Multidisciplinary clinics (MDCs) are gaining momentum throughout the medical field, having initially been pioneered in oncology clinics due to their inherent ability to streamline complex care and improve both patient outcomes and the patient care experience. Liver transplant and hepatobiliary tumor clinics are examples of established MDCs in hepatology. With the changing landscape of liver disease in regard to etiology and patient complexity and acuity, there is a clear need for efficient, highly coordinated care. These changes highlight opportunities for hepatology MDCs in alcohol-associated liver disease, metabolic dysfunction-associated steatotic liver disease, and palliative care. This review provides practical advice in navigating the complex logistics of establishing and maintaining a hepatology MDC while also reviewing the emerging evidence on clinical outcomes for patients seen in these MDCs. As hepatology looks to the future, establishment of MDCs in key clinical areas will be the cornerstone of patient care.

INTRODUCTION Hepatocellular adenomas (HCAs) are benign liver lesions that can present as incidental liver lesions, with abdominal pain, or rarely with bleeding or rupture. The risk of HCA bleeding is related to the size of the lesion with increased risk when >5 cm. Distinct molecular subclassifications result in histologic, radiographic, and clinically distinct groups, including a small subset of HCAs that contain beta-catenin activation on exon 3 that increases the risk of malignant transformation.1 HCA management is determined by lesion size, growth pattern, patient sex, and the presence of beta-catenin activation. The main risk factor for adenoma development is estrogen exposure by means of the use of combined hormonal contraceptives (CHCs). Pregnancy as a period of high estrogen exposure and hyperdynamic circulation raises concerns regarding HCA growth and the risk of bleeding. Pregnancy-related considerations for HCA management are dependent on lesion size, with lesions <5 cm having low bleeding risk.2 HCA BEHAVIOR AND MANAGEMENT PRIOR TO PREGNANCY Exogenous and endogenous estrogen exposure is the main risk factor for HCA development. There are growing data on the relationship between HCAs and endogenous estrogens from excess adipose tissue in obesity and the beneficial effect of weight loss on HCA regression.3 Exogenous estrogens, particularly in the form of CHCs, are associated with increased risk of HCA development with a rate of 3–4 per 100,000.4 Cessation of CHCs can result in regression and resolution of some HCAs.3 Two recent studies underscore the relationship between exogenous hormones and HCAs. A retrospective cohort study from 2000 to 2019 of 183 patients with 267 histologically confirmed HCAs assessed outcomes of malignant transformation (6%), symptomatic bleeding (11%), and HCA growth patterns after cessation of CHCs.3 The growth pattern was monitored in 120 patients who discontinued CHCs and were followed for a median of 5 years: 22% had progressive disease, 47% had stable disease, and 31% had partial or complete resolution. The authors developed an estrogen exposure score to predict HCA regression that accounted for duration of estrogen use and BMI. Of the 13 women who had HCAs after transitioning to progestin-only contraception, 10 women had stability, 2 had regression, and 1 had progression. Additional data regarding progestin-only contraception were outlined in a cohort of 27 patients accounting for 34 discrete time periods of hormone exposure between 2003 and 2021. This study showed the median percent change of HCAs in those on progestin-only contraception was −15% which was similar to those with no exogenous hormonal exposure at −7.4%, whereas it was 29.4% in periods of exogenous estrogen exposure.5 These studies support the recommendation to discontinue estrogen-containing CHCs in patients with HCAs; however, progestin-only containing contraceptives may be considered while awaiting further study. Expert opinion recommends women be monitored off CHCs for 6–12 months prior to pregnancy to establish baseline HCA size. Assessment of baseline HCA size prior to pregnancy is important to stratify for management. Up to three-fourths of women know of their HCA diagnosis prior to pregnancy.2 American Association for the Study of Liver Diseases (AASLD) guidelines (Figure 1) recommend treatment of HCA larger than 5 cm prior to pregnancy, whereas women with lesions <5 cm may proceed with pregnancy with close observation.6FIGURE 1: Approach to hepatocellular adenoma prior to and during pregnancy. Reprinted with permission from Sarkar et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 73(1):318-365, January 2021.6 Abbreviations: HCA, hepatocellular adenomas; US, ultrasound.HCA BEHAVIOR AND MANAGEMENT DURING PREGNANCY Pregnancy is characterized by high estrogen levels and hyperdynamic circulation, which raises concern about HCA growth and possible bleeding. The largest prospective study to assess for growth patterns during pregnancy included 48 women during 51 pregnancies enrolled from 2011 to 2019 with lesions <5 cm.2 The authors followed women throughout pregnancy with ultrasound at 14 +/−3, 20, 26, 32, and 38 weeks and 6–12 weeks postpartum. The median HCA size was 2.3 cm prior to pregnancy, and 25% had growth (defined as 20% increase in lesion size), 53% remained stable, and 22% regressed (defined as a decrease of 30%). Growth occurred between 14 and 32 weeks. One patient who had growth of a lesion to over 5 cm (from 4.9 to 7.6 cm) was treated with prophylactic embolization at 26 weeks. Similar predictions of HCA behavior were shown in a systematic review of 73 pregnancies including those of the aforementioned prospective cohort: 32% progressed, 53% were stable, 15% regressed.7 If growth is suspected on ultrasound, confirmation of lesion size can be assessed with a noncontrast MRI (gadolinium is contraindicated in pregnancy). Our understanding of the risk of HCA bleeding during pregnancy has evolved since early studies in the 1970s and 1980s that suggested high bleeding rates and maternal and fetal mortality8 to more contemporary analyses that show a much lower bleeding risk that is dependent on lesion size.2,7,9 There were no bleeding events in a 2011 prospective study of 17 pregnancies with 5 patients having HCAs over 5 cm.9 One patient was prophylactically treated with ablation in the first trimester to prevent growth. Likewise, there were no bleeding events in the prospective study of 51 pregnancies of lesions <5 cm.2 In a systematic review of 99 pregnancies, 15 HCA-related bleeds were reported all in lesions >6.5 cm: 8 during pregnancy (7 in the third trimester), 2 during labor, and 5 postpartum (4 within the first 2 weeks).7 The risk of bleeding postpartum may be related to the estrogen withdrawal and its effects on lesion behavior. Taken together, these data support the AASLD guideline recommendation that women with HCAs <5 cm can proceed with pregnancy.6 For patients with lesions over 5 cm, intervention is considered carefully based on the risk-benefit profile to the mother and fetus. Embolization is a potential treatment option prophylactically for large HCAs over 5 cm or in the case of bleeding HCA. The optimal timing for embolization is after 26 weeks gestation given the risk of radiation exposure to the fetus. Resection is rarely indicated, but if required it should be considered in the early second trimester. Case series and reviews include outcomes for intervention for bleeding HCA during pregnancy with resection or embolization,7 though many of the cases occurred prior to the 2000s and do not reflect modern advances in interventional radiology, surgical, and intensive care management. A key to optimizing maternal and fetal outcomes is early recognition of HCA bleeding as a potential cause of abdominal pain and/or shock in pregnant patients.

