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Background Most COVID‐19‐associated mucormycosis (CAM) cases are reported from India and neighbouring countries. Anecdotally cases from Europe have been presented. Objective To estimate the disease burden and describe the clinical presentation of CAM in Germany. Methods We identified cases through German mycology networks and scientific societies, and collected anonymised clinical information via FungiScope®. Results We identified 13 CAM cases from six tertiary referral hospitals diagnosed between March 2020 and June 2021. Twelve patients had severe or critical COVID‐19, eleven were mechanically ventilated for a median of 8 days (range 1‐27 days) before diagnosis of CAM. Eleven patients received systemic corticosteroids. Additional underlying medical conditions were reported for all but one patient, five were immunocompromised because of malignancy or organ transplantation, three were diabetic. Eleven patients developed pneumonia. Mortality was 53.8% with a median time from diagnosis of mucormycosis to death of 9 days (range 0–214 days) despite treatment with liposomal amphotericin B and/or isavuconazole in 10 of 13 cases. CAM prevalence amongst hospitalised COVID‐19 patients overall (0.67% and 0.58% in two centres) and those admitted to the intensive care unit (ICU) (1.47%, 1.78% and 0.15% in three centres) was significantly higher compared to non‐COVID‐19 patients (P

Background & Aims Clinical manifestation of hepatic involvement in sarcoidosis can vary from asymptomatic disease to severe complications such as cirrhosis and portal hypertension. However, data on hepatic sarcoidosis are limited, and evidence-based recommendations are lacking. Our study aimed to assess the features and clinical course of hepatic sarcoidosis in a predominantly Caucasian cohort. Methods We performed a retrospective study including all patients with hepatic sarcoidosis between 2004 and 2020 in 5 German centres. The median follow-up time was 36 months (range 0.0–195). Data on demographic parameters, clinical manifestations, diagnostic test results, treatment, and outcome were collected. Results A total of 1,476 patients with sarcoidosis and 62 patients with hepatic involvement (4.2%) were identified. Of the patients, 51.6% were female, and 80.6% were Caucasian. Most patients were asymptomatic and were observed to have a cholestatic pattern of liver enzyme elevations. Cirrhosis was detected in 9 patients (14.5%), of whom 6 developed clinical manifestations of portal hypertension. Fifty-four patients were medically treated, most commonly with glucocorticoids (69.4%) or ursodeoxycholic acid (UDCA) (40.3%). Levels of alkaline phosphatase (ALP) decreased by 60.8% on average from baseline in patients treated with glucocorticoids and by 59.9% in patients treated with UDCA. Seventeen patients received treatment augmentation with a second line agent, of whom 8 patients normalised ALP levels during follow-up. None of the patients underwent liver transplantation or developed hepatocellular carcinoma (HCC). Three of the patients died during follow-up owing to liver-related complications. Conclusions Hepatic involvement in sarcoidosis was found in 4.2% of patients with sarcoidosis and was clinically significant in 14.5% of those. These findings highlight the importance of early identifying, monitoring, and treating hepatic sarcoidosis, given its increased mortality when associated with end-stage liver disease. Lay summary Clinical diagnostic and surveillance of hepatic involvement in sarcoidosis has not been standardised, and management of hepatic involvement is a clinical challenge, since it remains poorly characterised in many ways. Our results show that one-third of patients with hepatic sarcoidosis presented with clinically significant portal hypertension, 14.5% suffered from cirrhosis, and 3 patients died owing to liver-related complications. Regarding pharmacological treatment options, corticosteroids and UDCA were the medical agents most frequently used, and both of them have been shown to induce biochemical response in the majority of patients. These findings highlight the importance of correctly and early identifying hepatic involvement in sarcoidosis, because of the potentially progressive course of disease., Graphical abstract, Highlights • There has been little research on clinical characteristics and the clinical outcome of patients with hepatic sarcoidosis. • One-third of patients with hepatic sarcoidosis presented with clinically significant portal hypertension, and 14.5% suffered from cirrhosis. • Biochemically, a cholestatic pattern of liver enzyme elevations was the most common abnormality. • The correct and early identification of hepatic involvement in sarcoidosis is crucial because of the potentially progressive course of disease.

