Liver transplantation and primary liver cancer in porphyria.

The porphyrias are a heterogeneous group of metabolic disorders that result from defects in heme synthesis. The metabolic defects are present in all cells, but symptoms are mainly cutaneous or related to neuropathy. The porphyrias are highly relevant to hepatologists since patients can present with symptoms and complications that require liver transplantation (LT), and some porphyrias are associated with a high risk for primary liver cancer (PLC). Among the cutaneous porphyrias, erythropoietic protoporphyria (EPP) can lead to cholestatic liver failure where LT cures the liver disease but not the porphyria. In acute porphyria (AP), neurotoxic porphyrin precursors are produced in the liver and LT is a curative treatment option in patients with recurrent severe neuropathic attacks. Patients with AP, mainly acute intermittent porphyria, have a significantly increased risk for PLC that warrants surveillance and adequate follow-up of high-risk groups. LT is well established in both EPP with liver failure and AP with recurrent attacks, but most transplant centres have little porphyria experience and cooperation between transplant hepatologists, and porphyria experts is important in the often-difficult decisions on timing and management of comorbid conditions.

Albumin and fibrinogen synthesis rates in advanced chronic liver disease.

Synthesis of plasma proteins is an important function of the liver that has sparsely been investigated by modern techniques in patients with advanced chronic liver disease (CLD). Twenty-eight well-characterized patients with CLD under evaluation for liver transplantation were included. Albumin and fibrinogen synthesis rates were measured by the flooding dose technique using stable isotope-labeled phenylalanine. Transcapillary escape rate of albumin and plasma volume were assessed by radioiodinated human serum albumin. The absolute albumin synthesis rates were low (65 mg/kg/day, range: 32-203) and were associated with impaired liver function, as reflected by the risk-scores Child-Pugh (P = 0.025) and model for end-stage liver disease (rs = -0.62, P = 0.0005). The fibrinogen synthesis rate (12.8 mg/kg/day, range: 2.4-52.9) was also negatively associated with liver function. The synthesis rates of albumin and fibrinogen were positively correlated. Plasma volume was high (51 ± 9 mL/kg body wt), which contributed to an almost normal intravascular albumin mass despite low plasma concentration. Autoimmune inflammatory etiologies to CLD were associated with higher fibrinogen synthesis. De novo synthesis rates of albumin and fibrinogen in advanced chronic liver failure were negatively correlated to prognostic scores of liver disease. Albumin synthesis rate was low and associated with both liver failure and autoimmune inflammation, whereas fibrinogen synthesis was often normal and positively associated with chronic inflammation. This is different from acute inflammatory states in which both albumin and fibrinogen synthesis rates are high.NEW & NOTEWORTHY Albumin and fibrinogen synthesis were positively correlated, but the high variation indicates that these are probably influenced by different mechanisms. There might be a limited metabolic reserve for the liver to increase both albumin and fibrinogen synthesis in response to longstanding inflammation in CLD and fibrinogen seems to be prioritized.

Maternal and fetal outcomes in acute hepatic porphyria: A Swedish National Cohort Study.

Current knowledge of pregnancy and perinatal outcomes in women with acute hepatic porphyria (AHP) is largely based on biochemical disease models, case reports, and case series. We performed a nationwide, registered-based cohort study to investigate the association between maternal AHP and the risk of adverse pregnancy and perinatal outcomes. All women in the Swedish Porphyria Register with confirmed AHP aged 18 years or older between 1987 and 2015 and matched general population comparators, with at least one registered delivery in the Swedish Medical Birth Register were included. Risk ratios (RRs) of pregnancy complications, delivery mode and perinatal outcomes were estimated and adjusted for maternal age at delivery, area of residency, birth year and parity. Women with acute intermittent porphyria (AIP), the most common form of AHP, were further categorized according to maximal lifetime urinary porphobilinogen (U-PBG) levels. The study included 214 women with AHP and 2174 matched comparators. Women with AHP presented with a higher risk for pregnancy-induced hypertensive disorder (aRR 1.73, 95% CI 1.12-2.68), gestational diabetes (aRR 3.41, 95% CI 1.69-6.89), and small-for-gestational-age birth (aRR 2.08, 95% CI 1.26-3.45). In general, RRs were higher among women with AIP who had high lifetime U-PBG levels. Our study shows an increased risk for pregnancy induced hypertensive disease, gestational diabetes, and small for gestational age births for AHP women, with higher relative risks for women with biochemically active AIP. No increased risk for perinatal death or malformations was observed.

