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Background & Aims: People who drink alcohol excessively are at increased risk of developing metabolic dysfunction and alcohol-related liver disease (MetALD) or the more severe form alcohol-related liver disease (ALD). One of the most significant challenges concerns the early detection of MetALD/ALD. Previously, we have demonstrated that the lysosomal enzyme cathepsin D (CTSD) is an early marker for metabolic dysfunction-associated steatohepatitis (MASH). Here, we hypothesized that plasma CTSD can also serve as an early indicator of MetALD/ALD. Methods: We included 303 persistent heavy drinkers classified as having MetALD or ALD (n = 152) and abstinent patients with a history of excessive drinking (n = 151). Plasma CTSD levels of patients with MetALD/ALD without decompensation were compared with 40 healthy controls. Subsequently, the relationship between plasma CTSD levels and hepatic histological scores was established. Receiver-operating characteristic curves were generated to assess the precision of plasma CTSD levels in detecting MetALD/ALD. Lastly, plasma CTSD levels were compared between abstainers and drinkers. Results: Plasma CTSD levels were higher in patients with MetALD/ALD compared to healthy controls. While hepatic disease parameters (AST/ALT ratio, liver stiffness measurement) were higher at advanced histopathological stages (assessed by liver biopsy), plasma CTSD levels were already elevated at early histopathological stages. Furthermore, combining plasma CTSD levels with liver stiffness measurement and AST/ALT ratio yielded enhanced diagnostic precision (AUC 0.872) in detecting MetALD/ALD in contrast to the utilization of CTSD alone (AUC 0.804). Plasma CTSD levels remained elevated in abstainers. Conclusion: Elevated levels of CTSD in the circulation can serve as an early indicator of MetALD/ALD. Impact and implications: Alcohol-related liver disease is the leading cause of liver disease-related morbidity and mortality worldwide. However, the currently available non-invasive methods to diagnose MetALD/ALD are only able to detect advanced stages of MetALD/ALD. Here, we demonstrate that plasma levels of the lysosomal enzyme cathepsin D are already elevated at early stages of MetALD/ALD. Moreover, cathepsin D levels outperformed the currently available non-invasive methods to detect MetALD/ALD. Plasma levels of cathepsin D could therefore be a useful non-invasive marker for detection of MetALD/ALD.

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Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease in adolescents with obesity. Nonetheless, the guidelines for screening and managing this disease are contradictory. The purpose of this study is to non-invasively assess the prevalence, patient characteristics, and potential associated factors of MASLD in this demographic. Methods: This study used baseline data from an RCT in adolescents eligible for bariatric surgery. MASLD was determined by measuring the hepatorenal index (HRI) with ultrasonography, blood liver tests, and the fatty liver index (FLI). Results: A total of 56 adolescents enrolled in the analyses; the majority were female n = 44 (79%); the mean age was 15.75 (±1.01) years; the average body mass index (BMI) was 44.08 (±5.16) kg/m2. In 35 (62.5%) of the patients, the HRI was abnormal. This group had a higher waist/hip ratio, elevated liver biochemistry, and significantly lower leptin levels (mean difference = -46.35, 95% CI -76.72, -15.99) compared to the group with a normal HRI. In 32 (55.2%) of the patients, ALT levels were elevated and the FLI was abnormal in all (100%) participants. Linear regression analysis indicated associations between the HRI and typical anthropometric and metabolic measurements; and an inverse association between HRI and leptin B = -0.003 (95% CI -0.005, -0.00), independently of sex- and age-adjusted BMI. Conclusions: MASLD is highly prevalent in adolescents with severe obesity. However, the prevalence strongly depends on which tool is used, namely the HRI (62.5%), alanine transaminase levels (55.2%), and FLI (100%). Our findings suggest that leptin may be a valuable biomarker in supporting the diagnosis of MASLD.

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With great interest, we read the article by Flatscher et al [...].

