Stephen A. Harrison

Correlation between insulin resistance and hepatitis C viral load.

Intrahepatic B cell clonal expansions and extrahepatic manifestations of chronic HCV infection. Eur J Immunol 2004;34:126-136. 9. Zignego AL, Giannelli F, Marrocchi ME, Mazzocca A, Ferri C, Giannini C, et al. T(14;18) translocation in chronic hepatitis C virus infection. HEPATOLOGY 2000;31:474-479. 10. Pham TNQ, MacParland SA, Mulrooney PM, Cooksley H, Naoumov NV, Michalak TI. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol 2004;78:5867-5874. 11. Dahari H, Feliu A, Garcia-Retortillo M, Forns X, Neumann AU. Second hepatitis C replication compartment indicated by viral dynamics during liver transplantation. J Hepatol 2005;42:491-498.

Thiazolidinedione therapy for nonalcoholic steatohepatitis: Go, stop, or proceed with caution?

The epidemic of obesity has been associated with a significant increase in nonalcoholic fatty liver disease (NAFLD). The pathogenesis of NAFLD in this setting is predicated on the premise that obesity-related insulin resistance is responsible for the development of hepatic steatosis. Our current understanding holds that in some patients, the increased free fatty acid (FFA) flux to the liver and decreased hepatic FFA oxidation results in lipotoxicity and progression to hepatocyte ballooning, lobular inflammation, and pericellular fibrosis—the histopathologic hallmarks of nonalcoholic steatohepatitis (NASH). To this end, investigators have predominantly focused on therapies that improve insulin resistance. Weight loss has been recommended for many years, and there is data to show that this therapy is efficacious. Bariatric surgery improves the underlying metabolic dysfunction seen in the morbidly obese patient and improves histopathology in most studies.1 In others, a modest weight loss ( 5%) improves insulin resistance while a weight loss of 10% is associated with improvement in steatosis, ballooning, inflammation, and NAFLD activity score (NAS).2 Unfortunately, the majority of patients with NAFLD are unable to lose weight and maintain their weight loss. Consequently, therapies aimed at improving insulin resistance either through augmenting or supplanting weight loss have been studied. The thiazolidinedione (TZD) class of insulin sensitizers has been the focus of attention for the past few years. Rosiglitazone and pioglitazone, both TZDs, were approved in 1999 for the treatment of type II diabetes. They are peroxisome proliferator-activated receptor(PPAR) agonists. PPARreceptors are located predominantly in adipose tissue, but can also be found elsewhere, to include pancreatic cells, vascular endothelium, and to a lesser extent in liver and skeletal muscle.3 The TZD mechanism of action is not completely understood, but they improve insulin resistance in liver, adipose tissue, and muscle. Data suggest that the TZDs decrease FFA flux to the liver and improve visceral adiposity in part through an increase in subcutaneous adipose tissue mass and up-regulation of specific adipocytokines such as adiponectin.3 Adiponectin expression, decreased in the setting of obesity, type II diabetes, metabolic syndrome, cardiovascular disease,4 and NAFLD,5 is increased by PPARagonists resulting in reduced hepatic gluconeogenesis as well as improved hepatic fatty acid oxidation (via increased adenosine monophosphate–activated protein kinase) and increased glucose disposal in skeletal muscle.4 Adiponectin also reduces inflammation, in part, by blocking nuclear factorB and inhibiting the release of proinflammatory cytokines6 and may suppress hepatic stellate cell proliferation.7 Recent evidence suggests that there are also differences between the two TZDs, at least when it comes to lipid metabolism.8 Pioglitazone has been shown to decrease plasma triglycerides, increase high-density lipoprotein (HDL), reduce low-density lipoprotein (LDL) concentration, and increase LDL particle size8 and decrease hepatic de novo lipogenesis by up to 40%.9 Rosiglitazone, alternatively, has no effect on hepatic de novo lipogenesis9 and actually has been shown to raise plasma LDL concentration and does not reduce triglyceride concentrations.8 This may explain, at least in part, why pioglitazone has positive cardiovascular effects (improved carotid intimal medial thickness10 and coronary atheroma volume11) whereas rosiglitazone does not. Thus, it appears that the two TZDs are not completely similar and pioglitazone may have additional PPARactivity.3 Focusing on NAFLD, both TZDs have now been studied in prospective, placebo-controlled trials ranging from 6-24 months duration. The results have been varied (Table 1). The TZDs most reliably improve steatosis, just as they do with insulin resistance. However, there are variable responses to other histopathologic lesions commonly seen in NASH to include lobular inflammation, ballooning degeneration, and fibrosis. Intuitively, we would all like to see fibrosis regression. However, no study has conclusively shown TZD therapy to improve fibrosis. Alternatively, no study has shown significant progression Abbreviations: FFA, free fatty acid; LDL, low-density lipoprotein; HDL, highdensity lipoprotein; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferatoractivated receptor; TZD, thiazolidinedione. Address reprint requests to: Stephen A. Harrison, M.D., Brooke Army Medical Center, Department of Gastroenterology, 3851 Roger Brooke Drive, Fort Sam Houston, TX 78234. E-mail: stephen.harrison@amedd.army.mil; fax: 210-9165611. Disclaimer statement: The opinion of ascertains contained herein are the private views of the authors and are not to be construed as official or reflecting the view of the Department of the Army or the Department of Defense. Copyright

