Hello and welcome to the General Hepatology Update as part of the 2020 Liver Meeting Digital Experience organized by the American Association for the Study of Liver Diseases. My name is George Baffi and I am Associate Professor of Medicine at Harvard Medical School and Chief of Gastroenterology at the VA Boston Healthcare System. With my co-chair, Dr. Michelle Mahmoud, who is Professor of Medicine at Duke University, it is a great pleasure to welcome you as you are about to participate in the first ever fully online General Hepatology Update. True to our tradition, this year's session has a stellar speaker lineup to discuss three major topics of great relevance in hepatology. Please note that if you are attending the session during its assigned presentation time in the conference program, you may be able to use a text chat to post questions and engage with the speakers. The first talk will address eating and drinking in non-alcoholic fatty liver disease and will be presented by Dr. Mariana Machado, who is Invited Auxiliary Professor of Medicine at Lisbon University in Portugal, where she received her M.D. and also defended her Ph.D. dissertation. Dr. Machado worked several years at Duke University, where her research addressed key translational aspects of NAFLD. Her main research focuses on the impact of diet and lifestyle on the progression of NAFLD. In her talk, she will discuss pragmatic questions, whether diet composition versus total caloric content drives NAFLD pathogenesis, what is the role of fructose, polyunsaturated fatty acids and macronutrients, how to approach alcohol consumption in NAFLD, and what are the benefits of the Mediterranean diet and the DASH diet. Finally, Dr. Machado will put her presentation in the context of recent efforts to rename NAFLD as MEFLD or metabolic dysfunction associated fatty liver disease. The second talk will be about autoimmune hepatitis, presented by Dr. John Wierling. Dr. Wierling is Professor of Medicine and Surgery, Chief of Hepatology and Director of Advanced Liver Therapies at Baylor College of Medicine in Houston, Texas. Dr. Wierling received his M.D. from Stanford University and his postgraduate training at the University of Rochester and the National Institutes of Health. Dr. Wierling completed his fellowship in gastroenterology at the University of California, San Francisco. Dr. Wierling is the 2006 President of the AASLD. His primary interests pertain to the immunopathogenic mechanisms involved in hepatobiliary injury caused by viral infection, autoimmunity, and metabolic dysfunction. In his presentation today, Dr. Wierling will provide an update on the pathogenesis, diagnosis, and management of autoimmune hepatitis. The third and final talk of the 2020 General Hepatology Update will tackle pregnancy-associated liver disease and will be presented by Dr. Carla Brady. Dr. Brady is Associate Professor of Medicine at Duke University. She received her M.D. from the University of Virginia and completed her internal medicine residency and G.I. fellowship at Drexel University in Philadelphia. In her talk, Dr. Brady will focus on studying and treating liver disease in pregnant women. She will discuss some unique forms of liver diseases related to pregnancy. In addition, Dr. Brady will discuss key aspects of diagnostics and management of liver disease in pregnancy and address important questions such as how to interpret liver tests, what radiographic assays are compatible with pregnancy, how safe is to perform endoscopy, and what is the role of liver biopsy in pregnancy versus using non-invasive fibrosis assessment to diagnose and monitor liver disease. On behalf of Dr. Mahmoud and the AASLD, I hope you will enjoy this year's session of General Hepatology Update and hope that the upcoming three presentations will provide you with useful information and guide your practice in managing patients with liver disease. I wish you a successful digital experience at the 2020 liver meeting. Good afternoon, everyone. I'm going to talk to you about an exciting topic, which is eating and drinking in NAFL. I have no financial disclosure to declare. Since non-alcoholic fatty liver disease NAFL was first named in 1986 till today, its prevalence increased more than 50% and is now the number one cause of liver disease worldwide. It strongly associates with obesity as well as other components of metabolic syndrome. As such, this year NAFL was renamed by a group of international experts to MAFL, metabolic dysfunction associated fatty liver disease. This new designation not only emphasizes the association between fatty liver and the metabolic syndrome, but also takes away negative connotation with alcohol intake. In fact, metabolic dysfunction associated and alcohol associated liver disease are not exclusive and may coexist in the same patient. Obesity and the metabolic syndrome have a very strong association with diet. We are what we eat. For sure, that is also the case for NAFL. The first important question we can make is whether diet composition is relevant to the development of NAFL or if, on the contrary, it all comes down to a mathematical equation of calories and consumption. Here are the eight top epidemiological studies regarding dietary habits of patients with NAFL and only two showed an increase in energy intake. Differences in the composition of diet were very heterogeneous. The most consistent one was an increase in the amount of proteins consumed. However, NAFL development does seem to be a consequence of excessive caloric intake. Different overfeeding studies in which excessive calories were presented as fat or as carbohydrates, both associated with similar increase in body weight and liver fat. The other way around, when two apocalyptic diets were given to overweight or obese patients, one with restriction of carbohydrates and the other with restriction of fat, both induced similar weight loss and decreases in liver fat content, aminotransferase levels and visceral fat. It is not just how much we eat that matters. Where we eat also influences whether we will develop NAFL. This is an overfeeding study with excessive calories given as sugar with or without high fat. The experiment consisted in giving the excessive calories at the main meals, hence increasing the size of the meal, or between meals as snacks, hence increasing the frequency of meals. Although the weight gain was not significantly different between groups, the group that increased the frequency of the meals, particularly when excessive calories were only derived from sugar, had a dramatic increase in the liver fat content. This was associated with an increase in visceral fat and, most importantly, an increase in hepato-de novo lipogenesis. Moving now for the main macronutrients. What is the role of carbohydrates in the development of NAFL? Epidemiological studies showed inconsistent results when assessing if NAFL associates with an increased intake of carbohydrates, hence the next question is whether, under isocaloric conditions, the type of carbohydrate ingested may promote NAFL. This is a small crossover study on 8 healthy men submitted to a 9-day isocaloric diet with 50% of energy intake from carbohydrates. In one group, half of the carbohydrate's energy intake was provided as fructose and in the other group almost all as complex carbohydrates. Fructose is associated with an increase in de novo lipogenesis and a significant increase in liver fat content. Fructose is theatogenic, being an unregulated source of substrates for de novo lipogenesis, because, unlike glucose, that to remain in the hepatocytes need to be phosphorylated in a step that is highly regulated, phosphorylation of fructose is not regulated by hepatic energy status. Furthermore, fructose induces SREP-BP1C, promoting lipogenesis, and carbohydrate response element, which downregulates PPR-alpha and hence decreases fatty acid oxidation. Also, fructose promotes small bowel bacterial overgrowth, increasing endotoxinemia and promoting insulin resistance. Genetics seems to modulate the theatogenic effect of fructose