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Dysautonomia is a disruption of the body's autonomic processes. Symptoms vary among patients, depending on the underlying disease pathways. Given that symptoms can affect all organ functions, dysautonomia often significantly impacts quality of life. However, due to its complex and varied presentation, early recognition of dysautonomia remains a challenge, yet it is crucial for improving patient outcomes. We report a case of a patient with a KRIT1 mutation presenting with dysautonomia causing urological, sexual, and bowel dysfunction. We hypothesize that the patient's symptoms are due to a pontine cavernous malformation (CM) caused by the KRIT1 mutation. A literature review was conducted to establish a link between pontine CM and dysautonomia.

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Hepatocellular carcinoma (HCC) is, to date, the most common malignant tumor of the liver and is commonly staged with the Milan criteria. While deceased-donor liver transplantations (DDLT) are reserved for patients within the Milan criteria, living-donor liver transplantation (LDLT) might be a curative option for patients outside the Milan criteria. We here report a case of a 32-year-old woman who developed a giant, unresectable HCC out of a hepatocellular adenoma (HCA) after a pregnancy. The genetically identical twin sister donated her left hemi-liver after ethical approval and preoperative screening. No long-term immunosuppressive therapy was necessary, and after more than eight years, both are in perfect health and the recipient gave birth to a second child. This case shows that in certain situations large HCCs outside the standard criteria can be cured by LT. Careful evaluation of both donor and recipient should be performed for indications like this to assure optimal clinical outcome.

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BACKGROUND: Hyperferritinemia is found in around 12 % of the general population. Analyzing the cause can be difficult. In case of doubt about the presence of major iron overload most guidelines advice to perform a MRI as a reliable non-invasive marker to measure liver iron concentration (LIC). In general, a LIC of ≥ 36 µmol/g dw is considered the be elevated however in hyperferritinemia associated with, for example, obesity or alcohol (over)consumption the LIC can be ≥ 36 µmol/g dw in abscence of major iron overload. So, unfortunately a clear cut-off value to differentiate iron overload from normal iron content is lacking. Previously the liver iron index (LII) (LIC measured in liver biopsy (LIC-b)/age (years)), was introduced to differentiate between patients with major (LII ≥ 2) and minor or no iron overload (LII < 2). Based on the good correlation between the LIC-b and LIC determined with MRI (LIC-MRI), our goal was to investigate whether a LII_MRI ≥ 2 is a good indicator of major iron overload, reflected by a significantly higher amount of iron needed to be mobilized to reach iron depletion. METHODS: We compared the amount of mobilized iron to reach depletion and inflammation-related characteristics in two groups: LII-MRI ≥ 2 versus LII-MRI <2 in 92 hyperferritinemia patients who underwent HFE genotyping and MRI-LIC determination. RESULTS: Significantly more iron needed to be mobilized to reach iron depletion in the LII ≥ 2 group (mean 4741, SD ± 4135 mg) versus the LII-MRI <2 group (mean 1340, SD ± 533 mg), P < 0.001. Furthermore, hyperferritinemia in LII-MRI < 2 patients was more often related to components of the metabolic syndrome while hyperferritinemia in LII-MRI ≥ 2 patients was more often related to HFE mutations. ROC curve analysis showed good performance of LII =2 as cut-off value. However the calculations showed that the optimal cut-off for the LII = 3.4. CONCLUSION: The LII-MRI with a cut-off value of 2 is an effective method to differentiate major from minor iron overload in patients with hyperferritinemia. But the LII-MRI = 3.4 seems a more promising diagnostic test for major iron overload.

