Vol. 8 Issue 4
On the cover: Official Journal of the Mexican Association of Hepatology and the Latin-American Association for the Study of the Liver
Liver cirrhosis is a major cause of morbidity and mortality worldwide and has very limited therapeutic options. Regardless of the aetiology, hepatic fibrosis is a characteristic feature of chronic liver disease. Our knowledge regarding the pathogenesis of this scarring has grown exponentially in the past 25 years. It has now clear that this is a highly dynamic process and the long-held dogma that it is irreversible and relentlessly progressive is now being challenged. In this review, we will summarise the key pathogenic mechanisms at play and will focus on the evidence demonstrating that liver fibrosis is reversible in humans and animal models. In particular, we will examine the role of hepatic stellate cells, MMPs, TIMPs and macrophages in this process. Finally, we will discuss some of the studies aimed to therapeutically target the resolution of fibrosis and their potential for translation into a badly-needed treatment modality in the clinical setting.
The main cause of liver cirrhosis and liver cancer in the western world is Hepatitis C virus (HCV) infection. Liver transplantation is the only effective treatment once the disease is decompensated. In viremic patients who undergo transplantation, disease recurrence is universal resulting in the development of a new cirrhosis in about one third of the patients after 5 to 10 years of follow-up. Initiation of the antiviral treatment with Peg-IFN and ribavirin prior to transplantation may prevent HCV recurrence if a sustained viral response (SVR) is achieved. Moreover, it might even be possible to achieve an improvement of the liver function degree so that transplantation may be differed. There are few studies that assess the efficacy and safety of the antiviral treatment in the cirrhotic setting. Available information shows SVR rates between 20 and 40%, lower with decompensated disease. The need for treatment withdrawal and dose reductions is significant in this setting. Cytopenias are one of the most frequent adverse effects; hematopoietic growth factors have shown to increase patient compliance, but it is still unclear whether they result in greater SVR. In addition, an increased risk of bacterial infections has been recently described, with a recommendation to use prophylactic therapy during antiviral treatment. In conclusion, antiviral therapy is an option for cirrhotic patients who have a good liver function but should not be recommended in patients with Child-Pugh-Turcotte class C, due to a high risk of severe complications.
It has been 4 years since the first, long-term (> 3 years) prospective comparison of adult-to-adult living donor liver transplantation (A2ALLTx) to adult deceased donor liver transplantation (ADDLTx) was reported.1 In this follow up, prospective, IRB approved, 10-year comparison of A2ALLTx to ADDLTx we expand on our initial observations. This data includes: age, gender, ethnicity, primary liver disease, waiting time, pretransplant CTP/MELD score, cold ischemia time (CIT), perioperative mortality, acute and chronic rejection, graft and patient survival, charges and post-transplant complications. In 10 years, 465 ADDLTx (81.3%) and 107 A2ALLTx (18.7%) were performed at VCUHS. Hepatitis C virus (HCV) was the most common reason for transplantation in both groups (54.5% vs. 48.2%). Data regarding overall patient and graft survival and retransplantation rates were similar. Comparison of patient/graft survivals, retransplantation rates in patients with and without HCV were not statistically different. A2ALLTx patients had less acute rejection (9.6% vs. 21.7%) and more biliary complications (27.1% vs. 17.6%). In conclusion, A2ALLTx is as durable a liver replacement technique as the ADDLTx. Patients with A2ALLTx were younger, had lower MELD scores, less acute rejection and similar histological HCV recurrence. Biliary complications were more common in A2ALLTx but were not associated with increased graft loss compared to ADDLTx.
