ABSTRACTBackground and Objectives:Nonalcoholic fatty liver disease (NAFLD) is linked to obesity. Obesity is associated with lower socioeconomic status (SES). An independent link between pediatric NAFLD and SES has not been elucidated. The objective of this study was to evaluate the distribution of socioeconomic deprivation, measured using an area‐level proxy, in pediatric patients with known NAFLD and to determine whether deprivation is associated with liver disease severity.Methods:Retrospective study of patients <21 years with NAFLD, followed from 2009 to 2018. The patients’ addresses were mapped to census tracts, which were then linked to the community deprivation index (CDI; range 0‐‐1, higher values indicating higher deprivation, calculated from six SES‐related variables available publicly in US Census databases).Results:Two cohorts were evaluated; 1 with MRI (magnetic resonance imaging) and/or MRE (magnetic resonance elastography) findings indicative of NAFLD (n = 334), and another with biopsy‐confirmed NAFLD (n = 245). In the MRI and histology cohorts, the majority were boys (66%), non‐Hispanic (77%–78%), severely obese (79%–80%), and publicly insured (55%–56%, respectively). The median CDI for both groups was 0.36 (range 0.15–0.85). In both cohorts, patients living above the median CDI were more likely to be younger at initial presentation, time of MRI, and time of liver biopsy. MRI‐measured fat fraction and liver stiffness, as well as histologic characteristics were not different between the high‐ and low‐deprivation groups.Conclusions:Children with NAFLD were found across the spectrum of deprivation. Although children from more deprived neighborhoods present at a younger age, they exhibit the same degree of NAFLD severity as their peers from less deprived areas.

Watch an interview with the author Watch a video presentation of this article Until 1980, hepatitis A virus (HAV) was considered to be the only enterically transmitted form of viral hepatitis, earning it the designation in common medical parlance of "infectious hepatitis" (also known as "infective hepatitis" in the United Kingdom). For prior decades, water-borne outbreaks of hepatitis with jaundice in India, central and southeast Asia, the Middle East, and North Africa were considered epidemiologically to be viral in nature, and had been attributed to HAV even though formal testing to make this determination was not routinely available. Indeed, infectious hepatitis was the first viral disease for which a water-borne route of infection was generally accepted.1 An outbreak of infectious hepatitis in 1978—characterized by a high case fatality rate in pregnancy—that occurred not far from Srinagar, the summer capital of Kashmir in India, led to the recognition of a hitherto unknown hepatitis virus that was distinct from HAV. This outbreak caused colossal human suffering, with an estimated 52,000 icteric cases and about 1,700 deaths.2 As the Cold War waned, Russian virologist Mikhail Balayan used an old but historically relevant method of discovery—he infected himself. In 1983, he investigated an outbreak of non-A, non-B hepatitis in Tashkent, Uzbekistan.3 Lacking the ability to refrigerate samples, he ingested a pooled fecal extract from ill patients. Subsequently, he came down with acute viral hepatitis. He passaged his own stool into monkeys and showed that they then produced virions visible on electron microscopy similar to that seen in his own stool. Serologically, this virus was not HAV and became known as hepatitis E virus (HEV), the same virus that had caused the 1978 Kashmir epidemic.2 HEV is a small, non-enveloped, positive sense, single-stranded RNA virus that is part of the Orthohepevirus genus under the Hepeviridae family, which has a fascinating evolutionary history (Fig. 1).4, 5 It is suspected that hepatitis E has been afflicting human beings for centuries, as evidenced by medieval literature illustrating jaundice. About 1344 years ago, the HEV progenitor evolved into two variants, anthropotropic and enzootic variants. The anthropotropic variant progressed into genotypes 1 and 2 and the enzootic variant into genotypes 3 and 4, as we know them today.5 Depending on the classification system, there are 7 to 10 distinct genotypes. Genotypes 1 and 2 infect only humans and non-human primates, with genotype 1 being predominant in Asia and North Africa and genotype 2 having a predilection for Mexico and central Africa. Other genotypes may also rarely infect humans. Genotypes 3 and 4 are zoonotic forms that easily cross to humans from animals, particularly swine and deer. Genotype 3 virus infection in humans has been reported throughout Europe, pockets of North and South America, and Japan, whereas genotype 4 has remained isolated to eastern Asia (Fig. 2 and Table 1).5, 6 Epidemiologically, HEV falls into four distinct categories of global distribution. Hepatitis E is hyperendemic, meaning it has persistently high levels of disease occurrence in Mexico, central, southern, and