The future of hepatology

Abstract

The field of hepatology has made impressive progress over its ~75 years of existence. Advances in understanding liver function and its dysregulation in disease, genetic determinants of disease, antiviral therapy, and transplantation have transformed the lives of patients. However, there are still significant challenges that require ongoing creativity and discipline, particularly with the emergence of fatty liver diseases, as well as managing autoimmune disease, cancer, and liver disease in children. Diagnostic advances are urgently needed to accelerate risk stratification and efficient testing of new agents with greater precision in enriched populations. Integrated, holistic care models should be extended beyond liver cancer to diseases like NAFLD with systemic manifestations or extrahepatic comorbidities such as cardiovascular disease, diabetes, addiction, and depressive disorders. To meet the growing burden of asymptomatic liver disease, the workforce will need to be expanded by incorporating more advanced practice providers and educating other specialists. The training of future hepatologists will benefit from incorporating emerging skills in data management, artificial intelligence, and precision medicine. Continued investment in basic and translational science is crucial for further progress. The challenges ahead are significant, but with collective effort, the field of hepatology will continue to make progress and overcome obstacles.

INTRODUCTION

The success of hepatology, a discipline founded ~75 years ago, should be celebrated thanks to the stunning advances that have transformed the outlook for patients with liver diseases. The future portends more successes as well as greater challenges. Liver transplantation has emerged as a life-saving therapy for many with end-stage liver disease. The identification and molecular insights of the HBV have led to the development of antiviral therapies, combined with effective vaccine programs that together have dramatically reduced the burden of the disease, particularly in younger populations within endemic areas.^[1] The cloning of the HCV leading to curative antiviral therapy, has been, similar to hepatitis B, a Nobel Prize-worthy achievement that has saved countless lives.

As Confucius said, “study the past if you would define the future”. Despite these and other success stories, new challenges in hepatology loom, and addressing them will test our community’s capacity to remain creative, nimble, and bold. In this article, the authors distill ~70 collective years together in the field to highlight trends in our discipline, and to project how the landscapes of science, education, and clinical care are likely to evolve to meet ongoing and new challenges by leveraging emerging scientific and educational concepts, care models, and technologies.

THE EVOLVING SPECTRUM OF LIVER DISEASE, THE ECOSYSTEM, AND THE ROLE OF THE HEPATOLOGIST

In Western nations and particularly the USA, hepatology has largely remained an academic specialty with the majority of board-certified hepatologists practicing in tertiary care centers, most with liver transplant programs. The rationale for this model has been that formal training and certification in hepatology have focused primarily on the care of end-stage liver disease, liver transplantation, and HCC, all of which require substantial health care resources and specialized expertise. Similarly, in the early days of interferon-based hepatitis C treatment, “it took a village” to manage these treatments. With highly effective HCV therapy now orally available and well tolerated, curative treatment can be overseen by nurses and advanced practitioners, as well as internists and infectious disease specialists.

Although the care of advanced liver disease remains compelling to trainees and practitioners, there is an increasing burden of liver disease that is silent or minimally symptomatic, imposing a larger onus on outpatient care by hepatologists as well as internists and primary care providers, with the goal of reducing the future burden of liver disease and demand for liver transplantation. Transplantation is an expensive option available to only a sliver of the population relative to the overall disease burden and is constrained by the limited availability of organs and resources. As already witnessed with HCV, detection and treatment of earlier diseases can profoundly improve life for patients and reduce costs for health care systems.^[2] This evolution toward outpatient care makes it incumbent upon hepatology to disseminate its expertise among providers beyond our own specialty.

LIFE-THREAT ASSESSMENT THROUGH THE LENS OF HEPATOLOGY

Modern life is hurtling forward at an astonishing pace, driven by the integration of technology into everyday life, as well as population growth that encroaches on natural reserves, which has implications for climate change and exposure to disease agents. These activities will affect the risk and prevalence of liver diseases.

