Malte H. Wehmeyer

Background and Aims: Sarcoidosis is a granulomatous multi‐systemic disorder of uncertain aetiology frequently involving the liver. This study aimed to delineate the histological characteristics, treatment effectiveness and factors predictive of liver‐related complications in individuals with hepatic sarcoidosis. Methods: This retrospective cohort study included patients diagnosed with hepatic sarcoidosis by liver biopsy, which was conducted at two tertiary care centres from January 2009 to December 2023. We analysed demographic, clinical and laboratory parameters, treatment response and outcome. Results: We enrolled 70 hepatic sarcoidosis patients with a median follow‐up of 45 months (IQR 11–97 months), including 37 males with a median age of 48 years (IQR 37–59 years). Elevated GGT (94%) and ALP (81%) were the most common liver‐specific biochemical alterations observed. Using mini‐laparoscopy for liver biopsy made it possible to macroscopically identify granulomatous disease in 71% of patients. While at baseline, 16% of the cohort showed evidence of potential portal hypertension, at the last follow‐up, 23% of patients developed complications related to portal hypertension. In addition to granulomatous changes, bile duct irregularities were found in 57% of liver biopsies, indicating cholangiopathy being part of the hepatic manifestation of sarcoidosis. Treatment with Ursodeoxycholic acid and prednisolone resulted in a significantly more pronounced decrease in ALT and ALP compared to untreated patients. Conclusions: Patients with hepatic sarcoidosis require careful assessment of disease manifestation with a particular focus on portal hypertension. Treatment with UDCA and prednisolone leads to a reduction of biochemical parameters in a significant proportion of these patients.

Background: In the third year of the SARS‐CoV‐2 pandemic, little is known about the vaccine‐ and infection‐induced immune response in liver transplant recipients (LTR) and liver cirrhosis patients (LCP).Objective: This cross‐sectional study assessed the vaccination coverage, infection rate, and the resulting humoral and cellular SARS‐CoV‐2‐specific immune responses in a cohort of LTR and LCP at the University Medical Center Hamburg‐Eppendorf, Germany between March and May 2023.Methods: Clinical and laboratory data from 244 consecutive patients (160 LTR and 84 LCP) were collected via chart review and a patient survey. Immune responses were determined via standard spike(S)‐ and nucleocapsid‐protein serology and a spike‐specific Interferon‐gamma release assay (IGRA).Results: On average, LTR and LCP were vaccinated 3.7 and 3.3 times, respectively and 59.4% of patients received ≥4 vaccinations. Altogether, 68.1% (109/160) of LTR and 70.2% (59/84) of LCP experienced a SARS‐CoV‐2 infection. Most infections occurred during the Omicron wave in 2022 after an average of 3.0 vaccinations. Overall, the hospitalization rate was low (<6%) in both groups. An average of 4.3 antigen contacts by vaccination and/or infection resulted in a seroconversion rate of 98.4%. However, 17.5% (28/160) of LTR and 8.3% (7/84) of LCP demonstrated only low anti‐S titers (<1000 AU/ml), and 24.6% (16/65) of LTR and 20.4% (10/59) of LCP had negative or low IGRA responses. Patients with hybrid immunity (vaccination plus infection) elicited significantly higher anti‐S titers compared with uninfected patients with the same number of spike antigen contacts. A total of 22.2% of patients refused additional booster vaccinations.Conclusion: By spring 2023, high vaccination coverage and infection rate have resulted in a robust, mostly hybrid, humoral and cellular immune response in most LTR and LCP. However, booster vaccinations with vaccines covering new variants seem advisable, especially in patients with low immune responses and risk factors for severe disease.