Background Patients with liver cirrhosis typically exhibit abnormal coagulation parameters in conventional coagulation tests (CCTs). Rotational thromboelastometry (ROTEM) is a holistic blood coagulation assay. This method provides an insight into the global hemostatic capabilities and has been suggested to provide a better overview of the coagulation system in liver cirrhosis. Methods The goal of this study was to examine hemostasis in patients with stable liver cirrhosis (Non-ACLF) and in acute-on-chronic liver failure (ACLF) by CCT and ROTEM including agreement of both tests and the prospective assessment of test performance based on clinical outcomes in ACLF patients. Therefore, ACLF patients were additionally subgrouped by bleeding events. Fifty-five Non-ACLF patients and twenty-two patients with ACLF were analysed in this prospective cohort study. Results Coagulation parameters analysed by CCT were outside the normal range in Non-ACLF and ACLF patients, but were significantly more aberrant in ACLF patients. Non-ACLF patients analysed by ROTEM revealed parameters largely within the normal limits, while significantly more ROTEM parameters in ACLF patients were affected. Maximum clot firmness (MCF) was significantly divergent between both patient groups and correlated well with levels of fibrinogen and platelet count. Using Cohen’s Kappa coefficient κ, the strength of agreement between CCT and ROTEM analyses was determined to be fair for Non-ACLF patients and moderate for ACLF patients. Bleeding events occurred significantly more often in ACLF group with significantly reduced A10 and MCF. Conclusions For assessing hemostasis in Non-ACLF and ACLF patients the underlying dataset shows advantages of ROTEM over CCT. A10 and MCF represent suitable prognostic parameters in predicting bleeding events in ACLF group.

Background Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder with increased intestinal iron absorption and therefore iron Overload. iron overload leads to increased levels of toxic non-transferrin bound iron which results in oxidative stress and lipid peroxidation. The impact of iron on lipid metabolism is so far not fully understood. The aim of this study was to investigate lipid metabolism including lipoproteins (HDL, LDL), neutral (triglycerides, cholesterol) and polar lipids (sphingo- and phospholipids), and PNPLA3 polymorphism (rs738409/I148M) in HH. Methods We conducted a cohort study of 54 subjects with HH and 20 healthy subjects. Patients were analyzed for their iron status including iron, ferritin, transferrin and transferrin saturation and serum lipid profile on a routine follow-up examination. Results HH group showed significantly lower serum phosphatidylcholine (PC) and significantly higher phosphatidylethanolamine (PE) compared to healthy control group. The ratio of PC/PE was clearly lower in HH group indicating a shift from PC to PE. Triglycerides were significantly higher in HH group. No differences were seen for HDL, LDL and cholesterol. Hepatic steatosis was significantly more frequent in HH. PNPLA3 polymorphism (CC vs. CG/GG) did not reveal any significant correlation with iron and lipid parameters including neutral and polar lipids, grade of steatosis and fibrosis. Conclusion Our study strengthens the hypothesis of altered lipid metabolism in HH and susceptibility to nonalcoholic fatty liver disease. Disturbed phospholipid metabolism may represent an important factor in pathogenesis of hepatic steatosis in HH.

SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome with the need of invasive ventilation. Pulmonary herpes simplex-1 (HSV-1) reactivation in invasively ventilated patients is a known phenomenon. To date very little is known about the frequency and the predisposing factors of HSV-1 reactivation in COVID-19. Therefore, we evaluated our cohort of invasively ventilated COVID-19 patients with severe pneumonia for HSV-1 in respiratory specimens and combined these results with functional immunomonitoring of the peripheral blood. Tracheal secretions and bronchial lavages were screened by PCR for HSV-1 positivity. Comprehensive immunophenotyping and quantitative gene expression analysis of Interferon-stimulated genes (IFI44L, MX1, RSAD2, ISIG15 and IFIT1) and IL-1 beta were performed in whole blood. Time course of infection beginning at symptom onset was grouped into three phases (“early” phase 1: day 1–10, “middle” phase 2: day 11–30 and “late” phase 3: day 31–40). Pulmonary HSV-1 reactivation was exclusively observed in the later phases 2 and 3 in 15 of 18 analyzed patients. By FACS analysis a significant increase in activated CD8 T cells (CD38+HLADR+) in phase 2 was found when compared with phase 1 (p+HLADR+ CD8 T cells.

