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1.
Background
The prevalence of nonalcoholic fatty liver disease (NAFLD) continues to increase. An estimated 25?% of the adult population worldwide and more than 50?% of patients with type 2 diabetes or obesity have NAFLD.Objectives
An overview of the natural history and complications of NAFLD is provided.Materials and methods
Following an extensive literature research, the current guidelines, expert opinions and studies focusing on NAFLD were analyzed.Results
The term NAFLD includes the entities nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), which are defined by histological parameters. Importantly, “benign” NAFL may progress towards more aggressive NASH with the development of liver fibrosis. The grade of fibrosis is the most important predictor for overall and liver-related mortality in NAFLD patients and patients suffering from type 2 diabetes mellitus have a higher risk for progressive fibrosis. Progressive NAFLD can develop into liver cirrhosis with the potential of fatal complications of portal hypertension and liver failure. Notably, hepatocellular carcinoma may also develop in noncirrhotic NAFLD. Furthermore, NAFLD is an independent risk factor for cardiovascular disease and extrahepatic malignancy, which represent the two most frequent causes of death in NAFLD patients. To date, a lifestyle intervention aiming at weight reduction and increased physical activity is the first-line therapy for NAFLD.Conclusions
NAFLD is one of the most common liver diseases and is associated with relevant hepatic and extrahepatic morbidity and mortality.2.
Background
Diabetes is associated with a two- to three-fold increased risk of cardiovascular events, and cardiovascular disease is the leading cause of death in patients with diabetes. The association with cardiovascular disease is particularly strong in patients with type 2 diabetes who, in addition to hyperglycemia, exhibit other atherogenic stigmata of insulin resistance such as abdominal obesity, dyslipidemia, and arterial hypertension. However, patients with type 1 diabetes are also at an increased risk of cardiovascular events over the long term, which is partly explained by direct glucotoxic damage to the endothelium.Prophylaxis
Lowering glucose both in type 2 and type 1 diabetes over long observational periods has been found to be associated with a decreased risk of cardiovascular events; however, at least in the short term glucose lowering is less efficacious in decreasing cardiovascular risk than lowering LDL (low density lipoprotein) cholesterol or normalizing blood pressure. Overly aggressive glucose lowering at the price of frequent hypoglycemia can even negatively affect cardiovascular outcomes because hypoglycemia is associated with an increased cardiovascular event risk.Important cardiovascular diseases in diabetes
In addition to coronary diseases, the increased heart failure risk of patients with diabetes has attracted increasing interest.3.
H. Kahles 《Der Diabetologe》2016,12(4):232-239
Objective
Vitamin D is not only essential for bone metabolism, but also has an additional immune-modulating effect on the immune system, which may play a role in the pathogenesis of several endocrine diseases.Aim
In this review, we debate the effects and recommendations of vitamin D supplementation, especially in the context of the nonclassical effects.Results
Evidence from animal model and epidemiological studies supports a role for vitamin D in many endocrine conditions. Vitamin D supplementation may play a role in the prevention of type 1 diabetes mellitus.Conclusions
Although observational studies support a potential role of vitamin D in endocrine disease, high-quality evidence from clinical trials to establish a place for vitamin D supplementation in optimizing endocrine health are lacking. Based on observational studies, vitamin D deficiency should probably be avoided in individuals at high risk of developing type 1 diabetes, specifically in early life.4.
J. de Heer 《Der Diabetologe》2016,12(7):461-467
The role of the liver in carbohydrate metabolism
The liver plays a central role in carbohydrate metabolism. After food ingestion, glucose is taken up into the liver to be stored as glycogen, to be subject to glycolysis or conversion to fatty acids. In the fasted state, endogenous glucose is produced by degradation of glycogen or gluconeogenesis to warrant the peripheral tissues with a continuous supply of energy substrates.Glucose homeostasis
Glucose homoeostasis is based on the complex interplay of numerous factors, of which the pancreatic hormones insulin and glucagon are of particular importance. By both modification of gene expression and direct posttranslational effects on enzyme activity, they influence glucose metabolism and preclude extreme glucose variation. The exact molecular mechanisms underlying this regulation are still not fully understood.Conclusion
Considering the increasing prevalence of type 2 diabetes mellitus and obesity, as well as nonalcoholic fatty liver disease, efforts to explore the molecular mechanisms underlying the regulation of glucose metabolism should be intensified in order to discover new pharmacological targets to optimize treatment.5.
