of this study was to detect relationship between raise of serum levels of hepatic transaminase enzymes and liver injury, and if the degree of the rise may also correlate with the severity of hepatic injury after abdominal trauma. Methods: cross sectional, prospective study observational study of all patients admitted emergency department in Suez Canal university hospital. Patients with abdominal trauma were subdivided (according to either surgical record after abdominal exploration or CT scans reports released by radiology department) in two groups, group with liver injury (31) cases and those without liver injuries (31) cases. Results: As regard to alanine aminotransferases (ALT) our study showed that serum ALT was raised in 28 cases from 31 cases of liver injury and only 4 patients with raised serum ALT did not have liver trauma (sensitivity: 90.3%, specificity: 87% , CI: 88.7%). Regarding aspartate aminotransferases (AST) our study showed serum AST was raised in about 21 cases from 31 cases of liver injury and only 7 patients with raised serum AST did not have liver trauma (sensitivity: 93.5%, specificity: 77.4% , CI: 87.1%). Conclusions: An abnormal ALT and AST can predict the presence of hepatic injuries in abdominal trauma patients, while the level of the abnormality can determine the severity of the insult to the liver. Also we can conclude that ALT is more specific for liver injury more than AST, Although AST show high sensitivity for liver injury than ALT.

Ex Vivo Assessment of Carbon Tetrachloride (CCl4)-Induced Chronic Injury Using Polarized Light Spectroscopy

The liver performs various functions, such as the production and detoxification of chemicals; therefore, it is susceptible to hepatotoxins such as carbon tetrachloride (CCl4), which causes chronic injury. Thus, assessment of injury and its status of severity are of prime importance. Current work reports an ex vivo study for probing the severance of hepatic injury induced by CCl4 with polarized light over the spectral range 400-800 nm. Different concentrations of CCl4 were used to induce varying severity of hepatic injury in a rat model. Linear retardance, depolarization rates, and diagonal Mueller matrix elements (m22, m33, and m44), were successfully used as the distinguishing criterion for normal and different liver injuries. Our results show that linear retardance for injured liver samples with lower doses of CCl4 tends to increase when compared with normal liver samples, while samples injured at higher doses of CCl4 offer almost no retardance. Total, linear, and circular depolarizations follow decreasing trends with increased liver injury severity over the entire investigated wavelength range. Linear polarization states were observed to be better maintained as compared to circular polarization states for all samples. Furthermore, numerical values of diagonal elements of the experimentally measured Mueller matrix also increase with increasing doses of CCl4. Liver fibroses, change in transport albedo, and the relative refractive index of the extracellular matrix caused by CCl4 are responsible for the observed differences. These results will provide a pathway to gauge the severity of injury caused by toxic chemicals.

Kinetics of T Helper Subsets and Associated Cytokines Correlate Well with the Clinical Activity of Graft-Versus-Host Disease

BackgroundCD4+interferon (IFN)-γ+ T cell (Th1) and CD4+interleukin (IL)-4+ T cell (Th2) polarizations are crucial in the pathogenesis of graft-versus-host disease (GVHD). However, this hypothesis is largely based on animal experiments of Parent-into-F1 GVHD model. The causal relationship between kinetics of Th1, Th2 and associated cytokines and the clinical activity of GVHD in a real world situation remains unknown.MethodologyPeripheral blood was collected every week prospectively from Day 0 to Day 210 (patients without GVHD) or Day 300 (patients with chronic GVHD) after allogeneic peripheral blood stem cell transplantation in consecutive 27 patients. The frequencies of Th1 and Th2 within CD4+ T cells were determined by flow cytometry and pplasma IFN-γ, IL-12, IL-4, and IL-10 were determined by ELISA.Principal FindingsKinetics of Th1, Th2 frequency, and the plasma IL-10 and IFN-γ more commonly coincided with, rather than predicted, the activity of GVHD. These markers are significantly higher when acute or chronic GVHD developed. The kinetics of IL-10 is especially correlated well with the activity of GVHD during clinical course of immunosuppressive treatment. For patients with hepatic GVHD, there is a positive correlation between plasma IL-10 levels and the severity of hepatic injury. The frequency of Th2 is also significant higher in acute GVHD and tends to be higher in chronic GVHD. Interestingly, there is a very good positive correlation between the frequency of Th1 and Th2 (r = 0.951, p<0.001). The plasma level of IL-4 and IL-12 are not associated with the activity of GVHD.ConclusionsThe frequency of Th1, Th2 within CD4+ T cells and plasma IL-10 and IFN-γ are good biomarkers of GVHD. Plasma IL-10 can also be used to monitor the therapeutic responsiveness. Furthermore, both Th1 and Th2 likely contribute to the pathogenesis of GVHD.

