HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

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.

Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in a middle-aged population with overweight and normal liver enzymes, and diagnostic accuracy of noninvasive proxies.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Elevated liver enzymes are a primary reason to refer patients for further testing. However, liver enzymes within the normal range do not exclude the presence of MASLD. We examined the prevalence of MASLD in a middle-aged population with overweight and normal liver enzymes. In addition, we examined the accuracy of 4 sets of noninvasive proxies for MASLD. We included 1017 participants from the Netherlands epidemiology of obesity cohort study with body mass index ≥25 kg/m2 and liver enzymes (asparate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase) within normal range. The diagnostic accuracy of biomarker scores (fatty liver index, liver fat score [LFS], STEATO-ELSA, and hepatic steatosis index) was determined against elevated hepatic triglyceride content measured by 1proton magnetic resonance spectroscopy. Participants (mean age 56 years, 49% women), had a median body mass index of 29.6 kg/m2 and a median hepatic triglyceride content of 4.4%. MASLD was present in 42% of participants and was more common in men than women, with respectively 47% and 36% being affected. The LFS showed the highest accuracy with an area under the curve of 0.72. We identified metabolic syndrome as the prime predictor for MASLD with an odds ratio of 2.95 (95% confidence interval 2.20-3.98). The prevalence of MASLD in middle-aged men and women with overweight and liver enzymes within the normal range is over 40%. LFS showed the highest accuracy to detect MASLD, but, overall, biomarker scores performed relatively poor. The presence of metabolic syndrome was the prime predictor of MASLD.

Thermal ablation combined with transarterial chemoembolization for hepatocellular carcinoma: What is the right treatment sequence?

BACKGROUND: The combination treatment regimen of thermal ablation (TA) and transarterial chemoembolization (TACE) has gained a place in treatment of hepatocellular carcinoma (HCC) lesions > 3 cm unsuitable for surgery. Despite a high heterogeneity in the currently used treatment protocols, the pooled results of combined treatments seem to outperform those of TA or TACE alone. TACE preceding TA has been studied extensively, while results of the reverse treatment sequence are lacking. In this retrospective cohort study we compared the two treatment sequences. PATIENTS AND METHODS: 38 patients (median age: 68.5 yrs (range 40-84), male: 34, liver cirrhosis: 33, early stage HCC: 21, intermediate stage HCC: 17) were included in two tertiary referral centers, of whom 27 were treated with TA and adjuvant TACE (TA + TACE). The other 11 patients received TA with neoadjuvant TACE (TACE + TA). Overall survival (OS), time to progression (TTP) and local tumor progression (LTP) free survival were determined for the entire cohort and compared between the two treatment sequences. RESULTS: The median OS of all patients was 52.7 months and the median time to LTP was 11.5 months (censored for liver transplantation). No differences were found with respect to OS between the two treatment sequences. Median time to LTP for TACE + TA was 23.6 months and 8.1 months for TA + TACE (p = 0.19). DISCUSSION: No statistical differences were found for OS, TTP and time to LTP between patients treated with TA combined with neoadjuvant or adjuvant TACE.

Prevention of hepatic encephalopathy by administration of rifaximin and lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt (TIPS): a multicentre randomised, double blind, placebo controlled trial (PEARL trial).

