Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. METHODS: The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. DISCUSSION: This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021.

Health-related quality of life in patients with primary sclerosing cholangitis: A longitudinal population-based cohort study.

BACKGROUND & AIMS: Data regarding health-related quality of life (HRQoL) in primary sclerosing cholangitis (PSC) are sparse and have only been studied cross-sectionally in a disease which runs a fluctuating and unpredictable course. We aim to describe HRQoL longitudinally by using repeated measurements in a population-based cohort. METHODS: Every 3 months from May 2017 up to August 2020, patients received digital questionnaires at home. These included the EQ-5D, 5-D Itch, patient-based SCCAI and patient-based HBI. The SF-36, measuring HRQoL over eight dimensions as well as a physical component summary (PCS) and mental component summary (MCS) score, was sent annually. Data were compared with Dutch reference data and a matched IBD disease control from the population-based POBASIC cohort. Mixed-effects modelling was performed to identify factors associated with HRQoL. RESULTS: Three hundred twenty-eight patients completed 2576 questionnaires. A significant reduction of small clinical relevance in several mean HRQoL scores was found compared with the Dutch reference population: 46.4 versus 48.0, p = .018 for PCS and 47.5 versus 50.5, p = .004 for MCS scores. HRQoL outcomes were significantly negatively associated with coexisting active IBD (PCS -12.2, p < .001 and MCS -12.0, p < .001), which was not the case in case of quiescent IBD. Decreasing HRQoL scores were also negatively associated with increasing age (PCS -0.1 per 10 years, p = .002), female sex (PCS -2.8, p < .001), diagnosis of AIH overlap (PCS -3.7, p = .059), end-stage liver disease (PCS -3.7, p = .015) and presence of itch (PCS -9.2, p < .001 and MCS -3.1, p = .078). The odds of reporting a clinically relevant reduction in EQ-5D scores showed seasonal variation, being lowest in summer (OR = 0.48 relative to spring, p = .037). In patients with liver transplant, HRQoL outcomes were comparable to the Dutch general population. CONCLUSIONS: PSC patients report impaired HRQoL of small clinical relevance compared with the general population. After liver transplantation, HRQoL scores are at comparable levels to the general population. HRQoL scores are associated with potentially modifiable factors such as itch and IBD activity.

Assessing the efficacy and safety of mycophenolate mofetil versus azathioprine in patients with autoimmune hepatitis (CAMARO trial): study protocol for a randomised controlled trial.

BACKGROUND: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. METHODS: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. DISCUSSION: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. TRIAL REGISTRATION: EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016.

Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid.

: In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal Fgf15 mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.

Stress test of liver function using technetium-99m-mebrofenin hepatobiliary scintigraphy.

Technetium-99m (Tc) mebrofenin hepatobiliary scintigraphy (HBS) enables a quantitative assessment of liver function. This is normally performed in a fasting state and might therefore reflect the resting liver function. We evaluated the change in liver function using HBS after stimulation with an oral metabolic challenge. Healthy volunteers aged 50-60 (n=12) or older than or equal to 75 (n=12) years underwent two sequential HBS. The first scan was performed after an overnight fast and the second scan was performed after the administration of chocolate milk. Hepatic Tc-mebrofenin uptake rate (cMUR) was calculated and the difference was expressed as percentage. cMUR after fasting was 10.9±2.5%/min/m (mean±SD) and increased by 20% to 13.0±3.1%/min/m after stimulation with chocolate milk (P<0.001). cMUR increased markedly after the administration of an oral metabolic challenge in comparison with fasting. This may be a consequence of hepatocyte stimulation, reflecting the hepatic functional reserve capacity.

PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma.

Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8+ lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 (p < 0.001), Galectin-9 (p < 0.001) and HVEM (p < 0.001), and low CD8+TIL count (p = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8+TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; p <0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8+TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8+TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality.

Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion.

Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of cholesterol degradation pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4 weeks of treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a 4-fold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease.

The Long-Term Impact of Autoimmune Pancreatitis on Pancreatic Function, Quality of Life, and Life Expectancy.