Summary Background Racial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival. Aim To evaluate the impact of HCV treatment on such disparities. Methods In a retrospective cohort study, we analysed 6069 patients with HCV‐related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia. Results The mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%–15%, 20% vs. 10%–17% and 10% vs. 5%–7%, respectively; all p < 0.0001). Treatment rate with direct‐acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients ( p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10‐year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients ( p < 0.0001). There were no statistically significant differences among those with SVR ( p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non‐U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001). Conclusion DAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.

Patients with hepatocellular carcinoma meeting united network for organ sharing (UNOS)-downstaging (DS) criteria have excellent liver transplantation (LT) outcomes after DS. However, outcomes for "all-comers" (AC) patients with tumors initially exceeding UNOS-DS are poorly understood. Patients meeting AC (n = 82) or UNOS-DS (n = 229) at 7 LT centers in 4 UNOS regions were prospectively followed from 2015-2020. AC patients had a lower probability of successful DS (67% vs 83% within 12 months; P < .001). The 3-year survival was 69% for UNOS-DS vs 58% for AC (P = .05) and reduced to 30% in patients with Child-Pugh B/C cirrhosis or alpha-fetoprotein (AFP) ≥ 500. Five-year LT probability was 42% for AC vs 74% in UNOS-DS (P = .10). Thirty-eight percent were understaged on explant, with the increasing sum of the largest tumor diameter plus the number of lesions before LT (odds ratio 1.3; P = .01) and AFP ≥ 20 (odds ratio 5.9; P = .005) associated with understaging. Post-LT 3-year survival was 91% for AC vs 81% for UNOS-DS (P = .67). In this first prospective multiregional study of AC patients from the multicenter evaluation of reduction in tumor size before liver transplantation (MERITS-LT) consortium, we observed a 65% probability of successful DS. Three-year survival in AC was nearly 60%, though AC with Child-Pugh B/C or AFP ≥ 500 had poor survival. Explant pathology and 3-year post-LT outcomes were similar between cohorts, suggesting that LT is a reasonable goal in selected AC patients.