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This thematic review aims to provide an overview of the current state of knowledge about the occurrence of giant mitochondria or megamitochondria in liver parenchymal cells. Their presence and accumulation are considered to be a major pathological hallmark of the health and fate of liver parenchymal cells that leads to overall tissue deterioration and eventually results in organ failure. The first description on giant mitochondria dates back to the 1960s, coinciding with the availability of the first generation of electron microscopes in clinical diagnostic laboratories. Detailed accounts on their ultrastructure have mostly been described in patients suffering from alcoholic liver disease, chronic hepatitis, hepatocellular carcinoma and non-alcoholic fatty liver disease. Interestingly, from this extensive literature survey, it became apparent that giant mitochondria or megamitochondria present themselves with or without highly organised crystal-like intramitochondrial inclusions. The origin, formation and potential role of giant mitochondria remain to-date largely unanswered. Likewise, the biochemical composition of the well-organised crystal-like inclusions and their possible impact on mitochondrial function is unclear. Herein, concepts about the possible mechanism of their formation and three-dimensional architecture will be approached. We will furthermore discuss their importance in diagnostics, including future research outlooks and potential therapeutic interventions to cure liver disease where giant mitochondria are implemented.

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Background: Primary care has a crucial role to play in the prevention, early detection, referral, and risk factor management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD/NASH). In 2021, a team of European collaborators developed a continuing medical education (CME) program on NAFLD/NASH that consolidates evidence and clinical best practices tailored to the primary care setting. This article reports on the methodology used to design and develop the CME and the results of a feasibility study. Methods: An expert advisory group representing both European specialists and general practitioners supported the design of the CME to be implemented in three European settings (Greece, Spain, and Netherlands). The CME features four training modules and problem-based learning using clinical case studies. The CME was tested regarding feasibility and acceptability among a sample of primary care providers (PCPs) in Greece (n = 28) with measurements occurring before, immediately after, and 1 month following the training. Outcome measures included satisfaction with the CME, changes in PCPs' knowledge, attitudes, confidence, and self-reported clinical practices related to NAFLD/NASH. Results: The CME is available as an open-access e-learning course on the European Society for Primary Care Gastroenterology education platform in English, Greek, Spanish, and Dutch. The feasibility study documented high levels of satisfaction, with 96% of PCPs reporting they were extremely or very satisfied with the overall training. Statistically significant increases in PCPs' confidence in NAFLD/NASH-related clinical practices were documented between the pre- and post-assessments. At the follow-up, 62% of GPs reported that the CME had changed their clinical practices related to NAFLD/NASH to a great extent. Conclusion: This CME intervention developed by experts and tailored to PCPs in European settings may serve as an asset for increasing knowledge, confidence, and practice behaviors related to NAFLD/NASH.

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BACKGROUND AND AIM: Intestinal permeability (IP) plays an important role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). We assessed site-specific (gastroduodenum, small intestine, colon and whole gut) IP in NAFLD patients and healthy controls (HC) and its association with the degree of hepatic steatosis, hepatic fibrosis and dietary composition in these NAFLD patients. METHODS: In vivo site-specific IP was analysed with a validated multi-sugar test in NAFLD patients and HC. Furthermore, in NAFLD patients, hepatic steatosis (chemical shift MRI), hepatic fibrosis (transient elastography) and dietary composition (food frequency questionnaire) were assessed. RESULTS: Fifty-two NAFLD patients and forty-six HC were included in this study. Small intestinal (P <0.001), colonic (P = 0.004) and whole gut (P <0.001) permeability were increased in NAFLD patients compared to HC. Furthermore, colonic permeability (P = 0.029) was significantly higher in NAFLD patients with clinically significant fibrosis compared to those without. Colonic permeability remained positively associated with the presence of clinically significant fibrosis (P = 0.017) after adjustment for age, sex and BMI. CONCLUSION: Colonic permeability is increased in at least a subset of NAFLD patients compared to HC and is independently associated with clinically significant NAFLD fibrosis.