A 37-year-old male patient with Crohn's disease and multiple liver hemangiomas was referred to our hospital for an atypical hypervascular hepatic lesion detected on an external magnetic resonance imaging (MRI) scan. The patient was otherwise well and had no history of any liver disease. Liver values and tumor markers were normal. Contrast-enhanced ultrasound confirmed multiple hemangiomas in different liver segments and a hypervascular tumor with a hypovascular rim in segment II/IV. Repeat MRI showed a strongly enhancing neoplasm of 2.6 cm with a texture distinctly different from the otherwise relatively uniform hemangiomas, without evidence of interim growth. Ultrasound-guided biopsy revealed a hepatic small vessel neoplasm. Due to the unknown malignant potential, atypical segmental surgical resection was performed. Final histopathological analysis confirmed the complete resection of the lesion. The postoperative course was uneventful.Ein 37-jähriger M.-Crohn-Patient mit bekannten Leberhämangiomen wurde uns zur weiteren Abklärung einer unklaren, unscharf begrenzten Leberläsion zugewiesen. Vorerkrankungen der Leber bestanden nicht. Die Leberwerte und Tumormarker waren unauffällig. Ein Kontrastmittelultraschall bestätigte mehrere Hämangiome in der Leber und charakterisierte die Läsion in Segment II/IV als hypervaskularisiert mit einem hypovaskulären Randsaum. Das wiederholte MRT zeigte einen stark Kontrastmittel aufnehmenden 2,6 cm großen Tumor, der sich in der Textur deutlich von den ansonsten uniform aussehenden Hämangiomen unterschied und kein zwischenzeitliches Wachstum aufwies. Die sonografisch gesteuerte Biopsie ergab eine Gefäßneoplasie (“hepatic small vessel neoplasm”). Aufgrund der unbekannten Entartungstendenz dieser Entität wurde eine atypische Segmentresektion durchgeführt. Die endgültige Histopathologie bestätigte die Diagnose der vorherigen Biopsie und die vollständige Entfernung der Läsion. Der postoperative Verlauf war komplikationslos.

Scope Inadequate intake of choline commonly leads to liver diseases. Methionine- and choline-deficient diets (MCDD) induce fatty liver in mice which is partly mediated by triglyceride (TG) lipolysis in white adipose tissues (WATs). Because Fatp4 knockdown has been shown to increase adipocyte lipolysis in vitro, here, the effects of MCDD on WAT lipolysis in aP2-Cre Fatp4-knockout (Fatp4A-/- ) mice are determined. Methods and results Isolated WATs of Fatp4A-/- mice exposed to MCD medium show an increase in lipolysis, and the strongest effect is noted on glycerol release from subcutaneous fat. Fatp4A-/- mice fed with MCDD for 4 weeks show an increase in serum glycerol, TG, and leptin levels associated with the activation of hormone-sensitive lipase in subcutaneous fat. Chow-fed Fatp4A-/- mice also show an increase in serum leptin and very-low-density lipoproteins as well as liver phosphatidylcholine and sphingomyelin levels. Both chow- and MCDD-fed Fatp4A-/- mice show a decrease in serum ketone and WAT sphingomyelin levels which supports a metabolic shift to TG for subsequent WAT lipolysis CONCLUSIONS: Adipose Fatp4 deficiency leads to TG lipolysis and leptin release, which are exaggerated by MCDD. The data imply hyperlipidemia risk by a low dietary choline intake and gene mutations that increase adipose TG levels.