Mental health disorders are at an all-time high, and addiction-related morbidity and mortality are key drivers of lower life expectancy in the USA.^[3] Linked to these disorders are alcohol-associated and other forms of liver disease including viral hepatitis.^[4,5] Mental health and behavior are also linked to lifestyle and coupled with changes in food quality, quantity, and availability.^[6,7] Lifestyle and overnutrition have contributed to a global pandemic of metabolic ill-health associated with non-communicable disorders including type 2 diabetes, NAFLD, and atherosclerotic cardiovascular disease, among others.^[8,9] Many patients have several of these conditions, which represent competing threats to life and necessitate patient-centered team approaches rather than specialty-based tactics to address these problems.

War, social displacement, and refugee crises have led to mass population movements into unhealthy and often dangerous living environments. These foster nefarious efforts to promote the trade and use of drugs and products that are medically harmful and could lead to the resurgence of infectious diseases traditionally linked to illicit intravenous drug use, unregulated medications, and alcohol abuse. The threat of bioterrorism also persists within a politically, economically, and socially fractured planet.^[10] Several chemical and biological weapons carry the potential for devastation at a large scale and could also cause acute liver injury (eg, the Ebola hemorrhagic fever and ricin).^[11,12]

Finally, climate change, as noted, is altering fragile ecosystems, putting some species at risk of extinction making it not only an existential and ecological crisis but also a global health crisis.^[13] This development, along with human encroachment into uninhabited areas, has brought humans in contact with animals and novel pathogens that carry the potential for acute and chronic liver injury, of which COVID-19 is the latest example.^[14] Even when acute illness from acute infection resolves, post-COVID cholangiopathy can emerge, with some patients rapidly progressing to liver failure necessitating liver transplantation.^[15] Future pandemics associated with liver injury may well have similar or other long-term consequences.

In the following sections, we focus on anticipated progress and persistent unmet needs in the diagnosis and care of the most common liver diseases (Table 1). These components are followed by highlighting broader unmet needs that need to be addressed in the training, organization of clinical care, and social responsibilities of hepatology to advance the care and improve the outlook of patients with liver disease (Table 2).

TABLE 1.

Advances that will transform hepatology—disease-specific

• Alcohol-associated liver disease/AUD  ∘ Improved awareness, screening, and pharmacotherapy of AUD  ∘ Regenerative therapies to improve survival in alcohol- associated hepatitis

• NAFLD and nonalcoholic steatohepatitis  ∘ Standardization of nomenclature  ∘ Pathogenesis:   - Clarification of driver events  ∘ Diagnosis   - Subtype classification to refine therapies based on genetics and gene expression   - NITs that supplant biopsy  ∘ Treatment   - Personalized/combination therapies that translate into improved outcomes   - Multidisciplinary care practices to harmonize management and improve outcomes   - Incremental progress in treatments that will benefit all patients

• Liver cancer  ∘ Pathogenesis:   - Subtyping of disease-based tumor and stromal biology in HCC and iCCA  ∘ Diagnosis:   - Liquid biopsy to diagnose and classify tumors for screening and treatment   - Improved imaging for screening, diagnosis, and staging  ∘ Treatment:   - Primary and secondary prophylaxis in high-risk patients, defined using circulating gene markers   - Regenerative therapies to expand candidacy for liver resection   - Expanded options for ablative therapies   - Personalized immunotherapy  ∘ Viral hepatitis   - More effective screening, with the elimination of HCV worldwide   - Prophylactic HCV vaccines   - Cure of HBV and hepatitis delta

• End-stage liver disease and cirrhosis  ∘ Pathogenesis:   - Incorporation of microanatomical features to stage disease and clarify the cellular basis of portal hypertension   - Clarification of matrix degradation pathways—cells, proteases, and their inhibitors  ∘ Diagnosis:   - Digital methods to quantify scar and histologic features linked to outcomes  ∘ Treatment   - Effective antifibrotic and regenerative therapies, including small molecules and cell transplantation

• Immune diseases (AIH, PBC, and PSC)  ∘ Pathogenesis:   - Define cellular landscape using single-cell methodologies   - Clarify the source of fibrosis and its impact on the development of cholangiocarcinoma and liver failure  ∘ Diagnosis   - Leverage immunologic insights to classify and stage disease and define new targets  ∘ Treatment   - Highly selective personalized, immune-based therapies