OBJECTIVE: To evaluate the long-term outcome of autoimmune pancreatitis. METHODS: Patients with at least 2 years of follow-up were included. Information was collected regarding disease characteristics, treatment outcome, diagnosed malignancies, and mortality. In addition, pancreatic function and quality of life were assessed prospectively. RESULTS: 107 patients were included (87% men, 90% with type 1), with a median follow-up of 74 (interquartile range, 49-108) months. One third was operated for suspected pancreatic cancer (32%). Most patients were (successfully) treated with steroids (83%), but relapses were common (52%), for which no risk factors could be identified. Pancreatic carcinoma was not observed.Prospective data were obtained from 64%, as 17% had died, 7% were lost to follow-up, and 13% refused to participate. After a median of 75 (interquartile range, 50-106) months, 46% still used active treatment. Exocrine and endocrine insufficiencies were highly prevalent (82% and 57%, respectively). Quality of life and survival were not impaired, as compared with a reference population. CONCLUSIONS: Despite an excellent initial treatment response, relapses are common, even in type 2, and almost half of the patients require maintenance therapy. Pancreatic insufficiency is highly prevalent, which calls for active screening. Pancreatic cancer was not observed, and quality of life and survival are not impaired.

[A child with primary sclerosing cholangitis]. / Een kind met primaire scleroserende cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a rare liver disease which is mainly diagnosed in adults. This chronic progressive disease, characterised by inflammation, fibrosis and strictures of the intra- and extrahepatic bile ducts, leads to cirrhosis. There is a strong association between primary sclerosing cholangitis and inflammatory bowel disease (IBD). CASE DESCRIPTION: A 10-year-old boy presented at the accident and emergency department with fever, episodes of abdominal pain, nausea, vomiting, fatigue and hepatomegaly. Blood tests, pathology investigations, liver biopsy and magnetic resonance cholangiopancreatography (MRCP) led to the diagnosis of primary sclerosing cholangitis. The patient was treated with ursodeoxycholic acid and later, because of unbearable itching, sequentially with lidocaine 3% ointment, rifampicin, an endoprosthesis in the common bile duct and glucocorticoids. One year later he returned to the paediatrician with abdominal pain and bloody diarrhoea. Endoscopy revealed features of indeterminate colitis. Remission of the disease was achieved quickly after treatment with mesalazine. CONCLUSION: Primary sclerosing cholangitis can develop in childhood and is often associated with IBD.

Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands.

BACKGROUND AND AIMS: Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). METHODS: Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. RESULTS: The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3-19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5-2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1-44 years). Familial occurrence was reported in three cases. CONCLUSION: This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH.

A comparative study of diagnostic scoring systems for autoimmune pancreatitis.

OBJECTIVE: Several diagnostic scoring systems for autoimmune pancreatitis (AIP) have been proposed including the Asian, HISORt (Histology, Imaging, Serology, Other organ involvement and Response to therapy), and International Consensus Diagnostic Criteria (ICDC), which have been compared by a few studies. We evaluated the diagnostic performance of these criteria in patients diagnosed with AIP between May 1992 and August 2011. METHODS: Scoring systems were applied retrospectively using data obtained in the initial evaluation period, before pancreatic resection was performed. RESULTS: One hundred fourteen cases with AIP were included. Eighty-two percent met the diagnostic criteria for AIP according to either the Asian, HISORt, or ICDC criteria. Only 33% met the Asian criteria, probably mainly related to a low rate of diagnostic pancreatography. In 18%, all scoring systems failed to confirm the diagnosis, even though these patients were considered to have a firm diagnosis of AIP. CONCLUSIONS: In this cohort of AIP patients, the 3 major diagnostic scoring systems for AIP proved to be complementary rather than overlapping. Our data indicate that one-fifth of our AIP patients do not meet any of these scoring systems. The ICDC, Asian, and HISORt criteria should be considered as useful clinical tools but not as criterion standard for the diagnosis.

Comparable efficacy of low- versus high-dose induction corticosteroid treatment in autoimmune pancreatitis.