Fatty acid transport protein4 (FATP4) is upregulated in acquired and central obesity and its polymorphisms are associated with blood lipids and insulin resistance. Patients with FATP4 mutations and mice with global FATP4 deletion exhibit skin abnormalities characterized as ischthyosis prematurity syndrome (IPS). Cumulating data have shown that an absence of FATP4 increases the levels of cellular triglycerides (TG). However, FATP4 role and consequent lipid and TG metabolism in the hepatocyte is still elusive. Here, hepatocyte-specific FATP4 deficient (Fatp4L−/−) mice were generated. When fed with chow, these mutant mice displayed no phenotypes regarding blood lipids. However when fed low-fat/high-sugar (HS) or high-fat/high-sugar (HFS) for 12 weeks, Fatp4L−/− mice showed a significant increase of plasma TG, free fatty acids and glycerol when compared with diet-fed control mice. Interestingly, Fatp4L−/− mice under HS diet had lower body and liver weights and they were not protected from HFS-induced body weight gain and hepatic steatosis. Male mutant mice were more sensitive to HFS diet than female mutant mice. Glucose intolerance was observed only in female Fatp4L−/− mice fed with HS diet. Lipidomics analyses revealed that hepatic phospholipids were not disturbed in mutant mice under both diets. Thus, hepatic FATP4 deletion rendered an increase of blood lipids including glycerol indicating a preferential fatty-acid channeling to TG pools that are specifically available for lipolysis. Our results imply a possible risk of hyperlipidemia as a result of abnormal metabolism in liver in IPS patients with FATP4 mutations who consume high-sugar diets.

Fatty acid transport protein (FATP) 4 is a minor FATP in the liver but it has some activity towards palmitate 16:0 (Pal). We here chose FATP4 as a representative model enzyme for acyl-CoA synthetases (ACSs), and FATPs to determine whether Pal activation would lead to apoptosis and alteration in lipid metabolism. By using FATP4 overexpressed (FATP4) Huh-7 cells, we showed that FATP4 was localized in the endoplasmic reticulum (ER) and mitochondria of FATP4 cells. FATP4 cells were more responsive to Pal than the control GFP cells in increasing palmitoyl-CoA and oleoyl-CoA activities as well as apoptosis by ~2-3 folds. The lipoapoptosis susceptibility by FATP4 was coupled with the increased JNK, PUMA, caspase3, PARP-1 activation as well as Rac-1-mediated cytoskeletal reorganization, and decreased insulin sensitivity. This was associated with increased contents of neutral lipids and significant alteration in composition of phospholipids and sphingolipids including increased lysophosphatidylcholine (LPC), ceramide, and hexosylceramide, as well as an increase of saturated:polyunsaturated fatty acid ratio in LPC and PC, but a decrease of this ratio in phosphatidylethanolamine pool. By use of ceramide synthase inhibitors, our results showed that FATP4-sensitized lipoapoptosis was not mediated by ceramides. Moreover, FATP4 expression was increased in fatty livers in vivo. Thus, our model system has provided a clue that Pal activation FATP4 triggers hepatocellular apoptosis via altered phospholipid composition and steatosis by acylation into complex lipids. This may be a redundant mechanism for other ER-localizing ACSs and FATPs in the liver, and hence their involvement in the development of fatty liver disease.