southeast Asia, as well as eastern, western, and northern Africa. It is endemic, meaning HEV has a constant but not unusually high presence, in much of the Middle East, parts of southeast Asia, and regions of South America. Hepatitis E is sporadic in developed or industrialized countries and typically goes unrecognized with a low disease burden. Egypt is the sole country to have a distinctive pattern zone in the sense that the majority of the population develops immunity to the disease early on, and infection in pregnancy is minor or asymptomatic.5 This may be related to near-constant exposure to water from shallow wells in the Nile river drainage. However, given the advent of globalization, HEV should be on the differential for any patient with acute hepatitis with recent travel to any endemic region or known exposure to animals known to harbor the virus. The incubation period of HEV is typically 4 to 5 weeks postexposure. This is similar to hepatitis A and shorter than hepatitis B or C.6 Other viruses (e.g., West Nile, Yellow fever) that can cause viral hepatitis with jaundice as part of their spectrum of disease cannot be separated from HEV or HAV by the incubation period.7 Hepatitis E is typically underdiagnosed because of lack of clinician recognition, as well as the fact that there is no diagnostic assay currently approved by the US Food and Drug Administration. Commercial assays vary widely in sensitivity and specificity because of differences in binding and sensing. Adding to the challenge, the presence of HEV RNA is very transient in the serum, although it is shed in the stool for much longer. However, stool testing is challenging and rarely performed.8 The most common mode of HEV transmission is fecal-oral, and the majority of epidemic outbreaks have been associated with contaminated water supplies, particularly during periods of flooding from monsoons and other storms. Foodborne transmission of genotype 3 occurs after ingestion of undercooked pork or wild boar, although shellfish are sometimes implicated.4 Hunters who handle reservoir species are at particular risk. A study among German boar hunters found a 21% prevalence rate of prior HEV infection, which is significantly higher than the background population. This observation has prompted some authors to suggest that hunters wear gloves while handling blood or body fluids of these animals.9 Blood transfusion–associated transmission of hepatitis E is thought to be rare, but well-documented cases are described and seem to be increasing in Europe.4, 10 In response to the increasing incidence of HEV in Europe, multiple European countries including Ireland, the United Kingdom, and the Netherlands have begun HEV RNA screening of blood donations. Germany and France perform screening in blood intended for high-risk populations; however, Denmark has decided not to partake in HEV RNA screening because of look-back studies of living recipients with no evidence of transfusion-transmitted HEV.11 The United States does not routinely test donor blood for HEV RNA because there has been only one reported case of transfusion-associated transmission and an exceedingly low presence of HEV RNA in donor blood.12, 13 Evaluation of 18,829 blood donations from six geographic regions of the United States found that only two donations tested positive for HEV RNA and had a PCR that was not quantifiable.13 Hepatitis E must be on the differential in a patient with cirrhosis who has decompensated for unclear reasons. Treatment of HEV in the acute setting is not indicated; however, physicians must be hypervigilant because patients may experience development of acute-on-chronic liver failure (ACLF), causing rapid decompensation and even death. A retrospective study in India, a hyperendemic country for HEV, found that 61% of their 121 patients experienced ACLF caused by HEV. The 3-month mortality rate in these patients was 44%.14 Supportive care is the mainstay of treatment. Prevention of acute HEV in patients with chronic liver disease is critical, and patients should be counseled on appropriate precautions when traveling to endemic regions. Although HEV is typically an acute and self-resolving illness, risk for progression into chronic infection has been noted in immunosuppressed patients such as organ transplant recipients, patients with HIV, and those with underlying chronic liver disease that may warrant treatment of hepatitis E.4 An observational cross-sectional study in the United States found that almost 30% of their patients with underlying chronic liver disease possessed HEV IgG antibodies. These patients were more likely to be older in age and male.15 In addition, a prospective, predominantly European study of 85 solid organ transplant (SOT) recipients revealed that 66% of their patients experienced development of chronic hepatitis E. A multivariate analysis found that the independent predictive factors associated with chronic HEV development were the use of tacrolimus versus cyclosporine