Nonalcoholic fatty liver disease: Fibrosis portends a worse prognosis

A dvances in the treatment of chronic hepatitis C have led to a shift in focus to nonalcoholic fatty liver disease (NAFLD) as the fastest growing chronic liver disease of the Western world. More sedentary lifestyles, diets higher in processed carbohydrates, and burgeoning waistlines all have contributed to the obesity and diabetes epidemic and, subsequently, the meteoric rise in NAFLD prevalence. It is both fortunate and unfortunate that NAFLD is relatively easy to diagnose: steatosis on imaging with or without elevated liver-associated enzymes and a negative serologic evaluation for other chronic liver disease picks up the majority of the 30%-40% of the general population with NAFLD. However, the optimal management of NAFLD remains to be fully delineated as diet, weight loss, and exercise are difficult to achieve and sustain in the vast majority of NAFLD patients and Food and Drug Administration–approved therapies remain elusive. Furthermore, there appears to be a wide disparity in long-term outcomes depending on the severity of disease. Once a diagnosis of NAFLD is made, liver biopsy remains the gold standard second step in the diagnostic algorithm to evaluate for nonalcoholic steatohepatitis (NASH). Pragmatically, physicians who see NAFLD patients are left in a quandary. If there is no Food and Drug Administration–approved therapy for NASH, why differentiate given the cost and potential risk of complications, however small they may be? Conventional teaching has suggested that those patients who meet histopathologic criteria for NASH are at the greatest risk of progression to cirrhosis as well as the development of hepatocellular carcinoma. However, this group of patients makes up only about 25% of those with NAFLD, and the vast majority of patients will have non-NASH NAFLD. While most authorities in the field advocate a “NASH” or “non-NASH NAFLD” expert pathologist read in order to help identify those patients at greatest risk for progressive disease, the NAFLD activity score (NAS) has also been used by some in clinical practice. The NAS, which uses a sum score of steatosis, ballooning, and lobular inflammation, was originally developed as a research tool and has been used in most large randomized-controlled trials to measure “improvement” in disease with a particular therapy. A score greater than 4 is thought of as “probable NASH” but is not diagnostic, and NASH can occur with a lower NAS. Similarly, a score of 5 or 6 can be seen in patients who do not meet histopathologic criteria for NASH. Neither the NASH/non-NASH NAFLD approach (just defining the presence or absence of disease) nor the NAS necessarily takes into account hepatic fibrosis, which others have suggested is at least equally important in determining both the prognosis and the success of a particular therapy. This has left many questions unanswered and placed clinicians in a difficult position both when deciding whether or not to perform a biopsy and, if a biopsy is done, what to do with the information. In this issue of HEPATOLOGY, Ekstedt et al. provide some insights with their large natural history study of 229 biopsy-proven NAFLD patients followed for a mean of 26.4 years (65.6, range 6-33). One caveat that should be mentioned in this study, however, is that while patients were screened for other chronic liver diseases, it appears that only about 50% of the patients had hepatitis C excluded, so it is possible that a minority of patients with coexisting chronic hepatitis C are included in this cohort. There are a few key findings from this study that deserve to be highlighted. First, this study reiterates that NAFLD with fibrosis portended a worse Abbreviations: NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis. Received December 8, 2014; accepted December 22, 2014. Address reprint requests to: Stephen A. Harrison, M.D., Division of Gastroenterology and Hepatology, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, TX 78234. E-mail: Stephen.a.harrison.mil@mail. mil; fax: 11-210-916-2601. The opinion or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the view of the US Department of the Army or the US Department of Defense. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27680 Potential conflict of interest: Dr. Harrison advises and is on the speakers’ bureau for Abbvie. He advises Fibrogen, NGM, Merck, Nimbus, and Discovery. He is on the speakers’ bureau for Gilead and Janssen.

NASH, from diagnosis to treatment: Where do we stand?

