Summary
Background
High‐quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based.
Aim
...To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH.
Methods
A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH.
Results
Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S‐methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult‐to‐treat patients, mycophenolate mofetil is the most widely used second‐line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres.
Conclusions
There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second‐line therapies. Future prospective studies should address these issues, so that we move from an expert‐ to an evidence‐ and personalised‐based care in autoimmune hepatitis.
Linked ContentThis article is linked to Shen et al and de Boer et al papers. To view these articles visit https://doi.org/10.1111/apt.14630 and https://doi.org/10.1111/apt.14651.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Ten percent of patients with autoimmune hepatitis (AIH) are nonresponsive or intolerant to thiopurine therapy. A skewed metabolism, leading to the preferential generation of ...(hepato)toxic thiopurine metabolites (6‐MMPs) instead of the metabolic active 6‐tioguanine (thioguanine) nucleotides (6‐TGNs), may explain this unfavourable outcome. Co‐administration of allopurinol to low‐dose thiopurine therapy may effectively revert this deviant metabolism, as has been shown in inflammatory bowel disease.
Aim
To describe the effect of adding allopurinol to low‐dose thiopurine therapy in patients with AIH with intolerance or nonresponse to normal thiopurine dosages due to a skewed metabolism.
Methods
We describe the clinical efficacy and tolerability of allopurinol–thiopurine combination therapy with allopurinol 100 mg and low‐dose thiopurine (25–33% of the original dosage) in eight AIH patients with a skewed thiopurine metabolism. Patients were switched because of dose‐limiting intolerance (n = 3), nonresponse (n = 3) or loss of response (n = 2) to conventional thiopurine treatment.
Results
All eight patients showed biochemical improvement with a reduction in median alanine aminotransferase (ALT) levels of 62 U/L at start to 35 U/L at 1 month (P = 0.03). This clinical benefit was sustained in seven patients. Allopurinol–thiopurine combination therapy effectively bypassed thiopurine side effects in four of five patients. Median 6‐tioguanine nucleotides levels increased from 100 to 200 pmol/8 × 108 red blood cells (RBC) at 3 months (P = 0.04). Median 6‐MMP levels decreased in all patients from 6090 to 175 pmol/8 × 108 RBC (P = 0.01).
Conclusion
Allopurinol safely and effectively optimises thiopurine therapy in patients with autoimmune hepatitis with intolerance and/or nonresponse due to an unfavourable thiopurine metabolism.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The novel tridentate PNNOH pincer ligand L H features a reactive 2-hydroxypyridine functionality as well as a bipyridyl-methylphosphine skeleton for meridional coordination. This proton-responsive ...ligand coordinates in a straightforward manner to RuCl(CO)(H)(PPh3)3 to generate complex 1. The methoxy-protected analogue L Me was also coordinated to Ru(II) for comparison. Both species have been crystallographically characterized. Site-selective deprotonation of the 2-hydroxypyridine functionality to give 1′ was achieved using both mild (DBU) and strong bases (KOtBu and KHMDS), with no sign of involvement of the phosphinomethyl side arm that was previously established as the reactive fragment. Complex 1′ is catalytically active in the dehydrogenation of formic acid to generate CO-free hydrogen in three consecutive runs as well as for the dehydrogenative coupling of alcohols, giving high conversions to different esters and outperforming structurally related PNN ligands lacking the NOH fragment. DFT calculations suggest more favorable release of H2 through reversible reactivity of the hydroxypyridine functionality relative to the phosphinomethyl side arm.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
In this research, we model the color of optically dense colloidal dispersions of dyed and undyed zein particles using results from multiple light scattering theory. These particles, as well as ...monodisperse silica colloids, were synthesized and characterized to obtain particle properties such as particle size, particle size distribution, refractive index, and absorption spectrum of the dye. This information was used to model the diffuse transmission of concentrated particle dispersions, which was measured using a specially designed variable path length quartz glass cuvette. For the nonabsorbing silica dispersions, a transport mean-free path throughout the visible range was obtained. Results showed a difference of less than 5% from the values calculated with a multiple scattering model using the single-particle properties as an input. For undyed zein particles, which are off-white, the deviation between the model and the experiment was about 30% because of slight absorption at wavelengths below 550 nm but <7% at higher wavelengths. From these results, it was concluded that the model correctly describes diffuse transmission and that the measurements are sensitive to absorption. Finally, this method was applied to dispersions of dyed zein particles. Here, the transport mean-free path was first determined for wavelengths at which there is no absorption, which agreed with the theory better than 4%. The modeled transport mean-free path was then used to extract the reciprocal absorption mean-free path in the remaining parts of the visible spectrum, and a reasonable agreement with the absorption spectrum of the dye solution was obtained.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Linked Content
This article is linked to Liberal et al and Shen et al papers. To view these articles visit https://doi.org/10.1111/apt.13907 and https://doi.org/10.1111/apt.14630.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we ...imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background & Aims: Lynch syndrome family members have a high risk of developing colorectal (CRC), endometrial (EC), and other cancers. A large-scale surveillance program was introduced in The ...Netherlands in the late 1980s. The aims of the study were to evaluate the effectiveness of this program by assessing mortality because of CRC and EC before and after 1990 and to compare mortality because of all cancers (except CRC/EC) with mortality in the general population. Methods: Family members with at least 50% probability of being a carrier were selected for the study. The standardized mortality ratio (SMR) because of cancer and the absolute excess risk of death (AER) were calculated. Results: In the total cohort (N = 2788), 445 subjects had died because of cancer. The 3 most frequent causes of cancer-related deaths were CRC (50.3%), EC (6.7%), and brain tumors (6.7%). A significant decrease (70%) in SMR for CRC over time was observed (P < .001); the SMR for EC showed no decreasing trend over time. A significantly increased SMR was found for cancer of the small bowel (SMR = 18.3), brain (SMR = 9.1), kidney/ureter (SMR = 5.9), ovarium (SMR = 2.3), pancreas (SMR = 2.2), and stomach (SMR = 2.1). The AER was significantly increased for brain tumors only. Conclusions: Since the introduction of surveillance, the mortality because of CRC has decreased. Except for brain tumors, we did not find a significantly increased AER for tumors other than CRC/EC.
