Eric R. Kallwitz

Liver enzymes and histology in obese patients with obstructive sleep apnea.

Background and Aims Recent studies have shown an association between obstructive sleep apnea (OSA) and elevated liver enzymes in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the current study was to compare biochemical and histologic findings in patients with NAFLD as a function of OSA status. Methods Subjects consisted of 85 patients who had a sleep study followed by a liver biopsy performed at the time of obesity surgery. The diagnosis of OSA was based on an apnea hypopnea index of ≥15. Demographic and laboratory data were collected retrospectively. Liver biopsies were systematically evaluated for features of NAFLD including degree of steatosis, inflammation, and fibrosis. Results All but one patient had histologic evidence of NAFLD and 51% of the study population had OSA. A higher proportion of patients with OSA had elevated alanine aminotransferase levels (13/39) compared with those without OSA (3/34) (P=0.01). Only 19% of subjects had fibrosis on liver biopsy and still fewer (5%) had bridging fibrosis or cirrhosis. There was a trend toward a higher prevalence of OSA in patients with evidence of progressive liver disease, as indicated by inflammation plus fibrosis (11/15), compared with those with inflammation alone (22/48) (P=0.06). Conclusions In obese patients with NAFLD, OSA was associated with elevated alanine aminotransferase levels and a trend toward histologic evidence of progressive liver disease.

TIPS for Treatment of Variceal Hemorrhage: Clinical Outcomes in 128 Patients at a Single Institution over a 12-Year Period

PURPOSE To assess clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) treatment of variceal hemorrhage. MATERIALS AND METHODS A total of 128 patients (82 men and 46 women; mean age, 52 y) with liver cirrhosis and refractory variceal hemorrhage underwent TIPS creation from 1998 to 2010. Mean Child-Pugh and Model for End-stage Liver Disease (MELD) scores were 9 and 18, respectively. From 1998 to 2004, 12-mm Wallstents (n = 58) were used, whereas from 2004 to 2010, 10-mm VIATORR covered stent-grafts (n = 70) were used. Technical success, hemodynamic success, complications, shunt dysfunction, recurrent bleeding, and overall survival were assessed. RESULTS Technical and hemodynamic success rates were 100% and 94%, respectively. Mean portosystemic gradient reduction was 13 mm Hg. Complications at 30 days included encephalopathy (14%), renal failure (5.5%), infection (1.6%), and liver failure (0.8%). Shunt patency rates were 93%, 82%, and 60% at 30 days, 1 year, and 2 years, respectively. Dysfunction, or loss of TIPS primary patency, occurred more with Wallstent versus VIATORR TIPSs (29% vs 11%; P = .009). Recurrent bleeding incidences were 9%, 22%, and 29% at 30 days, 1 year, and 2 years, respectively, and were similar between Wallstent and VIATORR TIPSs (19% vs 19%; P = .924). Variceal embolization significantly reduced recurrent bleeding rates (5% vs 25%; P = .013). Overall survival rates were 80%, 69%, and 65% at 30 days, 1 year, and 2 years, respectively, and were similar between Wallstent and VIATORR TIPSs (35% vs 26% mortality rate; P = .312). Advanced MELD score was associated with increased mortality on multivariate analysis. CONCLUSIONS Wallstent and VIATORR TIPSs effectively treat variceal hemorrhage, particularly when accompanied by variceal embolization. Although TIPS with a VIATORR device showed improved shunt patency, patient survival is similar to that with Wallstent TIPS. These results further validate TIPS creation for refractory variceal bleeding.

Prognostic Capability of Different Liver Disease Scoring Systems for Prediction of Early Mortality after Transjugular Intrahepatic Portosystemic Shunt Creation

PURPOSE To compare the performance of various liver disease scoring systems in predicting early mortality after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS In this single-institution retrospective study, eight scoring systems were used to grade liver disease in 211 patients (male-to-female ratio = 131:80; mean age, 54 y) before TIPS creation from 1999-2011. Scoring systems included bilirubin level, Child-Pugh (CP) score, Model for End-Stage Liver Disease (MELD) and Model for End-Stage Liver Disease sodium (MELD-Na) score, Emory score, prognostic index (PI), Acute Physiology and Chronic Health Evaluation (APACHE) 2 score, and Bonn TIPS early mortality (BOTEM) score. Medical record review was used to identify 30-day and 90-day clinical outcomes. The relationship of scoring parameters with mortality outcomes was assessed with multivariate analysis, and the relative ability of systems to predict mortality after TIPS creation was evaluated by comparing area under receiver operating characteristic (AUROC) curves. RESULTS TIPS were successfully created for variceal hemorrhage (n = 121), ascites (n = 72), hepatic hydrothorax (n = 15), and portal vein thrombosis (n = 3). All scoring systems had a significant association with 30-day and 90-day mortality (P<.050 in each case) on multivariate analysis. Based on 30-day and 90-day AUROC, MELD (0.878, 0.816) and MELD-Na (0.863, 0.823) scores had the best capability to predict early mortality compared with bilirubin (0.786, 0.749), CP (0.822, 0.771), Emory (0.786, 0.681), PI (0.854, 0.760), APACHE 2 (0.836, 0.735), and BOTEM (0.798, 0.698), with statistical superiority over bilirubin, Emory, and BOTEM scores. CONCLUSIONS Several liver disease scoring systems have prognostic value for early mortality after TIPS creation. MELD and MELD-Na scores most effectively predict survival after TIPS creation.

Prevalence of Suspected Nonalcoholic Fatty Liver Disease in Hispanic/Latino Individuals Differs by Heritage

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) was shown to disproportionally affect Hispanic persons. We examined the prevalence of suspected NAFLD in Hispanic/Latino persons with diverse backgrounds. METHODS We studied the prevalence of suspected NAFLD among 12,133 persons included in the Hispanic Community Health Study/Study of Latinos. We collected data on levels of aminotransferase, metabolic syndrome (defined by National Cholesterol Education Program-Adult Treatment Panel III guidelines), demographics, and health behaviors. Suspected NAFLD was defined on the basis of increased level of aminotransferase in the absence of serologic evidence for common causes of liver disease or excessive alcohol consumption. In multivariate analyses, data were adjusted for metabolic syndrome, age, acculturation, diet, physical activity, sleep, and levels of education and income. RESULTS In multivariate analysis, compared with persons of Mexican heritage, persons of Cuban (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.57-0.85), Puerto Rican (OR, 0.67; 95% CI, 0.52-0.87), and Dominican backgrounds (OR, 0.71; 95% CI, 0.54-0.93) had lower rates of suspected NAFLD. Persons of Central American and South American heritage had a similar prevalence of suspected NAFLD compared with persons of Mexican heritage. NAFLD was less common in women than in men (OR, 0.49; 95% CI, 0.40-0.60). Suspected NAFLD associated with metabolic syndrome and all 5 of its components. CONCLUSIONS On the basis of an analysis of a large database of health in Latino populations, we found the prevalence of suspected NAFLD among Hispanic/Latino individuals to vary by region of heritage.