• Liver transplantation  ∘ Development of ex viv∘ liver support devices for organ maintenance  ∘ More selective immunosuppressive therapies  ∘ Cell transplantation as a bridge to liver transplantation  ∘ Xenotransplantation from humanized mammals

• Pediatric and genetic liver diseases  ∘ Pathogenesis   - Clarification and reclassification of neonatal liver disease   - Implementation of whole exome sequencing to identify genetic causes  ∘ Diagnosis   - Biomarkers and widespread genetic testing, which will broaden our understanding of the range of phenotypes, protective factors, and natural history  ∘ Treatment   - Gene therapy for monogenic diseases   - Clinics and interinstitutional research programs to optimize the care of adults following childhood

Abbreviations: AIH, autoimmune hepatitis; AUD, alcohol use disorder; iCCA, intrahepatic cholangiocarcinoma; NIT, noninvasive test; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.

TABLE 2.

Advances that will transform hepatology— organizational, technical, and educational

• Organizational  ∘ Greater emphasis on screening, early treatment, and prevention of disease  ∘ Enlarged public-private interactions and consortia  ∘ Engagement and comanagement with other specialties when appropriate (especially NAFLD); increased team-based care  ∘ Increased engagement of patients and their families in clinical trials, strategic planning, and treatment options  ∘ Improved reimbursement for liver disease care  ∘ Enlarging safety net and access to care for the marginalized and underserved communities  ∘ Education and advocacy to address the impact of climate change on liver health

• Technical  ∘ Widespread implementation of genetic testing to inform diagnosis, classify disease, and refine treatments  ∘ Single-cell methodologies that will redefine disease pathogenesis and subtyping  ∘ Cell and xeno-transplantation for end-stage liver disease  ∘ Al  ∘ Precision medicine  ∘ Big data analyses

• Educational  ∘ Evolving curriculum that focuses more on prevention and early treatment  ∘ Integration of hepatology training in medical school curricula  ∘ Accelerate education and recruitment of advanced practitioners  ∘ Cotraining with other specialties (especially for NAFLD and end-stage liver disease)  ∘ Education in palliative medicine for hepatologists

Abbreviation: Al, artificial intelligence.

ALCOHOL-ASSOCIATED LIVER DISORDERS

Approximately two-thirds of the adult population in Western nations consume alcohol and up to 20% engage in risky drinking behavior.^[16] Alcohol-associated liver disease is a major cause of liver-related morbidity and mortality, especially in Europe, which has the highest consumption of alcohol in the world.^[3,17] Along with opioid addiction, suicide, and gunshot injury, alcohol-associated liver disease is an independent driver of declining life expectancy in the USA.^[3] Furthermore, mortality from alcohol-associated liver disease has doubled from 2000 to 2016 in some Asian countries, for example, India.^[18]

Alcohol-associated liver disease is inextricably linked to underlying mental health disorders and addiction biology. Yet this relationship has been understudied. The future research agenda for alcohol-associated liver disease needs to integrate these disorders, with a particular focus on early identification and treatment of harmful alcohol use patterns and diagnosis of alcohol use disorder (AUD). Additional priorities include the identification of mechanisms underlying liver disease progression from alcohol, development of the clinical syndrome of alcohol-associated hepatitis and its related complications, and drivers of mortality in this population.

Clinically, identification of unhealthy alcohol consumption patterns before disease develops provides an opportunity to reduce alcohol-associated morbidity and mortality. Identification of such behavior along with counseling and education may reduce the prevalence of harmful drinking.^[19] These can be integrated with social approaches to reduce the growing trend of harmful alcohol consumption especially in young women.^[20]

Safer and more effective therapies for AUD, especially in those with liver disease, remain a significant unmet need in clinical care. Given the prevalence and impact of AUD on general and liver health and its contribution to declining life expectancy,^[3,16] this is a public health priority where the disciplines of primary care, hepatology, alcohol research, and mental health will benefit from coalescing to create new paradigms for primary prevention, early detection and intervention to reduce the overall impact of alcohol on public health.

Many patients have both harmful levels of alcohol consumption and metabolic risk factors for liver disease^[16] (https://www.cdc.gov/obesity/data/adult.html). Important clinical research efforts are needed to guide preventive and therapeutic approaches towards common pathways underlying these overlapping illnesses while integrating common genetic risks, rather than the siloed pursuit of etiology-specific pathways.^[21,22]

Some patients with underlying AUD and liver injury develop florid alcohol-associated hepatitis with the onset of jaundice and acute worsening of clinical status.^[23] Many of these patients already have underlying cirrhosis. There is a need for biomarkers to distinguish between alcohol-associated hepatitis and decompensated cirrhosis.

Patients with alcohol-associated hepatitis are particularly susceptible to acute kidney injury and/or sepsis, with progression to multiorgan failure and death.^[24–26] There is a clinical need for biomarkers for early detection and distinction from pre-existing kidney disease especially as creatinine measurements can be misleading due to underlying sarcopenia.^[27]

Sepsis is the leading cause of death in alcohol-associated hepatitis.^[28] Future needs include more sensitive methods to detect infection to reduce the need for empiric antibiotics with their potential to promote antibiotic-resistant infection and novel nosocomial pathogens.^[29,30]

Alcohol-associated cirrhosis can develop silently in individuals or may arise after bouts of alcohol-associated hepatitis.^[31] The return to alcohol consumption after bouts of alcohol-associated hepatitis is a key determinant of long-term outcomes.^[32] A focus on AUD identification and care is required in this population, with multidisciplinary care paradigms to prevent the development or progression to decompensation of alcohol-associated cirrhosis.

Finally, the role of liver transplantation for alcohol-associated hepatitis is rapidly evolving, with many centers reporting encouraging results in the acute setting.^[33] The conventional paradigm of abstinence for 6 months or more has been challenged, allowing for more liberal listing criteria.^[34] Standardization of these approaches and the establishment of best practices to optimize selection and outcomes for this population to undergo transplantation are key priorities for the future.

From a workforce development perspective, increased attention and training in alcohol-associated liver disease and its underlying behavioral and addiction drivers will help us better address the growing clinical burden. A focus on other end-organ–related comorbidities will also be essential. Postdoctoral fellowship training programs (eg, NIH T32 grants) that focus on research that promotes integrated care could accelerate the development of a new cadre with specialized skills to meet the workforce challenges of the future.

NONALCOHOLIC FATTY LIVER DISEASE

NAFLD affects up to a third of adults worldwide,^[35,36] and ~ 10% of children.^[37] Despite intense research efforts and steady advances, the burden of disease remains high and is projected to grow, underscoring the need for strategies to curb this public health threat.^[38,39]

The key risk factors in the majority of NAFLD cases are excess adiposity with associated insulin resistance.^[40] These factors connect the biology of NAFLD to obesity, type 2 diabetes mellitus, hypertension and atherogenic vascular disease, heart failure with preserved ejection fraction, and chronic kidney disease. Indeed, with the progression of liver disease, the incidence of other end-organ diseases also increases.^[41] Thus, NAFLD has emerged as part of a multisystem disorder rather than an isolated liver disease. This has important implications for future detection, staging, and treatment.

As with alcohol-associated liver disease, many patients with NAFLD do not have symptoms that are attributed to liver disease. Moreover, it has been estimated that 97% of patients with NAFLD are cared for by non-hepatologists.^[42] Despite this striking statistic there is a remarkable lack of awareness within the primary care community as well as among health care providers caring for heart disease, diabetes, and chronic kidney disease, leaving the majority of patients undiagnosed until there is an advanced symptomatic disease.^[43] This broad lack of knowledge among providers underscores the need for expanded hepatology training starting in medical school and extending through all relevant specialties including internal medicine and family practice, as well within specialty training programs in endocrinology and cardiovascular disease. Based on the gathering epidemic in fatty liver disease, improved primary care hepatology will be essential to better focus on undiagnosed viral hepatitis, NAFLD, AUD, and unexplained liver diseases.

Although progress is being made in the development of mono-therapies for NAFLD, “one size does not fit all”. The principal risks in those with early-stage disease are cardiovascular disease and cancer, whereas those with bridging fibrosis or cirrhosis are at the greatest risk of liver outcomes and death.^[41,44] Assessment of cardiovascular risk and use of therapies that will benefit cardiovascular disease and reduce NAFLD activity—and thus risk of progression to cirrhosis—are likely to become the preferred approach for individuals with early-stage disease, whereas agents with stronger antifibrotic benefits may be more useful in those with advanced fibrosis especially bridging fibrosis.^[45,46]

Those with bridging fibrosis, especially with high disease activity, are most likely to progress to cirrhosis.^[47] These patients may need intensive therapy with combined antifibrotic and metabolically targeted therapies. In those with cirrhosis, the burden of scar and fibrogenic activity are key determinants of outcomes.^[48] In the future, targeted approaches to reduce fibrogenic activity in this population, and to assess risks of portal hypertension and HCC will be key elements of NAFLD management. A recent study from one of our laboratories (Scott L. Friedman) has discovered that fibrogenic signaling evolves with progressive disease, from paracrine signaling toward largely autocrine HSC crosstalk.^[49] This finding suggests that effective antifibrotic treatments in late-stage NASH may require different therapies that are specific for advanced fibrosis. Development and qualification of biomarkers to identify, which pathways are engaged as the disease advances will help guide risk-based management strategies.

For those who are treated with combination therapies, the optimal approach is yet to be defined but a more thoughtful framework is essential. A rational, high-throughput drug screening strategy will likely yield greater success, wherein multiple combinations of candidate agents at different doses are tested in a short-term ex vivo model of NASH (eg, organoids), with detailed cellular analysis of gene and protein expression to identify synergistic, rather than additive activity.

Historically, the development of therapeutics for NAFLD and its associated comorbidities has evolved solely within organ-specific specialties. Multidrug approaches for the treatment of dyslipidemia, hypertension, glycemic control, heart failure, and kidney disease represent current best practices but contribute to polypharmacy in this population.^[50] The burden of multiple medications may negatively impact the quality of life, increase the potential for drug-drug interactions that may be difficult to ascertain, and increase the cost of care. Future clinical care should include a more holistic assessment of these competing threats to life integrated with risk-based treatment strategies. From a workforce development perspective, this will benefit from integrated efforts across specialties including endocrinology, cardiology, obesity medicine, nephrology, and hepatology.

LIVER CANCER

HCC is among the fastest-rising cancers in the world.^[51] Both alcohol-associated liver disease and NAFLD are key etiological factors underlying this increase.^[52,53] In specific regions of the world, particularly Asia and Africa, viral infections remain the major causes of HCC.^[54] The overall outcomes of HCC remain poor, underscoring the need for progress.

HCC typically develops in the setting of chronic liver disease with advanced fibrosis;^[55] however, especially in NAFLD and in chronic hepatitis B, those who do not yet have cirrhosis are still at risk.^[56,57] The growing population of individuals with NAFLD at risk for HCC imposes unique challenges to developing effective surveillance strategies in this population.^[58] This underscores the need for enrichment strategies to identify populations at greatest risk for HCC, and thus likely to benefit from surveillance. Genetic approaches have uncovered gene signatures within liver tissue and in circulating blood that predicts the likelihood of primary or recurrent HCC, information that could greatly refine screening guidelines for those at risk or treated for this cancer.^[59] Development of such liquid biopsy techniques will require clinical validation.^[60,61]

Even for those with established indications for HCC surveillance,^[62] implementation is disappointingly low in clinical practice.^[60] Improved implementation of surveillance may be facilitated by leveraging electronic medical records and digital technologies to provide automatic reminders for regular screening, however, this approach requires validation.^[63]

Vaccination for HBV is one of the most impactful cancer prevention strategies in the world.^[64] Effective antiviral therapy also reduces the risk of HCC in those with hepatitis B and C but does not eradicate the risk.^[65,66] Further research to establish primary preventive approaches, especially for other etiologies of underlying liver disease will be an important area for future research. Although transplantation will remain a life-saving option for selected patients with HCC, limited organ availability underscores the need for early detection, medical therapy, and secondary prevention.