Adenovirus-mediated peroxisome proliferator activated receptor gamma overexpression prevents nutritional fibrotic steatohepatitis in mice

Objective. The pathogenesis of non-alcoholic steatohepatitis is still unclear. We have demonstrated previously that peroxisome proliferator activated receptor gamma (PPARγ) ligand protects against inflammation and fibrogenesis in experimental non-alcoholic steatohepatitis. We aim to elucidate the effect and the mechanism of PPARγ itself on nutritional fibrotic steatohepatitis in mice. Methods. C57BL/6J mice were fed with methionine-choline deficient (MCD) diet for 8 weeks to induce fibrotic steatohepatitis. Mice fed the MCD diet were treated with adenovirus carrying PPARγ (Ad-PPARγ), Ad-PPARγ plus PPARγ agonist rosiglitazone, or PPARγ antagonist 2-chloro-5-nitrobenzaniliden (GW9662), respectively. The effects of up-regulation of PPARγ in the presence or absence of its agonist/or antagonist were assessed by comparing the severity of hepatic injury, activation of hepatic stellate cells and the expression of adiponectin, heme oxygenase-1, and fibrogenic related genes. Results. Mice fed with MCD diet for 8 weeks showed severe hepatic injury including hepatic steatosis, inflammatory infiltration, and fibrosis. Administration of Ad-PPARγ significantly lowered serum alanine aminotransferase level and ameliorated hepatic steatosis, necroinflammation, and fibrosis. These effects were associated with enhanced expression of PPARγ, up-regulated expression of adiponectin and heme oxygenase-1, and down-regulated expression of tumor necrosis factor alpha, interleukin-6, α-smooth muscle actin, transforming growth factor beta 1, matrix metallopeptidase-2, and -9. Administration of GW9662 promoted the severity of liver histology. Conclusions. The present study provided evidences for the protective role of overexpressing PPARγ in ameliorating hepatic fibrosing steatohepatitis in mice. Modulation of PPARγ expression might serve as a therapeutic approach for fibrotic steatohepatitis.

Correlation of peripheral blood Vα24 NK T cell count with the severity of hepatic injury in patients with chronic hepatitis B virus infection

Correlation of peripheral blood Vα24 NK T cell count with the severity of hepatic injury in patients with chronic hepatitis B virus infection

Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin‐based chemotherapy for colorectal liver metastases

The current study evaluated the effect of bevacizumab added to fluoropyrimidine-plus-oxaliplatin (5FU/OX) chemotherapy for colorectal liver metastases (CLM) on the pathologic response and nontumorous liver histology. A total of 105 consecutive patients treated preoperatively with 5FU/OX chemotherapy with (n = 62) or without (n = 43) bevacizumab were analyzed. The response to chemotherapy was evaluated by pathologic analysis of tumor viability (percentage of viable tumor in relation to tumor surface area). The incidence and grade of hepatic sinusoidal dilation were also investigated. Bevacizumab-containing regimens significantly reduced the degree of tumor viability compared with 5FU/OX-only chemotherapy (32.9% vs 45.3%; P = .02). After stratification according to the magnitude of tumor viability, a higher proportion of patients treated with bevacizumab than without had <25% residual viable tumor cells (45% vs 23%; P = .02). However, the addition of bevacizumab to 5FU/OX did not appear to increase the incidence of complete pathologic response (11.3% vs 11.6%; P = .59). The incidence and severity of sinusoidal dilation was lower in patients treated with bevacizumab than in those treated with 5FU/OX only (any grade: 27.4% vs 53.5%; moderate or severe: 8.1% vs 27.9%; both P < .01). In patients treated with 5FU/OX chemotherapy, bevacizumab improves the pathologic response, as demonstrated by a reduction of the degree of tumor viability, and reduces the incidence and severity of hepatic injury. This retrospective study provides additional evidence supporting the use of bevacizumab in combination with 5FU/OX for CLM.

Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period

Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period

Ornithine breath test as a method to evaluate functional liver volume 1

The purpose of this study was to investigate whether the functional liver volume can be measured from changes in expiratory 13CO2 levels after intravenous administration of L-[1, 2-13C] ornithine, using a rat model of hepatectomy. Under pentobarbital anesthesia, 30%, 70%, or 90% hepatectomy was performed. In the control group, simple laparotomy was performed. Then, 20 mg/kg L-[1, 2-13C] ornithine was administered to rats via the femoral vein. A breath test was conducted 20 min after laparotomy. We examined the correlation of the sum of 13CO2 output (S) or a single point of 13CO2 level (SP) with liver weight/body weight (LW/BW) (%) every 15 min. In all of the groups, the ornithine breath test (OBT) graph reached a plateau level at about 6 min. The correlation coefficient between S15 and LW/BW was highest 0.952 (P <0.0001). The correlation coefficient between SP14 and LW/BW was highest, 0.944 (P <0.0001). The severity of hepatic injury could be evaluated, with significant differences in S5-15 and SP5-15 in all comparisons between groups. In the breath test with intravenously administered L-[1, 2-13C] ornithine, functional liver volume could be evaluated accurately in a short period.

Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients

AbstractLiver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 μM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P = .04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P = .07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 μM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 μM (4-6.9 mg/dL; 20%), 119.7 to 169.29 μM (7.0-9.9 mg/dL; 17%), and 171.0 μM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival.