Faculty Bibliography

INTRODUCTION:Bevacizumab is a humanized anti-vascular endothelial growth factor monoclonal antibody used in the treatment of cervical cancer, ovarian cancer, colorectal cancer, lung cancer, renal cell cancer, and recurrent glioblastomas. Its approval by US FDA was issued with a black box warning that its use has been associated with a risk of gastrointestinal (GI) tract perforation and that it should be discontinued in patients who have experienced such. The reported incidence of GI perforation in those receiving bevacizumab is as high as 3%. However, the incidence of GI perforation in those receiving bevacizumab undergoing GI endoscopic procedures has not been well studied. METHODS:A retrospective, single-center observational study was conducted at Memorial Sloan Kettering Cancer Center (MSKCC) between 2011 and 2018. All patients who underwent upper GI endoscopy with percutaneous endoscopic gastrostomy (PEG) or percutaneous endoscopic jejunostomy (PEJ) tube placement and received bevacizumab within 6 months of their endoscopic procedure were included. RESULTS:We identified 176 patients who underwent PEG or PEJ tube placement and received bevacizumab within 6 months. Eighty-one percent of patients were female (n = 144) and the median age was 61 years. Prior to endoscopic procedures, patients received a median of seven doses of bevacizumab. Patients received bevacizumab from 170 days before to 170 days after their endoscopic procedures (median 44 days). No GI perforations were observed during or after the time of the endoscopic procedures. CONCLUSION:Our study demonstrated that receiving bevacizumab within 6 months prior to their endoscopic procedure was not associated with an increased risk of GI tract perforation and thus not an absolute contraindication to proceeding with PEG and PEJ tube placement in these patients.

Nonalcoholic fatty liver disease (NAFLD) develops when the liver is unable to oxidize or export excess free fatty acids generated by adipose tissue lipolysis, de novo lipogenesis, or dietary intake. Although treatment has generally been centered on reversing metabolic risk factors that increase the likelihood of NAFLD by influencing lifestyle modifications, therapeutic modalities are being studied at the cellular and molecular level. The endocannabinoid system has been of recent focus. The agonism and antagonism of cannabinoid receptors play roles in biochemical mechanisms involved in the development or regression of NAFLD. Exocannabinoids and endocannabinoids, the ligands which bind cannabinoid receptors, have been studied in this regard. Exocannabinoids found in cannabis (marijuana) may have a therapeutic benefit. Our recent study demonstrated an inverse association between marijuana use and NAFLD among adults in the United States. This commentary combines knowledge on the role of the endocannabinoid system in the setting of NAFLD with the findings in our article to hypothesize different potential mechanisms that may influence the inverse relationship between cannabis and NAFLD.

The Asian-American population is characterized by remarkable diversity. Studying Asians as an aggregate group may obscure clinically-meaningful heterogeneity. We performed a population-based study using data from the United States (US) National Vital Statistics System. We determined the trends in age-standardized mortality rates for chronic liver disease stratified by etiology among the most populous US-based Asian subgroups (Asian Indians, Chinese, Filipino, Japanese, Korean, and Vietnamese) and compared it to non-Hispanic whites. Annual percentage change was calculated to determine temporal mortality patterns using joinpoint analysis.Hepatitis C virus-related mortality rates were higher in non-Hispanic whites compared to individual Asian subgroups, but a sharp decline in mortality rates was noted in 2014 among non-Hispanic whites and all Asian subgroups. Age-standardized hepatitis B virus-related mortality rates were higher in all Asian subgroups as compared to non-Hispanic whites in 2016, with the highest mortality among Vietnamese followed by Chinese. Mortality rates for alcoholic liver disease have been steadily trending upwards in all Asian subgroups, with the highest mortality in Japanese. Overall, age-standardized cirrhosis-related mortality rates were highest in non-Hispanic whites, followed by Japanese, and more distantly by Vietnamese and other subgroups. However, hepatocellular carcinoma-related mortality rates were higher in most Asian subgroups led by Vietnamese, Japanese and Koreans compared to non-Hispanic whites. In this population-based study utilizing a nationally representative database, we demonstrated a marked heterogeneity in the mortality rates of etiology-specific chronic liver disease among Asian subgroups in the US.

The two main subsets of nonalcoholic fatty liver disease (NAFLD) include: (1) nonalcoholic fatty liver (NAFL), the more common and non-progressive subtype; and (2) nonalcoholic steatohepatitis (NASH), the less common subtype, which has the potential to progress to advanced liver damage. Current treatment strategies have focused on lifestyle management of modifiable risk factors, namely weight, and on the optimization of the management of individual components of metabolic syndrome. Various hypothetical pathogenic mechanisms have been proposed, leading to the development of novel drugs with the potential to effectively treat patients with NASH. Numerous clinical trials are ongoing, utilizing these experimental drugs and molecules targeting specific mechanistic pathway(s) to effectively treat NASH. Some of these mechanistic pathways targeted by experimental pharmacologic agents include chemokine receptor 2 and 5 antagonism, inhibition of galectin-3 protein, antagonism of toll-like receptor 4, variation of fibroblast growth factor 19, agonism of selective thyroid hormone receptor-beta, inhibition of apoptosis signal-regulating kinase 1, inhibition of acetyl-coenzyme A carboxylase, agonism of farnesoid X receptor, antibodies against lysl oxidase-like-2, and inhibition of inflammasomes. Emerging data are promising and further updates from ongoing clinical trials are eagerly awaited.

Although the mortality rates of cirrhosis are underestimated, its socioeconomic burden has demonstrated a significant global impact. Cirrhosis is defined by the disruption of normal liver architecture after years of chronic insult by different etiologies. Treatment modalities are recommended primarily in decompensated cirrhosis and specifically tailored to the different manifestations of hepatic decompensation. Antifibrogenic therapies are within an active area of investigation. The endocannabinoid system has been shown to play a role in liver disease, and cirrhosis specifically, with intriguing possible therapeutic benefits. The endocannabinoid system comprises cannabinoid receptors 1 (CB1) and cannabinoid receptor 2 (CB2) and their ligands, endocannabinoids and exocannabinoids. CB1 activation enhances fibrogenesis, whereas CB2 activation counteracts progression to fibrosis. Conversely, deletion of CB1 is associated with an improvement of hepatic fibrosis and steatosis, and deletion of CB2 results in increased collagen deposition, steatosis, and enhanced inflammation. CB1 antagonism has also demonstrated vascular effects in patients with cirrhosis, causing an increase in arterial pressure and vascular resistance as well as a decrease in mesenteric blood flow and portal pressure, thereby preventing ascites. In mice with hepatic encephalopathy, CB1 blockade and activation of CB2 demonstrated improved neurologic score and cognitive function. Endocannabinoids, themselves also have mechanistic roles in cirrhosis. Arachidonoyl ethanolamide (AEA) exhibits antifibrogenic properties by inhibition of HSC proliferation and induction of necrotic death. AEA induces mesenteric vasodilation and hypotension via CB1 induction. 2-arachidonoyl glycerol (2-AG) is a fibrogenic mediator independent of CB receptors, but in higher doses induces apoptosis of HSCs, which may actually show antifibrotic properties. 2-AG has also demonstrated growth-inhibitory and cytotoxic effects. The exocannabinoid, THC, suppresses proliferation of hepatic myofibroblasts and stellate cells and induces apoptosis, which may reveal antifibrotic and hepatoprotective mechanisms. Thus, several components of the endocannabinoid system have therapeutic potential in cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is comprised of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). It is defined by histologic or radiographic evidence of steatosis in the absence of alternative etiologies, including significant alcohol consumption, steatogenic medication use, or hereditary disorders. NAFLD is now the most common liver disease, and when NASH is present it can progress to fibrosis and hepatocellular carcinoma. Different mechanisms have been identified as contributors to the physiology of NAFLD; insulin resistance and related metabolic derangements have been the hallmark of physiology associated with NAFLD. The mainstay of treatment has classically involved lifestyle modifications focused on the reduction of insulin resistance. However, emerging evidence suggests that the endocannabinoid system and its associated cannabinoid receptors and ligands have mechanistic and therapeutic implications in metabolic derangements and specifically in NAFLD. Cannabinoid receptor 1 antagonism has demonstrated promising effects with increased resistance to hepatic steatosis, reversal of hepatic steatosis, and improvements in glycemic control, insulin resistance, and dyslipidemia. Literature regarding the role of cannabinoid receptor 2 in NAFLD is controversial. Exocannabinoids and endocannabinoids have demonstrated some therapeutic impact on metabolic derangements associated with NAFLD, although literature regarding direct therapeutic use in NAFLD is limited. Nonetheless, the properties of the endocannabinoid system, its receptors, substrates, and ligands remain a significant arena warranting further research, with potential for a pharmacologic intervention for a disease with an anticipated increase in economic and clinical burden.

The prevalence of latent tuberculosis infection (LTBI) in the United States in 2011 and 2012 was estimated at 4.4⁻4.8%. As of 2015, 12.4 million people still possessed LTBI. Isoniazid, or isonicotinic acid hydrazine (INH), is the most commonly used medication among varying regimens that exist in the treatment of tuberculosis and LTBI. INH-related hepatotoxicity is a well-known adverse effect of its use, often causing asymptomatic elevations in serum aminotransferase levels. These elevations are typically transient and reversible, but can cause acute, clinically-significant liver injury in rare cases. We report a case of a 67-year old male who developed subacute hepatic injury secondary to INH treatment for LTBI, and ultimately underwent liver transplantation due to the progression to hepatic decompensation, despite withdrawal of the medication. Because symptoms of INH hepatotoxicity are nonspecific and prognosis can be variable, clinicians must maintain a high index of suspicion for this adverse effect. As exemplified by this case, early recognition may be life-saving.

The prevalence of hepatitis C in pregnancy is as high as 3.6% in large cohorts. The prevalence of hepatitis C acquired by vertical transmission is 0.2% to 0.4% in the United States and Europe. Although screening is not recommended in the absence of certain risk factors, the importance of understanding hepatitis C in pregnancy lies in its association with adverse maternal and neonatal outcomes. There is potential for those infants infected by vertical transmission to develop chronic hepatitis C, cirrhosis or hepatocellular carcinoma. The risk of vertical transmission is increased when mothers are co-infected with Human Immunodeficiency Virus (HIV) or possess a high viral load. There is no clear data supporting that mode of delivery increases or reduces risk. Breastfeeding is not associated with increased risk of transmission. Premature rupture of membranes, invasive procedures (such as amniocentesis), intrapartum events, or fetal scalp monitoring may increase risk of transmission. In pregnant patients, hepatitis C is diagnosed with a positive ELISA-3 and detectable Hepatitis C Virus (HCV) RNA viral load. Infants born to HCV-infected mothers should be tested for either HCV RNA on at least two separate occasions. Although prevention is not possible, there may be a role for newer direct acting anti-viral medications in the future.