J. H. Stupin 《Der Diabetologe》2016,12(1):13-21
Background
Exclusive breastfeeding provides optimal nutrition and health protection for mothers and their offspring.Health benefits of breastfeeding for diabetic women
Diabetic mothers who breastfeed in the first 4 months postpartum have improved metabolic parameters, e.g., lower blood lipids, lower blood glucose, and greater insulin sensitivity. Studies have reported that longer duration of breastfeeding in women with a history of gestational diabetes may reduce long-term risks of cardiometabolic disease, including type 2 diabetes.Health benefits of breastfeeding for children
Children of diabetic mothers may benefit from breastfeeding in that they have lower rates of hypoglycemia immediately after birth and lower rates of obesity in later life. It has been suggested that the latter benefits may only be observed if breastfeeding is continued beyond a certain period where breastmilk composition would have normalized over time.Conclusion
Due to several risk factors and pathophysiological mechanisms, diabetic women are less likely and for a shorter duration to breastfeed. Therefore, diabetic women should be encouraged to breastfeed exclusively for at least 4–6 months to improve maternal and child morbidity, to prevent noncommunicable diseases in later life, and to decrease health care costs.6.
C. Lebherz 《Der Diabetologe》2016,12(2):80-87
Background
Patients with type 2 diabetes are at increased risk of developing cardiovascular diseases and have been shown to greatly benefit from tight control not only of the blood glucose but also of LDL (low density lipoprotein) cholesterol levels.Cardiovascular risk reduction
So far an aggressive treatment regimen with potent statins has been recommended. The IMPROVE IT study caused a paradigm shift in that it showed additional cardiovascular risk reduction if LDL cholesterol was reduced below target levels independent of the pleiotropic statin actions. These effects were even more significant in patients with type 2 diabetes.Conclusions
Therefore even though statins are still first choice, a combination with ezetimibe or the novel PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors is warranted to further reduce cardiovascular risk. As secondary targets, non-HDL (high density lipoprotein) cholesterol or ApoB (apolipoprotein B) levels serve as surrogate markers for atherogenic lipid particles. Depending on the individual lipid levels, combination therapy with fibrates or ω?3 fatty acids might be of benefit.7.
Thorsten Feige 《Der Diabetologe》2018,14(7):465-469
Background
Most type 1 diabetes mellitus patients are not capable of achieving close to normal glucose levels and thus face a constant risk of severe hypoglycemia and diabetic ketoacidosis.Objectives
Patients develop their own personal non-approved medical devices to compensate for gaps in the existing medical technology.Materials and methods
Current studies are assessed and basic work and challenges are discussed.Results
The authorization of such systems from patients themselves results in the development of medical devices suitable for use but approved only based on freely available algorithms. Legal framework conditions, lack of standards on the interoperability of medical devices and uncertainties about future technology trends are giving rise to ongoing controversies.Conclusions
There is a need to validate these new approaches, agree upon success criteria and provide solid evidence of their effectiveness.8.