consumption. This is an overfeeding study in which subjects increased their fructose intake 75 grams during 12 weeks. The changes in weight and liver fat were highly variable. They also observed that there was a dose response increase in liver fat according to the number of genetic variants the subject harbored in three genes that are known to associate with MAFLD, such as PNPLA3. The main source of fructose in Western diets are the sugar-sweetened beverages, which are rich in high fructose corn syrup. Different epidemiological studies show that fructose intake and particularly soft drinks consumption associated with MAFLD. In fact, one can per day of an average soft drink increased almost 50% the risk of having MAFLD. Drinking soft drinks also associated with an increased risk for liver fibrosis in patients with MAFLD. We need to keep in mind that soft drinks are not only rich in fructose, but also in other components such as caramel and aspartame, both with pro-inflammatory and diabetogenic properties. Sugar-containing drinks, unlike solid foods, induce lower satiety and thus promote an increase in caloric ingestion. The next question is whether artificially sweetened beverages and 100% fructose can also promote MAFLD. In this meta-analysis, it is clear that not only sugar-sweetened beverages, but also artificially sweetened beverages can similarly induce obesity. Also, this study with two large prospective cohorts found that similarly to sugary beverages, consumption of artificially sweetened beverages and fruit juices associated with an increased risk for type 2 diabetes mellitus. Regarding fruits and fruit juices, if most fruit intakes seem to associate with a decreased risk for type 2 diabetes mellitus, 100% fruit juice consumption associated with an increased risk. Interestingly, the effect of fruit intake was different according to the fruit ingested. I usually tell my patients that we should eat fruit, not drink it. The same prospective cohorts also showed an association with increased mortality not only with sugar-sweetened, but also with artificially sweetened beverages, particularly cardiovascular mortality. This is the only study that I know of that also showed artificially sweetened beverages to associate with an increased risk for MAFLD. Why artificially sweetened beverages are diabetogenic and steatogenic may be related not only to an increase in appetite and dense in caloric intake, but also in modulation of gut microbiota as suggested in preclinical studies. Fibers intake was consistently shown to be decreased in patients with MAFLD and NASH, even though a small randomized control trial did not show an effect in the treatment of MAFLD. Fibers not only delay gastric emptying, hence promoting satiety and decreasing caloric intake, they also may act as prebiotics, modulating the gut microbiota. Epidemiological studies showed an inverse non-linear association between vegetables, a source of fibers, and risk for hepatocellular carcinoma. This is a short-term interventional study that administered an isocaloric low-carbohydrates diet for 14 days and verified an improvement in liver fat, liver metabolism, and inflammatory markers. This beneficial effect seemed to be a result in a decrease in de novo lipogenesis and increase in lipid oxidation, improvement in one-carbon metabolism as a result of repletion of ATP cellular levels, as well as modulation of gut microbiota increasing bacteria that produce folic acid. Longer-duration studies regarding carbohydrates-restricted diets showed an initial benefit in body weight that was lost after one year. Benefits in lipid metabolism seemed to be more durable, particularly regarding improvement in serum triglycerides and HDL cholesterol. Similarly, liver fat seems to decrease more rapidly with a low-carbohydrates diet, but the effect is similar to isocaloric-carbohydrate non-restricted diets once the target weight loss is accomplished. Moving on to fats. Some studies show that patients with MAFL tend to eat higher quantities of fat, particularly saturated fatty acids and cholesterol. Saturated fatty acids have only a single bond between carbons in their hydrocarbon backbone. The molecules in saturated fat are packed close together, and the fat is solid at room temperature and very heat-stable. Saturated fatty acids are present mainly in animal products such as red meat, butter, and whole milk dairy products. Some vegetable products, such as coconut oil and palm oil, and prepared foods such as desserts and sausages. They not only are lipogenic, increasing the flux of free fatty acids from the deposed tissue by inducing insulin resistance, as well as by promoting de novo lipogenesis. Saturated fatty acids are also toxic to hepatocytes by inducing oxidative stress, ER stress, and apoptosis. They also promote inflammation directly and remodulation of gut microbiota. This is an interesting overfeeding experiment in which excessive fat was levered as saturated or polyunsaturated fatty acids. Saturated fatty acids associated with an increase in liver fat, even though there was no difference in body weight and visual fat between the different fat supplementation. Polyunsaturated fatty acids are natural ligands of PPR and thus promote fatty acids oxidation which may explain this difference in liver fat. Monounsaturated fatty acids have one double carbon bond and are mainly present in olive oil, avocado, nuts, and seeds. Monounsaturated fatty acids are liquid at room temperature and less heat-stable as saturated fats, and are known to promote lipid oxidation while protecting from insulin resistance. A small trial did find a beneficial decrease in liver fat with a diet high in monounsaturated fatty acids. Olive oil is a major source of monounsaturated fatty acids. Extra virgin olive oil contains 80% monounsaturated fatty acids, but it also contains polyphenols and other antioxidant phytochemicals. When refined or heated, olive oil loses its natural compounds. Its benefits in cardiovascular disease prevention are well known. Three small clinical trials in MAFLD also suggested benefits in serolipid profile and improvement in hepatic steatosis. Polyunsaturated fatty acids have multiple double carbon bonds and are classified as omega-3 or omega-6 according to the position of the first double carbon bond. Examples of omega-6 polyunsaturated fatty acids are linoleic and arachidonic acid. They derive from sunflower and meat eggs and dairy respectively and have pro-inflammatory and pro-thrombotic properties. Examples of omega-3 polyunsaturated fatty acids are EPA and DHA and derive mainly from fatty fish. Unlike omega-6, omega-3 tend to have anti-inflammatory, insulin sensitizer and anti-lipogenic properties. Polyunsaturated fatty acids omega-3 inhibit lipogenesis and stimulate lipolysis. Systemically, they have other functions that promote cardiovascular health such as anti-inflammatory and vasodilator actions. However, trials with supplementation with omega-3 polyunsaturated fatty acids did not result in histological improvement of MAFLD. However, the response to polyunsaturated fatty acids seemed to be modulated by genetic traits that associate with MAFLD. This study demonstrated a beneficial effect with the wild-type variant of PNPLA3. Trans fats differ from unsaturated fatty acids because of a double bond in the trans instead of cis configuration, making them straighter and resembling the structure of saturated fatty acids. This kind of fats are abundant in processed foods such as margarines and fast food. Animal studies suggest that trans fats associate with worse MAFLD and worse liver injury. Increased protein consumption by MAFLD patients seems to be the most consistent finding in epidemiological studies, which is in contrast with experimental studies that show that high protein diets decrease the stratogenic effect of high-fat diets. Also, both high animal and plant diet associated with a decrease in liver fat, irrespective of body weight. High protein diets have some limitations. For instance, they are associated with an increased risk