Management, vaccination status and COVID-19 morbidity of patients with Gaucher disease in Germany during the COVID-19 pandemic.

BACKGROUND: Continuation of standard management of Gaucher disease (GD) has been challenging during the COVID-19 pandemic, resulting in infrequent/missed infusions and follow-up appointments. Little data are available on the consequences of these changes and on the SARS-CoV-2 vaccinations in German GD patients. METHODS: A survey with 22 questions about GD management during the pandemic was sent to 19 German Gaucher centres. It was answered by 11/19 centres caring for 257 GD patients (almost ¾ of the German GD population); 245 patients had type 1 and 12 had type 3 GD; 240 were ≥ 18 years old. RESULTS: Monitoring intervals were prolonged in 8/11 centres from a median of 9 to 12 months. Enzyme replacement therapy (ERT) was changed to home ERT in 4 patients and substituted by oral substrate reduction therapy (SRT) in 6 patients. From March 2020 to October 2021, no serious complications of GD were documented. Only 4 SARS-CoV-2 infections were reported (1.6%). Two infections were asymptomatic and two mild; all occurred in adult type 1, non-splenectomized patients on ERT. Vaccination rate in adult GD was 79.5% (95.3% mRNA vaccines). Serious vaccination complications were not reported. CONCLUSIONS: The COVID-19 pandemic has lowered the threshold for switching from practice- or hospital-based ERT to home therapy or to SRT. No major GD complication was documented during the pandemic. Infection rate with SARS-CoV-2 in GD may rather be lower than expected, and its severity is mild. Vaccination rates are high in GD patients and vaccination was well tolerated.

Survey to estimate the prevalence of type 2 diabetes mellitus in hospital patients in Germany by systematic HbA1c measurement upon admission.

OBJECTIVES: The objective of this survey was to estimate the prevalence of type 2 diabetes mellitus (T2DM) in hospitalised patients ≥55 years based on routine HbA1c measurement upon admission, using the diagnosis algorithm according to the German National Diabetes Care Guideline. DESIGN: Non-interventional survey. SETTING: Four German maximum care hospitals. POPULATION: Consecutive patients ≥55 years of age admitted to hospital. MAIN OUTCOME MEASURES: Participating hospitals measured HbA1c upon admission and applied the algorithm for diagnosing T2DM per the clinical recommendations of the American Diabetes Association (ADA) and the German National Diabetes Care Guideline as part of the clinical routine and allocated patients to three diagnostic categories: T2DM, increased risk for T2DM, no T2DM. RESULTS: Between Oct 2014 and May 2015, the survey documented data from 6092 patients; the analyses included 5820 patients fulfilling validity criteria (95.5%). Of these, 1906 (32.7%) had a known history of T2DM. Among the 3914 remaining patients, 2181 had no T2DM (55.8%), 1180 an increased risk for T2DM (30.1%) and 553 unrecognised T2DM (14.1%; 95% CI: 13.1%-15.3%). The overall prevalence of known and unrecognised T2DM was 42.3% (95% CI: 41.0%-43.5%). Patients with previously unrecognised T2DM were admitted to hospital predominantly for cardiac disorders (21.9%), nervous system disorders such as cerebral infarction (15.0%) and infections/infestations (13.4%). CONCLUSIONS: This survey revealed an overall prevalence of known and unrecognised T2DM of more than 40%. Among patients with unrecognised T2DM on admission, the prevalence of T2DM was 14%. These data indicate that systematic documentation of T2DM in in-patients is clinically useful. Hospitals should consider using the diagnostic algorithm and to streamline pathways of care to secure adequate care considering patients' diabetic risk profiles, and to manage related additional costs.

Chronic obstructive pulmonary disease and diabetes mellitus: a systematic review of the literature.

The objective of this systematic review was to discuss our current understanding of the complex relationship between chronic obstructive pulmonary disease (COPD) and type-2 diabetes mellitus (T2DM). We performed a systematic search of the literature related to both COPD and diabetes using PubMed. Relevant data connecting both diseases were compiled and discussed. Recent evidence suggests that diabetes can worsen the progression and prognosis of COPD; this may result from the direct effects of hyperglycemia on lung physiology, inflammation or susceptibility to bacterial infection. Conversely, it has also been suggested that COPD increases the risk of developing T2DM as a consequence of inflammatory processes and/or therapeutic side effects related to the use of high-dose corticosteroids. In conclusion, although there is evidence to support a connection between COPD and diabetes, additional research is needed to better understand these relationships and their possible implications.