Backgrounds/Aims: Liver diseases may affect the liver heterogeneously, especially in autoimmune hepatitis (AIH). Hence, the aim of this study was to assess the added benefit of double biopsy of both liver lobes during minilaparoscopy in guiding treatment decisions in patients with AIH. Methods: We identified all patients with AIH or variant syndromes (AIH/PBC and AIH/PSC) at our center, who underwent a double biopsy of both liver lobes via minilaparoscopy between 01/2016 and 12/2020. Results: A total of 114 patients received a biopsy of both liver lobes (AIH: N = 83, AIH/PBC: N = 26, AIH/PSC: N = 7). Differences in inflammatory activity as assessed by Ishaks's modified hepatitis activity index (mHAI) were observed in 72 (63%) patients. The difference was >= 2/18 points and >= 3/18 points in 32 (28%) and 11 (10%) patients, respectively. Starting or intensification of immunosuppression should be discussed at a mHAI of 4-5, while a mHAI=6 prompts intensified immunosuppression in most cases. In 19/114 (17%) and 17/114 (15%) patients mHAI >= 4 or >= 6 was found in only one liver lobe, respectively. In ten patients, severe fibrosis (>= F3) was only found in one liver biopsy. Overall, therapeutically relevant histological differences were observed in 39/114 (34%) patients, which had a direct impact on treatment decisions in 24 patients (21%). No major adverse outcome occurred by taking biopsies from both liver lobes. Conclusions: Obtaining a double biopsy of both liver lobes is a safe procedure during minilaparoscopy that results in more accurate grading and staging and that may impact on treatment decisions in patients with AIH.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide. In mice and humans, NAFLD progression is characterized by the appearance of TREM2-expressing macrophages in the liver. However, their mechanistic contributions to disease progression have not been completely elucidated. Here, we show that TREM2⁺ macrophages prevent the generation of a pro-inflammatory response elicited by LPS-laden lipoproteins in vitro. Further, Trem2 expression regulates bone-marrow-derived macrophages (BMDMs) and Kupffer cell capacity to phagocyte apoptotic cells in vitro, which is dependent on CD14 activation. In line with this, loss of Trem2 resulted in an increased pro-inflammatory response, which ultimately aggravated liver fibrosis in murine models of NAFLD. Similarly, in a human NAFLD cohort, plasma levels of TREM2 were increased and hepatic TREM2 expression was correlated with higher levels of liver triglycerides and the acquisition of a fibrotic gene signature. Altogether, our results suggest that TREM2⁺ macrophages have a protective function during the progression of NAFLD, as they are involved in the processing of pro-inflammatory lipoproteins and phagocytosis of apoptotic cells and, thereby, are critical contributors for the re-establishment of liver homeostasis.

Background: Asplenia or functional hyposplenism are risk factors for severe infections, and vaccinations against encapsulated bacteria are advised. There are only limited data regarding the spleen function of cirrhotic patients. Methods: We evaluated spleen function in patients with liver cirrhosis, who were prospectively enrolled in this study. Spleen function was evaluated by the measurement of pitted erythrocytes. Functional hyposplenism was defined as a percentage of PE of >15%. Results: 117 patients, mean age 58.4 years and 61.5% (n = 72) male with liver cirrhosis were included. Functional hyposplenism was diagnosed in 28/117 patients (23.9%). Pitted erythrocytes correlated with albumin (p = 0.024), bilirubin (p<0.001), international normalized ratio (INR; p = 0.004), model of end-stage liver disease (MELD) score (p<0.001) and liver stiffness (p = 0.011). Patients with functional hyposplenism had higher MELD scores (median 13 vs. 10; p = 0.021), liver stiffness (46.4 kPa vs. 26.3 kPa; p = 0.011), INR (1.3 vs. 1.2; p = 0.008) and a higher Child-Pugh stage (Child C in 32.1% vs. 11.2%; p = 0.019) as compared to patients without functional hyposplenism. Functional hyposplenism was not associated with the etiology of cirrhosis. Importantly, 9/19 patients with Child C cirrhosis had functional hyposplenism. Conclusion: A quarter of patients with liver cirrhosis and almost 50% of patients with Child C cirrhosis have functional hyposplenism. Functional hyposplenism is associated with poor liver function and the degree of portal hypertension, which is characterized by higher liver stiffness measurements in transient elastography.

Background: Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication. Methods: The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021. Discussion: The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis. Trial registration: EU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). ClinicalTrials.gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).