for colon cancer and progression of chronic kidney disease. Animal proteins seem to associate with an increased risk for diabetes mellitus, whereas plant proteins do not. Red meat, unlike white meat, also associates with an increased all-cause mortality as well as cancer, cardiovascular, and liver-related mortality. Red meat intake associates with an increased risk for menfall. Unhealthy cooking methods, such as cooking at high temperatures for a long time, increases the production of heterocyclic amines which is also diabetogenic and steatogenic. Regarding alcohol, a meta-analysis of weight studies found moderate alcohol consumption to be protective for NAFLD and NASH. However, studies were highly heterogeneous. In this study, in patients with NAFLD, moderate alcohol consumption also associated with a decreased risk for advanced fibrosis. However, the protective effect was lost with binge drinking and was present for wine but not for beer. Lastly, moderate alcohol consumption, that is less than 1.5 drinks a day, associated with decreased mortality in patients with NAFLD. That protection did not occur in women nor in patients with advanced fibrosis. In 2018, a large study showed that even though there may be a U effect of alcohol intake in mortality from diabetes and cardiovascular disease, the net effect of alcohol consumption showed a linear increase in harm for any amount of alcohol intake. Mortality was increased, mainly cancer-associated mortality. Furthermore, there is a synergism between alcohol and BMI. Whereas in subjects with normal weight, alcohol harm may occur for three drinks a day, patients obese may have harm when more than one drink a day is consumed. And finally, in patients with liver cirrhosis, any amount of alcohol intake increases the risk for hepatocellular carcinoma. So we should be very careful in these patients. Regarding coffee, coffee intakes associate with a lower risk for NAFLD and liver fibrosis in a dose-dependent manner in epidemiological studies. Not all coffee seems protective. For instance, in this study, regular coffee was protective, whereas espresso was not. On the other hand, decaf coffee also seems to be protective for liver injury. Interestingly, coffee intake was associated with a dose-dependent risk for hepatocellular carcinoma in a recent meta-analysis. What diets should we advise to NAFLD patients? Mediterranean diet is a dietary pattern originally inspired in the traditional diet in Mediterranean countries, characterized by a high consumption of plant-based foods such as vegetables, fruits, whole grains, seeds, nuts and legumes, and moderate consumption of protein source foods such as fish and poultry. It is rich in monounsaturated fatty acids, primarily from olive oil and olives, and it reduces fat-derived products and has low red meat intake. It associates with an increased omega-3, omega-6 polyunsaturated fatty acids ratio and the high fiber foods. It is well known to have beneficial effects in cardiovascular health, and the recent meta-analysis from 13 small studies also suggested a beneficial effect of a Mediterranean diet in BMI, lipid profile, and liver osteoporosis. Another diet is DASH diet, Dietary Approaches to Stop Hypertension. It was designed in 1990 to regulate blood pressure. It is similar to a Mediterranean diet, but emphasizes also a low sodium intake and the consumption of minimal processed and fresh foods. This study is a small study that showed that adherence to a DASH diet also associated with lower weight, better liver enzymes, and better liver lipid profile. So, to finalize, how should we advise patients with MIFLD regarding diet? We should advise a balanced hypocholeric diet in order to promote weight loss, consider a Mediterranean or a DASH diet with high intake of vegetables and legumes. For instance, suggest vegetable soup as a starter in every meals, food should be eaten, not drunk, two or three portions a day, avoid added sugars, a bullish sugar or even artificially sweetened beverages. Olive oil should be the preferred oil while avoiding eating olive oil, even though better than other oils, avoid processed food, desserts, fats, foods which are high in saturated and trans fats, prefer fish over meat, eat at least two or three portions of fatty fish a week, avoid red meat, not more than three times per week, and prefer plant proteins, for example, soy. Do not restrict coffee, the calf can also be protective, moderate alcohol intake is still a matter of debate, for sure in liver cirrhosis you should strongly advise against any alcohol intake. And finally, when the pandemic is over, I invite you to my country, Portugal, which has a lot of wonderful products that will make the Mediterranean diet shine. I'm John Veerling, Professor of Medicine and Surgery and Chief of Hepatology at the Baylor College of Medicine. As a co-author of AASLD guidelines for autoimmune hepatitis, it is a pleasure to provide this update. Here are my disclosures. AIH is defined as a syndrome of progressive hepatitis caused by putative loss of tolerance to hepatic autoantigens that is characterized by elevated ALT and AST levels, autoantibodies, elevated IgG, non-pathogenic histopathology, and responsiveness to immunosuppression. The demographics and epidemiology of AIH indicated that it is an uncommon or orphan disease. It preferentially afflicts female children and adults of all races and ethnicities. Its incidence is increasing, but its global prevalence in children and adults varies widely. Age at diagnosis exhibits two bimodal peaks, the first in adolescence and young adulthood, and the second in older adults, including the elderly. AIH is an indication for up to six percent of liver transplants in the U.S. The natural history of untreated or inadequately treated AIH is that of a progressive disease culminating in decompensated cirrhosis, liver failure, and hepatocellular carcinoma. Progression is often so insidious that many patients have advanced fibrosis or even cirrhosis at the time of diagnosis. AIH rarely presents as acute liver failure, which constitutes a medical emergency requiring transfer to a transplant center. Approximately 25 percent present with acute ecteric hepatitis, while 75 percent present with chronic hepatitis, which is asymptomatic in up to 25 percent. There is no biomarker specific for AIH. Currently, we classify AIH into two subtypes based on the characteristic autoantibody profiles. Type 1 accounts for 95 percent of cases and is characterized by ANA and SMA autoantibodies. Type 2 accounts for 5 percent of AIH cases and is characterized by LKM1 autoantibodies. Two autoantibodies are specific for liver antigens, LC1 and ASGPR. In addition, both LC1 and SLA are specific for the disease autoimmune hepatitis. SLA is present in less than 10 percent of patients with either type 1 or type 2 AIH. If ANA, SMA, or LKM1 are positive, SLA testing is optional. When tests for type 1 and type 2 autoantibodies are negative, testing for SLA and LCM1 is appropriate. Keep in mind that a minority of AIH patients is seronegative for all autoantibodies. Since neither type 1 nor type 2 autoantibodies are specific for AIH, it's not surprising that they are detected in several other liver diseases. The most important consideration is Wilson disease, which can fully mimic AIH. A liver biopsy is mandatory in AIH because histopathological features play key roles in diagnosis. Classic features include severe portal inflammation with interface hepatitis and plasma cell infiltrates. Central zonal perivenulitis may be the only lesion observed and is frequent in acute AIH or acute liver failure. In addition, imperiopelesis, which is phagocytosis of CDAT cells by hepatocytes and hepatocytes regenerating as rosettes, are characteristic of AIH. However, none of these findings is pathognomonic. Regardless of the presence or absence of plasma cell infiltrates, IgG-secreting B cells are abundant within portal inflammatory infiltrates and have been therapeutically targeted with rituximab. AIH has strong HLA associations for susceptibility, most notably HLA-DR3 and DR4 alleles, as well as other genetic associations outside the HLA complex. The figure on the right shows that these HLA associations are not specific for AIH as they are commonly present in multiple autoimmune diseases. As is true for autoimmune diseases in general, AIH is associated with multiple extrahepatic autoimmune diseases beginning in childhood and continuing throughout adulthood. Associated autoimmune diseases are more frequent in type 2 AIH. The key spectrum include Hashimoto's thyroiditis, Graves' disease, rheumatoid arthritis, and ulcerative colitis. Celiac sprue deserves special note because it can be an associated AI disease or an independent cause of elevated ALT and AST. Thus, testing for tissue transglutaminase is appropriate in seropositive and seronegative AIH. The International AIH Group developed and validated revised diagnostic criteria to aid in selection of AIH patients for clinical trials. Points are assigned for clinical, biochemical, immunogenic, associated AI diseases, histopathologic features, and response to empiric steroids. Adding points for autoantibody titers is often problematic because autoantibody detection using ELISA precludes scoring based on titers. The total score classifies the likelihood of AIH as definite or probable. Probable cases responding to immunosuppression or worsening with its withdrawal can meet criteria for a definite diagnosis. The International Autoimmune Hepatitis Group also validated simplified diagnostic criteria to identify classical cases of AIH. Once again, autoantibody detection using ELISA precludes assignment of extra points based on titers. Worldwide retrospective analyses showed high sensitivity and specificity. Caveats include the need to rescore probable or indefinite cases using the revised diagnostic criteria, which are better suited for complex or unusual cases. It is important to note that neither the RDC nor the SDC have been validated for diagnosis of AIH cholestatic variants or so-called overlap syndromes. The increasingly frequent diagnosis of AIH-PBC overlap in 10 to 15 percent of PBC patients raises concern about misdiagnosis due to failure to apply rigorous diagnostic criteria. Our 2019 AASLD practice guideline endorsed the PARIS criteria for diagnosis of this overlap. Note that a liver biopsy is mandatory, but neither moderate nor severe interface hepatitis is sufficient for diagnosis unless at least one other biochemical or serologic feature is present. The infrequency of overlap syndrome in the Mayo Clinic study in the bottom right contrasts sharply with the current estimate in clinical practice. Two features of PBC may contribute to misdiagnosis of AIH-PBC overlap. First, as seen on the left, interface hepatitis occurs universally during progression of untreated PBC, along with significant frequencies of both lobular inflammation and hepatitis. Second, as seen on the right, portal inflammatory infiltrates in PBC contain abundant plasma cells and B cells that can result in confusion. AIH-PSC overlap most frequently occurs in children. In adult patients, it is more frequently developed in pre-existing PSC and less often occurs in patients with pre-existing AIH. The diagnostic criteria on the right remain unvalidated, especially the use of simplified diagnostic criteria for AIH. The role of drug-induced autoimmunity in AIH remains poorly defined. As seen on the left, drug metabolism frequently generates autoimmune responses against either SIPs or UGTs. In contrast, the table on the right shows that drug-induced AIH is predominantly associated with type 1 autoantibodies instead of autoantibodies against SIPs or UGTs. It remains unclear whether idiosyncratic drug metabolism unmasks pre-existing AIH, mimics AIH, or triggers the novo-onset of AIH. Drug-induced AIH, or immune-mediated hepatitis, has become an important adverse event of immunotherapies using checkpoint inhibitors of CTLA-4, PD-1, or its PD-1 ligand. Checkpoint inhibitors prevent functional exhaustion and apoptosis of activated T-cells, resulting in promiscuous cytolysis of not only tumor cells, but also normal cells. It is clinically important to recognize the kinetics of hepatitis in the context of other bystander organ injuries resulting from checkpoint inhibition. It is equally important to note that there is no compelling evidence that loss of tolerance to autoantigens is involved. AIH has also an IgG plasma cell subtype. This is diagnosed by quantifying the number of IgG-positive B-cells and plasma cells in portal infiltrates. As is true for IgG-4-related diseases in general, this AIH subtype responds well to steroids. Pregnancy requires special attention because AIH often occurs in women of childbearing age, and it adversely impacts both planned and unplanned pregnancies. Counseling about birth control and planned pregnancies is important because therapeutic control of AIH promotes fertility, even in women with cirrhosis. Pregnancy in AIH patients requires co-management of a hepatologist and a high-risk obstetrician due to serious risk to the fetus, the potential for complications of portal penis hypertension caused by expansion of blood volume and hyperdynamic circulation, and need for immunosuppression. Immunosuppression should be continued with at least steroid monotherapy. Placental production of pre-implantation factor, or PIF, causes systemic immunosuppression, often allowing dose reductions in prescribed immunosuppressions. However, cessation of PIF production postpartum results in the risk of AIH flares that must be prevented by reintroduction of maintenance doses of immunosuppression after delivery. The 2010 AASLD practice guideline introduced a new, stringent definition of remission for AIH, seen on the right, to replace the less stringent 2002 AASLD definition of remission as reduction of ALT-AST levels to 1.5 to 2 times the upper limit of normal, with confining of inflammatory infiltrates to the portal tracts. Both the 2010 and 2019 guidelines defined biochemical remission as normalization of ALT and IgG levels, and histologic remission as elimination of portal inflammation and interface hepatitis. Redefinition of remission was prompted by evidence of the adverse impact on survival of residual hepatic inflammation, which was associated with persistent low elevations of ALT and AST, shown on the left, and the significant risks of progression to cirrhosis despite immunosuppressive therapy, shown on the right. Evidence-based support of the 2010 AASLD redefinition of remission first came from an Italian retrospective analysis of the long-term outcomes of AIH patients treated with standard immunosuppression. The risk of disease progression during remission was substantially reduced in patients who achieved 2010 remission criteria compared to those meeting 2002 remission criteria. The low rates of remission, shown in blue, in this 2018 cross-sectional cohort study from the United Kingdom Consortium, are quite distressing and clearly indicate that biochemical remission is a serious unmet need for far too many AIH patients. Unfortunately, as we strive for normalization of ALT, AST, and IgG levels in AIH, we must contend with comorbid non-alcoholic fatty liver disease as an independent cause of liver injury in approximately 30% of AIH adult patients. Over half of the patients in this U.S. study had NASH, and the frequency of cirrhosis was higher among patients with AIH and NASH. Three induction regimens using standard-of-care steroids with or without azathioprine are evidence-based. The first is combination prednisone and azathioprine. The second is budesonide plus azathioprine using weight-based azathioprine dosing in non-cirrhotics, in whom high first-pass hepatic extraction of budesonide prevents systemic steroid toxicities, and finally prednisone monotherapy for four weeks, followed by the addition of azathioprine. After sustained biochemical remission, responders may be eligible for carefully monitored tapering with a goal of withdrawal of immunosuppression. Alternatively, patients may continue maintenance therapy with the goal of discontinuing steroids and continuing azathioprine monotherapy. It is important to emphasize that remission can result in resolution of advanced fibrosis and even cirrhosis as seen on the left. Non-invasive transient elastography can monitor fibrosis in both progression and regression in patients who are on therapy. First-line therapy for acute severe AIH also requires special attention. This algorithm from our 2019 AASLD practice guidelines emphasizes use of prednisone or IV methylprednisolone and contraindications for budesonide and azathioprine. Optimally, such patients should be treated in a transplant center capable of salvaging non-responders. If biochemical relapse occurs during or after withdrawal, promptly resume immunosuppression at doses necessary to reach remission and then readjust doses for maintenance therapy. It is important to note that the flares of hepatic necroinflammation causing increased ALT and AST levels are not benign. Each flare during attempted withdrawal increases the risk for progression to cirrhosis, liver transplantation, or hepatic-related death. Thus, immunosuppression withdrawal should be attempted only once. Second-line immunosuppressive therapies are appropriate for AIH patients intolerant of standard of care immunosuppression and for those who fail to achieve remission due to partial or non-response. Before initiating alternative therapies for inadequate responses, clinicians should first verify the diagnosis of AIH, assess adherence, test for azathioprine metabolites, and then proceed to remission. Assess adherence, test for azathioprine metabolites and optimize thyoguanine nucleotide levels. The table lists the current second-line therapies and their mechanisms of action. The 2019 ASLD guidelines recommend testing for thiopurine methyltransferase enzyme activity to prevent azathioprine toxicity. And also note that azathioprine and 6MP metabolites as seen on the left may be used to assess adherence and to detect excessive formation of 6-thiouridine metabolites. In such patients, allopurinol redirects metabolism to form immunosuppressive thyoguanine nucleotides, preventing the need for second-line therapies. Sadly, our systematic review and meta-analysis of second-line therapies identified only two studies suitable for analysis. The rates of remission as shown here were similar for treatment with either mycophenolate methotil or tecrolimus. The International Autoimmune Hepatitis Group members expressed a preference for MMF over tecrolimus or cyclosporine for second-line immunosuppression. However, transplant hepatologists disproportionately use tecrolimus or cyclosporine, presumably due to their expertise in transplant immunosuppression. As shown on the right, MMF has a favorable adverse event profile except for teratogenicity. The results of this European survey provide insights into the efficacy of MMF as a second-line therapy. Complete responses were greatest in patients intolerant of azathioprine or 6MP, intermediate in patients with partial response to standard of care, and only achieved in 10% of patients with non-response to standard of care. Thus, MMF appears to be inadequate for treatment of non-response to standard of care immunosuppression. The same survey also provided insights into the efficacy of tecrolimus as second-line therapy. As seen with MMF, complete responses were greatest in patients intolerant of azathioprine or 6MP, substantial in patients with partial response to standard of care, and only achieved in 45% of patients with non-response. Thus, TAC appears preferable to MMF for treatment of non-response to standard of care immunosuppression. Both TAC and cyclosporine cause similar systemic adverse events, except that cyclosporine is not diabetogenic, which is an important consideration in an era of comorbid metabolic syndrome. However, TAC has gained favor over cyclosporine as second-line therapy. Unfortunately, TAC doses are often adjusted to achieve trough levels comparable to those used to prevent transplant rejection, which predictably results in nephrotoxicity, as shown on the right for serum creatinine in this series. In this series, intolerance or toxicity also resulted in frequent discontinuation. Unraveling the immunopathogenesis of AIH is a work in progress. However, emerging knowledge has refined our concept of future therapies to target cytokines and chemokines and enhance the function of antigen-specific T regulatory and B regulatory cells to achieve regulatory control over AIH. Current understanding of immunopathogenesis of AIH has led not only to the emergence of new therapies, led not only to the use of MMF and calcineurin inhibitors, but also to investigational use of TNF-alpha and mTOR inhibitors, as well as B cell depleting monoclonal antibodies. The right panel calls attention to the first ever randomized controlled trial of an anti-B cell activating factor monoclonal antibody, Ion-Alumab, for the treatment of patients who have failed standard of care immunosuppression. It is currently enrolling in the US and Europe. Finally, orthotopic liver transplantation is indicated for AIH patients with acute liver failure, decompensated cirrhosis, or hepatocellular carcinoma within UNOS criteria. UNOS database indicates that both allograft and patient survivals are excellent. AIH recurs in allografts in approximately 23% of patients. The diagnostic criteria include biochemical, serological, and histopathological features and exclusion of other etiologies. Importantly, the risk of AIH recurrence is unaffected by either continuation or discontinuation of steroids. Effective immunosuppression promotes allograft in patient survivals after recurrence of AIH. Recurrent AIH causes loss of approximately only 10% of allografts after nearly 14 years. Now for the key points. Diagnostic criteria are well-established and codified in scoring systems. First-line immunosuppression includes steroids plus azathioprine or 6-mercaptopurine. Thyropurinemethyltransferase testing is now recommended before initiating azathioprine to detect the enzyme deficiency and prevent toxicity. Metabolite testing is useful as a surrogate for adherence, adjusting doses, and identifying the need for allopurinol. Remission is now defined as normalization of ALT, AST, and IgG levels, and elimination of hepatic inflammation. It is associated with excellent patient outcomes. However, remission represents an unmet need for far too many patients worldwide. The choice of second-line therapies to achieve remissions remains empiric in the absence of prospective randomized controlled trials. Our 2019 ASLD practice guidelines and meta-analyses recommend either MMF or TAC. The first-ever randomized controlled trial of a second-line therapy is now enrolling, and multiple candidate drugs exist for future randomized controlled trials. Cholestatic variant or overlap syndromes are increasingly diagnosed, but lack validated diagnostic criteria. In such patients, the 2019 ASLD guidelines recommend treating the predominant autoimmune disease, assess the outcome and response, and then consider additional therapy. Pregnancy in AIH is classified as high-risk due to adverse maternal and fetal outcomes. Recognition of the risks of portal venous hypertensive complications in serotics is important, as is the adequate postpartum immunosuppression to prevent flares. Finally, OLT is indicated for acute liver failure, decompensated cirrhosis, and patients with hepatocellular carcinoma within UNOS criteria. Transplantation results in excellent allograft in patient survivals, despite recurrence of AIH in 23% of allografts. Thank you very much for your attention. Greetings, and welcome to this talk, which is entitled Pregnancy-Associated Liver Disease. I am Dr. Carla Brady, an associate professor in the division of gastroenterology at Duke University. I am a transplant hepatologist with a specialized focus on the management of liver disease and liver transplant-related care in pregnancy. I have no disclosures. I will begin this talk with review of epidemiological data on liver disease in pregnancy. Increasing rates of liver disease have been observed in women of childbearing age and in pregnancy. Data from the National Health and Nutrition Examination Survey during 1988 to 1994 and 1999 to 2012 demonstrated an increased prevalence of chronic liver disease in women aged 15 to 39 years of age. In particular, increased rates of non-alcoholic fatty liver disease and alcohol-associated liver disease were observed in this study cohort. Additional data from the National Vital Statistics System have shown increased rates of death due to cirrhosis in women aged 25 to 44 years. Data from the nationwide inpatient sample of the Healthcare Cost and Utilization Project have shown increasing rates of liver disease across 2002 through 2010 among hospitalized patients. The most common liver diseases associated with hospitalization were gallstone disease and liver diseases that are unique to pregnancy. Furthermore, cost associated with liver disease rose over the study period with the syndrome of hemolysis elevated liver test in low platelets or HELP syndrome being the most costly of the various observed liver diseases. Collectively, these data indicate that women of childbearing age and those who are pregnant are at risk of liver-related morbidity and mortality. Now, what do we understand about how pregnancy affects liver-related physiology? How does pregnancy affect our interpretation of liver-related lab testing? What diagnostic tools are compatible with pregnancy? During pregnancy, there is up to a 50% increase in maternal cardiac output. There are substantial increases in blood flow and in uterus and skin, yet there is little change in hepatic blood flow and liver size. As expected, there are increases in estrogen and progesterone and hormonal changes can lead to the presence of telangiectasias and palmar erythema, findings that would therefore be expected in pregnancy and thus not necessarily mean that liver disease is present. In pregnancy, we can see increases in placental-derived alkaline phosphatase and in alpha-feta proteins, seruloplasmin, white blood cell counts, triglyceride levels, and cholesterol levels. Expansion in blood volume during pregnancy can lead to decreased albumin and hemoglobin levels. However, little to no change in AST, ALT, bilirubin, INR, and total bile acids would be expected in a normal pregnancy. Thus, elevations in these liver enzyme levels indicate a need for investigation. Liver enzyme abnormalities are seen in three to 5% of pregnant women, and liver diseases that can be diagnosed in pregnancy are categorized as liver diseases that are specific to pregnancy, liver diseases that are exacerbated by pregnancy, and liver diseases that occur coincidentally in pregnancy. Investigation of elevated liver enzymes often involves radiographic investigations. To perform such investigations in pregnancy, it is important to understand which imaging studies can be used in pregnancy. The imaging modality of choice in pregnancy is abdominal ultrasound. Animal data have demonstrated an association of lung hemorrhage with the use of contrast in ultrasound, and thus, use of contrast is not widely accepted. If additional imaging is needed, abdominal CT scan and MRI without gadolinium are acceptable in pregnancy. Radiation risk with CT are reportedly seen between two and 25 weeks of gestation, with greatest risk between eight and 15 weeks of gestation. Iodinated contrast can potentially cause neonatal hypothyroidism, but most CT studies now use non-ionic contrast which does not affect the thyroid gland. There's no absolute contraindication to the use of iodinated contrast agents in pregnancy, but their use is recommended if absolutely needed to obtain diagnostic information that would affect the care of the fetus or mother. Breastfeeding after iodinated contrast or gadolinium is considered safe. Liver biopsy can occur in pregnancy and during lactation. It is important to note that a transjugular liver biopsy confers radiation exposure. Regarding outcomes of liver biopsy in pregnancy, recently reported data from Sweden indicate that there is an increased observed risk of small for gestational age compared to the general population and those with liver disease. No congenital malformations or stillbirths were seen. In a smaller study of liver transplant patients who underwent liver biopsy during pregnancy or in the first eight weeks postpartum, no complications were noted. Noninvasive assessments of liver fibrosis have become increasingly investigated and utilized in liver related care. Transient elastography has become an important tool in the assessment of hepatic fibrosis and liver disease. However, it is important to note that it is not approved by the U.S. Food and Drug Administration for use in pregnancy. Studies outside of the U.S. have investigated the use of transient elastography in pregnancy. These studies have shown significantly higher liver stiffness scores in women who developed preeclampsia or enteropatic cholestasis of pregnancy. However, liver stiffness scores have also been shown to significantly increase in pregnancy in the absence of a liver disease diagnosis. The reasons for this are not fully clear. Upper endoscopy and ERCP are endoscopic modalities that can be used in the diagnosis and management of complications of liver disease, and both are acceptable to conduct in pregnant women. It is preferred that EGD and ERCP occur in the second trimester. Choices for sedation during endoscopy that are acceptable for use in pregnancy are midazolam, miparidine, fentanyl, and propofol. In cases in which EGD is used as screening or surveillance for varices, banding of medium to large esophageal varices can occur in pregnancy. Regarding ERCP, it is important to minimize the duration of radiation exposure and to use lead shields on the lower abdomen and pelvis. Pre-procedure consultation with maternal fetal medicine specialists can aid in ensuring coordination of care for fetal monitoring and sedation. Data are limited on the use of transjugular intraepatic portosystemic shunt, or TIPS, in pregnancy. Earlier reports cited safety concerns about radiation exposure. However, there have been case reports of successful use of TIPS insertion in uncontrolled gastroesophageal variceal hemorrhage in pregnancy and to decompress abdominal wall varices in pregnancy to facilitate cesarean section when vaginal delivery was contraindicated. Now that we have reviewed expected physiology in pregnancy, how to interpret liver-related lab testing in pregnancy, and what diagnostic modalities can be used in pregnancy, let's examine specific pregnancy-associated liver diseases by taking a look at liver diseases that are unique to pregnancy. Liver diseases that are unique to pregnancy include hyperemesis gravidarum, which typically occurs in the first trimester. Disorders that are typically occurring in the second to third trimester, including intraepatic cholestasis of pregnancy, preeclampsia eclampsia, and HELP syndrome, as well as acute fatty liver of pregnancy, which is typically a third trimester disorder. Hyperemesis gravidarum occurs in 0.3 to 2% of pregnancies and is marked by the presence of intractable nausea and vomiting that can lead to dehydration, electrolyte imbalance, nutritional deficiency, and weight loss. Liver involvement is seen in 50 to 60% of cases and may manifest as elevations in transaminases and or jaundice. Liver biopsy is not required to aid in diagnosis. Management involves intravenous fluids, vitamin and mineral supplementation, anti-emetics, and in severe cases, enteral or parenteral nutrition. Biochemical abnormalities, including liver enzyme derangements, usually correct with treatment, and it is rare for this disorder to progress throughout pregnancy. Hypertensive disorders of pregnancy are on a spectrum, and those that are specific to pregnancy include preeclampsia eclampsia and HELP syndrome. These disorders are thought to result from immunologic maladaption with increases in inflammatory cytokines