Background
The gut microbiome has emerged as a key player in the modulation of the immune system and metabolism. Changes in the composition of the gut microbial ecosystems have been reported to be associated with metabolic diseases but also with the development and progression of cardiovascular diseases, inflammatory bowel disease, certain types of cancer and psychiatric diseases.Objective
The role of the gut microbiome in the pathophysiology of obesity and type 2 diabetes, and treatment approaches based thereon are discussed.Microbiome and pathophysiology
The pathophysiology in humans is not entirely understood. Studies in mice suggest a strong causal link between changes in the microbiome and the development of metabolic diseases. Potential mechanisms how the microbiome is linked to diseases of the host include signaling through lipopolysaccharides from gram-negative bacteria and interactions with the host immune system, fermentation of indigestible fiber to short chain fatty acids, modulation of bile acids, and bile acid signaling. Interactions between gut microbiota, its products, and the immune system may lead to an increased gut permeability resulting in visceral fat and liver inflammation with subsequent systemic subclinical inflammation (leaky gut hypothesis). Moreover, host-specific factors and environmental factors have been discussed to have a role.Conclusion
Increasing knowledge in this area could contribute to the treatment of obesity and type 2 diabetes with fecal or targeted microbiota transplantation.9.
Background
A paradigm shift in therapeutic management of sigmoid diverticulitis has occurred with increasing reluctance regarding surgical treatment. While there is still a clear surgical indication in cases of complications such as strictures, fistulas, perforations or persistent bleeding, an elective indication for sigmoid resection is not clearly defined, especially in chronic-recurrent courses.Objectives
The main aspects of elective surgery for sigmoid diverticulitis are discussed.Materials and methods
Relevant studies were selected and the reference lists from those studies were also searched.Results
An uncomplicated form of acute diverticulitis (Classification of Diverticular Disease [CDD] type 1a/b) is not an indication for surgery (exception: immunosuppressed patients). In acute complicated diverticulitis (except free perforation), elective surgery should only be recommended in case of a macroabscess (CDD type 2b). In chronic recurrent, uncomplicated diverticulitis (CDD typ 3a/b), indication for surgery should be individualized. However, indications for elective surgery are complications such as strictures or fistulas (CDD type 3c). Recent data show that patients with type 2b and 3 diverticulitis benefit from elective surgery, especially in terms of quality of life.Conclusions
Although the majority of patients with diverticulitis can be treated conservatively, elective surgery should also be considered in terms of better quality of life compared to conservative therapy.10.
D. F. Braus 《Der Diabetologe》2016,12(5):346-351
Background
One of four patients with type 2 diabetes mellitus (T2DM) has clinically relevant depression. On the other hand, depression increases the risk for T2DM as well as micro- and macrovascular complications.Objectives
This association may reflect a shared pathophysiology consisting of complex bidirectional interactions, which may influence therapy and prognosis.Materials and methods
Recent findings, reviews and basic literature are analysed and an update is presented and discussed.Results
Overall, accumulating evidence indicates a metabolic–mood syndrome with a linkage that includes stress sensitivity, insulin resistance (IR), neurohormonal dysregulation and inflammation. IR alters dopamine turnover and causes depression-like behaviour. Furthermore IR is associated with worse memory performance. Metabolic risk influences neurodevelopment. However, cross-sectional data do not support a genetic association between T2DM and depression.Conclusions
T2DM may promote depression and interact with neurodevelopment and neurodegeneration. Comorbidity seems to be particularly toxic. Both prevention of T2DM in depressed patients and treatment of depression in T2DM are of considerable significance. Serotonin reuptake inhibition (SSRI) and psychotherapy are effective in the treatment of depression.11.
Background
Patients with type 2 diabetes are at increased risk of dying from cardiovascular (CV) complications despite optimal lipid-reducing and blood pressure-lowering treatments.Studies
ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Trial), VADT (Veterans Affairs Diabetes Trial), and ACCORD (Action to Control Cardiovascular Risk in Diabetes) have shown intensive glucose lowering to reduce risk of diabetes-related microvascular disease. However, these studies failed to show CV risk reduction by intensive glucose lowering. Only the 20-year follow-up data of UKPDS (UK Prospective Diabetes Study) suggest a long-term beneficial effect on macrovascular outcome in patients with newly diagnosed diabetes without prior CV disease. Since 2008 the Federal Drug Administration requires that new antidiabetes drugs undergo testing for CV outcomes to show cardiovascular safety. As a consequence many cardiovascular outcome trials with noninferiority designs have been initiated. Various trials with DDP-4 inhibitors (DPP: dipeptidylpeptidase) and GLP-1 agonists (GLP: glucagon-like peptide) could prove cardiovascular safety but did not show CV risk reduction. The very recently published landmark trial EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes Trial) could show for the first time that the antidiabetic drug SGLT-2 inhibitor empagliflozin (SGLT: sodium-dependent glucose transporter) reduces CV mortality in patients with type 2 diabetes at high risk for CV events after 3 years.Conclusions
From the results of the EMPA-REG OUTCOME trial, the underlying mechanisms are still not completely understood, since reduction of glucose, blood pressure, and body weight by empagliflozin cannot completely explain the beneficial effect on CV outcomes. Further studies are required to clarify this question.12.