and a lower platelet count at the time of diagnosis. Regarding treatment, 32% of patients had resolution of infection and viral clearance simply with reduction in tacrolimus dosing after a mean time of almost 20 months. Notably, no patient experienced acute cellular rejection with reduction of immunosuppression.16 For those SOT patients who do not respond with reduction in immunosuppression or those who warrant treatment of HEV for reasons other than those mentioned earlier, ribavirin and pegylated interferon therapies have been studied. Ribavirin should be first-line therapy in SOT recipients because of interferon's notorious side effects and risk for graft rejection, particularly in kidney and heart recipients.4 A retrospective, multicenter study found that 78% of SOT patients achieved SVR after about 3 months of ribavirin therapy.17 In patients with HIV with low CD4 counts and subsequent severe immunosuppression, coinfection with HEV can accelerate liver fibrosis and lead to decompensated cirrhosis.18 In addition, HEV should be considered in patients with HIV with unexplained and persistently elevated transaminases.19 Hepatitis E has been associated with neurological, renal, and hematological extrahepatic manifestations. The most notable and morbid neurological manifestations include Guillain-Barré syndrome and meningoencephalitis. Renal manifestations include membranoproliferative glomerulonephritis, membranous glomerulonephritis, and cryoglobulinemia. Neurological and renal manifestations are the most common; however, there have been cases of autoimmune hemolytic anemia, aplastic, anemia, thrombocytopenia, and pancreatitis.20 Among hepatologists, there are many "truths" that are frequently cited, even if they are not true. We will explore some of the common assertions made by experts regarding HEV. Acute HEV infection has been implicated in causing acute liver failure (ALF) and maternal mortality during the third trimester in up to 20% to 25% of cases. Apart from maternal morbidity, HEV during pregnancy has been associated with miscarriage, premature delivery, or stillbirth. The placenta secretes certain enzymes and cytokines that suppress cell-mediated immunity at the interface of maternal-fetal circulation, thus allowing a method for HEV transmission.21 In addition, there have been reports of HEV replicating within the placenta.22 Proposed mechanisms include the greater virulence of genotypes 1 and 2, because those are the only genotypes known to cause complications in pregnancy, together with immunological and hormonal changes during pregnancy.4 Pregnancy is postulated to cause suppression of T cell–mediated immunity including suppression of CD4 cells and increased steroid hormone production leading to augmented viral replication.21 Although HEV has an ostensible role in mortality during pregnancy, there are notable regional differences that cannot be overlooked. Hepatitis E is particularly feared in northern India. A large, prospective study in New Delhi found that HEV comprised almost 60% of cases of acute hepatitis among pregnant women, a result comparable with prior studies. In the patients with HEV infection, a staggering 41% of them developed ALF with significantly higher maternal mortality, antepartum hemorrhage, and intrauterine fetal demise in HEV-infected women as compared with non-HEV-infected patients.23 In contrast, other areas where HEV is endemic, such as Egypt and southern India, have experienced minimal to no mortality from HEV.21 These regional discrepancies beg the question of whether there are other factors such as age of exposure, nutritional status, or lack of access to health care that are also playing a neglected but pivotal role in disease outcomes. The age-specific prevalence of antibodies to HEV is variable and may be fundamental to understanding why mortality among pregnant women is discordant. By the age of 15, 90% of Egyptians have been exposed to hepatitis E and possess antibodies. Conversely, the Indian antibody prevalence rate peaks at just 40%, and this comparatively dismal rate of population immunity does not develop until the late teenage years.6 Conceivably, women in India have their initial exposure to HEV at an older age, coinciding around the time of pregnancy, given the mean age of 22 years in the New Delhi study. Therefore, although high mortality during pregnancy does occur in some places, this appears to be an epidemiological artifact of exposure. It is well known that children infected with hepatitis A have few symptoms but jaundice; morbidity and mortality are significantly more common when adult infection occurs. The same seems to be true of hepatitis E. Pregnant women once again became collateral damage in the wake of a HEV outbreak in Africa's Lake Chad region, fueled by thousands of refugees escaping the political violence inflicted by Boko Haram.24 Per a World Health Organization report, by May 2017 there were 282 cases of HEV in Niger, with 26 out of 27 deaths occurring in pregnant women.24 It is no coincidence that this outbreak occurred in the setting of unsanitary living conditions in refugee displacement camps, where residents are often forced to dig latrines in the same area in which they cook and sleep. To make matters worse, heavy rains caused flooding and spread contaminated water.25 Risk factors associated with infection included sharing of sanitation facilities, lack of soap during hand washing, and animals sleeping inside living quarters.26 In addition, there is often a dearth of access to health care and food supplies inside a refugee camp. One can argue that the deleterious effects of unsanitary living conditions, limited access to health care, and poor nutritional status are what are killing pregnant women in these HEV outbreaks. Perhaps we find solace in blaming HEV for the death of these women rather than our own human-made deplorable living conditions during a humanitarian crisis. In the United States, our diet consists of processed foods. Some blame this lifestyle as the root of our epidemic of obesity and nonalcoholic fatty liver disease. Many call for a return to farm-to-table eating. The bucolic life of collecting one's fresh pork sausage from your local farmer barely exists in regions of the country. Instead, most Americans can find a grocery store aisle of neatly packaged sausages bearing minimal resemblance to their original state—exactly how Americans prefer their food nowadays. In contrast, Europeans still believe in the concept of open-air farmers' markets and frequenting their local charcuterie (from the French, literally pork butcher shop) (Fig. 3). However, this zest for fresh pork may come at a heavy cost. Since 2005, Europe has experienced a 10-fold surge in the number of HEV infections over the span of a decade, the bulk of which occurred in France, Germany, and the United Kingdom. The majority are secondary to genotype 3, which happens to be the same genotype isolated in European pigs.27 In the United Kingdom, sausages, pork pie, and ham were found to be the guilty culprits.28 In the United States, rates of HEV antibody prevalence have decreased over the last two decades, a sharp contrast with our European friends (Fig. 4).29-32 In this case, processed food makes our food supply safe, and we should be thankful for the frozen, precooked breakfast sausage we eat. Hepatitis E infection has long been an underrecognized entity causing acute hepatitis and also underappreciated for the impact it can have in developed nations. It has been thought of as a disease unrelated to the Western world because of its associations with unsanitary living conditions and contaminated water supplies in developing countries and war-torn regions. Perhaps now that it is affecting patients in developed nations, because of exposure from blood and food products, and affecting affluent populations that have benefited from the miracle of organ transplantation, it is now being more closely scrutinized. The first essential stepping-stone in the quest to rein in HEV is to broaden recognition among physicians. Second, we must have reliable diagnostic assays. Finally, we need effective treatment for the chronically infected. Thus far, ribavirin holds the most promise for the treatment of HEV, but it is not globally effective and it is difficult to tolerate. Although there is an effective vaccine in use in China, its applicability to other genotypes is unknown.8, 33 The incidence of HEV in Europe continues to increase, but prevention seems distant. Depending on whether your historical point of view is sociopolitical or evolutionary, one could say that the history of HEV either barely dates back to 1978 to an outbreak in India of waterborne acute hepatitis that was ultimately distinguishable from hepatitis A, or had affected humans for centuries according to descriptions of jaundice in medieval sources and Bayesian analysis of viral molecular sequences that are related by an evolutionary tree, respectively. Irrespective of one's historical perspective, both approaches are explained in this admirable essay by Aradhna Seth and Kenneth E. Sherman, which describes the discovery, isolation, and identification of HEV; delineates its viral genotypes and their global geographical distribution and epidemiology; describes its myriad clinical features; and highlights the significance of its detection, especially in patients who might otherwise be thought to have nonviral liver injury. The realization that this classically viral cause of acute hepatitis can persist chronically in immunosuppressed individuals seems all the more surprising because infection with HAV, which is so similar to HEV in many ways, does not yet appear in chronic form even though relapsing cases do exist. Finally, it is intriguing to be disabused of the convictions that HEV infection in pregnancy is usually fatal and that eating processed foods is bad. In the case of meat products that are contaminated with HEV, processing makes the food supply safe.