Risk for incident comorbidities, nonhepatic cancer and mortality in acute hepatic porphyria: A matched cohort study in 1244 individuals.

The acute hepatic porphyrias (AHP) are associated with long-term complications such as primary liver cancer, hypertension, and chronic kidney disease. Data on other related comorbidities are scarce. In this register-based, matched cohort study, we assessed the risks of nonhepatic cancers, cardiovascular diseases, renal diseases, psychiatric disorders, and mortality in relation to porphyria type, sex, and biochemical disease activity. All patients in the Swedish porphyria register with a verified AHP diagnosis during 1987-2015 were included. The biochemical activity of acute intermittent porphyria was assessed using recorded maximal urinary porphobilinogen (U-PBG). Data on incident comorbidities and mortality were collected from national health registries. Cumulative incidences, rates, and hazards were compared to reference individuals from the general population, matched 1:10 by age, sex, and county. We identified 1244 patients with AHP with a median follow-up of 19 years. Health registries identified 149 AHP-subjects (12.0%) with nonhepatic cancer, similar to 1601 (13.0%) in the matched reference population (n = 12 362). Patients with AHP had a higher risk of kidney cancer (0.8% vs. 0.2%, p < 0.001), hypertension, and chronic kidney disease but no increase in risk for cardiovascular disease, except for cerebrovascular disease in patients with elevated U-PBG, (aHR = 1.40 [95% CI:1.06-1.85]). Mortality risk during follow-up was higher among patients with AHP (21% vs. 18%, p = 0.001), and associated with primary liver cancer, female sex, and biochemical activity. In conclusion, AHP is associated with an increased risk of kidney cancer, hypertension, chronic kidney disease, and mortality but not with cardiovascular disease or other nonhepatic cancers.

Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients.

Acute intermittent porphyria (AIP) is a rare hereditary metabolic disease characterized by acute attacks and accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP have a high risk of primary liver cancer (PLC). We aimed to assess the association between porphyrin precursor excretion and the risk for PLC in patients with AIP. We studied 48 patients with AIP who developed PLC between 1987 and 2015 and 140 age and sex matched controls with AIP but no PLC. Data on all available urinary PBG and ALA samples collected from 1975 until 1 year before PLC diagnosis were analyzed and compared between cases and controls using logistic regression. Porphyrin precursor excretion was higher in patients with PLC (PBG median 7.9 [IQR 4.4-21.9] mmol/mol creatinine) than in controls (3.8 [1.2-9.8]) (adjusted odds ratio 1.07, 95% confidence interval: 1.02-1.12). None of the 28 patients with all registered samples below the upper limit of normal (ULN) developed PLC, and only one of the 45 patients with all samples <2× ULN developed PLC. Among non-PLC controls, ALA and PBG levels decreased after age 50-60 while an increasing trend was observed after age 65 among those who developed PLC. Increased urinary porphyrin precursors are associated with a high risk of developing PLC. Patients with normal levels appear to have a low risk while high or increasing ALA and PBG after age 65 indicates high risk, which should be considered in surveillance decisions.

Clinical outcomes and sick leave in relation to UDCA treatment in Swedish patients with primary biliary cholangitis.

