Current Management and Future Treatment of Alcoholic Hepatitis.

Excessive alcohol consumption is responsible for approximately 50% of all deaths due to cirrhosis. Although the duration and amount of alcohol consumption are the primary factors responsible for the liver injury caused by consuming alcohol, the pathogenesis of the 3 stages of alcohol-associated liver disease (ALD)-fatty liver, alcoholic hepatitis (AH), and cirrhosis- is likely multifactorial. Preexisting obesity, dysbiosis of the gut microbiome, activation of proinflammatory cytokines, and genetic factors can all contribute to the risk of developing ALD. The cornerstone of therapy for all stages of ALD is abstinence from drinking alcoholic beverages. Severe AH, defined by a Maddrey discriminant function greater than 32, warrants additional therapy. The results of multiple studies evaluating the use of glucocorticoids in the treatment of severe AH led to guidelines from international societies that recommend glucocorticoid therapy in patients with severe AH without active infection. Liver transplantation provides an effective treatment option for patients who fail glucocorticoid therapy. Recent advances in understanding the pathogenesis of AH have led to the investigation of potential therapies directed at preventing the development of steatosis, inhibiting the innate immune response, modifying the gut microbiome, and stimulating liver regeneration.

TGF-ß/ß2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. Epigenetic silencing of ß2-spectrin (ß2SP, encoded by SPTBN1), a SMAD adaptor for TGF-ß signaling, is causally associated with BWS; however, a role of TGF-ß deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous Sptbn1+/- Smad3+/- mice, which have defective TGF-ß signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. Moreover, tumorigenesis-associated genes IGF2 and telomerase reverse transcriptase (TERT) were overexpressed in fibroblasts from BWS patients and TGF-ß-defective mice. We further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF-ß inducible and facilitates TGF-ß-mediated repression of TERT transcription via interactions with ß2SP and SMAD3. This regulation was abrogated in TGF-ß-defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-ß pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.

Effect of hepatitis C virus infection in patients with cancer: addressing a neglected population.

BACKGROUND: Hepatitis C virus (HCV) infection is a neglected disease in patients with cancer. Therefore, this study examined the impact of HCV infections in these patients. METHODS: The records of HCV-infected patients with cancer seen at The University of Texas MD Anderson Cancer Center (2008-2011) were reviewed. The outcomes of those who underwent HCV treatment were analyzed. RESULTS: Of 1291 patients who had positive test results for an antibody to HCV (anti-HCV), 744 (58%) were tested for HCV-RNA; 642 (86%) of which had chronic HCV infections. Most had solid tumors (72%) and genotype-1 (G-1) infections (66%). HCV therapy was administered in 348 patients (98 of them after cancer diagnosis). Sustained virologic response (SVR) occurred in 27 (35%) of the 78 patients treated for whom outcome data were available. Compared with patients who experienced an SVR, more patients who did not were black (29% vs 4%; P=.007), had G-1 infections (72% vs 6%; P<.0001), and had higher baseline aspartate aminotransferase (78 vs 47 IU/L; P=.006) and alanine aminotransferase levels (71.1 vs 43.3 IU/L; P=.009). Overall, progression to cirrhosis (hazard ratio [HR], 0.38; P=.03) and portal hypertension (HR, 0.19; P=.009) was less common in those treated, irrespective of the treatment outcome (SVR or non-SVR). Hepatocellular carcinoma (HCC) developed as a second primary malignancy in 7% of patients with non-HCC cancer. CONCLUSIONS: This is the largest series to analyze HCV infections in patients with cancer. HCV therapy is feasible and prevents liver disease progression in this forgotten population. A treatment algorithm is provided.

Clinical decision-making by gastroenterologists and hepatologists for patients with early hepatocellular carcinoma.

BACKGROUND: Choice of therapy in early hepatocellular carcinoma (HCC) is controversial, and no broad consensus exists as to how patient and tumor characteristics should be used to guide choice of therapy. We have previously reported on decision making in early HCC by liver surgeons. In the present study, we quantified the impact of clinical factors on choice of therapy for early HCC by gastroenterologists and hepatologists. METHODS: Physicians who treat HCC were invited to complete a web-based survey including ten case scenarios that systematically varied across seven clinical factors. Choice of therapy-liver transplantation (LT), liver resection (LR), radiofrequency ablation or intra-arterial therapy-was analyzed using multinomial logistic regression models. RESULTS: Tumor number and size, type of resection required, biological Model for End-Stage Liver Disease (MELD) score, and platelet count had the largest effects on choice of therapy. For example, LR was more likely to be recommended over LT for patients with small solitary tumors versus multiple tumors [relative risk ratio (RRR) 3.63], those who would require a minor versus major LR (RRR 3.39), those with lower biological MELD score (6 vs. 10; RRR 1.95), and those with a higher platelet count (150,000/µL vs. 70,000/µL; RRR 2.77). In contrast, serum α-fetoprotein level and etiology of cirrhosis were not associated with choice of therapy. No physician-related factors studied had an impact on choice of therapy. CONCLUSION: The clinical factors weighed most heavily by gastroenterologists and hepatologists are quite similar to those considered important by surgeons. There was good consensus among gastroenterologists and hepatologists as to the factors used to choose therapy.

Treatment of refractory ascites.