The leading cause of non-HIV-related mortality is liver disease. Fatty liver disease can be characterized as alcoholic or nonalcoholic in nature. Alcohol use is prevalent among individuals with HIV infection and can lead to medication nonadherence, lower CD4+ cell count, inadequate viral suppression, and disease progression. The pathogenesis of nonalcoholic fatty liver disease (NAFLD) in individuals with HIV infection includes metabolic syndrome, hyperuricemia, HIV-related lipodystrophy, genetic polymorphisms, medications, HIV itself, and the gut microbiome. The prevalence of NAFLD in persons with HIV infection ranges from 30% to 65% depending on the modality of diagnosis. Individuals with HIV infection and NAFLD are at higher risk of cardiovascular disease; however, there is a dearth of longitudinal outcomes studies on this topic. Current therapies for NAFLD, such as vitamin E and pioglitazone, have not been studied in persons with HIV infection. There are several drugs in phase II and III clinical trials that specifically target NAFLD in HIV, including CC chemokine receptor 5 inhibitors, growth hormone-releasing factor agonists, and stearoyl-CoA desaturase inhibitors. Persons with HIV should be screened for NAFLD while pursuing aggressive risk factor modification and lifestyle changes, given the increased risk of cardiovascular mortality.

Summary Background Paediatric non‐alcoholic fatty liver disease (NAFLD) is highly prevalent among children with obesity. The primary objective of this study was determining whether obesity severity is associated with NAFLD severity. By using paediatric classifications for severe obesity, clinicians may be able to better risk stratify patients, which in turn would guide more effective management and treatment. Methods Retrospective cohort study including patients followed at Cincinnati Children's Medical Center for NAFLD. Patients were categorized as overweight or class I, II, III obese based on established body mass index (BMI) cut‐offs. Liver disease severity was determined using biochemical, imaging (magnetic resonance elastography [MRE]), and histologic evidence of liver injury. Results Three cohorts were studied individually based on the method used to assess disease severity (biochemical n = 767, imaging n = 366, and histology n = 249). Between the three cohorts, there were significant differences in age, proportion of patients with class II and class III obesity, and serum alanine transaminase (ALT) levels. In the biochemistry cohort, the odds of having ALT > 80 U/L were highest in patients with class III obesity ( P = .026). In the imaging cohort, liver stiffness was significantly different between BMI groups of patients ( P = .001). In the histology cohort, those with class III obesity had significantly higher odds of NAFLD activity score (NAS) ≥ 5 ( P = .012). Discussion Obesity severity is associated with liver disease severity. Patients with more severe obesity are more likely to have more advanced liver disease, a finding that can assist in risk stratification, as well as monitoring and treatment approaches.