O ver one-third of individuals in developed countries are overweight or obese, and the prevalence of fatty liver disease parallels this. Only a fraction of such individuals have nonalcoholic steatohepatitis (NASH), but it is very important to be able to diagnose and treat those individuals in order to avoid long-term complications. There are a number of emerging opportunities to improve our ability to do this.

High prevalence of hepatic fibrosis in the setting of coexisting diabetes and hepatic steatosis: A case for selective screening in the general population?

C hronic liver disease, accounting for one in 40 deaths worldwide, is a major cause of morbidity and mortality globally. With rising rates of obesity, diabetes mellitus (DM), and metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the leading etiology of chronic liver disease worldwide. Prevalence estimates of NAFLD vary depending on the population studied and the accuracy of the diagnostic test. Despite these limitations, it is currently estimated that the global prevalence of NAFLD is as high as 1 billion. In the United States, there are an estimated 75Îmillion to 100 million individuals with NAFLD. Moreover, nonalcoholic steatohepatitis (NASH), the more advanced form of NAFLD, is the most rapidly growing indication for liver transplantation in the United States. To counter these alarming trends, improved understanding of predictive factors associated with poor outcomes is needed. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD, and no other histologic features are associated with long-term outcomes of patients with NAFLD. In the largest cross-sectional study to date, Koehler et al. investigated the prevalence of and factors associated with clinically relevant liver fibrosis diagnosed by employing transient elastography (TE) in a general population of older ( 45 years) Caucasians living in Ommoord, a district of Rotterdam, The Netherlands. It must be noted that limited literature exists on this important but difficult-to-study group. Their study underscores the utility of TE as a noninvasive technique to detect clinically relevant liver fibrosis while avoiding the risks associated with liver biopsy. Between January 2011 and September 2013, 3041 participants underwent TE with liver stiffness measurement (LSM). LSM 8.0 kPa was defined as the surrogate marker of clinically relevant liver fibrosis. Of 3041 participants (age 66.0 6 7.6 years) with reliable LSM, 169 (5.6%) demonstrated LSM 8.0 kPa. In a multivariate analysis, increased age, higher alanine aminotransferase level, current or former smoking, larger spleen size, positive viral serologies (hepatitis B surface antigen or anti-hepatitis C virus positivity), and combined presence of DM and steatosis (detected by ultrasound) were independently associated with LSM 8.0 kPa. However, only increased age, higher alanine aminotransferase, and combined DM and steatosis demonstrated statistically significant P values <0.001 (see Koehler et al., table 3). In addition, this study demonstrated the independent relationship of aging and advanced hepatic fibrosis (higher LSM values). Notably, LSM increased with each higher age decade among participants without DM or steatosis but not among those with DM and steatosis. While the finding that LSM increased with age among those without DM or steatosis was not surprising, the latter result raises opportunities for further studies. Although there may admittedly be an element of survival effect bias influencing the reduced impact of age on LSM among participants with DM and steatosis in the oldest age groups, further investigation is warranted to confirm these observations. In comparison to other population-based cross-sectional studies with similar conclusions, a selection bias may have occurred in this study due to increased mean age, a disproportionately higher number of women, and a greater prevalence of metabolic syndrome. More importantly, this study demonstrates the significant associations between DM and hepatic steatosis with clinically relevant liver fibrosis as LSM 8.0 kPa was Abbreviations: DM, diabetes mellitus; LSM, liver stiffness measurement; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TE, transient elastography. Received September 2, 2015; accepted October 7, 2015. The opinions in this article do not constitute endorsement by the San Antonio Military Medical Center, the US Army Medical Department, the US Army Office of the Surgeon General, the Department of the Army, the Department of Defense, or the US government of the information contained therein. Address reprint requests to: Stephen A. Harrison, M.D., Division of Gastroenterology, San Antonio Military Medical Center, Fort Sam Houston, TX 78234. E-mail: Stephen.a.harrison.mil@mail.mil; fax: 11-210-916-2601. Copyright VC 2015 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.28277 Potential conflict of interest: Dr. Harrison consults, advises, and is on the speakers’ bureau for Gilead. He consults for NGM, Nimbus, and Fibrogen.