BACKGROUND & AIMS: United Network of Organ Sharing (UNOS) has adopted uniform criteria for downstaging (UNOS-DS) of hepatocellular carcinoma (HCC) before liver transplantation (LT), but the downstaging success rate and intention-to-treat outcomes across broad geographic regions are unknown. METHODS: In this first multiregional study (7 centers, 4 UNOS regions), 209 consecutive patients with HCC undergoing downstaging based on UNOS- DS criteria were prospectively evaluated from 2016 to 2019. RESULTS: Probability of successful downstaging to Milan criteria and dropout at 2 years from the initial downstaging procedure was 87.7% and 37.3%, respectively. Pretreatment with lectin-reactive a-fetoprotein >= 10% (hazard ratio, 3.7; P = .02) was associated with increased dropout risk. When chemoembolization (n = 132) and yttrium-90 radioembolization (n = 62) were compared as the initial downstaging treatment, there were no differences in Modified Response Evaluation Criteria In Solid Tumors response, probability of or time to successful downstaging, waiting list dropout, or LT. Probability of LT at 3 years was 46.6% after a median of 17.2 months. In the explant, 17.5% had vascular invasion, and 42.8% exceeded Milan criteria (understaging). The only factor associated with understaging was the sum of the number of lesions plus largest tumor diameter on the last pre-LT imaging, and the odds of understaging increased by 35% per 1-unit increase in this sum. Post- LT survival at 2 years was 95%, and HCC recurrence occurred in 7.9%. CONCLUSION: In this first prospective multiregional study based on UNOS- DS criteria, we observed a successful downstaging rate of >80% and similar efficacy of chemoembolization and yttrium-90 radioembolization as the initial downstaging treatment. A high rate of tumor understaging was observed despite excellent 2-year post-LT survival of 95%. Additional LRT to reduce viable tumor burden may reduce tumor understaging.

Metabolic-associated fatty liver disease (MAFLD) is a major cause of liver-related complications, including hepatocellular carcinoma (HCC). While MAFLD-related HCC is known to occur in the absence of cirrhosis, our understanding of MAFLD-related HCC in this setting is limited. Here, we characterize MAFLD-related HCC and the impact of cirrhosis and screening on survival. This was a multicenter, retrospective, cohort study of MAFLD-related HCC. MAFLD was defined based on the presence of race-adjusted overweight, diabetes, or both hypertension and dyslipidemia in the absence of excess alcohol use or other underlying cause of liver disease. The primary outcome of interest was overall survival, and the primary dependent variables were cirrhosis status and prior HCC screening. We used Kaplan-Meier methods to estimate overall survival and Cox proportional hazards models and random forest machine learning to determine factors associated with prognosis. This study included 1,382 patients from 11 centers in the United States and East/Southeast Asia. Cirrhosis was present in 62% of patients, but under half of these patients had undergone imaging within 12 months of HCC diagnosis. Patients with cirrhosis were more likely to have early stage disease but less often received curative therapy. After adjustment, cirrhosis was not associated with prognosis, but the presence of cancer-related symptoms at diagnosis was associated with poorer prognosis. Conclusion: Cirrhosis was not associated with overall survival in this cohort of MAFLD-related HCC, while diagnosis in the presence of symptoms was associated with poorer prognosis. The HCC surveillance rate in patients with MAFLD-related HCC was disappointingly low in a multicenter cohort.

BACKGROUND & AIMS There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. METHODS We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). RESULTS Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70-1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70-1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. CONCLUSION In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.