Physical activity and metabolic syndrome in liver transplant recipients

There is a high prevalence of metabolic syndrome in liver transplant recipients, a population that tends to be physically inactive. The aim of this study was to characterize physical activity and evaluate the relationship between physical activity and metabolic syndrome after liver transplantation. A cross‐sectional analysis was performed in patients more than 3 months after transplantation. Metabolic syndrome was classified according to National Cholesterol Education Panel Adult Treatment Panel III guidelines. Physical activity, including duration, frequency, and metabolic equivalents of task (METs), was assessed. The study population consisted of 204 subjects, with 156 more than 1 year after transplantation. The median time after transplantation was 53.5 months (range = 3‐299 months). The mean duration of exercise was 90 ± 142 minutes, and the mean MET score was 3.6 ± 1.5. Metabolic syndrome was observed in 58.8% of all subjects and in 63.5% of the subjects more than 1 year after transplantation. In a multivariate analysis involving all subjects, metabolic syndrome was associated with a time after transplantation greater than 1 year [odds ratio (OR) = 2.909, 95% confidence interval (CI) = 1.389‐6.092] and older age (OR = 1.036, 95% CI = 1.001‐1.072). A second analysis was performed for only patients more than 1 year after transplantation. In a multivariate analysis, metabolic syndrome was associated with lower exercise intensity (OR = 0.690, 95% CI = 0.536‐0.887), older age (OR = 1.056, 95% CI = 1.014‐1.101), and pretransplant diabetes (OR = 4.246, 95% CI = 1.300‐13.864). In conclusion, metabolic syndrome is common after liver transplantation, and the rate is significantly higher in patients more than 1 year after transplantation. The observation that exercise intensity is inversely related to metabolic syndrome after transplantation is novel and suggests that physical activity might provide a means for reducing metabolic syndrome complications in liver transplant recipients. Liver Transpl 19:1125–1131, 2013.

Liver Injury with Features Mimicking Autoimmune Hepatitis following the Use of Black Cohosh

There are a growing number of cases detailing acute hepatic necrosis in patients taking black cohosh (Cimicifuga racemosa), an over-the-counter herbal supplement for management of menopausal symptoms. Our aim is to illustrate two cases of liver injury following the use of black cohosh characterized by histopathological features mimicking autoimmune hepatitis. Both patients reported black cohosh use for at least six months and had no evidence of another cause of liver disease. Their liver biopsies showed a component of centrilobular necrosis consistent with severe drug-induced liver injury. In addition, the biopsies showed characteristics of autoimmune-like liver injury with an interface hepatitis dominated by plasma cells. Although serum markers for autoimmune hepatitis were not particularly elevated, both patients responded to corticosteroids, supporting an immune-mediated component to the liver injury. Liver injury following the use of black cohosh should be included in the list of differential diagnoses for chronic hepatitis with features mimicking autoimmune hepatitis.

Sarcopenia and liver transplant: The relevance of too little muscle mass.

Loss of muscle mass and function is a common occurrence in both patients with decompensated cirrhosis and those undergoing liver transplantation. Sarcopenia is associated with morbidity and mortality before and after liver transplantation. The ability of skeletal muscle mass to recover after transplant is questionable, and long term adverse events associated with persistent sarcopenia have not been well studied. Limited data is available examining mechanisms by which decreased muscle mass might develop. It is not clear which interventions might reduce the prevalence of sarcopenia and associated health burdens. However, measures to either decrease portal hypertension or improve nutrition appear to have benefit. Research on sarcopenia in the liver transplant setting is hampered by differing methodology to quantify muscle mass and varied thresholds determining the presence of sarcopenia. One area highlighted in this review is the heterogeneity used when defining sarcopenia. The health consequences, clinical course and potential pathophysiologic mechanisms of sarcopenia in the setting of cirrhosis and liver transplantation are further discussed.

Recurrent hepatitis C virus after transplant and the importance of plasma cells on biopsy

Hepatitis C virus (HCV) is the leading indication for liver transplantation in the United States. It recurs universally after transplant but the rate of fibrosis and the development of graft failure is variable. Different donor and recipient features have been demonstrated to impact fibrosis. Plasma cell hepatitis, a histologic finding, is one feature associated with poor graft and patient outcomes. The pathogenic mechanism resulting in plasma cell hepatitis is poorly understood, with evidence suggesting a role for both the HCV and the immune system.A recent publication described plasma cell hepatitis in a larger context of immune medicated graft dysfunction in transplant recipients receiving interferon based therapy. This manuscript will highlight the topic of plasma cell hepatitis and provide commentary on the lack of recognition, the data regarding pathophysiologic mechanisms and the potential management options.