[Clinical acute and emergency medicine curriculum-focus on internal medicine : Recommendations for advanced training in internal medicine in the emergency department]. / Curriculum Klinische Akut- und Notfallmedizin ­ Schwerpunkt Innere Medizin : Empfehlung zu Weiterbildungsinhalten der Inneren Medizin in der Notaufnahme.

In Germany, physicians qualify for emergency medicine by combining a specialty medical training-e.g. internal medicine-with advanced training in emergency medicine according to the statutes of the State Chambers of Physicians largely based upon the Guideline Regulations on Specialty Training of the German Medical Association. Internal medicine and their associated subspecialities represent an important column of emergency medicine. For the internal medicine aspects of emergency medicine, this curriculum presents an overview of knowledge, skills (competence levels I-III) as well as behaviours and attitudes allowing for the best treatment of patients. These include general aspects (structure and process quality, primary diagnostics and therapy as well as indication for subsequent treatment; resuscitation room management; diagnostics and monitoring; general therapeutic measures; hygiene measures; and pharmacotherapy) and also specific aspects concerning angiology, endocrinology, diabetology and metabolism, gastroenterology, geriatric medicine, hematology and oncology, infectiology, cardiology, nephrology, palliative care, pneumology, rheumatology and toxicology. Publications focussing on contents of advanced training are quoted in order to support this concept. The curriculum has primarily been written for internists for their advanced emergency training, but it may generally show practising emergency physicians the broad spectrum of internal medicine diseases or comorbidities presented by patients attending the emergency department.

[Hypercholesterolemia - who, when, how to treat?] / Hypercholesterinämie ­ Wen, wann, wie behandeln?

In recent years, clinical scientific data on LDL cholesterol and atherosclerosis has led to lowering of LDL-C targets and the expansion of the indication for lipid drug therapy to larger populations or patients. The calculators SCORE2 and SCORE-OP were newly developed to calculate the cardiovascular risk in primary prevention. When assessing the cardiovascular risk of patients, in addition to e.g., pre-existing cardiovascular disease, familial hypercholesterolaemia and type II diabetes, type I diabetes, diabetic complications, renal insufficiency and subclinical arteriosclerosis are also considered. Statins are the basic therapy for hypercholesterolemia. Alternative medication are ACL inhibitors e.g., Bempedoic acid and Inclisiran which represent new drug therapy options for statin intolerance. Nevertheless, a dietary intervention belongs at the beginning of every lipid-lowering therapy.

Characterisation and differential diagnosis of neurological complications in adults with phenylketonuria: literature review and expert opinion.

OBJECTIVE: Phenylketonuria (PKU) is a rare inherited metabolic disorder characterised by elevated phenylalanine (Phe) concentrations that can exert neurotoxic effects if untreated or upon treatment discontinuation. This systematic review supported by expert opinion aims to raise awareness among the neurological community on neurological complications experienced by adults with PKU (AwPKU). METHODS: The PubMed database was searched for articles on neurological signs and symptoms in AwPKU published before March 2022. In addition, two virtual advisory boards were held with a panel of seven neurologists and two metabolic physicians from Germany and Austria. Findings are supported by three illustrative patient cases. RESULTS: Thirty-nine articles were included. Despite early diagnosis and treatment, neurological signs and symptoms (e.g. ataxia, brisk tendon reflexes, tremor, visual impairment) can emerge in adulthood, especially if treatment has been discontinued after childhood. In PKU, late-onset neurological deficits often co-occur with cognitive impairment and psychiatric symptoms, all of which can be completely or partially reversed through resumption of treatment. CONCLUSION: Ideally, neurologists should be part of the PKU multidisciplinary team, either to bring lost to follow-up patients back to clinic or to manage symptoms in referred patients, considering that symptoms are often reversible upon regaining metabolic control. The current findings have been combined in a leaflet that will be disseminated among neurologists in Germany and Austria to create awareness.

The German CaRe high registry for familial hypercholesterolemia - Sex differences, treatment strategies, and target value attainment.

