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HIV and GI Tract Complications A Comprehensive Clinical Guide Lisa M. Chirch
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To Lucija and Marta, who have brought joy to our life.
Preface
The prevalence of diabetes has reached epidemic proportions worldwide. Chronic diabetic complications represent the major cause of morbidity and mortality, accounting for the majority of the social and economic burden. While the importance of both micro- and macrovascular complications is widely recognized, the gastrointestinal (GI) tract has not been traditionally associated with diabetic complications. However, the fact that as many as 75% of diabetic patients report GI symptoms calls for attention. Diabetes may affect the entire GI tract from the oral cavity and esophagus to the large bowel and anorectal region, resulting in heterogeneous clinical presentation. The involvement of the hepato-biliary system further contributes to symptom diversity. The pathogenesis is complex and not completely elucidated. Nevertheless, the relationship between longer disease duration, poor glycemic control, and the development of all diabetic complications, including GI, has been well established. Many GI complications of diabetes seem to be associated with the dysfunction of neurons supplying the enteric nervous system, which causes abnormalities in intestinal motility, sensation, secretion, and absorption. Besides the complexity of the clinical manifestations of diabetic GI complications, the need to exclude other possible causes of gastrointestinal morbidity makes the approach to diagnosis very challenging. Optimal management of gastrointestinal complications requires a multidisciplinary approach focusing on a combination of glycemic control and symptom relief.
The aim of this textbook is to provide a comprehensive, state-of-the art review of the GI complications of diabetes, their pathophysiology, clinical manifestations, diagnostic evaluation, and management. We hope it will serve as a valuable guide to practical management of diabetic patients with GI complications for physicians dealing with diabetes or gastrointestinal disorders as well as for researchers interested in this multidisciplinary problem. It has been written by a group of experienced clinicians whom we would like to thank for their great commitment, perseverance, and enthusiasm.
We are grateful to Prof. George Wu for valuable suggestions and support, and to Springer publisher and editors Mr. Andy Kwan and Ms. Saanthi Sankhraraman for kind assistance.
Special thanks to Dr. Doris Ogresta and Sanja Stojsavljević for their great contribution throughout the process of writing this book.
We sincerely hope that physicians and students will find this book useful and interesting, making our efforts worthwhile.
Zagreb, Croatia Marko Duvnjak
Zagreb, Croatia Lea Smirčić-Duvnjak
Radovan Prijić and Silvija Čuković-Čavka
Agata Ladić and Silvija Čuković-Čavka
Mislav Jelaković and Silvija Čuković-Čavka
Marinko Marušić, Rosana Troskot Perić, and Antonio Klemenčić
Marinko Marušić, Rosana Troskot Perić, and Nikolina Tolj Karaula Part V
J. Enrique Domínguez-Muñoz and Beatriz Cigarrán
Tajana Pavić, Dominik Kralj, Jelena Forgač, Davor Hrabar, Doris Ogresta, Vedran Tomašić, and Ivan Lerotić
18 Diagnostic Approach
Mario Tadić, Tajana Štoos-Veić, and Ivica Grgurević
19 Treatment of Pancreatic Diseases
Milan Kujundžić, Zeljko Čabrijan, and Tomislav Bokun
Lucija Virović-Jukić and Mario Živković
21 Clinical Manifestations of Liver Disease in Diabetes Mellitus
Lucija Virović-Jukić, Jelena Forgač, Doris Ogresta, Tajana Filipec-Kanižaj, and Anna Mrzljak
22 Diagnostic Approach
Marko Duvnjak and Nina Blažević
23 Nonalcoholic Fatty Liver Disease Treatment
Marko Duvnjak and Dominik Kralj Index
Contributors
Marko Banić Department of Gastroenterology, Hepatology and Clinical Nutrition, Dubrava University Hospital, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
Alen Bišćanin Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
School of Medicine, University of Zagreb, Zagreb, Croatia
Nina Blažević Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
Tomislav Bokun Department of Gastroenterology, Hepatology and Clinical Nutrition, Dubrava University Hospital, University of Zagreb School of Medicine, Zagreb, Croatia
Tomislav Bulum Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic Diseases, University Hospital Merkur, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
Zeljko Čabrijan Department of Gastroenterology, Hepatology and Clinical Nutrition, Dubrava University Hospital, Zagreb, Croatia University of Zagreb School of Medicine, Zagreb, Croatia
Beatriz Cigarrán Department of Internal Medicine, Hospital Barbanza, A Coruña, Spain
Silvija Čuković-Čavka Division of Gastroenterology and Hepatology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
Lea Smirčić Duvnjak Department of Diabetology, Department of Neurology, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Disease, UH Merkur, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
Marko Duvnjak Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
J. Enrique Domínguez-Muñoz Department of Gastroenterology and Hepatology, Health Research Institute, University Hospital of Santiago de Compostela, A Coruña, Spain
Tajana Filipec-Kanižaj Department of Gastroenterology, University of Zagreb School of Medicine, University Hospital Merkur, Zagreb, Croatia
Jelena Forgač Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