FATP4 expression is upregulated in acquired obesity and polymorphisms in the FATP4 gene are associated with increased blood triglycerides (TG). Since non‐alcoholic fatty liver disease (NAFLD) is a manifestation of obesity, it is of interest to understand how FATP4 upon fat overload mediates alterations of lipids that lead to pathogenesis of fatty liver. A model system with FATP4‐overexpressed (FATP4) and control Huh‐7 cell lines is used to determine FATP4 response to palmitate (Pal). By lipidomics methods, cellular phospholipids (PL), neutral lipids TG, free cholesterol (FC), and cholesterol esters (CE) as well as lipoprotein secretion are determined. Without Pal, FATP4 cells show a significant increase of TG, phosphatidylcholine (PC), and the release of TG‐rich and cholesterol‐rich low density lipoproteins. Pal‐treated FATP4 cells show an increase of all PL subclasses except for phosphatidylserine (PS), TG, FC, and CE. By analyses of ratios among PL subclasses and between PL and neutral lipids, it is determined that FATP4 in response to Pal causes sequentially fatty‐acid channeling with a shift from PC and phosphatidylinositol (PI) to neutral lipids and from neutral lipids to PS and phosphatidylethanolamine (PE). This response is concomitant with an activation of CAAT/enhancer binding homologous protein and MAP Kinase JNK. Thus, FATP4 overexpression in response to Pal leads to enhancement of neutral lipids which play a central role in fatty‐acid distribution from PC and PI to PE and PS that led to an alteration of ER and mitochondrial membranes and subsequent stress signalling. Practical Applications: Activation of fatty acids by fatty acid transport proteins (FATP) plays an important role in development of obesity and NAFLD. This work highlights functional role of FATP4 on fatty‐acid distribution among neutral lipids and phospholipids upon fat overload. These changes may contribute to stress signalling in the pathogenesis of NAFLD. Compositional shift among total PL subclasses and neutral lipids.

A 26-year-old female patient presented with the clinical picture of an acute ileus. Since childhood the patient has been diagnosed as having a MELAS syndrome, a mitochondriopathy. A subtotal colectomy was performed some years ago because of a similar ileus episode. The further diagnostic work-up revealed an expanded small intestine in abdominal radiography. Laboratory analysis showed increased levels of serum lactate with a consecutive respiratory compensated metabolic acidosis. A conservative treatment regime with nasogastric tube, fluid therapy, parental nutrition via peripheral veins and peristalsis inducing drugs was initiated, but did not resolve ileus symptoms. Under the hypothesis that in MELAS syndrome the ileus-related catabolic state aggravates the ileus symptoms in terms of a circulus vitiosus, we started high-caloric parenteral nutrition by using a central venous catheter. A few hours after this intervention, a clear clinical improvement could be observed. Since this initial presentation, the patient was admitted to our hospital several times with the same ileus symptoms. Each of the episodes was successfully and rapidly treated by this high-caloric parenteral nutrition therapy. The reproducible rapid clinical improvement after starting parenteral nutrition supports the hypothesis that an optimal energy supply is the key therapy not only for cerebral but also for gastrointestinal symptoms in patients with MELAS syndrome.

Current guidelines favor the use of chelating agents (d-penicillamine, trientine) in first line therapy of symptomatic Wilson disease patients. Development of chelator induced immunological adverse events are a concern especially under d-penicillamine therapy. This study assessed the prevalence of co-existing or therapy-related immune-mediated diseases in Wilson disease patients, and evaluated the role of antinuclear antibodies in therapy monitoring. We retrospectively analyzed 235 Wilson disease patients. Medical regimens were classified and analyzed in relation to adverse events and antinuclear antibody courses. Coexisting immune-mediated diseases were evident in 19/235 (8.1 %) patients, of which 13/235 (5.5 %) had pre-existing autoimmune diseases. Six patients (2.6 %) developed an autoimmune disease under therapy, all of them under long-term d-penicillamine treatment. Data relating to antinuclear antibody courses during treatment and adverse events were available for patients treated with d-penicillamine (n = 91), trientine (n = 58), and zinc salts (n = 58). No significant increase in antinuclear antibody titers in patients treated with d-penicillamine (16/91; 17.6 %), trientine (12/58; 20.7 %), and zinc (7/58; 12.1 %) were found. Under long-term d-penicillamine therapy a minority of patients developed immune-mediated disease. Elevations in antinuclear antibodies were found frequently, but no correlations were evident between increases in antinuclear antibodies and the development of immune-mediated diseases or medical regimes. Thus, the value of antinuclear antibodies for monitoring adverse events under chelator therapy seems to be limited.