OBJECTIVES: Primary biliary cholangitis (PBC) is an autoimmune liver disease that may progress into liver cirrhosis. Ursodeoxycholic acid (UDCA) is known to prevent or delay the disease progression, but little is known about work incapacity in PBC patients. We aimed to compare clinical outcomes (transplantation-free survival; cirrhosis development) and sick leave in patients with PBC with and without UDCA therapy. METHODS: The medical records of 526 patients with PBC diagnosed from 2004 to 2016 were reviewed retrospectively. Sick leave data retrieved from the Swedish Social Insurance Agency were analysed for a sub-cohort of patients and matched controls. Cox regression was used for analysis of clinical outcomes. Logistic and conditional logistic regressions were used for sick leave analysis. RESULTS: A total of 10.6% of patients died and 3.4% received liver transplantation over a median follow-up time of 5.7 years. UDCA-untreated patients (HR 3.62 (95%CI 2.02-6.49)) and UDCA non-responders (HR 3.78 (95% CI 1.87-7.66)) had higher mortality or transplantation rates than UDCA responders. Patients with PBC had higher odds of sick leave (OR 2.50; 95% CI 1.69-3.70) than matched controls. Untreated patients were more likely to be on sick leave (OR 3.22; 95% CI 1.12-9.25) two years after diagnosis than UDCA responders. CONCLUSION: Both untreated patients and UDCA non-responders had lower liver transplantation-free survival rates than UDCA responders. Patients with PBC were more likely to be on sick leave compared to matched controls from the general population.

Risk of primary liver cancer in acute hepatic porphyria patients: A matched cohort study of 1244 individuals.

BACKGROUND: The acute hepatic porphyrias (AHP) are associated with a risk of primary liver cancer (PLC), but risk estimates are unclear, and what AHP characteristics that predict PLC risk are unknown. In this register-based, matched cohort study, we assessed the PLC risk in relation to biochemical and clinical porphyria severity, genotype, age, and sex. METHODS: All patients in the Swedish porphyria register with acute intermittent porphyria (AIP), variegate porphyria (VP), or hereditary coproporphyria (HCP) during 1987-2015 were included. This AHP cohort was compared with age-, sex-, and county-matched reference individuals from the general population. National register-based hospital admissions for AHP were used to indicate the clinical severity. For AIP, the most common AHP type, patients were stratified by genotype and urinary porphobilinogen (U-PBG). Incident PLC data were collected from national health registers. RESULTS: We identified 1244 individuals with AHP (1063 [85%] AIP). During a median follow-up of 19.5 years, we identified 108 incident PLC cases, including 83 AHP patients (6.7%) and 25 of 12,333 reference individuals (0.2%). The adjusted hazard ratio for AHP-PLC was 38.0 (95% confidence interval: 24.3-59.3). Previously elevated U-PBG and hospitalizations for porphyria, but not AIP genotype or sex, were associated with increased PLC risk. Patients aged >50 years with previously elevated U-PBG (n = 157) had an annual PLC incidence of 1.8%. CONCLUSION: This study confirmed a high PLC risk and identified a strong association with clinical and biochemical AIP activity. Regular PLC surveillance is motivated in patients older than 50 years with a history of active AIP.

SARS-CoV-2 vaccination and risk of severe COVID-19 outcomes in patients with autoimmune hepatitis.

BACKGROUND: Data regarding outcome of Coronavirus disease 2019 (COVID-19) in vaccinated patients with autoimmune hepatitis (AIH) are lacking. We evaluated the outcome of COVID-19 in AIH patients who received at least one dose of Pfizer- BioNTech (BNT162b2), Moderna (mRNA-1273) or AstraZeneca (ChAdOx1-S) vaccine. PATIENTS AND METHODS: We performed a retrospective study on AIH patients with COVID-19. The outcomes of AIH patients who had acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection after at least one dose of COVID-19 vaccine were compared to unvaccinated patients with AIH. COVID-19 outcome was classified according to clinical state during the disease course as: (i) no hospitalization, (ii) hospitalization without oxygen supplementation, (iii) hospitalization with oxygen supplementation by nasal cannula or mask, (iv) intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v) ICU admission with invasive mechanical ventilation or (vi) death, and data was analyzed using ordinal logistic regression. RESULTS: We included 413 (258 unvaccinated and 155 vaccinated) patients (81%, female) with a median age of 52 (range: 17-85) years at COVID-19 diagnosis. The rates of hospitalization were (36.4% vs. 14.2%), need for any supplemental oxygen (29.5% vs. 9%) and mortality (7% vs. 0.6%) in unvaccinated and vaccinated AIH patients with COVID-19. Having received at least one dose of SARS-CoV-2 vaccine was associated with a significantly lower risk of worse COVID-19 severity, after adjusting for age, sex, comorbidities and presence of cirrhosis (adjusted odds ratio [aOR] 0.18, 95% confidence interval [CI], 0.10-0.31). Overall, vaccination against SARS-CoV-2 was associated with a significantly lower risk of mortality from COVID-19 (aOR 0.20, 95% CI 0.11-0.35). CONCLUSIONS: SARS-CoV-2 vaccination significantly reduced the risk of COVID-19 severity and mortality in patients with AIH.