Care of the Liver Transplant Patient

iver transplantation provides a means for patients with advanced liver isease to attain long-term survival with good quality of life. Data from he United Network for Organ Sharing (UNOS) show that 4000-5000 dult liver transplants are performed annually in the United States, with 1-year patient survival of 87% and graft survival of 84%. The 5-year atient and graft survival were 73% and 63%, respectively. Once stable, iver transplant patients often return to the care of their Internal Medicine r Family Practice specialist, with periodic visits to the transplant enter. Long-term management of liver transplant patients requires an nderstanding of immunosuppression, common complications in translant recipients, and recurrent liver diseases.

Hepatic fibrosis developing in morbid obesity independent of steatohepatitis: new mechanism or the Rube Goldberg machine?

Obesity represents a major health burden. Nonalcoholic fatty liver disease (NAFLD) is strongly associated with visceral obesity. NAFLD encompasses a broad spectrum of pathology from steatosis alone, to nonalcoholic steatohepatitis (NASH), with or without fibrosis. As the prevalence of steatosis and NASH was recently estimated to be 46 and 12 % [1], respectively, understanding the mechanism of fibrosis that leads to hepatic complications is crucial. In the current issue of Hepatology International, Ciupinska-Kajor et al. [2] present data suggesting the mechanism of fibrosis in NAFLD might differ based on the degree of adiposity, and that early angiogenesis could be the distinguishing feature. Prognosis in NAFLD is variable, dependent on histologic findings. Bland steatosis alone has a benign prognosis, whereas NASH leads to increased fibrosis and mortality. A recent review of natural history data spanning a mean follow-up of 15 years found a 0.7 % prevalence of cirrhosis in cohorts with steatosis alone, compared to a 10.8 % prevalence of cirrhosis in cohorts with NASH [3]. Steatohepatitis was also shown to be associated with increased mortality. When 118 persons with NAFLD were followed up for a mean period of over 20 years, persons with NASH had a significant increase in mortality, whereas those with steatosis alone did not [4]. With different prognostic ramifications, it is important to understand the pathophysiologic mechanisms that distinguish bland steatosis from NASH. Unfortunately, events that differentiate NASH from steatosis are not well defined. Theories do exist. The ‘‘two-hit’’ hypothesis involves a sequential process where first steatosis develops and a second hit is caused by oxidative stress resulting in lipid peroxidation and steatohepatitis [5]. A second theory involves ‘‘multiple parallel hits’’ [6]. These multiple hits include gut-derived signals such as endotoxin, adiposederived signals such as adipocytokines, innate immunity, endoplasmic reticulum stress, and genetic differences. Important to this hypothesis is the potential for inflammation to precede steatosis in some cases. Different theories highlight the concept that NAFLD and NASH represent a heterogenous group of disorders where a histologic endpoint can be represented by numerous contributing pathogenic mechanisms. One pathophysiologic mechanism of progressive liver disease in NAFLD is angiogenesis. Angiogenesis is associated with hepatic inflammation [7], hepatic fibrosis [8], the formation of portosystemic collateral vessels [9], and hepatic carcinogenesis [10]. In animal models of steatohepatitis, the expression of vascular endothelial growth factor (VEGF) and angiogenesis occurred in parallel to fibrosis and carcinogenesis [11]. In human tissue, angiogenesis, measured by CD 34-positive staining cells, occurred in NASH, but not normal liver or bland steatosis [12, 13]. Angiogenesis in NASH was associated with both hepatocellular apoptosis and insulin resistance [13]. The association between hepatic inflammation and angiogenesis is not unique to NAFLD. In persons with chronic hepatitis C, serum levels of proangiogenic markers, VEGF and angiopoietin-2, were elevated at baseline and decreased after interferon-based therapy [14]. The study by Ciupinska-Kajor et al. [2] mirrors the potential heterogeneity seen in the pathogenesis of NAFLD. The authors examined angiogenic markers, including VEGF A and CD 34 staining, in a population of morbidly E. R. Kallwitz (&) Section of Hepatology, University of Illinois, 840 S Wood Street MC 787, Chicago, IL 60612, USA e-mail: Kallwitz@uic.edu