We compared the bone mineral density (BMD) of adult Wilson disease (WD) patients (n = 148), with an age- and gender-matched healthy control population (n = 148). Within the WD cohort, correlations of BMD with WD disease parameters, lab results, type of treatment and known osteoporosis risk factors were analysed.Hip and lumbar spine absolute BMD and T-score were measured by dual-energy X-ray absorptiometry. Osteoporosis and osteopenia were defined as a T-score ≤ -2.5, and between -1 and -2.5, respectively.There were significantly more subjects with abnormal T-scores in the WD population (58.8%) than in the control population (45.3%) (χ(2) = 6.65, df = 2, p = 0.036), as there were 50.0% osteopenic and 8.8% osteoporotic WD patients, vs. 41.2% and 4.1%, respectively, in the controls. Especially L2-L4 spine BMD measurements (BMD and T-scores) differed significantly between the WD population and matched controls. L2-L4 spine BMD for WD patients was on average 0.054 g/cm(2) (5.1%) lower than in matched normal controls (0.995 ± 0.156 vs 1.050 ± 0.135; p = 0.002). We found no significant correlation between BMD values and any of the WD disease parameters (e.g. the severity of liver disease), lab results, type of treatment or known osteoporosis risk factors. Duration of D-penicillamine treatment was negatively correlated with femoral BMD value, but in a clinically irrelevant manner, compared to age and gender. Importantly, BMD remained significantly lower in WD patients (n = 89) vs. controls after excluding WD patients with cirrhosis (p = 0.009).Our study suggests that WD is intrinsically associated with bone demineralisation.

Introduction Wilson disease (WD) is an inherited disorder of human copper metabolism, characterised by accumulation of copper predominantly in the liver and brain, leading to severe hepatic and neurological disease. Interesting findings in animal models of WD (Atp7b-/- and LEC rats) showed altered lipid metabolism with a decrease in the amount of triglycerides and cholesterol in the serum. However, serum lipid profile has not been investigated in large human WD patient cohorts to date. Patients and Methods This cohort study involved 251 patients examined at the Heidelberg and Dresden (Germany) University Hospitals. Patients were analysed on routine follow-up examinations for serum lipid profile, including triglycerides, cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL). Data on these parameters at time of diagnosis were retrieved by chart review where available. For statistical testing, patients were subgrouped by sex, manifestation (hepatic, neurological, mixed and asymptomatic) and treatment (D-penicillamine, trientine, zinc or combination). Results A significant difference in total serum cholesterol was found in patients with hepatic symptoms, which diminished under therapy. No alterations were observed for HDL, LDL and triglycerides. Conclusion Contradictory to previous reports using WD animal models (Atp7b-/- and LEC rats), the most obvious alteration in our cohort was a lower serum cholesterol level in hepatic-affected patients, which might be related to liver injury. Our data suggested unimpaired cholesterol metabolism in Wilson disease under therapy, independent of the applied medical treatment.

Wilson disease (WD) is a rare inherited disorder of copper metabolism, which can lead to severe liver failure and to a variety of neuropsychiatric symptoms. Previous animal studies and case reports suggest that hepatic iron overload and alterations in iron processing are associated with WD. The aim of this study was the assessment of iron metabolism and of the frequency of the most common HFE gene polymorphisms in WD patients. Patients and methods Data from 143 patients with WD were analysed. Clinical presentation, liver function and iron metabolism parameters were recorded. Blood samples of the patients were analysed for HFE gene alterations (H63D; C282Y). Twenty-seven liver biopsies of these patients were studied with regard to iron content and fibrosis score. Results Contrary to previous reports of HFE gene polymorphisms in WD patients, in our cohort the allele frequencies (C282Y: 2.1%; H63D: 7.3%) were in line with frequencies obtained for general population. Male WD patients with decreased serum ceruloplasmin (Cp), showed increased serum ferritin levels. Hepatic iron content was normal in most cases. Discussion Male patients with very low Cp serum concentrations showed slightly elevated median serum ferritin concentrations, probably related to lack of ferroxidase acitivity. However, in consideration of absolute numbers of ferritin concentrations, these changes seem to be of minor clinical relevance.