Objective
The Psychosocial Assessment Tool (PAT) was developed to screen for psychosocial risk, aimed to be supportive in directing psychosocial care to families of a child with cancer. This study ...aimed to determine (i) the match between PAT risk score and provided psychosocial care with healthcare professionals blind to outcome of PAT assessment, and (ii) the match between PAT risk score and team risk estimation.
Methods
Eighty‐three families of children with cancer from four pediatric oncology centers in the Netherlands participated (59% response rate). The PAT and team risk estimation was assessed at diagnosis (M = 40.2 days, SD = 14.1 days), and the content of provided psychosocial care in the 5‐month period thereafter resulting in basic or specialized care.
Results
According to the PAT, 65% of families were defined as having low (universal), 30% medium (targeted), and 5% high (clinical) risk for developing psychosocial problems. Thirty percent of patients from universal group got basic psychosocial care, 63% got specialized care, and 7% did not get any care. Fourteen percent of the families at risk got basic care, 86% got specialized care. Team risk estimations and PAT risk scores matched with 58% of the families.
Conclusions
This study showed that families at risk, based on standardized risk assessment with the PAT, received more specialized care than families without risk. However, still 14% of the families with high risks only received basic care, and 63% of the families with standard risk got specialized care. Standardized risk assessment can be used as part of comprehensive care delivery, complementing the team.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Display omitted
CD4+ T cells are thought to have a central role in the pathogenesis of autoimmune hepatitis (AIH). Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) directs homing of CD4+ T cells ...in the alimentary tract and is a therapeutic target in inflammatory bowel diseases. Here we assessed MAdCAM-1 expression in AIH and viral hepatitis and related its expression with immune infiltrate analysis and histopathological key features.
Hepatic portal areas of pretreatment biopsies (n=10) and follow-up biopsies (n=9) of patients with a confirmed diagnosis of AIH were assessed for MAdCAM-1 expression and infiltrate composition using immunohistochemistry and multispectral imaging (Vectra® Polaris™). Controls consisted of biopsies of patients with untreated chronic viral hepatitis B or C (n=22).
MAdCAM-1 expression on endothelium was sparsely present in portal fields of two treatment-naïve AIH patients. Three patients showed MAdCAM-1 expression within lymphoid aggregates. No expression of significance (including single-cell expression) was observed in the remaining 6 patients. In contrast, viral hepatitis C biopsies showed endothelial MAdCAM-1 expression in 8 of 13 untreated patients. Densities of both B-cells (CD20+) and CD4+ T-cells (CD3+ CD8-) were increased in AIH and viral hepatitis patients with MAdCAM-1 expression.
MAdCAM-1 was detected in liver biopsies in a minority of patients with AIH at the time of diagnosis suggesting no central role in its pathophysiology. Lymphoid or reticular MAdCAM-1 pattern expression was associated with more dense infiltrates of both B-cells and CD4+ T-cells, and may be related to the formation of secondary lymphoid follicles.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and aims
Juvenile autoimmune liver disease (JAILD) includes paediatric forms of autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC). Since evidence is scarce, there are ...currently no evidence-based management guidelines for juvenile AIH. This survey was carried out amongst the paediatric members of the International AIH Group (IAIHG) to describe their practices in the management of JAILD.
Methods
An online survey questionnaire was distributed to members of the IAIHG with active practice (https://www.surveymonkey.de/r/Juvenile_AILD). The questionnaire consisted of four clinical scenarios on different presentations of AIH.
Results
Fifty-eight surveys were sent to the IAIHG members, out of which 43 (74%, 22 countries, four continents) were returned. None reported budesonide as a first-line induction agent for the acute presentation of AIH. Sixteen (37%) routinely perform liver biopsy at three years of biochemical remission. Thirty-five respondents (81%) perform magnetic resonance cholangiography (MRC) at presentation. Ciclosporin is the most widely used second-line agent (number of patients treated = ∼360, 21 centres). Mycophenolate mofetil (n = ∼225, 31 centres), tacrolimus (n = ∼130, 21 centres) and sirolimus (n = ∼5, 3 centres) are less often reported. Rescue therapy with infliximab and rituximab has been tried in eight centres (n = ∼19) and nine centres (n = ∼16), respectively.
Conclusions
Prednisolone remains the preferred first-line induction agent in JAILD. MRC at presentation is performed by the large majority of participants. Participants reported a wide variation in performing liver biopsy for therapy evaluation during follow-up. Within the paediatric members of the IAIHG there is considerable experience with second-line therapeutic agents.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PDF