BACKGROUND & AIMS:There is controversy regarding the benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). We performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs and patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy.METHODS:We conducted a retrospective cohort study of patients with HCV-related HCC who achieved a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy, from January 2013 through December 2017 at 31 health care systems throughout the United States and Canada. We used Cox proportional hazards regression to determine the association between receipt of DAA therapy, modeled as a time-varying covariate, and all-cause mortality, accounting for informative censoring and confounding using inverse probability weighting.RESULTS:Of 797 patients with HCV-related HCC, 383 (48.1%) received DAA therapy and 414 (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow-up, compared with 103 deaths during 526.6 person-years of follow-up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% confidence interval [CI], 0.16-0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio, 0.54; 95% CI, 0.33-0.90). This association differed by sustained virologic response to DAA therapy; risk of death was reduced in patients with sustained virologic response to DAA therapy (hazard ratio, 0.29; 95% CI, 0.18-0.47), but not in patients without a sustained virologic response (hazard ratio, 1.13; 95% CI, 0.55-2.33).CONCLUSIONS:In an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death.

BACKGROUND & AIMS:Single-center studies have reported excellent outcomes of patients who underwent liver transplantation for hepatocellular carcinoma (HCC) after successful down-staging (reduction of tumor burden with local-regional therapy), but multi-center studies are lacking. We performed a multi-center study, applying a uniform down-staging protocol, to assess outcomes of liver transplantation and performed an intention to treat analysis. We analyzed factors associated with treatment failure, defined as dropout from the liver transplant waitlist due to tumor progression, liver-related death without transplant, or recurrence of HCC after transplant. METHODS:We performed a retrospective multi-center study of 187 consecutive adults with HCC enrolled in the down-staging protocol at 3 liver transplant centers in California (Region 5), from 2002 through 2012. All patients underwent abdominal imaging 1 month after each local-regional treatment, and at a minimum of once every 3 months. The primary outcome was probability of treatment failure. RESULTS:Liver transplantation was performed after successful down staging in 109 patients (58%). Tumor explant from only 1 patient had poorly differentiated grade and 7 (6.4%) had vascular invasion. Based on Kaplan-Meier analysis of data collected a median 4.3 years after liver transplantation, 95% of patients would survive 1 year and 80% of patients would survive 5 years; probabilities of recurrence-free survival were 95% and 87%, respectively. There were no center-specific differences in survival in the intention to treat analysis (P = .62), in survival after liver transplantation (P = .95), or in recurrence of HCC (P = .99). Patients were removed from the liver transplantation waitlist due to tumor progression in (n = 59; 32%) or liver-related death without liver transplantation (n = 9; 5%). Factors associated with treatment failure, based on multivariable analysis, were pre-treatment levels of alpha-fetoprotein (AFP) >1000 ng/mL (hazard ratio, 3.3; P < .001) and Child Pugh class B or C (hazard ratio, 1.6; P < .001). The probability of treatment failure at 2 years from the first down-staging procedure was 100% for patients with levels of AFP >1000 and Child Pugh class B or C vs 29.4% for patients with neither risk factor (P < .001). CONCLUSIONS:In a retrospective, multi-center study on HCC down staging under a uniform protocol, we found patients to have excellent outcomes following liver transplantation, with no center-specific effects. Our findings support application of the down-staging protocol on a broader scale. Patients with Child Pugh class B or C and AFP >1000 are unlikely to benefit from down staging.

Patients undergoing antiviral therapy for chronic hepatitis C often develop anemia secondary to ribavirin and interferon. Recombinant erythropoietin has been used to improve anemia associated with antiviral therapy and to minimize dose reductions, which are associated with decreased rates of sustained virologic response. A rare potential side effect of recombinant erythropoietin is anti-erythropoietin antibody associated pure red cell aplasia. In chronic kidney disease patients with this entity, there have been good outcomes associated with renal transplant and subsequent immunosuppression. In this case, a chronic liver disease patient developed anti-erythropoietin associated pure red cell aplasia and recovered after liver transplantation and immunosuppression. It is unclear whether it is the transplanted organ, the subsequent immunosuppression, or the combination that contributed to the response. In conclusion, anti-erythropoietin associated pure red cell aplasia is a serious complication of erythropoietin therapy, but this entity should not be considered a contraindication for solid organ transplantation.