Despite many advances in HCC therapy, there is a significant need for improvement. The explosive growth in immune oncology is already improving outcomes in patients with HCC ^[67] and intrahepatic cholangiocarcinoma.^[68] Studies increasingly have defined specific dysregulated immune pathways in individual patients that will lead to more personalized immune-oncology therapy.^[69,70] Recent studies have illuminated the important regulatory role of stromal cells, especially macrophages and hepatic stellate cells in liver cancer (HCC and intrahepatic cholangiocarcinoma). For example, there are distinct subsets of cancer-associated fibroblasts derived from hepatic stellate cells, some of which are growth-promoting, and others that are growth-inhibitory^[71] Findings like these have emerged because of extraordinary technical advances, with widespread implementation of single-cell analytic methods for analysis and localization of mRNA and protein expression. Large data sets generated by these single-cell methods have further driven the refinement of analytical methods to interrogate them, integrating the information to yield novel biological insights that are not readily apparent through traditional means.

From a workforce development perspective, there is a need for greater training in oncological principles for those pursuing advanced transplant hepatology training. Conversely, expanded exposure to hepatology for those receiving advanced gastrointestinal oncology training will be ideal. These are likely to enhance current multidisciplinary care paradigms for hepatobiliary cancer.

VIRAL LIVER DISEASE

The discovery and elucidation of viral hepatitis is perhaps the greatest success story in hepatology if not modern medicine. Challenges in hepatitis B remain, however, despite the development of highly effective and durable antivirals that have markedly improved the outlook for patients with chronic infection.^[72] Prospects for HBV cure are brightening and likely to become reality in the next decade.^[73,74] Similarly, hepatitis delta therapies are advancing rapidly, and together these developments will transform the diagnosis and treatment for viral hepatitis.

Remarkably, we have witnessed a complete success story with the discovery and development of direct-acting antivirals for treating hepatitis C, which now hold the promise of eliminating the disease from our populations.^[75] Although there have been remarkable achievements around the world in large-scale cures, for example, in Egypt,^[76] many nations are still lagging in their efforts to screen, detect, and treat HCV, including the United States.^[77] Although recent studies offer hope of an HCV vaccine, the availability of curative therapies could largely eliminate this infection from our landscape, if only screening can improve.

IMMUNE-MEDIATED AND DRUG-INDUCED LIVER DISEASES

Despite remarkable advances in our technologies and understanding of human immunology, this progress has not yet translated into effective new therapies for autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, or drug-induced liver disease, which are largely immunologic diseases. Nonetheless, the longstanding use of ursodeoxycholic acid, combined with the availability of obeticholic acid and newer drugs on the horizon for primary biliary cholangitis has already significantly improved the outlook for this condition.^[78] In contrast, we still have much to learn about autoimmune hepatitis and primary sclerosing cholangitis, where there are unmet needs at every step of translation, from discovery science to preclinical studies, to human trials. The current testing of small molecule immunologic mediators and antifibrotic compounds for primary sclerosing cholangitis is a heartening sign, but it is tempered by challenges in elucidating its pathogenesis and defining suitable endpoints in clinical trials. Indeed, we do not know whether the reduction in fibrosis will be clinically meaningful in either slowing disease progression, avoiding transplantation, and/or reducing the risk of cholangiocarcinoma.