Background and aims: Familial hypercholesterolemia (FH) is among the most common genetic disorders in primary care. However, only 15% or less of patients are diagnosed, and few achieve the goals for low-density lipoprotein cholesterol (LDL-C). In this analysis of the German Cascade Screening and Registry for High Cholesterol (CaRe High), we examined the status of lipid management, treatment strategies, and LDL-C goal attainment according to the ESC/EAS dyslipidemia guidelines. Methods: We evaluated consolidated datasets from 1501 FH patients diagnosed clinically and seen either by lipid specialists or general practitioners and internists. We conducted a questionnaire survey of both the recruiting physicians and patients. Results: Among the 1501 patients, 86% regularly received lipid-lowering drugs. LDL-C goals were achieved by 26% and 10% of patients with atherosclerotic cardiovascular disease (ASCVD) according to the 2016 and 2019 ESC/EAS dyslipidemia guidelines, respectively. High intensity lipid-lowering was administered more often in men than in women, in patients with ASCVD, at higher LDL-C and in patients with a genetic diagnosis of FH. Conclusions: FH is under-treated in Germany compared to guideline recommendations. Male gender, genetic proof of FH, treatment by a specialist, and presence of ASCVD appear to be associated with increased treatment intensity. Achieving the LDL-C goals of the 2019 ESC/EAS dyslipidemia guidelines remains challenging if pre-treatment LDL-C is very high.

[Triglycerides - assessment as risk factor and therapeutic goals]. / Triglyzeride ­ Aktuelle Bewertung als Risikomarker und Therapieziele.

Elevated triglycerides and their lipidological consequences (small, dense LDL, residual particles (remnants), reduced HDL cholesterol) are an important and independent cardiovascular risk factor. Particularly in diabetes mellitus, hypertriglyceridemia is regarded as the main cause of high cardiovascular morbidity and mortality; very high triglyceride levels can cause acute pancreatitis. This article provides an overview of the current scientific status of the pathogenesis and clinical significance of hypertriglyceridemia.

Photosensitivity and cGAS-Dependent IFN-1 Activation in Patients with Lupus and TREX1 Deficiency.

The exonuclease TREX1 safeguards the cells against DNA accumulation in the cytosol and thereby prevents innate immune activation and autoimmunity. TREX1 mutations lead to chronic DNA damage and cell-intrinsic IFN-1 response. Associated disease phenotypes include Aicardi‒Goutières syndrome, familial chilblain lupus, and systemic lupus erythematosus. Given the role of UV light in lupus pathogenesis, we assessed sensitivity to UV light in patients with lupus and TREX1 mutation by phototesting, which revealed enhanced photosensitivity. TREX1-deficient fibroblasts and keratinocytes generated increased levels of ROS in response to UV irradiation as well as increased levels of 8-oxo-guanine lesions after oxidative stress. Likewise, the primary UV-induced DNA lesions cyclobutane pyrimidine dimers were induced more strongly in TREX1-deficient cells. Further analysis revealed that single-stranded DNA regions, frequently formed during DNA replication and repair, promote cyclobutane pyrimidine dimer formation. Together, this resulted in a strong UV-induced DNA damage response that was associated with a cGAS-dependent IFN-1 activation. In conclusion, these findings link chronic DNA damage to photosensitivity and IFN-1 production in TREX1 deficiency and explain the induction of disease flares on UV exposure in patients with lupus and TREX1 mutation.

Scavenger receptor CD36 mediates uptake of high density lipoproteins in mice and by cultured cells.

The mechanisms of HDL-mediated cholesterol transport from peripheral tissues to the liver are incompletely defined. Here the function of scavenger receptor cluster of differentiation 36 (CD36) for HDL uptake by the liver was investigated. CD36 knockout (KO) mice, which were the model, have a 37% increase (P = 0.008) of plasma HDL cholesterol compared with wild-type (WT) littermates. To explore the mechanism of this increase, HDL metabolism was investigated with HDL radiolabeled in the apolipoprotein (¹²5I) and cholesteryl ester (CE, [³H]) moiety. Liver uptake of [³H] and ¹²5I from HDL decreased in CD36 KO mice and the difference, i. e. hepatic selective CE uptake ([³H]¹²5I), declined (-33%, P = 0.0003) in CD36 KO compared with WT mice. Hepatic HDL holo-particle uptake (¹²5I) decreased (-29%, P = 0.0038) in CD36 KO mice. In vitro, uptake of ¹²5I-/[³H]HDL by primary liver cells from WT or CD36 KO mice revealed a diminished HDL uptake in CD36-deficient hepatocytes. Adenovirus-mediated expression of CD36 in cells induced an increase in selective CE uptake from HDL and a stimulation of holo-particle internalization. In conclusion, CD36 plays a role in HDL uptake in mice and by cultured cells. A physiologic function of CD36 in HDL metabolism in vivo is suggested.

[Diabetic Dyslipidemia]. / Dyslipidämie bei Diabetes.