Background
Nonalcoholic fatty liver disease (NAFLD) is defined by hepatocellular fat accumulation of more than 5?% (fatty liver, NAFL, steatosis) and also comprises steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. No specific drug treatment for NAFLD in type 2 diabetes mellitus (T2D) is approved.Methods
In a Medline search, randomized controlled trials on weight- and/or blood glucose-lowering therapies in NAFLD and T2D with the primary endpoints reduction of liver fat content and/or improvement in liver histology were identified.Results
Lifestyle modification (weight loss of >7?%) and bariatric surgery reduce inflammation and hepatocellular ballooning in NASH. Pioglitazone therapy can improve inflammation and ballooning in prediabetes or T2D within 6 months. This effect remains for at least 3 years. Liraglutide results in reduction of liver fat content and improvement of inflammation and ballooning in NASH, with fewer liraglutide-treated individuals showing an aggravation of fibrosis. Metformin, sulfonylureas and insulin have no clinically relevant effect on liver fat content and liver histology.Conclusions
Beyond lifestyle modification, the benefit of pioglitazone, liraglutide and bariatric surgery for reduction of liver fat content and NASH must be balanced against the risks and costs. Further specific therapeutic recommendations will require studies on novel drugs and longer-term controlled prospective trials.13.
T. Luedde C. Roderburg M. Binnebösel U. P. Neumann C. Trautwein 《Der Gastroenterologe》2016,11(6):479-488
Background
Liver metastases occur in every second patient with colorectal carcinoma.Objectives
Therapeutic options for patients with hepatic metastases from colorectal cancer (CRC), specific indications, and interdisciplinary concepts are presented.Methods
Based on the current literature and guidelines, novel study results and expert opinions are discussed.Results
Surgical resection of primarily resectable liver metastases from CRC is standard and allows long-term control or healing in up to 36?% of cases. Adjuvant chemotherapy after resection can be performed, but the current study data are insufficient to generally recommend perioperative chemotherapy in this setting. Secondary resectability of primarily irresectable metastases can be reached by interventional induction of liver hypertrophy or neoadjuvant chemotherapy (conversion therapy). New study results suggested a benefit for more intensive combination chemotherapies, but possible side effects have to be considered. Finally, locoregional ablative therapies have gained increasing importance in the multimodal treatment of hepatic CRC metastases, and current clinical trials suggest a possible benefit of combination strategies together with chemotherapy and surgery even in early therapy lines.Conclusions
Liver metastases from CRC require an multidisciplinary approach. Therefore, patients should be presented to a multidisciplinary tumor board not only at the beginning, but also along different therapy lines.14.
Background
Fractures are common in the elderly, have a detrimental effect on the quality of life and are associated with increased mortality. Patients with type 2 diabetes have a further moderately elevated risk of fractures although they show a comparable or even increased bone mineral density. This is clinically relevant due to the widespread occurrence of type 2 diabetes.Objectives
Possible causes and mechanisms of the elevated risk of fractures in diabetics are discussed and advice for clinical management is given taking the higher fracture risk in this population into account.Material and methods
This article is based on the currently available review articles on type 2 diabetes and bone health. Furthermore, the most relevant original articles on this topic are cited.Results and discussion
Increased falls related to diabetic complications, longer disease duration and lack of glucose control are associated with a higher fracture risk in patients with type 2 diabetes. Even though the bone density is normal, a higher cortical porosity and alterations in collagen structure reduce bone quality. Some oral antidiabetic agents have detrimental effects on bone metabolism. General recommendations for optimal calcium and vitamin D intake in patients without diabetes are also appropriate in this population. Evidence regarding a possible altered effectiveness of pharmacological treatment of osteoporosis in diabetics is limited. According to post hoc analyses this does not appear to be the case; however, treatment of osteoporosis in patients with type 2 diabetes follows the current guidelines for non-diabetic postmenopausal women and men with osteoporosis.15.