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BACKGROUND: It is unclear whether the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C-to-G single nucleotide polymorphism, resulting in the substitution of isoleucine to methionine at position 148 (I148M), impedes regression of hepatic steatosis when treating non-alcoholic fatty liver disease (NAFLD). OBJECTIVES: Investigate if carriage of the PNPLA3 148M allele affects the anti-steatotic efficacy of all possible anti-NAFLD interventions, identify gaps in current knowledge and provide guidance for individual treatment. METHODS: Research available in public databases was searched up to 13 November 2022. Studies were included if a treatment in NAFLD patients decreased hepatic steatosis in the pooled patient group or a PNPLA3 I148M polymorphism subgroup (II/IM/MM). The risk of bias was assessed using the Cochrane Risk-Of-Bias 2 Tool and the Newcastle-Ottawa Scale. RESULTS: Moderate evidence indicates that NAFLD patients homozygous for the PNPLA3 148M allele benefit less or not at all from omega-3 carboxylic acids to decrease liver fat, while the PNPLA3 148I allele shows moderate benefit. Low evidence suggests that interventions employing lifestyle changes are more effective to reduce liver fat in NAFLD patients homozygous for the PNPLA3 148M allele compared to patients with wild-type PNPLA3. CONCLUSIONS: NAFLD patients homozygous for the PNPLA3 148M allele might not benefit from omega-3 carboxylic acids to reduce hepatic steatosis in contrast to patients with wild-type PNPLA3. Instead, patients with two PNPLA3 148M alleles should be especially advised to adopt lifestyle changes. Genotyping for PNPLA3 I148M should be encouraged in therapeutic studies for NAFLD. REGISTRATION NUMBER (PROSPERO): CRD42022375028.

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Clusterin is a multifunctional protein that is recognized to mediate cellular stress response associated with organ failure, systemic inflammation, and metabolic alterations. The aim of this study was to determine the value of clusterin as a clinical biomarker in critical ill patients with or without sepsis. We analyzed clusterin plasma concentrations in 200 critically ill patients (133 with sepsis, 67 without sepsis) on admission to the medical intensive care unit (ICU). The results were compared with 66 healthy controls. Clusterin plasma concentration was significantly elevated in critically ill patients compared to healthy subjects. Clusterin levels were significantly higher in non-septic ICU patients than in patients with sepsis. Clusterin correlated inversely with routinely used biomarkers of inflammatory response. Furthermore, clusterin levels were higher in ICU patients with pre-existing obesity and type 2 diabetes. Clusterin was not associated with disease severity, organ failure, or mortality in the ICU. This study highlights significantly elevated clusterin levels in critically ill patients, predominantly in non-sepsis conditions, and associates circulating clusterin to inflammatory and metabolic dysfunctions.

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Background & aims: There are approximately 49,000 people (0.34%) in the Netherlands with a chronic hepatitis B virus (HBV) infection. It is unclear how many are linked to care and under follow-up in hepatitis outpatient clinics. This study determined the cascade of care and identified predictors for not being linked to care and loss to follow-up in Maastricht, the Netherlands. Methods: All hepatitis B surface antigen (HBsAg)-positive patients between December 1, 1996 and September 30, 2018 were retrospectively identified. Results: In total, 644 HBsAg-positive patients were identified; of whom 75 had acute HBV infection, 471 chronic HBV infection and 98 unknown. Out of 569 individuals with a chronic/unknown HBV status, 134/569 (23.6%) were not linked to care and 58.7% (195/332 after excluding those who died or achieved HBsAg-seroclearance) were loss to follow-up (LTFU). A predictor for not being linked to care was Caucasian ethnicity (odds ratio (OR) = 2.76 (95% Confidence Interval (CI) = 1.21-6.29); p = .015). Predictors for LTFU were older age (OR = 0.97 (CI = 0.94-0.99); p = .008), HBV DNA >20,000 IU/mL (OR = 0.44 (CI = 0.21 - 0.93); p = .033) and Asian ethnicity (OR = 0.46, (CI = 0.21-1.00); p = .050). Rates of not being linked to care and LTFU decreased over time from 12.7% in 1996 to 4.4% in 2018 and from 79.2% in 1996 to 37.2% in 2018, respectively. Conclusions: A considerable amount of HBsAg-positive individuals were not linked to care or LTFU. This study indicates that ethnicity plays a role in linkage to care and follow-up. Further research is needed to elaborate on those results.