INTRODUCTION: Cirrhotic patients with portal hypertension can suffer from variceal bleeding or refractory ascites and can benefit from a transjugular intrahepatic portosystemic shunt (TIPS). Post-TIPS hepatic encephalopathy (HE) is a common (20%-54%) and often severe complication. A prophylactic strategy is lacking. METHODS AND ANALYSIS: The Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a TIPS (PEARL) trial, is a multicentre randomised, double blind, placebo controlled trial. Patients undergoing covered TIPS placement are prescribed either rifaximin 550 mg two times per day and lactulose 25 mL two times per day (starting dose) or placebo 550 mg two times per day and lactulose 25 mL two times per day from 72 hours before and until 3 months after TIPS placement. Primary endpoint is the development of overt HE (OHE) within 3 months (according to West Haven criteria). Secondary endpoints include 90-day mortality; development of a second episode of OHE; time to development of episode(s) of OHE; development of minimal HE; molecular changes in peripheral and portal blood samples; quality of life and cost-effectiveness. The total sample size is 238 patients and recruitment period is 3 years in six hospitals in the Netherlands and one in Belgium. ETHICS AND DISSEMINATION: This study protocol was approved in the Netherlands by the Medical Research Ethics Committee of the Academic Medical Centre, Amsterdam (2018-332), in Belgium by the Ethics Committee Research UZ/KU Leuven (S62577) and competent authorities. This study will be conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Study results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov (NCT04073290) and EudraCT database (2018-004323-37).

Quantitative Volumetric Assessment of Ablative Margins in Hepatocellular Carcinoma: Predicting Local Tumor Progression Using Nonrigid Registration Software.

PURPOSE: After radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC), pre- and postinterventional contrast-enhanced CT (CECT) images are usually qualitatively interpreted to determine technical success, by eyeballing. The objective of this study was to evaluate the feasibility of quantitative assessment, using a nonrigid CT-CT coregistration algorithm. MATERIALS AND METHODS: 25 patients treated with RFA for HCC between 2009 and 2014 were retrospectively included. Semiautomated coregistration of pre- and posttreatment CECT was performed independently by two radiologists. In scans with a reliable registration, the tumor and ablation area were delineated to identify the side and size of narrowest RFA margin. In addition, qualitative assessment was performed independently by two other radiologists to determine technical success and the anatomical side and size of narrowest margin. Interobserver agreement rates were determined for both methods, and the outcomes were compared with occurrence of local tumor progression (LTP). RESULTS: CT-CT coregistration was technically feasible in 18/25 patients with almost perfect interobserver agreement for quantitative analysis (κ = 0.88). The interobserver agreement for qualitative RFA margin analysis was κ = 0.64. Using quantitative assessment, negative ablative margins were found in 12/18 patients, with LTP occurring in 8 of these patients. In the remaining 6 patients, quantitative analysis demonstrated complete tumor ablation and no LTP occurred. CONCLUSION: Feasibility of quantitative RFA margin assessment using nonrigid coregistration of pre- and postablation CT is limited, but appears to be a valuable tool in predicting LTP in HCC patients (p=0.013).

Plasma arginine vasopressin and atrial natriuretic peptide concentration in patients with hyponatremia at diagnosis and following treatment.

BACKGROUND: Much evidence for arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) in the pathogenesis of hyponatremia in humans is based on single measurements. To study the roles of AVP and ANP in the pathogenesis and recovery of hyponatremia, sequential measurements of ANP and AVP were taken during treatment in a group of hyponatremic patients with different etiologies. METHODS: Consecutive adult patients with hyponatremia (serum Na <130 mmol/l) and healthy controls were studied. Volume status was determined by clinical and laboratory criteria. Plasma AVP and ANP, fractional sodium excretion, and urine osmolality were determined daily until serum Na was above 135 mmol/l or for at most 7 days. RESULTS: A total of 16 controls and 40 hyponatremic patients (12 normovolemic, 9 hypervolemic, and 19 hypovolemic) were studied. Patients' plasma AVP on the first day [1.0 (0.3-2.3) ng/l] and on the last day [1.1 (0.3-2.5) ng/l] of the study did not differ from that of controls [0.7 (0.5-1.0) ng/l]. Serum sodium concentration increased significantly in patients between the first and the last day. Patients had significantly lower ANP concentrations, both on the first day [25 (15-46) ng/l] and on the last day [29 (17-46) ng/l], than controls [41 (28-51) ng/l]. Plasma AVP was elevated relative to serum osmolality on the first day and to a lesser extent on the last day of the study. CONCLUSIONS: AVP is inappropriately high in a majority of hyponatremic patients. Plasma AVP and ANP concentrations do not change during treatment in hyponatremic patients despite a significant increase in serum osmolality. A low ANP concentration in clinically normovolemic and hypovolemic patients indicates volume depletion, which may lead to baroreceptor-stimulated AVP secretion.

Hyponatremia in intracranial disorders.

Hyponatremia is a common electrolyte disturbance following intracranial disorders. Hyponatremia is of clinical significance as a rapidly decreasing serum sodium concentration as well as rapid correction of chronic hyponatremia may lead to neurological symptoms. Especially two syndromes leading to hyponatremia in intracranial disorders need to be distinguished, as they resemble each other in many, but not all ways. These are the syndrome of inappropriate ADH secretion (SIADH) and the cerebral salt wasting syndrome (CSW). The syndrome of inappropriate ADH secretion is characterized by water retention, caused by inappropriate release of ADH, leading to dilutional hyponatremia. The cerebral salt wasting syndrome on the other hand, represents primary natriuresis, leading to hypovolemia and sodium deficit. SIADH should be treated by fluid restriction, whereas the treatment of CSW consists of sodium and water administration. However, in the literature there is abundant evidence that hyponatremia in intracranial diseases is mostly caused by CSW. Therefore, treatment with fluid and salt supplementation seems indicated in patients with intracranial disorders who develop hyponatremia and natriuresis.

[Invasive infections due to group A beta-haemolytic streptococci in two families]. / Invasieve infecties door beta-hemolytische streptokokken uit groep A binnen twee families.

An invasive beta-haemolytic Lancefield group A streptococcal (GAS) infection was diagnosed in 4 patients: a 70-year-old woman, her 71-year-old husband, a 62-year-old woman and her 43-year-old son. In the married couple the infection was caused by GAS-type TB3264M100. The woman had a pneumonia, whilst her husband developed a streptococcal toxic shock-like syndrome; he died. The other woman and her son were infected with GAS-type T6M6. The son died of a circulatory arrest due to necrotizing fascitis from a wound in his arm. His mother recovered following a severe tonsillitis. The number of invasive GAS infections has increased in the past decades. GAS infections occur mostly in isolated cases, but clusters of patients are also seen, like the two described here. The risk of an invasive GAS-infection is greatest if one has been in the neighbourhood of the index patient during the week prior to the diagnosis in that patient. According to the latest (American) guidelines, there is no reason for prophylactic treatment of the close contacts of patients.

Acute cellular rejection is associated with matrix metalloproteinase-2 genotype chimerism after orthotopic liver transplantation.

PURPOSE: Chimerism in transplantation medicine refers to the coexistence of cells of donor and recipient origin. Their existence in relation to possible pathological mechanisms remains largely unknown. We used donor-recipient mismatches for matrix metalloproteinases (MMP) gene polymorphisms in liver biopsies and in blood as a marker for chimerism after orthotopic liver transplantation (OLT). The second aim of this study was to evaluate these polymorphisms in relation to clinical outcome such as ischemia-reperfusion injury (IRI) and acute cellular rejection (ACR). METHODS: MMP-2 and MMP-9 promoter polymorphism donor-recipient mismatches were determined in 147 OLT patients. The relationship between these MMP polymorphism mismatches in donor and recipient DNA with the development of IRI and ACR after OLT was evaluated. Liver biopsy specimens and peripheral blood samples were subsequently evaluated for the presence of chimerism, also in relation to these complications. RESULTS: MMP polymorphism donor-recipient mismatches were found in 53.7% (MMP-2) and 35.5% (MMP-9) of the OLT patients but no relation was observed with IRI or ACR. Chimerism in liver biopsy specimens was found to be present in 28.8% (MMP-2) and 16.2% (MMP-9) of the cases. Liver chimerism in MMP-2 was found to be significantly associated with ACR after OLT (χ(2) 6.4, P = .01). Multivariate analysis revealed MMP-2 chimerism to be an independent risk factor for ACR after OLT even adjusted for Model for End-stage Liver Disease score (hazard ratio = 3.83, P = .03). In addition, evidence of donor chimerism was found in peripheral blood samples of the recipients in some cases. CONCLUSION: Chimerism after OLT can be found in liver biopsy specimens and in peripheral blood. MMP donor-recipient polymorphism mismatches are good markers for assessing chimerism after OLT. In the multivariate analysis, liver chimerism in MMP-2 was found to be significantly associated with the development of ACR after OLT.