Diabetic dyslipidemia is a major cause of the increased cardiovascular risk in diabetes. This lipid disorder is characterized by increased plasma triglycerides, increased remnant particles of triglyceride-rich lipoproteins, small dense LDL particles and reduced HDL cholesterol. The main pathogenetic triggers are obesity and insulin resistance. In addition to lifestyle measures, statins, ezetimibe and eventually PCSK9 inhibitors are available to treat diabetic dyslipidemia and to reduce the cardiovascular risk. Fibrates and omega-3 fatty acids currently do not play a significant therapeutic role. A consistent and target-oriented therapy of diabetic dyslipidemia is a prerequisite for a cardiovascular risk reduction in patients with diabetes, which has been well proven in clinical studies.

[Pathophysiological principles of dyslipoproteinaemia]. / Pathophysiologische Prinzipien von Dyslipoproteinämien.

The effective reduction of atherogenic lipoproteins has contributed to the rate of atherosclerosis-related cardiovascular complications being approximately halved over the last 50 years. Nevertheless, cardiovascular disease will be the leading cause of death worldwide in the coming years. The focus of this review is on the clinical significance of the pathophysiology of changes in lipid and lipoprotein metabolism. Elevated levels of atherogenic lipoproteins are a causal risk factor for atherosclerotic cardiovascular disease. Primary forms of hypercholesterolaemia have a significantly higher ASCVD risk because of the already lifelong LDL elevation (higher cumulative LDL exposure for the vessel wall). Secondary changes in lipid and lipoprotein metabolism (e. g. in diabetes or hypothyroidism) must be excluded or treated. Regulatory key steps in the pathophysiology of lipid metabolism and atherosclerotic plaque are "drug targets" for existing and new lipid and lipoprotein modifying therapies.

[Obesity: ectopic fat distribution and the heart]. / Adipositas: ektope Fettverteilung und Herz.

The metabolic syndrome is usually associated with insulin resistance and visceral fat distribution, which appear to play a direct role in the development of clinical criteria of metabolic syndrome, like elevation of arterial blood pressure and dyslipidemia. In this review, the authors will first introduce the concept, that insulin resistance and increased visceral adipose tissue are also regularly associated with an abnormal or ectopic accumulation of lipids in nonadipocytes, like steatosis hepatis. Then, they will provide some evidence that epicardial fat can be associated with insulin resistance in a similar fashion as visceral intraabdominal fat. Furthermore, epicardial fat might directly affect the vessels and function of the heart. Accordingly, ectopic accumulation of fat within cardiac muscle cells can impair their function and possibly be related to heart failure. These new relations between obesity, fat distribution and cardiac function might help to identify and treat individuals at risk earlier and more appropriately.

Deficient knowledge in adult Turner syndrome care as an incentive to found Turner centers in Germany.

OBJECTIVE: Turner syndrome (TS) is characterized by the complete or partial loss of the second sex chromosome and associated with a wide range of clinical manifestations. We aimed to assess the medical care of adult patients with TS in Germany. DESIGN: Retrospective multicenter observational study. METHODS: Data were collected from medical records of 258 women with TS treated between 2001 and 2017 in five non-university endocrinologic centers in Germany. RESULTS: Mean age was 29.8 ± 11.6 years, mean height 152 ± 7.7 cm, and mean BMI 26.6 ± 6.3 kg/m2. The karyotype was known in 50% of patients. Information on cholesterol state, liver enzymes, and thyroid status was available in 81-98% of women with TS; autoimmune thyroiditis was diagnosed in 37%. Echocardiography was performed in 42% and cardiac MRI in 8.5%, resulting in a diagnosis of cardiovascular disorder in 28%. Data on growth hormone therapy were available for 40 patients (15%) and data concerning menarche in 157 patients (61%). CONCLUSION: In 258 women with TS, retrospective analysis of healthcare data indicated that medical management was focused on endocrine manifestations. Further significant clinical features including cardiovascular disease, renal malformation, liver involvement, autoimmune diseases, hearing loss, and osteoporosis were only marginally if at all considered. Based on this evaluation and in accordance with recent guidelines, we compiled a documentation form facilitating the transition from pediatric to adult care and further medical management of TS patients. The foundation of Turner Centers in March 2019 will improve the treatment of TS women in Germany.

Give me A5 for lipoprotein hydrolysis!

APOA5 is a newly identified apolipoprotein that plays a crucial role in the regulation of plasma triglyceride levels. In several human studies, common APOA5 single nucleotide polymorphisms have been strongly associated with elevated plasma triglyceride levels. In this issue of the JCI, Marçais et al. report that the rare Q139X mutation in APOA5 leads to severe hypertriglyceridemia by exerting a dominant-negative effect on the plasma lipolytic system for triglyceride-rich lipoproteins. The presented data support the idea that the molecular mechanism of APOA5 function may include the enhancement of binding between lipoproteins and proteoglycans at the vascular wall and activation of proteoglycan-bound lipoprotein lipase.