Outcome of COVID-19 in Patients With Autoimmune Hepatitis: An International Multicenter Study.

BACKGROUND AND AIMS: Data regarding outcome of COVID-19 in patients with autoimmune hepatitis (AIH) are lacking. APPROACH AND RESULTS: We performed a retrospective study on patients with AIH and COVID-19 from 34 centers in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes, defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity score-matched cohort of patients without AIH but with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase > 2 × the upper limit of normal) during COVID-19 was also evaluated. We included 110 patients with AIH (80% female) with a median age of 49 (range, 18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (P = 0.041; OR, 3.36; 95% CI, 1.05-10.78), while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (P = 0.009; OR, 0.26; 95% CI, 0.09-0.71). The rates of severe COVID-19 (15.5% versus 20.2%, P = 0.231) and all-cause mortality (10% versus 11.5%, P = 0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (P < 0.001; OR, 17.46; 95% CI, 4.22-72.13). Continuation of immunosuppression or presence of liver injury during COVID-19 was not associated with severe COVID-19. CONCLUSIONS: This international, multicenter study reveals that patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID-19 in patients with AIH. Maintenance of immunosuppression during COVID-19 was not associated with increased risk for severe COVID-19 but did lower the risk for new-onset liver injury during COVID-19.

Hepatocellular carcinoma in Stockholm, Sweden 2003-2018: a population-based cohort study.

BACKGROUND AND AIMS: Available epidemiological data on hepatocellular carcinoma (HCC) originate mainly from centre-based or disease-specific cohorts and may not reflect the general population. This population-based register study presents the incidence, aetiologies, treatments, survival, and differences related to sex or socioeconomic status in patients with HCC from Stockholm, which constitutes more than a fifth of the Swedish population. METHODS: ICD-10 codes identified incident HCC cases in the regional administrative health care database 2003-2018. Administrative coding on diseases, socioeconomic status, and dispensed drugs were used to identify risk factors and therapies. Two validation analyses 2014-2015 studied the correctness of register-based aetiologies and reasons for providing only best supportive care (BSC). RESULTS: We identified 2,245 incident cases of HCC. The incidence increased from 6 to 7.5 per 100,000 inhabitants over the time-period. The most common aetiologies were hepatitis C (26%), non-alcoholic fatty liver disease (22%), and alcohol-related liver disease (19%). Five-year survival probability was 79% after liver transplantation, 60% after resection, and 35% after ablation but <10% for chemoembolization, Sorafenib, and BSC. The proportion receiving any treatment increased but half of the patients only received BSC. At least 14% of potentially treatable HCC (surveillance indicated but not performed) received only BSC 2014-2015. We found no significant differences in treatments or outcomes between socioeconomic groups. CONCLUSIONS: The incidence of HCC is rising in Stockholm, Sweden but is still low by global comparison. Near half of all patients still receive only BSC and study data suggest that surveillance practices are incomplete.

Liver Transplantation for Acute Intermittent Porphyria.

Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18-58), and 34 (89%) of the patients were women. A total of 9 patients died during follow-up, and 2 patients were retransplanted. The 1-year and 5-year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5-year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy (P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.

Extrahepatic autoimmune diseases in primary biliary cholangitis: Prevalence and significance for clinical presentation and disease outcome.