Background. Available prognostic scores for mortality after acute variceal bleeding are mainly based on logistic regression analysis but may have some limitations that can restrict their clinical value. Aims. To assess the efficacy of a novel prognostic approach based on Classification and Regression Tree -CART- analysis to common easy-to-use models (MELD and Child-Pugh) for predicting 6-week mortality in patients with variceal bleeding. Methods. Sixty consecutive cirrhotic patients with acute variceal bleeding. CART analysis, MELD and Child-Pugh scores were performed to assess 6-week mortality. Receiver operating characteristic (ROC) curves were constructed to evaluate the predictive performance of the models. Results. Six-week rebleeding and mortality were 30% and 22%, respectively. Child-Pugh and MELD scores were clinically relevant for predicting 6 weeks mortality. CART analysis provided a simple algorithm based on just three bedside-available variables (albumin, bilirubin and in-hospital rebleeding), allowing accurate discrimination of two distinct prognostic subgroups with 3% and 80% mortality rates. All MELD, Child-Pugh and CART models showed excellent and comparable predictive accuracy, with areas under the ROC curves (AUROC) of 0.88, 0.84 and 0.91,respectively. Conclusions. A simple CART algorithm combining albumin, bilirubin and in-hospital rebleeding allows an accurate predictive assessment of 6-week mortality after acute variceal bleeding.
Background and Rationale. Anemia is a major side effect of combination therapy for chronic hepatitis C. In this study, severity, potential risk factors for and potential underlying mechanisms of anemia were evaluated. Patients and methods. 44 chronic hepatitis C patients on interferon-ribavirin treatment were included. Anemia-related parameters were measured before and during treatment. Potential changes in membrane phospholipids composition of erythrocytes of patients on anti-viral treatment and potentially increased erythrocyte susceptibility to osmotic or bile salt induced stress were explored. Results. Anemia was almost universal during treatment, with evidence of hemolysis. Decrease of Hb after six months of therapy was 2.1 ± 0.1 mmol/L (range -0.6-4.1). Higher pre-treatment Hb, highest ribavirin dose (15-17.5 mg/kg) and lower pre-treatment platelet level were independent risk factors for decrease of Hb. Serum erythropoietin levels increased during treatment with negative correlation to Hb levels at week 12 (r = -0.70, p = 0.002) and 24 (r = -0.72, p = 0.002). Erythrocyte membrane phospholipid composition did not differ between anemic patients and healthy controls. Also, resistance to osmotic or bile salt induced stress was normal in anemic patients. Phosphatidylserine exposure at the outer membrane leaflet did not change upon 24 hrs ex vivo incubation with pharmacological ribavirin concentration. Conclusions. Anemia is almost universal during anti-HCV treatment. The extent of anemia correlates with pre-treatment levels of thrombocytes and Hb and with high ribavirin dosing. Although we found hemolysis as contributing factor, our data do not indicate that altered membrane phospholipids composition is an important factor in pathogenesis of anemia.
Background and objective. Prophylaxis therapy is indicated in cirrhotic patients with large esophageal varices or small varices with red wale signs (high risk esophageal varices; HREV). Endoscopic surveillance to detect HREV is currently recommended. The objective of this study is to identify non-invasive predictors of HREV in cirrhotic patients. Design and methods. Adult cirrhotic patients without previous variceal bleeding were prospectively included. All patients underwent a complete biochemical workup, upper digestive endoscopy, and ultrasonographic measurement of spleen bipolar diameter. Platelet count/spleen diameter ratio (PC/SD) was calculated for all patients. The association of these variables with the presence of HREV in upper endoscopy was tested using univariate and multivariate analysis. Receiver operating characteristic (ROC) curves were constructed for variables associated with HREV. Results. Sixty-seven patients were included. The prevalence rate of HREV was 50%. Age, gender (female), platelet count, spleen diameter, PC/ SD ratio, total bilirrubin, prothrombin activity (INR), Child-Pugh score, clinical and ultrasonographic ascites were significantly associated with presence of HREV in univariate analysis. Age and PC/SD ratio were the parameters independently associated with HREV in a multivariate analysis, with OR 8.81 (CI 95%: 1.7-44.9) and OR 11.21 (CI 95%: 2.8-44.6) respectively. A PC/SD ratio cut-off value under 830.8 predicted HREV with 76.9% sensitivity, 74.2% specificity and 77.8% negative predictive value (ROC curve area: 0.78). Conclusions. The PC/SD ratio was significantly associated with HREV, but with suboptimal sensitivity and specificity. Therefore, the results of this study do not support the routine clinical use of PC/SD ratio for screening of HREV.