ADVANCED FIBROSIS AND END-STAGE LIVER DISEASE

Regardless of etiology, progressive fibrosis, especially the development of bridging fibrosis and cirrhosis, has emerged as a key driver of outcomes.^[79,80] Major unmet needs in understanding fibrosis progression require a greater exploration of the heterogeneity of fibrosis dynamics (progression and regression) in different regions of the hepatic lobule and their relationship to changes in microcirculation, overall liver function, or risk of decompensation.^[81–83]. Future approaches may leverage innovations such as organs-on-a-chip to clarify some of these issues.^[84] These efforts could be coupled with the development of noninvasive tools for diagnostic, risk stratification, disease monitoring, and treatment response contexts of use. High-quality noninvasive tests are also required to identify those with clinically silent but significant fibrosis in primary care settings.^[85,86]

There is significant progress in elucidating the mechanisms of liver regeneration, which could lead to novel therapies for those with advanced fibrosis or cirrhosis.^[87,88] In fact, there is reason to expect that the stimulation of liver regeneration could indirectly lead to fibrosis reduction and normalization of liver function, as has been seen after HCV cure or suppression of HBV. Future research will need to establish the therapeutic potential of regenerative approaches while derisking them from potential pro-oncogenic effects. Once regenerative therapies are available, we also may be better able to define the “point of no return,” after which transplantation is the only viable option for patients with advanced liver disease.

Clinically, future paths to pursue are the identification of those with clinically relevant, severe fibrosis and its link to outcomes using tools that are widely available and acceptable. Measuring HVPG is one method to track this insidious progression,^[89,90] but it is costly and not widely used in routine practice in many regions. Current measures using transient elastography and other technologies, although useful, leave considerable room for improvement, especially for disease monitoring. Therefore, additional tools and studies require development to yield clinically actionable guidelines that minimize the risk of misclassification.^[91,92,93]

Once decompensation develops, there is an inexchange decline with episodes of acute on chronic liver failure and dysfunction of other systems, often culminating in multiorgan dysfunction and death. We are still unable to reduce overall mortality in this setting without liver transplantation.^[94,95]

Finally, refinements in transplant medicine and further improvements in both peritransplant outcomes and long-term management are likely to continue. Efforts to improve graft function through machine perfusion, extracorporeal ex vivo liver support, xenotransplantation, cell-based transplantation, and genetic humanization of liver tissue, coupled with improved immunosuppression, are all steadily progressing and may be part of the future therapeutic armamentarium.^[96–100]

PEDIATRIC LIVER DISEASE

Although liver disease is relatively rare in children, these illnesses are often devastating for the patients and their families. A key priority of future research is the development of approaches for more widespread genetic testing, early detection, and development of therapeutics, especially beyond liver transplantation, which are available to all. For those developmental disorders caused by a single gene defect, the technology for gene corrective therapy has already arrived, using either siRNA or CRISPR technologies. A major future direction will be to leverage and build on these technologies to develop targeted delivery of cargo to specific cells and correct the defects from specific genetic disorders.^[101]

In older children, pediatric obesity with its implications for liver disease in young people is a very worrisome dilemma. The impact of maternal obesity and metabolic syndrome on the metabolic health of their offspring is likely to be a major area of research.^[102] The development of noninvasive tools, identification of subsets of patients who are progressing, and safe and effective therapeutics remain key unmet needs.

The transition from childhood to adulthood is a critical period, and new exposures during adolescence such as alcohol, and recreational drugs impose additional health challenges. Some children with pediatric liver disease grow into adulthood^[103] and are lost from pediatric care but do not transition into adult medical care, yet these young adults are more susceptible to the harmful effects of alcohol, among other risks, underscoring the need to develop expertise in managing these patients among adult hepatologists. There is a relative paucity of data on how to optimize these transitions, and there are no standardized care pathways in this setting. One future approach is to establish formal pediatric-to-adult hepatology transition clinics in major medical centers to optimize care transition.

RARE LIVER DISEASES

Rare diseases are not often discussed as a public health problem. They are also infrequently considered, and thus often diagnosed late in the course of the disease. Owing to the rarity of these disorders, individual centers cannot aggregate enough patients to generate high-quality evidence-based management approaches grounded in rigorous translational and clinical studies. There is a need for national networks of expert research centers where patients are evaluated and tracked, and linked by data centers to harmonize case definitions and approaches, by which data are collected.

WORKFORCE ISSUES: WHO SHOULD CARE FOR PATIENTS WITH LIVER DISEASE AND HOW SHOULD THEY BE TRAINED?