Nucleoside plus nucleotide analogs and cessation of hepatitis B immunoglobulin after liver transplantation in chronic hepatitis B is safe and effective.

BACKGROUND: After orthotopic liver transplantation (OLT) in chronic hepatitis B (HBV), adequate prophylaxis for recurrence of HBV in the graft is mandatory. OBJECTIVES: Evaluate safety of HBV prophylaxis with tenofovir and emtricitabine (TDF/FTC) after cessation of hepatitis B immunoglobulin (HBIG) after OLT in chronic HBV. STUDY DESIGN: In 17 consecutive patients after OLT in chronic HBV we started TDF/FTC after cessation of HBIG. All had received HBIG >6 months. 15/17 were HBsAg negative and 16/17 had undetectable HBV-DNA. RESULTS: After mean follow-up of 2 years 16/17 patients were alive, one died due to urosepsis. All 16 with undetectable HBV-DNA remained HBV-DNA negative. From 15 HBsAg negative patients at start, in one seroconversion to positive HBsAg occurred, without detectable HBV-DNA. Liver biochemistry remained within the normal ranges. There were no cases of drug discontinuation. No major side effects were reported. TDF/FTC use saves €16,262/year over standard-of-care (HBIG+LAM). This prospective follow-up study shows that in liver transplantation for chronic hepatitis B, after initial treatment including HBIG for at least 6 months combined with or followed by (dual) nucleos(t)ide analog therapy, TDF/FTC provides adequate prophylaxis against recurrent HBV infection without major side effects and leads to substantial cost savings over a regimen with HBIG. CONCLUSION: Combined prophylaxis with TDF/ETV nucleoside plus nucleotide analogs and cessation of immunoglobulin after liver transplantation in chronic hepatitis B is safe and effective.

The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes.

BACKGROUND: Treatment failure occurs in 20% of autoimmune hepatitis patients on prednisolone and azathioprine (AZA). There is no established second line treatment. AIM: To assess the efficacy of mycophenolate mofetil as second line treatment after AZA-intolerance or AZA-nonresponse in autoimmune hepatitis and overlap syndromes. METHODS: Consecutive patients from the Dutch Autoimmune Hepatitis Group cohort, consisting of 661 patients, with autoimmune hepatitis or overlap syndromes, AZA-intolerance or AZA-nonresponse and past or present use of mycophenolate mofetil were included. Primary endpoint of mycophenolate mofetil treatment was biochemical remission. Secondary endpoints were biochemical response (without remission), treatment failure and prevention of disease progression. RESULTS: Forty-five patients treated with mycophenolate mofetil were included. In autoimmune hepatitis remission or response was achieved in 13% and 27% in the AZA-nonresponse group compared to 67% and 0% in the AZA-intolerance group (P = 0.008). In overlap-syndromes remission or response was reached in 57% and 14% in the AZA-nonresponse group and 63% and 25% of the AZA-intolerance group (N.S.); 33% had side effects and 13% discontinued mycophenolate mofetil. Overall 38% had treatment failure; this was 60% in the autoimmune hepatitis AZA-nonresponse group. Decompensated liver cirrhosis, liver transplantations and death were only seen in the autoimmune hepatitis AZA-nonresponse group (P < 0.001). CONCLUSIONS: Mycophenolate mofetil induced response or remission in a majority of patients with autoimmune hepatitis and azathioprine-intolerance and with overlap syndromes, irrespective of intolerance or nonresponse for azathioprine. In autoimmune hepatitis with azathioprine nonresponse mycophenolate mofetil is less often effective.