BACKGROUND AND AIM: The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). METHODS: The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. RESULTS: A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5% vs 86.1%, P < 0.001) and seropositive for anti-mitochondrial antibodies (88% vs 84%, P = 0.05) and antinuclear antibodies and/or smooth muscle antibodies (53.8% vs 43.6%, P = 0.005). At presentation, patients with EHAIDs had significantly lower levels of alkaline phosphatase (1.76 vs 1.98 × upper limit of normal [ULN], P = 0.006), aspartate aminotransferase (1.29 vs 1.50 × ULN, P < 0.001), and total bilirubin (0.53 vs 0.58 × ULN, P = 0.002). Patients with EHAIDs and without EHAIDs had similar rates of GLOBE high-risk status (12.3% vs 16.1%, P = 0.07) and Paris II response (71.4% vs 69.4%, P = 0.59). Overall, event-free survival was not different in patients with and without EHAIDs (90.8% vs 90.7%, P = 0.53, log rank). Coexistence of each autoimmune thyroid diseases (10.6%), Sjögren disease (8.3%), systemic sclerosis (2.9%), rheumatoid arthritis (2.7%), systemic lupus erythematosus (1.7%), celiac disease (1.7%), psoriasis (1.5%), and inflammatory bowel diseases (1.3%) did not influence the outcome. CONCLUSIONS: Our study confirms that EHAIDs are frequently diagnosed in patients with PBC. The presence of EHAIDs may influence the clinical phenotype of PBC at presentation but has no impact on PBC outcome.

Validation of Risk Scoring Systems in Ursodeoxycholic Acid-Treated Patients With Primary Biliary Cholangitis.

INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.

Hepatocellular carcinoma in acute hepatic porphyrias: A Damocles Sword.

Porphyrias are inherited diseases with low penetrance affecting the heme biosynthesis pathway. Acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP) together constitute the acute hepatic porphyrias (AHP). These diseases have been identified as risk factors for primary liver cancers (PLC), mainly hepatocellular carcinoma (HCC: range 87-100%) but also cholangiocarcinoma, alone or combination with HCC. In AHP, HCC annual incidence rates range from 0.16 to 0.35% according to the populations studied. Annual incidence rates are higher in Swedish and Norwegian patients, due to a founder effect. It increases above age 50. The pathophysiology could include both direct toxic effects of heme precursors, particularly δ-aminolevulinic acid (ALA), compound heterozygosity for genes implied in heme biosynthesis pathway or the loss of oxidative stress homeostasis due to a relative lack of heme. The high HCC incidence justifies radiological surveillance in AHP patients above age 50. Efforts are made to find new biological non-invasive markers. In this respect, we describe here the first report of PIVKA-II clinical utility in the follow-up of an AIP patient that develop an HCC. In this manuscript we reviewed the epidemiology, the physiopathology, and the screening strategy of HCC in AHP.

Characteristics and outcome of hepatocellular carcinoma in patients with NAFLD without cirrhosis.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is a growing cause of hepatocellular carcinoma (HCC). In NAFLD, HCC occurs more commonly in the absence of cirrhosis compared with other liver diseases; yet, patients with non-cirrhotic NAFLD-HCC are poorly characterized. Here, we characterized a large cohort of HCC cases and assessed the outcomes of patients with non-cirrhotic NAFLD-HCC. METHODS: We identified all cases of HCC treated at the Karolinska University Hospital, Stockholm, Sweden from 2004 to 2017. Patient charts were manually reviewed for variable extraction. Cases were followed passively for all-cause and HCC-related mortality until the end of April 2018. Cox regression was performed to estimate mortality rates and identify mortality risk factors in patients with non-cirrhotic NAFLD-HCC. RESULTS: Totally, 1562 cases with HCC were identified. Of these, 225 (14.4%) had NAFLD-HCC, of which 83 (37%) did not have cirrhosis. Compared with patients with cirrhotic NAFLD-HCC, patients with non-cirrhotic NAFLD-HCC were older (74 vs 70 years, P < 0.001), had a lower prevalence of type 2 diabetes (T2DM) (66% vs 80%, P = 0.02), larger tumours, less frequently underwent liver transplantation (0% vs 11%, P = 0.002), but more frequently underwent resection (35% vs 8%, P < 0.001). Mortality was similar (aHR for non-cirrhotic NAFLD-HCC vs cirrhotic NAFLD-HCC 0.93, 95% CI 0.58-1.51, P = 0.78). Parameters independently associated with increased mortality included the Barcelona Clinic Liver Cancer stage, number of tumours, lower albumin and presence of T2DM. CONCLUSIONS: Patients with non-cirrhotic NAFLD-HCC differ from those with cirrhosis in age, tumour size and allocated treatments. Despite these differences, survival is similar.