and in the maternal inflammatory response to trophoblast, leading to chronic placental ischemia. In preeclampsia, vasospasm may result from hemoconcentration and imbalance between vasoconstrictors and vasodilators. Thrombocytopenia is seen due to increased platelet activation and consumption. Preeclampsia occurs in 3% to 8% of pregnancies and is defined by new onset hypertension and maternal organ dysfunction with renal, hepatic, neurologic, or hematologic complications. Proteinuria is often present, but not required for the diagnosis. Eclampsia occurs in 1.4% of pregnancies and is defined by preeclampsia findings and seizures. Liver involvement includes fibrin deposition and prairie portal hemorrhage with potential for hepatocyte necrosis and infarction. Microvesicular fat infiltration has also been observed. HELP syndrome occurs in 0.2 to 0.6% of pregnancies and may complicate up to 10 to 20% of preeclampsia-eclampsia cases. Historically, the Mississippi and Tennessee classifications for HELP syndrome, as outlined on this slide, were created to aid in the diagnosis of HELP syndrome. Management of hypertensive disorders of pregnancy involves the use of low-dose aspirin. Meta-analyses and systematic reviews have demonstrated reductions in the risk of preeclampsia, fetal growth restriction, and fetal death with use of low-dose aspirin. Thus, it is recommended that low-dose aspirin is instituted between 12 and 28 weeks of gestation in patients with high-risk factors for preeclampsia. Other medical therapies include antihypertensive therapy and intravenous magnesium and dexamethasone. Surgical intervention is required for enlarging subcapsular hematomas or hepatic rupture, and hepatic rupture can also be managed with hepatic artery embolization. The only curative therapy is delivery of the fetus, and ongoing hepatic, renal, or hematologic complications beyond 72 hours postpartum signal potential life-threatening complications that require urgent therapy. Liver transplantation has been performed in cases of hepatic decompensation, despite medical therapy, and in cases of hepatic rupture or hematoma. Intra-hepatic cholestasis of pregnancy is a common liver disorder of pregnancy. Its prevalence is 0.1 to 10%, with increased prevalence seen in South American and Scandinavian countries. Multiple genetic mutations, as shown on this slide, have been commonly cited in association with intra-hepatic cholestasis of pregnancy. Risk factors include advanced maternal age, multi-parity, and a history of cholestasis with contraceptive use. Clinical and lab findings include pruritus, which is a hallmark symptom, epigastric pain, fatigue, anorexia, and jaundice. Total bile acid levels are elevated, and liver enzymes may be normal or elevated up to 10 to 20 times the upper limit of normal. Whereas there are no sequelae to the mother, there are important adverse obstetric and fetal outcomes, including preterm birth, meconium-stained amniotic fluid, fetal distress, and stillbirth. It is unclear as to why fetal distress and stillbirth are seen, but data suggests a potential effect of bile acids on the fetal heart as observations have been made of fetal tachyarrhythmias in cases of intra-hepatic cholestasis of pregnancy. Complications have been reported to occur with maternal bile acid levels of greater than 40 micromoles per liter. And more recent data from a systematic review on perinatal outcomes in intra-hepatic cholestasis of pregnancy identified an increased risk of stillbirth with serum bile acid levels of 100 micromoles per liter or higher. Data have also demonstrated that the presence of other concurrent pregnancy-related conditions, such as preeclampsia and gestational diabetes, are associated with adverse outcomes, including stillbirth. Intra-hepatic cholestasis of pregnancy has been shown to be associated with hepatitis C infection, and thus women with intra-hepatic cholestasis of pregnancy should be tested for hepatitis C. Treatment consists of ursodeoxycholic acid with consideration for other agents, such as antihistamines, cholesteramine, rifampin, and S-adenosyl L-methionine in cases of refractory pruritus. There should be consideration for delivery by 37 weeks of gestation. Acute fatty liver of pregnancy is a rare liver disorder in pregnancy. It is thought to be due to impaired fatty acid oxidation in the fetus and placenta, and the most investigated fatty acid oxidation defect that is associated with acute fatty liver of pregnancy is a deficiency in long-chain 3-hydroxyacyl coenzyme A dehydrogenase, or LCHAD, deficiency. The presentation of acute fatty liver of pregnancy can be similar to preeclampsia and HELP syndrome. Interestingly, the coagulopathy of acute fatty liver of pregnancy is due to liver dysfunction, whereas the coagulopathy of preeclampsia eclampsia is due to derangements in consumption. Liver biopsy is rarely indicated and carries a risk of hemorrhage in the setting of coagulopathy. But when performed in this setting, the classic finding is that of microvesicular fat that is confirmed with oil red O stain or electron microscopy. Due to concerns about risk of liver biopsy and a presentation that can be similar to other liver diseases of pregnancy, SWANCEA criteria have been created to aid in the diagnosis. Management involves prompt delivery of the fetus, and infants born to mothers with acute fatty liver of pregnancy should be monitored for liver failure, cardiomyopathy, non-ketotic hypoglycemia, myopathy, and neuropathy. It should be noted that laboratory and clinical abnormalities may persist for up to a week postpartum, and the rare progression to liver failure may be an indication for liver transplantation. We have discussed liver diseases that are unique to pregnancy, and now we will look at two liver diseases that are exacerbated by pregnancy. Gallstones may be seen in up to 10% of pregnancies, yet complications of gallstones leading to disease occur in 0.5 to 0.8% of pregnancies. It is believed that gallstones in pregnancy result from hormonal changes that lead to decreased gallbladder motility and lithogenic bile. Presentations of gallstone-related disease include biliary colic, pancreatitis, acute cholecystitis, and cholangitis. The diagnosis of gallstones can be made by abdominal ultrasound. The first-line treatment is supportive care, but recurrence suggests the need to consider cholecystectomy or ERCP. It is important to note that cholecystitis is associated with preterm birth and spontaneous abortion, and that gallstone pancreatitis is associated with fetal death, thus increasing concern about the need for possible laparoscopic cholecystectomy and or ERCP, which can occur more safely in the second trimester of pregnancy. Bud-Chiari syndrome can occur due to pregnancy-related hypercoagulability, and its presentation includes ascites and abdominal pain. It is diagnosed with a Doppler study of the liver. Therapy occurs similar to presentations of Bud-Chiari in non-pregnant patients. However, anticoagulation options are limited to low molecular weight heparin in pregnancy. Vitamin K antagonists should be avoided due to teratogenicity and fetal hemorrhage. However, these can be used postpartum and in lactation. In summary of this discussion on pregnancy-associated liver diseases, I offer the following key takeaways. Abdominal ultrasound is the preferred imaging modality in pregnancy. EGD and ERCP are acceptable endoscopic procedures in pregnancy, ideally occurring in the second trimester. In preeclampsia, delivery by 37 weeks is recommended with close monitoring for development of eclampsia or HELP syndrome. When eclampsia, HELP, or acute fatty liver of pregnancy is suspected, delivery should occur after stabilization of the mother. HELP syndrome that is complicated by hepatic rupture or acute liver failure should prompt transfer to a transplant center. First-line management of enteropatic cholestasis of pregnancy is ursodeoxycholic acid. Refractory pruritus may be treated with antihistamines, cholesteramine, rifampin, or S-adenosyl L-methionine, although the