Due to the clinically silent nature of early-stage liver disease, many patients with liver disease are seen only in primary care settings. In addition to the workforce needs outlined in the preceding paragraphs, a major ongoing goal of its future development is training to improve awareness and enhance the detection and management of early-stage liver disease. This is especially important for alcohol-associated liver disease and NAFLD in primary care settings. There is also a need for greater awareness and willingness to screen for liver disease by those caring for mental health disorders, addiction disorders, and metabolic diseases such as type 2 diabetes mellitus. Adapting to the unmet needs will necessitate both training programs and professional societies to develop evidence-based guidance for the holistic management of these major public health threats.

Within the fields of gastroenterology and hepatology, the growing demand for care can be addressed in part by training nurse practitioners and allied health service providers to meet the gap between the clinical need and the availability of a physician workforce.^[104] As better therapeutics for NAFLD and alcohol-associated liver disease emerge, it is likely that these advanced practice providers will assume a substantial burden of care. Hepatology training will need to expand to include greater training in the behavioral underpinnings of liver disease, addiction, and metabolic disorders, which are all common in patients cared for by hepatologists. Further training in the use of noninvasive tools for clinical care, oncology, and emerging technologies for the management of advanced liver disease and those being considered for transplant will also be valuable. The recent focus on inclusivity, health disparities, and social determinants of health needs to inform the development of care paradigms that address the important societal trend toward a more just and equitable health system.

The workday of the average hepatologist is likely to change with the demand for care and evolving trends in hepatology. As with viral hepatitis, with the development of effective therapies for NASH and alcohol-associated liver disease, a substantial burden of care is likely to shift to advanced practice providers. Caring for liver disease, particularly in tertiary care settings, will increasingly be provided in a multidisciplinary setting. Hepatologists are likely to be focused primarily on those who require complex therapeutic decision making such as patients with cirrhosis, especially after decompensation and before as well as after liver transplantation. Although in some countries, HCC care is borne almost entirely by hepatologists, care for such patients is likely to be provided in a multidisciplinary setting with input from oncology, transplant surgery, interventional radiology, and hepatology. A growing number of programs have established a multidisciplinary model for the care of liver cancer.^[105]

Hepatologists have an expanding menu of career options after their training. Although advanced hepatology has largely been an academic career path, there are growing opportunities within the community as well for clinical hepatologists. There is also a trend for some transplant hepatologists to be part of a transplant care model, in which remuneration is based on the number of patients listed and transplant outcomes. Such care models carry the risk of reduced attention to those with the liver disease before the need for transplantation.

These changes could also diminish the academic workforce that conduct research. The long training road to becoming a hepatologist, challenges in obtaining grant funding, and the difference in remuneration between conventional academic hepatologists and transplant hepatologists, or those performing endoscopy, present major challenges to maintaining an academic research workforce.^[106]

The continuing investment in research training programs, loan repayment programs, and enhanced funding opportunities for early-stage investigators will be critical to sustaining a high-quality research workforce to meet the challenges ahead. The future of hepatology as a science will increasingly rely on large data sets and their management, requiring support for data analysts and scientists working alongside those with a basic science background in hepatology to maintain an intellectually diverse workforce. Hepatologists will also benefit from assimilating new skills and technologies, in particular precision medicine and artificial intelligence. The astonishing potential of artificial intelligence is sweeping through our world, and will likely transform how we practice medicine to an extent we cannot yet imagine.

Finally, the need for high-quality mentorship has never been greater and formal training in mentorship and engagement in mentorship activities throughout the lifecycle of hepatologists will be essential to maintain the workforce, reduce professional isolation, and sustain equal opportunities to preserve expertise around the world.

In summary, there are both challenges as well as growing opportunities to improve liver health among our populations. The success of hepatology will be contingent on all stakeholders being fully engaged nationally and internationally to pursue a common vision of progress to transform the outlook for patients at risk of or suffering from liver disease.

Abbreviations:

AI

artificial intelligence

AUD

alcohol use disorder

iCCA

intrahepatic cholangiocarcinoma

NIT

noninvasive test

PBC

primary biliary cholangitis

PSC

primary sclerosing cholangitis