N. Junge J. Dingemann C. Petersen M. P. Manns N. Richter J. Klempnauer U. Baumann A. Schneider 《Der Internist》2018,59(11):1146-1156
Background
A growing number of patients with biliary atresia and congenital cholestatic syndromes are reaching adulthood. These patients often have a number of typical medical features, including specific characteristics of liver transplantation medicine.Objective
What are the special features in the care of adults suffering from liver diseases with manifestation in childhood and adolescence, both before and after liver transplantation (LTX). How does the progression of individual diseases differ depending on age at manifestation? What are specific aspects following pediatric LTX?Patients and methods
Evaluation and discussion of existing guidelines and recommendations of the individual disciplines and professional societies as well as the current literature. Joint discussion of the recommendations between disciplines (gastroenterology, pediatric gastroenterology, surgery). Inclusion of center-specific experiences with transition from existing transition outpatient departments and training.Results
The recommendations are presented specifically for each disease. Special features in individual diseases after LTX are also discussed. Diagnosis-independent general treatment concepts for cholestasis and chronic liver disease are presented.Conclusion
Patients with biliary atresia and congenital cholestatic syndromes have a life-long chronic liver disease with and without LTX and require specific medical care. The patients benefit from the pooling of expertise in the individual disciplines.16.
Background
Incretin-based glucose-lowering medications (IBGLM) exert their effects exclusively (GLP-1-RA [GLP: glucagon-like peptide, RA: receptor agonist]) or mainly (DPP-4 inhibitors [DPP: dipeptidylpeptidase]) by enhancing the stimulation of GLP-1 receptors. In contrast to established glucose-lowering drug classes, they are less likely to increase body weight or to provoke hypoglycaemic episodes. These properties promoted the hope that incretin-based glucose-lowering medications will have a positive effect on the elevated cardiovascular risk in patients with type 2 diabetes. GLP-1 receptors have also been found in the cardiovascular system.Effects of IBGSM
Clinical studies have described weight loss, lowering of systolic blood pressure, a slightly increased heart rate (GLP-1-RA) and a favourable influence on serum lipoproteins (all IBGLM). Initial results of a slightly reduced rate in cardiovascular events could not be confirmed in dedicated cardiovascular safety studies, in which mainly “neutral” results concerning cardiovascular events (myocardial infarction, stroke, cardiovascular death [MACE]) were reported for DPP-4 inhibitors and GLP-1-RA so far. Regarding DPP-4 inhibitors, treatment with saxagliptin showed a significant, with alogliptin a trend towards an elevation in hospitalization rates for congestive heart failure, while this was not confirmed for sitagliptin or for lixisenatide (GLP-1-RA).Conclusion
Most likely, studies including patients with less advanced cardiovascular damage at baseline, with a longer diabetes duration, and allowing for significant differences in glucose control between the drugs that are to be compared will probably be needed to meaningfully analyze and, possibly, confirm a cardiovascular benefit of IBGLM .17.