OBJECTIVE: The objective of this study was to compare efficacy of high versus low doses of prednisone for induction of remission in autoimmune pancreatitis (AIP). METHODS: This is a retrospective, multicenter study including patients diagnosed with AIP between May 1992 and August 2011. Clinical, laboratory and imaging findings were assessed before treatment and at 1, 3, and 6 months after starting treatment. RESULTS: A total of 65 patients (57 males; median age, 63 years) were treated with an initial low dose (10-20 mg/d, n = 14), a medium dose (30 mg/d, n = 15), or a high dose (40-60 mg/d, n = 36) of prednisone. There were no significant differences in baseline characteristics between the treatment groups including age, presenting symptoms and laboratory results. During a follow-up period of 6 months, in nearly all patients, symptoms (jaundice, weight loss) resolved completely. After 6 months, treatment response with respect to symptomatic, radiological, and laboratory improvement was comparable for the different dosage groups. CONCLUSIONS: Response to therapy was comparable for AIP patients treated with doses of prednisone in the range of 10 to 60 mg/d. A prospective trial should be conducted to confirm efficacy of lower-dose prednisone treatment.

Management of giant liver hemangiomas: an update.

Liver hemangiomas are the most common benign liver tumors and are usually incidental findings. Liver hemangiomas are readily demonstrated by abdominal ultrasonography, computed tomography or magnetic resonance imaging. Giant liver hemangiomas are defined by a diameter larger than 5 cm. In patients with a giant liver hemangioma, observation is justified in the absence of symptoms. Surgical resection is indicated in patients with abdominal (mechanical) complaints or complications, or when diagnosis remains inconclusive. Enucleation is the preferred surgical method, according to existing literature and our own experience. Spontaneous or traumatic rupture of a giant hepatic hemangioma is rare, however, the mortality rate is high (36-39%). An uncommon complication of a giant hemangioma is disseminated intravascular coagulation (Kasabach-Merritt syndrome); intervention is then required. Herein, the authors provide a literature update of the current evidence concerning the management of giant hepatic hemangiomas. In addition, the authors assessed treatment strategies and outcomes in a series of patients with giant liver hemangiomas managed in our department.

[Giant haemangioma of the liver: diagnosis and treatment]. / Het reuzenhemangioom in de lever: diagnostiek en behandeling.

A liver haemangioma is a benign, usually small tumour comprised of blood vessels, which is often discovered coincidentally; giant haemangiomas are defined as haemangiomas larger than 5 cm. The differential diagnosis includes other hypervascular tumours, such as hepatocellular adenoma, hepatocellular carcinoma, metastasis of a neuro-endocrine tumour or renal cell carcinoma.- The diagnosis is based on abdominal ultrasonography and can be confirmed by a CT or MR scan. A wait-and-see approach is justified in patients without symptoms or with minimal symptoms, even in the presence of a giant haemangioma. Surgical resection of a giant haemangioma is only necessary when the preoperative diagnosis is inconclusive, or when the haemangioma leads to mechanical symptoms or complications. Extirpation is the only effective form of treatment of the giant haemangioma; enucleation is preferred over partial liver resection. A known complication of a giant haemangioma is the occurrence of disseminated intravascular coagulation, the Kasabach-Merritt syndrome; intervention is then demanded.

Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial.

AIMS: A randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD). METHODS AND RESULTS: Thirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28. The other efficacy endpoints were per cent change in apoB and lipoprotein a [Lp(a)]. Safety was determined using the incidence of treatment-emergent adverse events (AEs) and clinical laboratory evaluations. After 26 weeks of mipomersen administration, LDL-c was reduced by 47 ± 18% (P < 0.001 vs. placebo). apoB and Lp(a) were also significantly reduced by 46 and 27%, respectively (P < 0.001 vs. placebo). Four mipomersen (19%) and two placebo subjects (17%) discontinued dosing prematurely due to AEs. Persistent liver transaminase increases ≥ 3× the upper limit of normal were observed in seven (33%) subjects assigned to mipomersen. In selected subjects, liver fat content was assessed, during and after treatment, using magnetic resonance spectroscopy. Liver fat content in these patients ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis. CONCLUSION: The present data suggest that mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD. The long-term follow-up of liver safety is required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00707746.