Background. Emerging evidence has linked the presence of non-alcoholic fatty liver disease (NAFLD) with an increased risk for cardiovascular events. We hypothesised that altered clot kinetics and platelet function may contribute to this increased risk. This study compared whole blood clotting kinetics in patients with 1) non-cirrhotic NAFLD (n = 28) and 2) healthy control subjects (n = 22). Methods. Clotting kinetics were assessed in whole blood using thromboelastography (TEG) and assessed for correlations with cardiovascular risk factors. Results. Clot kinetics in patients with NAFLD showed significantly stronger clot development (maximum amplitude (MA); 58.3 ± 6.3 mm vs. 52.0 ± 10.1 mm, p = 0.01) and reduced clot lysis in the presence of thrombin (35 ± 30% vs. 51 ± 26% clot lysis 30 minutes after MA, p = 0.03) compared to control subjects. Clot strength was independently positively associated with body mass index in NAFLD, but not in control subjects. There was a greater platelet contribution to clot strength in patients with NAFLD compared to controls despite similar platelet counts. There was no association between clot kinetics and features of the metabolic syndrome or presence of type 2 diabetes. Conclusion. Patients with NAFLD have disturbances in ex-vivo clot kinetics including increased clot strength and clots that are more resistant to thrombin-stimulated lysis.
Serum hepatitis B virus (HBV) DNA level is a predictor of the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis B patients. Nevertheless, the distribution of viral load levels in chronic HBV patients in Brazil has yet to be described. This cross-sectional study included 564 participants selected in nine Brazilian cities located in four of the five regions of the country using the database of a medical diagnostics company. Admission criteria included hepatitis B surface antigen seropositivity, availability of HBV viral load samples and age ³ 18 years. Males comprised 64.5% of the study population. Mean age was 43.7 years. Most individuals (62.1%) were seronegative for the hepatitis B e antigen (HBeAg). Median serum ALT level was 34 U/L. In 58.5% of the patients HBV-DNA levels ranged from 300 to 99,999 copies/mL; however, in 21.6% levels were undetectable. Median HBV-DNA level was 2,351 copies/mL. Over 60% of the patients who tested negative for HBeAg and in whom ALT level was less than 1.5 times the upper limit of the normal range had HBV-DNA levels > 2,000 IU/mL, which has been considered a cut-off point for indicating a liver biopsy and/or treatment. In conclusion, HBV-DNA level identified a significant proportion of Brazilian individuals with chronic hepatitis B at risk of disease progression. Furthermore, this tool enables those individuals with high HBV-DNA levels who are susceptible to disease progression to be identified among patients with normal or slightly elevated ALT.
Introduction. Epidemiological studies indicate that nonalcoholic steatohepatitis (NASH) is a common cause of cirrhosis described as cryptogenic. To address this from a histological perspective and to examine the significance of residual histological findings as an indication of prior NASH, we looked back at biopsies in patients who presented with cirrhosis without sufficient histological features to diagnose NASH but who had prior histologically confirmed non-cirrhotic NASH. Methods. Seven patients were identified with biopsy pairs showing non-specific (cryptogenic) cirrhosis in the latest specimen and a prior biopsy showing non-cirrhotic NASH. Using an expanded NASH-CRN system scored blindly by light microscopy, we compared the early and late biopsies to each other and to a cohort of 13 patients with cirrhosis due to hepatitis C without co-existing metabolic syndrome. Results. Macrosteatosis, although uniformly present in the noncirrhotic NASH specimens, declined in the late stage cirrhotic NASH specimens and was not useful in the distinction of late cirrhotic NASH from cirrhotic viral hepatitis. However, the presence of ballooned cells, Mallory-Denk bodies, and megamitochondria and the absence of apoptotic bodies were significantly different in late stage cirrhotic NASH compared to cirrhosis due to hepatitis C. Conclusions. Histologically advanced NASH presenting as non-specific or cryptogenic cirrhosis has residual changes which are consistent with prior steatohepatitis but which differ from cirrhosis due to hepatitis C. These results provide histological support for the more established epidemiological associations of NASH with cryptogenic cirrhosis and for criteria used in several proposed classifications of cryptogenic cirrhosis.