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BACKGROUND: Primary biliary cholangitis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are autoimmune liver diseases associated with distinct autoantibodies. Diagnosis is based upon clinical, serological, and histopathology findings. The role of autoantibodies in the diagnosis of these autoimmune liver diseases, with the focus on PBC and AIH, will be discussed. CONTENT: When AIH or PBC is suspected, testing for multiple autoantibodies can be requested. In this mini-review, the different ways in which autoantibodies can be tested (indirect immunofluorescence and antigen-specific tests) in the context of PBC and AIH are discussed, as well as the pitfalls in interpreting the test results. SUMMARY: For appropriate interpretation of test results, an important prerequisite is that the doctor knows which test is used in the laboratory of choice and that the laboratory specialist is aware of what the doctor wants to test for. Good communication between clinician and laboratory specialist can, therefore, aid in the diagnosis of autoimmune liver diseases.

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Adapted fixation methods for electron microscopy allowed us to study liver cell fine structure in 217 biopsies of intact human livers over the course of 10 years. The following novel observations and concepts arose: single fat droplets in parenchymal cells can grow to a volume four times larger than the original cell, thereby extremely marginalizing the cytoplasm with all organelles. Necrosis of single parenchymal cells, still containing one huge fat droplet, suggests death by fat in a process of single-cell steatonecrosis. In a later stage of single-cell steatonecrosis, neutrophils and erythrocytes surround the single fat droplet, forming an inflammatory fat follicle indicating the apparent onset of inflammation. Also, fat droplets frequently incorporate masses of filamentous fragments and other material, most probably representing Mallory substance. No other structure or material was found that could possibly represent Mallory bodies. We regularly observe the extrusion of huge fat droplets, traversing the peripheral cytoplasm of parenchymal cells, the Disse space and the endothelium. These fat droplets fill the sinusoid as a sinusoidal lipid embolus. In conclusion, adapted methods of fixation applied to human liver tissue revealed that single, huge fat droplets cause necrosis and inflammation in single parenchymal cells. Fat droplets also collect Mallory substance and give rise to sinusoidal fat emboli. Therefore, degreasing of the liver seems to be an essential therapeutic first step in the self-repairing of non-alcoholic fatty liver disease. This might directly reduce single-cell steatotic necrosis and inflammation as elements in non-alcoholic steatohepatitis progression.

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INTRODUCTION: For the maintenance treatment of patients with hereditary hemochromatosis (HH), it is advised to keep the transferrin saturation (TSAT) <70% to prevent formation of non-transferrin-bound iron and labile plasma iron. The period of the initial iron depletion may last up to 1 year or longer and during this period, the patient is exposed to elevated TSAT levels. Therapeutic erythrocytapheresis (TE) is a modality which has proven to reduce treatment duration of patients with iron overload from HH. In this study, we investigated the time to reach TSAT <70% for both treatment modalities. METHODS: From a previous randomized controlled trial comparing erythrocytaphereses with phlebotomies (PBMs), we performed an analysis in a subgroup of patients who presented with TSAT >70%. Mann-Whitney U tests were performed to compare the number of treatments and the number of weeks to reach the interim goal of a persistent level of <70% for TSAT between TE and PBM. RESULTS: The period to reach TSAT levels of <70% was statistically significant shorter for the TE group compared to the PBM treatment group (median treatment procedures [IQR] 2.0 (5) vs 16.0 (23), P-value: <.001, and median treatment duration [IQR]: 5.5 (11) vs 19.0 (29) weeks, P-value: .007). CONCLUSION: Patients with HH reach a safe TSAT <70% significantly sooner and with less treatment procedures with TE compared to PBM.