Ivica Grgurević Department of Gastroenterology, Hepatology and Clinical Nutrition, University of Zagreb, Zagreb, Croatia
Faculty of Pharmacy and Biochemistry, University Hospital Dubrava, Zagreb, Croatia
Davor Hrabar Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
Mislav Jelaković Division of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb, Croatia
Nikolina Tolj Karaula Department of Internal Medicine, GH Zabok and Croatian Veterans Hospital, Zabok, Croatia
Antonio Klemenčić Institute of Emergency Medicine of the City of Zagreb, Zagreb, Croatia
Dominik Kralj Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
Milan Kujundžić Department of Gastroenterology, Hepatology and Clinical Nutrition, Dubrava University Hospital, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
Agata Ladić Division of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb, Croatia
Ivan Lerotić Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
Marinko Marušić Department of Hepatology and Gastroenterology, University Hospital Sveti Duh, Zagreb, Croatia
Medical School, J.J. Strossmayer University of Osijek, Osijek, Croatia
Faculty of Health Studies, University of Rijeka, Rijeka, Croatia
Anna Mrzljak Department of Gastroenterology, University of Zagreb School of Medicine, University Hospital Merkur, Zagreb, Croatia
Ayah Oglat Lynda K. and David M. Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, TX, USA
Doris Ogresta Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
Tajana Pavić Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
Rosana Troskot Perić Department of Hepatology and Gastroenterology, University Hospital Sveti Duh, Zagreb, Croatia
Medical School, J.J. Strossmayer University of Osijek, Osijek, Croatia
Faculty of Health Studies, University of Rijeka, Rijeka, Croatia
Radovan Prijić Division of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb, Croatia
Lidija Prka Department of Gastroenterology, Hepatology and Clinical Nutrition, Dubrava University Hospital, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
Eamonn M. M. Quigley Lynda K. and David M. Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, TX, USA
Sandra Vučković Rebrina Department of Diabetology, Department of Neurology, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Disease, UH Merkur, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
Tajana Štoos-Veić Department of Pathology and Cytology, University Hospital Dubrava, Zagreb, Croatia
Mario Tadić Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, Zagreb, Croatia
Faculty of Pharmacy and Biochemistry, Zagreb, Croatia
Vedran Tomašić Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
Marija Crnčević Urek Department of Gastroenterology, Hepatology and Clinical Nutrition, Dubrava University Hospital, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
Lucija Virović-Jukić Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia
Mario Živković Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
Part I
Diabetes and the Gastrointestinal Tract: The Basics
Chapter 1 Diabetes Mellitus
Lea Smirčić Duvnjak and Sandra Vučković Rebrina
Pathophysiology, Diagnostic and Therapeutic
Approach
Diabetes mellitus (DM) is a group of heterogeneous diseases caused by defects in insulin secretion and/or action. It is characterized by chronic hyperglycemia, impairment of the carbohydrate, lipid, and protein metabolism, and it is associated with the development of chronic complications.
Diabetic complications represent the main cause of patients’ morbidity and mortality, accounting for the majority of the social and economic burden.
According to the latest World Health Organization (WHO) data, 422 million adults are living with DM worldwide; the global prevalence is projected to almost double by 2030. As its prevalence has reached epidemic proportion, DM is considered as one of four priorities for non-communicable diseases targeted for action by WHO [1].
Current DM classification includes four different categories: Type 1 DM, Type 2 DM, gestational DM and specific types of DM due to other causes (monogenic diabetes syndromes, diseases of the exocrine pancreas, and drug- or chemical-induced diabetes).
Two major forms are type 1 and type 2 DM. Type 2 represents the most common form, accounting for 85–90% of all DM cases [2].
L. S. Duvnjak (*) · S. V. Rebrina
Department of Diabetology, Department of Neurology, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Disease, UH Merkur, Zagreb, Croatia
University of Zagreb School of Medicine, Zagreb, Croatia e-mail: lduvnjak@idb.hr; svuckovi@idb.hr
Pathophysiology of DM is complex, with multiple factors leading to diminished insulin secretion or insulin sensitivity. However, during the natural course of the disease the two defects often coexist.
Type 1 DM is a consequence of autoimmune destruction of the β-cells occurring in genetically predisposed individuals in conjunction with environmental factors. Autoimmune destruction, defined by the presence of autoantibodies to islet cells (ICA), glutamic acid decarboxylase (GAD), insulin (the tyrosine phosphatases— IA-2), and zinc transporter (ZnT8), leads to insulin deficiency [2, 3].
The majority of patients are diagnosed with type 1 DM in childhood and adolescence, and require insulin treatment for survival. Patients often present with markedly elevated blood glucose levels, accompanied by clinical symptoms, while in some cases life-threatening ketoacidosis may be the first manifestation of the disease.