Introduction. Hepatitis A virus can evolve to acute liver failure with a fatal outcome if it is not reversed. Objective. We describe the clinical course of 12 children who presented with hepatitis A acute liver failure and received treatment with oral N-acetylcysteine (NAC). Materials and methods. Of the seventy-two patients with viral hepatitis A, 12 patients who had acute hepatic failure were included. The variables evaluated were age, sex, duration of clinical features prior to hospitalization, signs and symptoms, laboratory parameters [alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin time (PT), partial thromboplastin time (PTT), internal normalization ratio and ammonia], treatment (oral NAC 100 mg/kg/ day, lactulose, neomycin and general measures) and clinical course during hospitalization. Results. Six males and six females were included. School-aged and adolescent children predominated. All presented with jaundice, nausea, vomiting and hepatomegaly. Two had stage 2 neurological signs as per the WestHaven scale. All had altered laboratory parameters. All received NAC, six patients for a week and the remaining six for 9-36 days. Treatment was not ceased until patients showed clinical and laboratory improvement. All data were analyzed using both students t test and Wilcoxon signed rank with alpha = 0.05, the ALT with P = 0.0003 and 0.005, AST with P = 0.0001 and 0.0005, PT with P = 0.0237 and 0.0005, PTT with P = 0.0515 and 0.0039, ammonia with P = 0.0197 and 0.0015 and direct bilirubin with P = 0.0190 and 0.068. There was good tolerance to medications and a satisfactory clinical course. Discussion. The use of oral NAC appears to be an effective therapeutic alternative for hepatitis A-induced liver failure if it is offered appropriately. It can modify the clinical course to a favorable one and prevent the fatal outcome of hepatic encephalopathy.
Due to time constraints, fewer physicians are performing large volume paracentesis (LVP) resulting in a longer wait time and more emergency department (ED) and hospital admissions. At our institution, after initial supervision, a certified nurse practitioner (NP) has independently performed LVP in a dedicated cirrhosis clinic. The purpose of our study was to evaluate the feasibility and safety of LVP performed by a NP. A retrospective review of patients undergoing LVP between January 2003 and May 2007 was performed. Baseline patient information and the practitioner performing LVP (physician or NP) were recorded. Complications including post paracentesis hypotension, bleeding, local leakage of ascitic fluid, infection, perforation, and death were compared between the two groups. A total of 245 procedures in 41 patients were performed by a single NP, and 244 in 43 patients by physicians. Baseline characteristics of patients undergoing LVP were similar in two groups. Alcohol was the most common etiology of cirrhosis (46% in NP and 51% in physician group) followed by a combination of alcohol plus HCV (37% in NP and 28% in physician group). There was similar distribution of Childs class B and C patients in the two groups, as well as average MELD score. Total volume of ascites removed, number of needle attempts, and complications including post paracentesis hypotension, local leakage of ascitic fluid, bleeding, infection, and death were not statistically different between the two groups. Our study shows no difference between physician and NP performance of LVP and complication rates. LVP performed by a NP is feasible and has acceptable rate of complications.
The present study was conducted to investigate effect of pentoxifylline (PTX) on acute liver injury caused by galactosamine (D-Gal) in rats and the underlying mechanism involved in this setting. Moreover, we attempted to compare its effect to the well-established hepatoprotective agent, silymarin (SYM). The rats were randomly assigned 5 groups, control, PTX-treated (100 mg/kg, 3 weeks), SYM-treated (100 mg/kg, 3 weeks) and their combination. Hepatic injury was induced by intraperitoneal single dose injection of D-Gal (800 mg/kg). Hepatic functions parameters, including serum albumin and alkaline phosphatase (ALP) levels were determined. Antioxidants enzyme activities such as superoxide dismutase (SOD), catalase (CAT) as well as lipid peroxides and hepatic total nitrites were measured. Besides, histopathological examination was also performed using portions of liver tissues. Results showed that the liver injury induced by D-Gal was improved in the three pretreated groups to variable extents. Pretreatment with PTX prevented D-Galinduced reduction of antioxidante enzyme activities, SOD and CAT, and attenuated the elevated malonaldahyde (MDA) level in hepatic tissue as marker of lipid peroxidation. In addition, pretreatment with PTX resulted in an increase in hepatic triglycerides, normalization of nitric oxide level, and lowering serum ALP activity as well as inhibited the decreased serum albumin level caused by D-Gal. These biochemical changes were reflected on attenuation the structural alterations of the liver integrity. Collectively, our data suggest that PTX exhibits a potential hepatoprotective effect against D-Gal-induced hepatotoxicity and this effect might be attributed to its antioxidant properties.
The circadian oscillations of many physiological processes provide an endogenous temporal program for the adaptive synchronization of mammals to the fluctuating external world. The lack of exposure to light causes the circadian system to undergo a process of dark adaptation similar to dark adaptation in the visual system. The aim of the present work was investigate the effect of acute treatment of constant darkness on mitochondrial ATP synthase activities and membrane fluidity in liver from male rat. We found that ATP synthase activity was not changed by the treatment. However ATPase activity and membrane fluidity were significantly diminished and pH gradient driven by ATP hydrolysis was incremented, in comparison from samples from rats kept on normal light/dark cycles. Additionally, the treatment of constant darkness diminishes the passive proton permeability of the inner mitochondrial membrane. In conclusion constant darkness induces a more efficient coupling between proton transport and catalysis, and increment the efficiency of the enzyme because the ratio of ATP synthase/ATPase activity was higher. These results exhibited the physiological adaptation of liver mitochondria to acute treatment of constant darkness in order to satisfy the cellular energy demand.
Primary sclerosing cholangitis (PSC) is a chronic, progressive, inflammatory and obstructive disease of the intra- and extra-hepatic bile ducts of unknown etiology. Currently, orthotopic liver transplantation (OLT) is the only definitive treatment for PSC-related end-stage liver disease. However, PSC has been known to recur in the grafted liver. Roux-en-Y hepaticojejunostomy is more commonly performed than choledochocholedochostomy for PSC, although choledochocholedochostomy has been found to be safe and efficacious for PSC if the distal common bile duct is uninvolved at the time of OLT. Our case is unique in that it describes a patient who developed de-novo cholangiocarcinoma in the remnant portion of the native common bile duct six years after OLT with choledochocholedochostomy for PSC-associated end-stage liver disease without having PSC recurrence. In conclusion, our case report indicates that choledochocholedochostomy may not be desirable in PSC due to an increased risk of developing cholangiocarcinoma in the native common bile duct. This risk exists as well with a Roux-en-Y hepaticojejunostomy in the remaining intra-duodenal and intra-pancreatic biliary epithelium, although in theory to a lesser extent. Therefore, the risk of developing cholangiocarcinoma in the recipient common bile duct can only be completely eliminated by performing a Whipple procedure at the time of OLT.
Spontaneous rupture of hepatic metastasis causing hemoperitoneum is a rare entity. Ruptured hepatic metastasis has typical imaging findings on biphasic CT which may help in clinching the diagnosis. We present a case of rupture hepatic metastasis from choriocarcinoma in a young-female patient who was managed by transcatheter hepatic artery embolization. A brief review of the imaging features and therapeutic options for the ruptured hepatic metastases is discussed along with the case.
Noncirrhotic portal hypertension (NCPH) represents a relatively infrequent group of conditions that causes portal hypertension in the absence of cirrhosis. An association between NCPH and patients infected with human immunodeficiency virus (HIV) has been reported. Six consecutive patients with HIV infection and NCPH were the subject of this series. Case histories, including medication lists, liver biopsy and laboratory data were reviewed. Age at diagnosis was 43 ± 3 years (range, 37-47). Liver disease was diagnosed 12 ± 4 years (range, 8-18) after initiation of antiretroviral therapy (ART). All patients developed esophageal varices, 5 patients presented at least one bleeding episode and 2 required TIPS. Serum liver tests showed a mean total bilirubin of 1.4 ± .7 mg/dL (range, .5-2.5) and INR was 1.2 ± .14 (range, 1.0-1.4). CD4 count was 326 ± 124 cells/mL (range, 198-467) and all patients presented HIV viral load < 75 copies/mL. Didanosine (ddI) was the most common ART drug being used by 4 patients. Portal vein thrombosis was diagnosed in 2 patients. Hepatic portal sclerosis (HPS) alone was observed in 1 patient, nodular regenerative hyperplasia (NRH) alone in 2 patients and combined HPS/NRH in 3 patients. In conclusion, NCPH should be included in the differential diagnosis of HIV-individuals presenting with clinical manifestations of portal hypertension and well preserved liver synthetic function. Prolonged exposure to ART, specially ddI, can play a pathogenic role. Rarely, liver synthetic function is sufficiently severe to warrant liver transplantation.
Hepatic artery thrombosis (HAT) is relatively infrequent, but possibly a devastating complication of orthotopic liver transplantation (OLT). It often requires urgent retransplantation. Two main forms of HAT are recognized as early and late HAT (diagnosis within or after 30 days following LT). Early HAT typically results in graft failure. Late HAT features biliary obstruction, cholangitis, and hepatic abscess formation. We report here the case of a patient of Wilsons disease who presented twelve years post-liver transplant symptoms typical of acute HAT and hepatic infarction. On diagnostic imaging, celiac axis and hepatic artery were thrombosed, resulting in ischemic necrosis of the left hepatic lobe. The resulting sepsis and transient hepatic insufficiency were managed conservatively, and repeat OLT was avoided. The patient remains stable more than one year later. To the best of our knowledge this case report is unique in the literature for the unusually long interval between OLT and late acute HAT, as well as celiac and portal vein occlusion. The acute presentation of sub massive hepatic necrosis is also uncharacteristic of late HAT and more typical of acute HAT. This report describes our experience in managing this and a literature review of the topic.
Original Abstract Aim. To compare the efficacy of pentoxifylline and prednisolone in the treatment of severe alcoholic hepatitis and to evaluate the role of different liver function scores in predicting prognosis. Methods. Sixty-eight patients with severe alcoholic hepatitis (Maddrey score ³ 32) received pentoxifylline (n = 34, group I) or prednisolone (n = 34, group II) for 28 d in a randomized double-blind controlled study, and subsequently in an open study (with a tapering dose of prednisolone) for a total of 3 mo, and were followed up over a period of 12 mo. Results. Twelve patients in group II died at the end of 3 mo in contrast to five patients in group I. The probability of dying at the end of 3 mo was higher in group II as compared to group I (35.29% vs. 14.71%, p = 0.04; log rank test). Six patients in group II developed hepatorenal syndrome as compared to none in group I. Pentoxifylline was associated with a significantly lower model for end-stage liver disease (MELD) score at the end of 28 d of therapy (15.53 ± 3.63 vs 17.78 ± 4.56, p = 0.04). Higher baseline Maddrey score was associated with increased mortality. Conclusion. Reduced mortality, improved risk-benefit profile and renoprotective effects of pentoxifylline compared with prednisolone suggest that pentoxifylline is superior to prednisolone for treatment of severe alcoholic hepatitis. Abstract published under the permission of the editor of World J Gastroenterol.