Acute liver failure (ALF) is defined as hepatic injury resulting in coagulopathy and encephalopathy in the absence of underlying liver disease. In the US, the most common causes of ALF are acetaminophen overdose, ALF of unknown etiology, and other drugs. In patients with previously unrecognized cirrhosis, infiltrative hepatocellular carcinoma (HCC) may mimic ALF due to absence of typical radiographic findings. A 53-year-old female with history of Hepatitis C (treatment non responder) presented with two weeks of right upper quadrant pain associated with nausea, non-bloody, non-bilious emesis, new onset ascites and lower extremity edema. She denied fever, chills, preceding weight loss, changes in bowel habits, skin rash, recent travel, sick contacts or alcohol use. A liver biopsy eleven years ago showed mild fibrosis. On admission, vital signs were T 98.2° F, BP 110/80 mmHg, HR 110, oxygen saturation 99% on room air. Physical exam revealed jaundice, a distended abdomen with fluid wave, right upper quadrant tenderness with no rebound or guarding, bilateral pitting edema, and asterixis. Magnetic resonance imaging (MRI) demonstrated a cirrhotic-appearing liver with portal hypertension and no definite mass. Labs included glucose 50 mg/dL, venous lactate 30 mg/dL, alkaline phosphatase 372 U/L, total bilirubin 9 mg/dL, direct bilirubin 5.8 mg/dL, aspartate transaminase (AST) 515 U/L, alanine transaminase (ALT) 71 U/L, lipase 48 U/L, creatinine 0.93 mg/dL, platelets 136 K/CU, international normalized ratio (INR) 2.0 U, and alpha fetoprotein (AFP) 80,000 ng/mL. Based on her presentation and elevated AFP, HCC was suspected and confirmed on biopsy. She died five days after admission. The diagnosis of infiltrative HCC is difficult due to lack of typical radiographic findings and variable AFP values. Infiltrative HCC is a macroscopic subtype of HCC in which the tumor spreads as an ill-defined mass blending into the background of a cirrhotic liver. Risk factors for development of this subtype are not well defined. Radiographic findings can be subtle, including miliary enhancement on immediate post-contrast MRI images or presence of portal vein thrombosis with neovascularity in computed tomography arterial phase. Patients are generally not surgical candidates with limited to no treatment options. High index of suspicion is crucial for diagnosis in patients with sudden decompensation of cirrhosis with no definite identifiable cause and negative imaging.Figure 1

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease in the United States. NAFLD prevalence is highest among Hispanics. Several non-invasive scores for predicting fibrosis in NAFLD patients have been well validated; however these were derived and validated in majority Caucasian cohorts. Evidence in Hispanics is lacking. The aim of this study was to assess the accuracy of four non-invasive scores in predicting advanced fibrosis in our predominantly Hispanic NAFLD patient population. Methods: This was a retrospective cross-sectional study among 137 adults with NAFLD who underwent liver biopsies between 2010-2014 at our county hospital in Houston,TX. Exclusion criteria were: evidence of heavy alcohol use (>30 g/day in men;>20 g/day in women), secondary liver disease, drug induced liver injury, or HIV infection.The NAFLD fibrosis score (NFS), FIB-4, BARD, and aspartate aminotransferase to platelet ratio (APRI) were calculated from labs obtained within six months of liver biopsy and compared to histologic stage of fibrosis. Microsoft Excel and Stata were used to calculate descriptive statistics, area under the receiver operating curve (AUROC), sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). Results: The overall mean age and BMI were 47± 11.9 years and 32 ± 6.7kg/m2; 77% (n=105) were Hispanic and 78% (n=107) women; 50% were diabetic (n=69) with mean hemoglobin A1c of 7.5%. 40% had advanced fibrosis (n=55). Advanced fibrosis patients were older (p=0.026), had lower platelets (p< 0.001), and lower albumin (p< 0.001). The NFS, FIB-4, BARD, and APRI had NPV's of: 85%, 78.2%, 78.3%, and 73.4%, respectively. The FIB-4 had the highest PPV of 92.6% followed by the NFS (81.5%), APRI (58.5%), and BARD (54.5%). The diagnostic accuracies were relatively similar with NFS having the highest (AUROC 0.80). Using the NFS and FIB-4 scores, liver biopsy could have been avoided in 63% and 77% of patients respectively. Subgroup analyses among only Hispanic patients revealed similar results. Conclusion: Our results compared to the original literature suggest that the NFS and APRI may be used safely in the Hispanic patient population. Overall, the four scores, especially the NFS, appear more reliable for excluding advanced fibrosis versus predicting it. Albeit the PPV for the FIB-4 and NFS were quite high suggesting that they may be the best of the four models for prediction of advanced fibrosis.Table 1: Statistical Analysis