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Perilipin 2 (PLIN2) is a lipid droplet protein with various metabolic functions. However, studies investigating PLIN2 in the context of inflammation, especially in systemic and acute inflammation, are lacking. Hence, we assessed the relevance of serum PLIN2 in critically ill patients. We measured serum PLIN2 serum in 259 critically ill patients (166 with sepsis) upon admission to a medical intensive care unit (ICU) compared to 12 healthy controls. A subset of 36 patients underwent computed tomography to quantify body composition. Compared to controls, serum PLIN2 concentrations were elevated in critically ill patients at ICU admission. Interestingly, PLIN2 independently indicated multiple organ dysfunction (MOD), defined as a SOFA score > 9 points, at ICU admission, and was also able to independently predict MOD after 48 h. Moreover, serum PLIN2 levels were associated with severe respiratory failure potentially reflecting a moribund state. However, PLIN2 was neither a predictor of ICU mortality nor did it reflect metabolic dysregulation. Conclusively, the first study assessing serum PLIN2 in critical illness proved that it may assist in risk stratification because it is capable of independently indicating MOD at admission and predicting MOD 48 h after PLIN2 measurement. Further evaluation regarding the underlying mechanisms is warranted.

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Previous studies associated plasma cathepsin D (CTSD) activity with hepatic insulin resistance in overweight and obese humans. Insulin resistance is a major feature of non-alcoholic fatty liver disease (NAFLD) and is one of the multiple hits determining the progression towards non-alcoholic steatohepatitis (NASH). In line, we have previously demonstrated that plasma CTSD levels are increased in NASH patients. However, it is not known whether insulin resistance associates with plasma CTSD activity in NAFLD. To increase our understanding regarding the mechanisms by which insulin resistance mediates NAFLD, fifty-five liver biopsy or MRI-proven NAFLD patients (BMI>25kg/m2) were included to investigate the link between plasma CTSD activity to insulin resistance in NAFLD. We concluded that HOMA-IR and plasma insulin levels are independently associated with plasma CTSD activity in NAFLD patients (standardized coefficient ß: 0.412, 95% Cl: 0.142~0.679, p=0.004 and standardized coefficient ß: 0.495, 95% Cl: 0.236~0.758, p=0.000, respectively). Together with previous studies, these data suggest that insulin resistance may link to NAFLD via elevation of CTSD activity in plasma. As such, these data pave the way for testing CTSD inhibitors as a pharmacological treatment of NAFLD.

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BACKGROUND: The prevalence of duodenogastroesophageal reflux (DGER) and its effect on symptoms and oesophageal lesions in gastroesophageal reflux disease (GERD) is unclear. AIMS: To conduct a systematic review to determine the prevalence of DGER among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER. METHODS: We searched Pubmed and MEDLINE for full text, English language articles until October 2020 that evaluated DGER prevalence among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER. RESULTS: We identified 3891 reports and included 35 which analysed DGER prevalence in GERD, 15 which evaluated its effect in non-erosive reflux disease (NERD), 17 on erosive oesophagitis, 23 in Barrett's, and 13 which evaluated the treatment of DGER. The prevalence of DGER, when evaluated by Bilitec, among all GERD patients ranged from 10% to 97%, in NERD 10%-63%, in erosive oesophagitis 22%-80% and in Barrett's 50%-100%. There were no differences in the presence or degree of DGER among patients who were asymptomatic or symptomatic on proton pump inhibitors (PPI). The most commonly evaluated treatments for DGER were PPIs and DGER reduced post-PPI therapy in all studies. CONCLUSIONS: The prevalence of DGER increased with more advanced oesophageal lesions and did not explain persisting symptoms among patients taking PPI therapy. PPIs appear to be effective in the treatment of DGER. DGER remains an important consideration in patients with GERD and future therapies deserve more study.

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