Insulin resistance in chronic hepatitis C, genotypes 1 and 4: The unfortunate reality

BACKGROUND & AIMS: Our study was designed to test the association between insulin resistance (IR) and hepatitis C virus (HCV) genotypes, serum HCV RNA level and liver fibrosis stage in a large prospective cohort of chronic hepatitis C (CHC) patients. METHODS: Six hundred consecutive patients (CHC, n 500; chronic hepatitis B (CHB), n 100) were evaluated on the day of liver biopsy. IR (Homeostasis Model for Assessment of Insulin Resistance) and all components of the metabolic syndrome were assessed. By logistic regression, independent factors associated with IR and those associated with significant fibrosis were assessed in nondiabetic and noncirrhotic CHC, respectively. Parameters of IR were compared between hepatitis B and 240 CHC matched by epidemiologic, metabolic, and histologic features. RESULTS: IR was present in 32.4% of the 462 nondiabetic CHC and associated with the metabolic syndrome, genotypes 1 and 4, significant fibrosis, and severe steatosis. IR was diagnosed in 15% of 145 CHC without metabolic syndrome or significant fibrosis, and associated with genotypes 1 and 4, high serum HCV RNA level, and moderate-severe necroinflammation. Significant fibrosis was present in 51.1% of the 454 noncirrhotic CHC patients and associated with male sex, age >40 years, IR, moderate-severe necroinflammation, and severe steatosis. IR was less frequent in CHB than in matched CHC (5% vs 35%, respectively, P < .001). CONCLUSIONS: IR is a specific feature of CHC, associated with genotypes 1 and 4 and high serum HCV RNA level. Significant fibrosis is associated with IR independent from steatosis.

Nonalcoholic fatty liver disease and elastography: Incremental advances but work still to be done

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed countries, with an estimated prevalence of 20%-30% and increasing to 70% in obese individuals and as high as 90% in diabetics. Given the pathophysiological link with metabolic syndrome, rates of NAFLD are likely to continue to rise with the obesity pandemic. Within a community cohort, prevalence of patients with NAFLD who have nonalcoholic steatohepatitis (NASH) has been estimated at 3%-4% and rising as high as 12.2% in middle-aged patients. For diabetic patients, prevalence of NASH may be as high as 56%. Whereas advanced fibrosis has the highest risk of mortality, patients with NASH are 6 times more likely to develop liver-related mortality over 20 years than those with non-NASH NAFLD. It is precisely these individuals with NASH and fibrosis who have the greatest risk of progression to advanced disease, cirrhosis, hepatocellular carcinoma, and death. Therefore, it is critical to distinguish between patients with fibrosis, NASH, and nonNASH NAFLD. The current gold standard for diagnosis and histological assessment of NAFLD is a liver biopsy. Unfortunately, liver biopsy is invasive, subject to complications, costly, and limited by sampling errors and intraobserver variability. Furthermore, given the high prevalence of NAFLD, it is neither practical nor cost effective to perform liver biopsies in all patients who are at risk for NASH and fibrosis. Recently, several noninvasive imaging modalities based on elastography have been developed. To date, these imaging modalities have proven promising in the assessment of liver fibrosis in chronic liver disease, though rigorous comparative studies in patients with NAFLD are lacking. Furthermore, distinction of NASH from non-NASH NAFLD using noninvasive imaging remains elusive because the diagnosis of NASH historically relies on the observation of ballooning degeneration of hepatocytes as well as steatosis and inflammation—not simply steatosis and fibrosis. The most validated, commonly used elastography method is vibration controlled transient elastography (VCTE), which is also known as transient elastography (TE) and marketed as the FibroScan (Echosens, Paris, France). VCTE is ultrasound based, but is not used with image guidance. The velocity of a lowamplitude shear wave is measured in a region of interest and is converted into a measure of liver stiffness. Both point quantification shear wave elastography (pSWE) and two-dimensional shear wave elastography (SWE) use acoustic radiation force impulse (ARFI) technology to generate shear waves in the liver, and the shear wave speed is calculated in meters Abbreviations: ARFI, acoustic radiation force impulse; AUROC, area under the receiver operating curve; CAP, controlled attenuation parameter; LSM, liver stiffness measurement; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; pSWE, point quantification shear wave elastography; SSI, supersonic shear imaging; SWE, shear wave elastography; TE, transient elastography; VCTE, vibration controlled transient elastography. The views expressed are those of the authors and should not be construed as official views of the United States Air Force, United States Army, or Department of Defense.

Treatment of nonalcoholic fatty liver disease: Role of dietary modification and exercise

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H. pylori and platelet counts

Helicobacter pylori (HP) eradication therapy is a useful treatment for idiopathic thrombocytopenic purpura (ITP). Some investigators have also reported the effects of proton pump inhibitor (PPI) monotherapy on ITP. We performed a randomized study of HP eradication therapy and PPI monotherapy on ITP. Four of nine patients achieved complete remission (CR), two of nine achieved partial remission (PR) in HP eradication therapy, three of eight achieved CR, and two of eight achieved PR in PPI monotherapy. No significant differences were observed in the CR + PR of these patients between HP eradication therapy and PPI monotherapy. As for cost comparisons, HP eradication therapy is cheaper than PPI monotherapy, but it is less effective.