Comparison of lipiodol infusion and drug-eluting beads transarterial chemoembolization of hepatocellular carcinoma in a real-life setting.

Aim: Doxorubicin-eluting beads transarterial chemoembolization (DEB-TACE) is reported to improve survival and tolerability when compared with conventional lipiodol-TACE (cTACE) for the treatment of hepatocellular carcinoma (HCC). The aim of this study was to evaluate tolerability and long-term survival in patients treated with cTACE or DEB-TACE in a real-life setting. Methods: Incidence of adverse events and overall survival in HCC patients treated with either cTACE or DEB-TACE at Karolinska University Hospital 2004-2012 were analyzed retrospectively. Median follow-up was 7.1 years. Patients were censored when transplanted or at the end of follow-up. Patients receiving both cTACE and DEB-TACE, or treated with resection or ablation post-TACE were excluded from the survival analysis. Results: A total of 202 patients (76 cTACE and 126 DEB-TACE) were eligible for analysis of adverse events, and 179 patients (69 cTACE and 110 DEB-TACE) were included in the survival analysis. cTACE patients were younger and had fewer tumors but higher BCLC stage than DEB-TACE. Child-Pugh and ECOG performance status were similar between groups. Adverse events (abdominal pain, nausea and vomiting, fever, fatigue) were significantly less common in the DEB-TACE group. Median survival was 17.1 months in the cTACE group and 19.1 months in the DEB-TACE (NS). In multivariate Cox regression analysis, portal vein thrombosis and tumor size were associated with increased, and sorafenib treatment post-TACE with decreased mortality. Conclusion: In this retrospective real-life analysis, DEB-TACE had better tolerability compared to cTACE, but overall survival did not differ between the two treatments. Portal vein thrombosis, tumor size and sorafenib treatment after TACE influence survival.

Tacrolimus and Mycophenolate Mofetil as Second-Line Therapies for Pediatric Patients with Autoimmune Hepatitis.

BACKGROUND: We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine). PATIENTS AND METHODS: We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months (range 8-182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy. RESULTS: Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal. CONCLUSIONS: Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy.

Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis.

BACKGROUND & AIMS: Predniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. METHODS: We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS: Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

Treatment Response and Outcome with Two Different Prednisolone Regimens in Autoimmune Hepatitis.

BACKGROUND: Beyond available guidelines, therapy of autoimmune hepatitis (AIH) shows wide variation among physicians. We compared two regimens for treatment naive AIH: one recommended protocol with an initial prednisolone dose of 30 mg/day and our own 40 mg/day prednisolone with a slow dose tapering protocol. We analyzed the safety, response rates, and outcomes for two groups of treated patients. PATIENTS AND METHODS: We retrospectively evaluated data of 71 AIH patients including, group I (n = 32, prednisone 30 mg/day) and group II (n = 39, prednisone 40 mg/day). All patients also received azathioprine. RESULTS: The frequency of complete biochemical response was significantly higher in group II than in group I (69.2 vs. 43.8%, p = 0.031) after 3 months of therapy, but not after 6 and 12 months (79.5 vs. 59.4%, p = 0.065 and 89.5 vs. 80.6%, p = 0.30). In patients with severe interface hepatitis, the complete response rates were significantly higher in group II than in group I after 3 (63.6 vs. 23.1%, p = 0.02) and 6 months (72.7 vs. 38.5%, p = 0.046), but not after 12 months of therapy (86.4 vs. 69.2%, p = 0.221). Relapses were observed in 50% of group I and in 35.9% of group II during maintenance therapy (p = 0.23). Overall survival was significantly better in group II than in group I (100 vs. 87.5%, log-rank, p = 0.048). No severe steroid-related side effects were observed in either group. CONCLUSIONS: Our real-world experience suggests that an initial prednisolone dose of 40 mg/day with a slower tapering protocol induces earlier biochemical response, tends to result in less relapses during maintenance, and is associated with a better disease outcome.