evidence for use of these agents is low. Treatment of acute bud Chiari syndrome is the same as in non-pregnant patients, but the anticoagulation of choice for this syndrome during pregnancy is low molecular weight heparin. Initial management of gallstone disease in pregnancy is supportive, but ERCP or laparoscopic cholecystectomy may be considered, especially in the second trimester. Thank you for your attention. I am Mitchell Mahmood, one of the co-chairs of this session. I'm a general hepatologist and a faculty member in the Division of Gastroenterology at the Duke University School of Medicine. I'll be giving the closing remarks after these excellent presentations by our three previous speakers. I serve on the advisory board of Chronic Liver Disease Foundation otherwise I have no financial disclosures to declare. We have learned that eating and drinking are closely linked with metabolic syndrome, which also affects the development of non-alcoholic fat liver disease. Since the initial description of non-alcoholic fat liver disease in 1986, the prevalence of this disorder has increased to a point that now it is the primary cause of abdominal liver enzymes in the United States. Obesity, type 2 diabetes, hypertension, hyperlipidemia, male gender, or Hispanic race, as well as age are some of the independent factors associated with non-alcoholic fat liver disease. The new terminology of metabolic dysfunction associated fat liver disease was proposed by a group of international experts on this disorder. The rationale for this new designation is to emphasize the association of metabolic syndrome and non-alcoholic fat liver disease. In addition, it eliminates the stigma of alcohol intake with this disorder. In fact, metabolic dysfunction associated fat liver disease and alcohol associated fat liver disease may coexist in the same patient. Obesity and metabolic syndrome have a strong linkage to diets, which in turn affects the development of metabolic dysfunction associated fat liver disease. As we learned from our previous speaker on this topic, dietary factors play a major role in the development of this disorder. How much we consume and what kind of macronutrients we consume are all factors that promote or prevent the development of metabolic dysfunction associated fat liver disease. Excessive daily calorie intake, frequency of snacks with high calories during the day, excessive carbohydrate intake, and particularly fructose and sugar enriched diets have been observed to enhance the development of MFD. Other dietary factors that augment MFD are excessive saturated fatty acid intake, as well as unrestricted animal protein intake, such as red meat. In contrast, high fiber diet, hypocaloric as well as low carbohydrate enriched diet prevent the development of metabolic dysfunction associated fatty liver disease. Consumption of monounsaturated fatty acids, minimal intake of polyunsaturated fatty acids, fish and white meat, reduce visceral adipose tissue and hepatic lipogenesis. Regular coffee, including decaf drinking promotes healthy liver and reduces the risk of hepatocellular carcinoma in certain patients. Moderate alcohol use, even though maybe beneficial, is strongly discouraged in patients with advanced hepatic fibrosis. Certain diets, such as Mediterranean diet, have also been shown to be beneficial in patients with this disorder. Next, we have from another speaker on pregnancy-associated liver diseases. In general, these can be classified as diseases unique in pregnancy, liver diseases that are exacerbated by pregnancy and these liver diseases that can coexist during pregnancy, such as viral hepatitis and autoimmune hepatitis. We have been made aware of the increasing prevalence of liver diseases in women of childbearing age and in pregnancy. And these are largely driven by non-alcoholic fatty liver disease, or what we now call metabolic dysfunction associated fatty liver disease, alcohol-associated liver disease, viral hepatitis, gallstones, and liver diseases that are unique in pregnancy. As clinicians, we need to be familiar with their management. But in order to do that, we need to know which tools or tests that are available to us currently are safe and acceptable during pregnancy. For instance, abdominal ultrasound is safe and acceptable during pregnancy. Computerized tomography of the abdomen is performed outside weeks 8 to 15 of gestation is also acceptable. Magnetic resonance imaging, including MRCP without any contrast, is also acceptable. Transient elastography for liver stiffness measurement has not been approved by the FDA for use in pregnancy. Liver biopsy could be safely performed if needed, although one must be aware that preterm and low birth weight are potential complications. Endoscopy and ERCP are also acceptable if performed in the second trimester of pregnancy. Although in the case of ERCP, the appropriate protective measures must be used during the procedure. Data on tips is lacking, but there has been a case report of successful tips in patients who are pregnant who present with massive varicose hemorrhage that required test procedure for their control of the bleeding. Gallstone diseases can also complicate pregnancy and present with various manifestations such as biliary colic, pancreatitis, cholecystitis, and ascending cholangitis. The initial management for this case should be supportive care. ERCP and laparoscopic cholecystectomy should be reserved for recurrent cases and if needed, should be performed in the second trimester. Cholecystitis and gallstone pancreatitis, however, may result in poor fecal outcomes. Finally, we have also learned a great deal of information on autoimmune hepatitis. Autoimmune hepatitis affects both children and adults of all races and ethnicities. It has a bimodal age distribution around ages 30 to 10 to 30, and 45 to 85 years. It also has a female preponderance. It presents with a spectrum of manifestations ranging from acute liver failure to acute hepatitis, to chronic hepatitis, and asymptomatic cirrhosis. Simplified diagnostic criteria and refined diagnostic criteria are the two main diagnostic tools that are widely used in clinical studies. In terms of which one should be used, depends on the clinical scenario. Simplified diagnostic criteria is better for classic cases, whereas refined diagnostic criteria is better for complex or unusual cases. There has been increasing frequency of autoimmune hepatitis and primary blood cholestatic variant or the overlap syndrome. And this raised a concern about misdiagnosis. The Paris criteria for PBC and autoimmune hepatitis, the overlap syndrome, is a useful tool, although a validated diagnostic criteria is still needed. Drug-induced autoimmune hepatitis or immune-mediated hepatitis is an important adverse event of immunotherapy with checkpoint inhibitors. Pregnancy in autoimmune hepatitis is considered high risk and may result in certain complications such as preterm, low birth weight, and cesarean sections. Nonetheless, immunosuppression therapy is still indicated. The goal of treatment in patients with autoimmune hepatitis is achievement of remission, which is defined as normalization of liver enzymes, immunoglobulins, and minimal histologic evidence of inflammatory activity or liver biopsy. The first line of therapy remains steroids and azathioprine or 6-MP. Initial measurement of TPMT enzymatic activity adverts azathioprine toxicity and enhances adherence to therapy. For patients who fail to achieve remission with standard of care, or those who are intolerable of azathioprine or 6-MP, we have second line of therapy drugs that are available to all of us. Liver transplantation is indicated in patients with acute or autoimmune hepatitis who present with acute liver failure, decompensated cirrhosis, or hepatocellular carcinoma within the UNOS criteria. Thank you very much for your time.

hepatology

NAFLD

MAFLD

autoimmune hepatitis

AIH

pregnancy-associated liver diseases

dietary impact

diagnostic criteria

management

overlap syndromes

liver transplantation criteria

adherence