In 1996, the International Ascites Club defined "refractory ascites" as ascites that cannot be mobilized by medical therapy or that recurs early after initial mobilization despite continued treatment. Of all patients with ascites, 5% to 10% will become refractory to medical therapy. Management of refractory ascites should attempt to control fluid accumulation, reduce the likelihood of developing complications such as spontaneous bacterial peritonitis (SBP) and the hepatorenal syndrome, and improve the patient's nutritional status and overall well-being. Measures to control ascites accumulation include documenting medication and dietary compliance and eliminating potentially nephrotoxic agents that promote sodium retention. Large volume paracentesis is an effective first step in managing these patients and can be performed routinely in an outpatient setting. When more than 5 L of fluid are removed during a paracentesis, intravenous albumin should be infused to reduce the likelihood of the patient developing postparacentesis circulatory dysfunction. Transjugular intrahepatic portosystemic shunt (TIPS) placement effectively eliminates ascites; however, there is no convincing evidence that the shunt improves mortality. Furthermore, it is associated with frequent complications of encephalopathy and shunt malfunction. We feel TIPS should be reserved for patients requiring extremely frequent paracentesis, those who develop significant postparacentesis circulatory dysfunction, or those with hepatic hydrothorax. Patients who have evidence of SBP should be treated with antibiotics and intravenous albumin infusion. Patients who have had a previous episode of SBP or an ascitic fluid protein level of less than 1.0 should receive prophylactic antibiotics. Overall, the prognosis for patients with refractory ascites remains grim, and liver transplantation is the only definitive therapy. Appropriate candidates should be identified promptly and referred for transplant evaluation.

Screening tests for hepatocellular carcinoma in patients with chronic hepatitis C: a systematic review.

This systematic review addresses the following questions: (1) What is the efficacy of using screening tests for hepatocellular carcinoma (HCC) in improving outcomes in chronic hepatitis C, and (2) what are the sensitivity and specificity of screening tests for HCC in chronic hepatitis C? The search strategy involved searching Medline and other electronic databases between January 1985 and March 2002. Additional articles were identified by reviewing pertinent articles and journals and by querying experts. Articles were eligible for review if they reported original human data from studies of screening tests that used virological, histological, pathologic, or clinical outcome measures. Data collection involved paired reviewers who assessed the quality of each study and abstracted data. One nonrandomized prospective cohort study suggested that HCC was detected earlier and was more often resectable in patients who had twice yearly screening with serum alpha-fetoprotein (AFP) and hepatic ultrasound than in patients who had usual care. Twenty-four studies, which included patients with chronic hepatitis C or B or both, addressed the sensitivities and specificities of screening tests. They were relatively consistent in showing that the sensitivity of serum AFP for detecting HCC usually was moderately high at 45% to 100%, with a specificity of 70% to 95%, for a threshold of between 10 and 19 ng/mL. The few studies that evaluated screening with ultrasound reported high specificity, but variable sensitivity. In conclusion, screening of patients with chronic hepatitis C with AFP and ultrasound may improve detection of HCC, but studies are needed to determine whether screening improves clinical outcomes.

Treatment of chronic hepatitis C: a systematic review.

This systematic review addressed 3 issues regarding current treatments for chronic hepatitis C: (1) efficacy and safety in treatment-naive patients; (2) efficacy and safety in selected subgroups of patients; and (3) effects on long-term clinical outcomes. Electronic databases were searched for articles from January 1996 to March 2002. Additional articles were identified by searching references in pertinent articles and recent journals and by questioning experts. Articles were eligible for review if they reported original human data from a study that used virological, histological, or clinical outcome measures. For data collection, paired reviewers assessed the quality of each study and abstracted data. This systematic review found that the combination of high-dose peginterferon and ribavirin was more efficacious than standard interferon and ribavirin in persons infected with hepatitis C virus (HCV) genotype 1 (sustained virologic response [SVR] rate: 42% vs. 33%) and that ranges of SVR rates were higher with peginterferon than standard interferon monotherapy in naïve patients (10% to 39% vs. 3% to 19%). Reports were consistent in showing treatment with interferon and ribavirin was more efficacious than interferon monotherapy in treatment-naive persons and previous nonresponders and relapsers. Studies were moderately consistent in showing that treatment decreases the risk for hepatocellular carcinoma (HCC). The evidence on treatment in important subgroups was limited by a lack of randomized controlled trials. Thus, the combination of peginterferon and ribavirin was the most efficacious treatment in patients with HCV genotype 1. Long-term outcomes were improved in patients with hepatitis C who achieved an SVR with treatment.

Role of liver biopsy in management of chronic hepatitis C: a systematic review.

This systematic review addresses 2 questions pertinent to the need for pretreatment liver biopsy in patients with chronic hepatitis C: how well do liver biopsy results predict treatment outcomes for chronic hepatitis C? How well do biochemical blood tests and serologic measures of fibrosis predict the biopsy findings in chronic hepatitis C? Medline and other electronic databases were searched from January 1985 to March 2002. Additional articles were sought in references of pertinent articles and recent journals and by querying experts. Articles were eligible for review if they reported original human data from a study that used virological, histological, pathologic, or clinical outcome measures. Paired reviewers assessed the quality of each eligible study and abstracted data. Studies suggested that advanced fibrosis or cirrhosis on initial liver biopsy is associated with a modestly decreased likelihood of a sustained virological response (SVR) to treatment. Also, studies relatively consistently showed that serum aminotransferases have modest value in predicting fibrosis on biopsy; that extracellular matrix tests hyaluronic acid and laminin may have value in predicting fibrosis, and that panels of tests may have the greatest value in predicting fibrosis or cirrhosis. Biochemical and serologic tests were best at predicting no or minimal fibrosis, or at predicting advanced fibrosis/cirrhosis, and were poor at predicting intermediate levels of fibrosis. Thus, evidence suggests that liver biopsy may have some usefulness in predicting efficacy of treatment in patients with chronic hepatitis C, and biochemical blood tests and serologic tests currently have only modest value in predicting fibrosis on liver biopsy.