Background
Sodium glucose transporter 2 (SGLT2) inhibitors have been recently approved for the treatment of patients with type 2 diabetes mellitus.Effects
These new substances result in excretion of glucose via inhibition of the proximal tubular absorption apparatus, thus, eliminating glucose and consequently (with the molecules) calories from the body. Three SGLT2 inhibitors are currently available: dapagliflozin (Forxiga®), empagliflozin (Jardiance®) and canagliflozin (Invokana®). In addition to lowering glucose levels they also result in a decrease of body weight by about 2 kg, systolic blood pressure (by about 4 mmHg) and diastolic blood pressure (by about 2 mmHg). Secondary effects include e.?g. decreasing blood volume and lowering of uric acid concentrations. In a 2015 outcome study, empagliflozin reduced total mortality, cardiovascular mortality, and hospitalizations for congestive heart failure when compared to a standard diabetes regimen combined with placebo. Open questions are whether these effects can also be achieved with other substances of the same class. Moreover the mechanism must still be elucidated, whereby it is possible that many effects play positively together: blood pressure lowering, glucose lowering, weight reduction, plasma volume reduction, improved arterial stiffness, uric acid reduction, etc.Conclusion
For the practitioner it is important that this new class is well combinable with all other antidiabetic or glucose-lowering drugs. The priority of these drugs in the treatment of diabetes will be established by future guidelines. Decisive is that SGLT2 inhibitors have been approved for mono- and combination therapy.18.
Definition of terms
Under the term non-alcoholic fatty liver disease (NAFLD) both simple hepatic fat accumulation and non-alcoholic steatohepatitis (NASH) are combined. NASH is associated with liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC).Epidemiological importance
In 2020, NAFLD will be the leading cause for liver transplantation in the USA, with rising financial costs for the healthcare system.Comorbidities, diagnosis, and treatment
Type 2 diabetes (T2D) and metabolic syndrome (MetS) are important risk factors for the development of NAFLD, whereby these three diseases share similar pathophysiologic conditions, e.g., insulin resistance, obesity, and metabolic inflammation. Due to the rising number of patients with T2D and MetS, clinicians should aim to diagnose NAFLD early in this patient population and if necessary start treatment.Goal
The aim of this work is to give an overview over the topic of NAFLD and diagnostic approaches in patients with T2D.19.
Yongqiong Deng Hong Zhao Jiyuan Zhou Linlin Yan Guiqiang Wang China HepB-Related Fibrosis Assessment Research Group 《Infection》2017,45(1):75-81
Purpose
To investigate the association between serum complement 5a (C5a) concentration and liver fibrosis and cirrhosis in a large cohort of patients chronically infected with hepatitis B virus (HBV).Methods
Five hundred and eight patients with chronic HBV infection undergoing liver biopsy were included. Serum concentrations of C5a was measured by Luminex screening system. Ishak histological system was obtained.Results
C5a levels were negatively associated with liver fibrosis stages and significantly declined in patients with severe fibrosis and cirrhosis (P < 0.001). Multiple analysis showed C5a, AST, laminin, Co-IV, platelet count, albumin, HBsAg associated with liver fibrosis independently. Based on the markers above, we created two scores, Fib-model for significant fibrosis and Cirrh-model for earlier cirrhosis. Fib-model was performing better to differentiate from significant fibrosis, with an AUROC of 0.82 (95 % CI 0.78, 0.86), in comparison to existed models APRI, FIB-4 and Forns’ index with AUROCs of 0.71 (95 % CI 0.66, 0.76), 0.72 (95 % CI 0.67, 0.77), 0.77 (95 % CI 0.72, 0.81), respectively. Although, Cirrh-model showed AUROC of 0.85 (95 % CI 0.80, 0.91) for evaluation of earlier cirrhosis, superior to APRI, and Forns’ index, C5a + FIB-4 performed best with an AUROC of 0.94 (95 % CI 0.90, 0.97).Conclusion
In patients with chronic HBV infection, serum C5a concentration significantly decreased in severe fibrosis stages and earlier cirrhosis. Fib-model and C5a + FIB-4 performed better than existed models for assessment of significant fibrosis and earlier cirrhosis, respectively.20.
Rebecca A. Stokes Denbigh M. Simond Heather Burns Anita T. Patel Philip J. O’Connell Jenny E. Gunton 《Diabetologia》2017,60(10):1972-1976