Type 2 DM is characterized by insulin resistance and relative insulin deficiency resulting from interaction between genetic, environmental, and behavioral risk factors. It is commonly diagnosed in adults showing metabolic syndrome features, visceral obesity, dyslipidemia, and hypertension, and is associated with stronger genetic predisposition than type 1 DM. As hyperglycemia develops gradually, it frequently remains undiagnosed for many years. Insulin treatment might not be needed throughout the patient’s lifetime.
Traditionally, defects in insulin secretion or action, age of onset, and the presence of diabetes-associated autoantibodies have been used to identify patients with types 1 and 2 DM. However, it has become evident that both types may occur in all age groups and miss the typical clinical presentation [3].
Type 1 DM, often considered as a childhood disease, presents in adult life in a certain percentage of patients. A subgroup of adult patients presenting with clinical type 2 diabetes show some immunogenetic characteristics of type 1 DM, mainly glutamic acid decarboxylase antibodies (GADA) positivity, and are classified as latent autoimmune diabetes in adults (LADA).
Genetic factors
Environmental factors
Insulin resistance
Fig.
L. S. Duvnjak and S. V. Rebrina
Table 1.1 Diagnostic criteria for diabetes
Fasting plasma glucose (FPG)
Oral glucose tolerance test (OGTT)
>7 mmol/l 2 h plasma glucose >11.1 mmol/l
Fasting defined as no caloric intake for 8 h
Performed using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water
A1c
Random plasma glucose
>6.5% (48 mmol/mol) >11.1 mmol/l
Performed using a NGSP certified method and standardized to the DCCT assay
If classic symptoms of hyperglycemia or hyperglycemic crisis are present
The frequency of type 2 DM, usually diagnosed in adults, is markedly increasing in children. For these reasons, both types of DM should be viewed as a condition of progressive loss of beta cell mass or function caused by the interaction of genetic and environmental factors. In all types of DM, hyperglycemia is associated with the development of the same complications, although their progression may vary [3, 4] (Fig. 1.1).
Diagnostic Approach
The diagnose of DM is based on clinical symptoms of hyperglycemia and laboratory testing. Laboratory testing can be performed using fasting plasma glucose value (FPG), 2-h plasma glucose (2-h PG) value after a 75-g oral glucose tolerance test (OGTT), or A1C criteria. In the absence of unequivocal hyperglycemia, a second test is required for confirmation of the diagnosis. It is recommended to repeat the same test without delay using a new blood sample for confirmation. In case of discordant results from two different tests, the test result above the diagnostic cut point should be repeated. In the case of test results near the margins of the diagnostic threshold, it should be repeated in 3–6 months. FPG, 2-h PG after 75-g OGTT, and A1C are considered as equally appropriate for diagnostic testing. However, it should be noted that using the 2-h PG value instead of FPG and A1C cut points, more people will be diagnosed with diabetes. The A1C test should be performed using a method that is certified according to the “National Glycohemoglobin Standardization Program” (NGSP) and standardized to the Diabetes Control and Complications Trial (DCCT) reference assay. A1c is an indirect measure of average blood glucose levels. As a diagnostic parameter it shows greater preanalytic stability, less variability during acute illness, and is more convenient for patients. However, it is less sensitive at the designed cut point, more expensive, and might be influenced by age, ethnicity, and blood disorders such as anemia and hemoglobinopathies.
In patients presenting with hyperglycemic crisis or with classic symptoms of hyperglycemia and a random plasma glucose >11.1 mmol/l, a second test is not required for diagnosis (Table 1.1).
The same test are used to detect prediabetes, and may be applied in the screening of both general population and individuals with high risk for DM [2].
L. S. Duvnjak and S. V. Rebrina
Therapeutic Approach
Type 2 DM
For a very long period of time, newly diagnosed type 2 DM patients were treated with lifestyle modification for at least 3 months. In 2005 and 2006, the International Diabetes Federation (IDF), followed by the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD), recommended initiation of pharmacological therapy, in addition to lifestyle measures, at diagnosis. It was recognized that lifestyle modifications alone often fail to achieve treatment goals, and the introduction of drugs should not be delayed. Within the natural course of the disease, factors contributing to the atherosclerotic process might be present long before the diagnosis. Many type 2 DM cases present with macrovascular complications at the moment of diagnosis. It has been realized that the world of DM represents a complex interplay between hyperglycemia, insulin resistance, dyslipidemia, and obesity. Type 2 DM needs to be managed taking these facts into consideration. Currently, all guidelines recommend a step-wise approach to type 2 DM patients. Metformin is considered as a first-line therapy, except in cases of drug intolerance or contraindications. It is effective, safe, and inexpensive; its beneficial effects are supported by many studies. If the A1c target is not achieved after 3 months, the second agent should be introduced. In patients with initial A1C >9%, dual combination therapy should be considered. The choice of the second agent (or first in case of metformin intolerance or contraindication) should be based on many factors. Glycemic target and drug efficacy, impact on weight and hypoglycemia risk, patient’s comorbidities, and presence of complications, as well as drug cost and patient preferences should be taken into consideration. