Abdullah M. Al-Osaimi

Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis.

BACKGROUND/AIMS Non-alcoholic steatohepatitis (NASH) is a growing public health problem. Evaluation of risk factors for fibrosis in NASH will help to target resources to reduce development of cirrhosis. This study had two aims; the first to compile longitudinal histological data to characterize the natural history of fibrosis progression in NASH, and second, to identify predictive factors for progression to advanced fibrosis (stage 3 or greater) in NASH. METHODS Subjects had to have a histological diagnosis compatible with NASH on their initial biopsy, received no intervention of proven histological benefit, and undergone two liver biopsies with at least an interval of one year between them. RESULTS Ten studies were selected comprising 221 patients. 37.6% had progressive fibrosis over a mean follow-up interval of 5.3 years (SD, 4.2 years, median, 3.7 years, range 1.0-21.3 years). Proportional hazards regression analysis demonstrated that age (HR=0.98, p=0.009) and inflammation on initial biopsy (any inflammation, HR=2.5, p=0.001; grade 1, HR=2.5, p=0.001; grade 2, HR=2.4, p=0.003) are independent predictors of progression to advanced fibrosis. Other traditional parameters (e.g. obesity, diabetes, hypertension) were not statistically significant predictors. CONCLUSIONS Presence of inflammation on the initial biopsy and age are independent predictors of progression to advanced fibrosis in patients with NASH.

Endoscopic cyanoacrylate versus transjugular intrahepatic portosystemic shunt for gastric variceal bleeding: a single-center U.S. analysis

BACKGROUND AND OBJECTIVES Gastric variceal hemorrhage treatment remains a difficult issue for clinicians. There is controversy regarding whether first-line treatment should be endoscopic therapy with cyanoacrylate glue or placement of a transjugular intrahepatic portosystemic shunt (TIPS). We compared these methods on the basis of rebleeding, survival, and complications. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: This was a retrospective cohort analysis of cirrhotic patients with gastric variceal hemorrhage treated with endoscopic cyanoacrylate therapy or TIPS placement at a single U.S. center from 1997 to 2007. The groups were compared for rebleeding at 72 hours, 3 months, and 1 year; survival rates at 3 months and 1 year; and acute and extended complications and morbidity. MAIN OUTCOME MEASUREMENTS AND RESULTS A total of 105 patients were included. There were no significant pretreatment differences between the 2 groups in age, sex, MELD (Model for End-Stage Liver Disease) score at the time of admission, or cause of liver disease. There were no significant differences in rebleeding at 72 hours, 3 months, and 1 year; survival at 3 months and 1 year; and aggregate long-term survival or acute complications. However, the TIPS group had a higher rate of long-term morbidity requiring hospitalization (41% with a TIPS and 1.6% in the cyanoacrylate arm, P < .0001). LIMITATIONS Retrospective and uncontrolled samples. CONCLUSION In patients with similar characteristics, cyanoacrylate therapy performed as well as a TIPS in controlling and preventing gastric variceal hemorrhage with no significant differences in survival. Patients receiving cyanoacrylate therapy experienced significantly less long-term morbidity related to therapy than patients who received a TIPS. Cyanoacrylate therapy appears to be safe and effective and compares favorably with TIPS therapy.

Effects of n-3 fish oil on metabolic and histological parameters in NASH: A double-blind, randomized, placebo-controlled trial

BACKGROUND & AIMS This studys aim was to assess the histological and metabolic effects of n-3 polyunsaturated fatty acids (PUFAs) vs. placebo while adjusting for the impact of age and weight change in NASH patients. (ClinicalTrials.gov: NCT00681408). METHODS Forty-one subjects with non-cirrhotic NASH were enrolled, and 34 completed the study. 17 received n-3 fish oil 3000 mg/day and 17 received placebo daily for 1 year with typical counselling on caloric intake and physical activity for all subjects. RESULTS N-3- and placebo-treated groups showed no significant difference for the primary end point of NASH activity score (NAS) reduction ⩾ 2 points without fibrosis progression after adjustment for known covariates (n-3, 4/17 (23.5%); placebo, 3/17, (17.6%), p = 0.99). Among subjects with increased or stable weight, n-3 subjects showed a larger decrease in liver fat content by MRI than placebo-treated subjects (p = 0.014 for 2nd quartile, p = 0.003 for 3rd quartile of weight change). N-3 treatment showed significant fat reduction on the paired analysis of image-assisted fat morphometry regardless of weight loss or gain. Exercise capacity remained markedly reduced in all subjects. No independent effects on markers of hepatocyte injury or insulin sensitivity indices were observed. CONCLUSION N-3 PUFAs at 3000 mg/day for one year did not lead to an improvement in the primary outcome of histological activity in NASH patients (⩾ 2 point NAS reduction). N-3 led to reduced liver fat by multiple measures. Other metabolic effects were not seen, although no detrimental effects were apparent. Whether longer duration, higher dose, or different composition of n-3 therapy would lead to additional benefits is uncertain.

Therapy of NAFLD: antioxidants and cytoprotective agents.

Lipid peroxidation and secondary cellular injury are the dominant mechanism in the transition from relatively stable hepatic steatosis to potentially progressive steatohepatitis in nonalcoholic fatty liver disease (NAFLD). Oxidation of excessive fatty acids generates free radicals (reactive oxygen species) that damage organelles and stimulate signaling pathways leading to fibrosis and cellular injury. Both antioxidant agents (by breaking the chain reaction of lipid peroxidation) and cytoprotective agents (by stabilizing cellular and organelle phospholipid membranes) may be effective agents in treating an active steatohepatitis through amelioration of the driving force and attenuation of the secondary effects. Here we have reviewed the existing studies on such therapies, including vitamin E, S-adenosylmethionine (SAMe), betaine, and ursodeoxycholic acid. Small trials suggest possible improvement in liver enzymes with the use of these agents in NAFLD. However, controlled studies have not uniformly demonstrated benefit from these agents when compared with control groups treated with diet and weight loss alone, and measurement of reliable histologic endpoints is limited. These agents may show benefit in NAFLD through future larger controlled studies. Particular promise may exist in the use of these agents in combination therapy with ones that target other aspects in the pathogenesis of NAFLD, such as insulin-sensitizing agents.

Combined liver-kidney and liver transplantation in patients with renal failure outcomes in the MELD era.

With the implementation of the Model for End‐Stage Liver Disease (MELD) scoring system, the number of combined liver–kidney transplants (CLKT) has increased dramatically. The United Network for Organ Sharing (UNOS) dataset was analysed for adult recipients with renal failure for the period between February 2002 and April 2006. This group was subdivided into patients on hemodialysis (HD) and to those not on HD prior to transplantation. All recipients in renal failure (serum creatinine ≥2.5 mg/dl) at the time of transplantation were included. A total of 1397 subjects were in renal failure but not on HD (18% received a CLKT, 82% underwent LT alone). Another 1740 subjects were on HD prior to transplantation (41% received a CLKT while 59% received a LT). In dialysis‐dependent recipients, Cox regression analysis demonstrated CLKT had an independent protective effect. In subjects on HD, CLKT had improved survival at 1 year (79.4 vs. 73.7%, P = 0.004). In patients in renal failure without HD, CLKT was not protective. CLKT subjects had a nonsignificant difference in survival as compared with patients who had undergone liver transplantation alone, at 1 year (81.0% vs. 78.8%, P > 0.10). In subjects undergoing CLKT, there was improved survival at 1 year as compared with LT‐alone patients on hemodialysis; however, in patients with renal failure, but not on hemodialysis, there was no difference in survival when comparing CLKT to LT‐alone.

Accelerated treatment using intensity-modulated radiation therapy plus concurrent capecitabine for unresectable hepatocellular carcinoma.

Patients with unresectable hepatocellular carcinoma (HCC) have limited treatment options. In this study, the authors investigated the feasibility, toxicity, and efficacy associated with intensity‐modulated radiation therapy (IMRT) and concurrent, chronomodulated capecitabine in the treatment of unresectable HCC.

Mortality after percutaneous endoscopic gastrostomy in patients with cirrhosis: a case series

BACKGROUND Percutaneous endoscopic gastrostomy (PEG) tube placement can improve the nutritional status and the ability of a patient with cirrhosis to recover from surgery such as orthotopic liver transplantation. However, cirrhosis has been considered a significant contraindication to PEG tube placement. OBJECTIVE Our aim in this study was to describe the mortality and complications in a series of cirrhotic patients who underwent PEG at our institution. DESIGN Retrospective, single-institution case series. PATIENTS This study involved 26 consecutive patients with cirrhosis who underwent PEG between 1995 and 2005. INTERVENTION PEG tube placement. MAIN OUTCOME MEASUREMENTS AND RESULTS The 30-day mortality of the series of patients was 10 of 26 (38.5%), whereas the 90-day mortality was 11 of 26 (42.3%). Nine of the 10 patients who died in the first 30 days had ascites at the time of PEG tube placement. Two patients died as a direct consequence of complications from the PEG procedure, whereas the other deaths were related to progression of liver disease or factors not directly related to the PEG. LIMITATIONS The patients in this case series had varying levels of illness and reasons for PEG tube placement such that a generalization of outcomes may not be possible. CONCLUSIONS The overall mortality of patients with cirrhosis who underwent PEG is high. Although there is an increased risk, PEG tube placement in cirrhotic patients without ascites may be less risky. The benefits of PEG tube placement in patients with cirrhosis should be weighed heavily against the risks.

Therapy of NAFLD: insulin sensitizing agents.

Insulin resistance is an integral part of the underlying pathophysiology in most patients with nonalcoholic fatty liver disease (NAFLD). Insulin-sensitizing agents are therefore likely to be of key importance in the treatment of this disorder, especially in the histologically more severe form known as nonalcoholic steatohepatitis. Here we have reviewed the current literature on the two major insulin-sensitizing agents that have been studied in patients with NAFLD: the thiazolidinediones (or PPAR-gamma agonists) and metformin, the only available biguanide. Thiazolidinedione administration in human NAFLD has been shown to decrease hepatic fat by several different global measures and to decrease evidence of cellular injury, but it has also been associated with increased peripheral fat and weight gain. In contrast, metformin has been shown to improve biochemical markers without weight gain, but with more variable improvement in histology. Neither agent has been FDA approved for treating NAFLD, but existing studies have provided much hope for incorporating these medications into NAFLD management strategies in selected patients.Insulin resistance is an integral part of the underlying pathophysiology in most patients with nonalcoholic fatty liver disease (NAFLD). Insulin-sensitiziting agents are therefore likely to be of key importance in the treatment of this disorder, especially in the histologically more severe form known as nonalcoholic steatohepatitis. Here we have reviewed the current literature on the two major insulin-sensitizing agents that have been studied in patients with NAFLD: the thiazolidinediones (or PPAR-gamma agonists) and metformin, the only available biguanide. Thiazolidinedione administration in human NAFLD has been shown to decrease hepatic fat by several different global measures and to decrease evidence of cellular injury, but it has also been associated with increased peripheral fat and weight gain. In contrast, metformin has been shown to improve biochemical markers without weight gain, but with more variable improvement in histology. Neither agent has been FDA approved for treating NAFLD, but existing studies have provided much hope for incorporating these medications into NAFLD management strategies in selected patients.

Thiazolidinediones for the Treatment in Nash: Sustained Benefit After Drug Discontinuation?

Background Although of unproven benefit for nonalcoholic steatohepatitis (NASH), thiazolidinediones (TZDs) have emerged as a promising therapy. Little evidence exists, however, regarding sustained effects of TZDs in NASH after drug discontinuation. A recent clinical study suggests that relapse of NASH pathophysiology is inevitable and that lifelong therapy may be needed to maintain histologic response. Goal We reviewed extended follow-up data of NASH patients previously treated with troglitazone to evaluate the influence of weight and physical activity on clinical and histologic parameters related to NASH recurrence. Study After medical record review, 9 of 10 patients had complete data for follow-up and 5 had an extended follow-up biopsy 3 years or more after discontinuing troglitazone therapy. Results In contrast to recent work showing relapse of NASH to be nearly universal after discontinuation of TZD therapy, 2 of our patients had 1-stage improvement in fibrosis, normal aminotransferases, and absence of diabetes after median follow-up of 37 months after discontinuation of troglitazone. Both patients had sustained exercise programs and interval body mass index reduction. In contrast, active steatohepatitis, progression of fibrosis, and requirement of antidiabetic medications were seen in patients unable to achieve lifestyle modifications. Conclusions We conclude that sustained histologic response after short-term TZD therapy for NASH is not invariably lost after medication discontinuation but rather is intimately related to sustained changes in lifestyle, particularly physical activity. Activity and diet in the setting of thiazolidinedione or other drug therapy of NASH is an essential consideration that warrants careful incorporation into future drug trials.

Pre– and Post–Balloon-Occluded Retrograde Transvenous Obliteration Clinical Evaluation, Management, and Imaging: Indications, Management Protocols, and Follow-up

Patients with gastric variceal bleeding require a multidisciplinary team approach, which includes hepatologists, endoscopists, diagnostic radiologists, and interventional radiologists. Upper gastrointestinal endoscopy is the first-line diagnosis and management tool for bleeding gastric varices (GVs) as it is with all upper gastrointestinal bleeding scenarios. Traditionally, in the United States, when endoscopy fails to control gastric variceal bleeding, a transjugular intrahepatic portosystemic shunt (TIPS) is performed along the classic teachings of decompressing the portal circulation. However, TIPS has shown inconsistent effectiveness in controlling gastric variceal bleeding. Conversely, the balloon-occluded retrograde transvenous obliteration (BRTO) procedure has become common practice in Asia for the management of GVs. The BRTO procedure is gaining popularity in the United States. BRTO has shown to be effective in controlling gastric variceal bleeding with low gastric variceal rebleed rates. Regardless of the endovascular management (TIPS vs BRTO vs both), a multidisciplinary team with adequate preprocedural clinical assessment and management and endoscopic and imaging evaluation is required before and after the endovascular procedure. The article discusses the pre- and post-BRTO clinical evaluation and management, as well as endoscopic and imaging evaluation. Moreover, the article proposes indications, contraindications, and management protocols for the management of GVs.