Uptake of postprandial lipoproteins into bone in vivo: impact on osteoblast function.

Dietary lipids and lipophilic vitamins are transported by postprandial lipoproteins and are required for bone metabolism. Despite that, it remains unknown whether bone cells are involved in the uptake of circulating postprandial lipoproteins in vivo. The current study was performed to investigate a putative participation of bone in the systemic postprandial lipoprotein metabolism in mice, to identify potentially involved cell type populations and to analyze whether lipoprotein uptake affects bone function in vivo. As a model for the postprandial state, chylomicron remnants (CR) were injected intravenously into mice. Next to the liver and compared to other organs, bone appeared to be the second most important organ for the clearance of radiolabeled CR particles from the circulation in vivo. In addition, uptake of radiolabeled CR by primary murine osteoblasts and hepatocytes was quantified to be in a similar range in vitro. A complementary approach with fluorescently labeled CR and immunohistochemical staining for apoE proved that intact CR particles were taken up into bone and liver. Electron microscopy localization studies of bone sections revealed CR uptake into sinusoidal endothelial cells, macrophages and osteoblasts. The relative amount of radiolabeled CR uptake into femoral cortical bone, representing predominantly osteoblasts, and bone marrow, representing predominantly non-osteoblast cells, was within the same range. Most importantly, the injection of vitamin K1-enriched CR resulted in an increase of the degree of osteocalcin carboxylation in vivo while total osteocalcin concentrations remained unaffected, giving functional proof that osteoblasts process CR in vivo. In conclusion, here we demonstrate that bone is involved in the postprandial lipoprotein metabolism in mice. Osteoblasts participate in CR clearance from the circulation, which has a direct impact on the secretory function of osteoblasts.

Pregnancies in glycogen storage disease type Ia.

OBJECTIVE: Reports on pregnancies in women with glycogen storage disease type Ia (GSD-Ia) are scarce. Because of improved life expectancy, pregnancy is becoming an important issue. We describe 15 pregnancies by focusing on dietary treatment, biochemical parameters, and GSD-Ia complications. STUDY DESIGN: Carbohydrate requirements (milligrams per kilogram per minute), triglyceride and uric acid levels, liver ultrasonography, and creatinine clearance were investigated before, during, and after pregnancy. Data from the newborn infants were obtained from the records. RESULTS: In the first trimester, a significant increase in carbohydrate requirements was observed (P = .007). Most patients had acceptable triglyceride and uric acid levels during pregnancy. No increase in size or number of adenomas was seen. In 3 of 4 patients, a decrease in glomerular filtration rate was observed after pregnancy. In 3 pregnancies, lactic acidosis developed during delivery with severe multiorgan failure in 1. All but 1 of the children are healthy and show good psychomotor development. CONCLUSION: Successful pregnancies are possible in patients with GSD-Ia, although specific GSD-Ia-related risks are present.

Dietary methionine effects on plasma homocysteine and HDL metabolism in mice.

The effects of dietary manipulation of folate and methionine on plasma homocysteine (Hcy) and high-density lipoprotein cholesterol (HDL-C) levels in wild-type and apolipoprotein-E-deficient mice were determined. A low-folate diet with or without folate and/or methionine supplementation in drinking water was administered for 7 weeks. Fasted Hcy rose to 23 microM on a low-folate/high-methionine diet, but high folate ameliorated the effect of high methionine on fasted plasma Hcy to approximately 10 microM. Determination of nonfasted plasma Hcy levels at 6-h intervals revealed a large diurnal variation in Hcy consistent with a nocturnal lifestyle. The daily average of nonfasted Hcy levels was higher than fasted values for high-methionine diets but lower than fasted values for low-methionine diets. An acute methionine load by gavage of fasted mice increased plasma Hcy 2.5 h later, but mice that had been on high-methionine diets had a lower fold induction. Mice fed high-methionine diets weighed less than mice fed low-methionine diets. Based on these results, two solid-food diets were developed: one containing 2% added methionine and the other containing 2% added glycine. The methionine diet led to fasted plasma Hcy levels of >60 microM, higher than those with methionine supplementation in drinking water. Mice on methionine diets had >20% decreased body weights and decreased HDL-C levels. An HDL turnover study demonstrated that the HDL-C production rate was significantly reduced in mice fed the methionine diet.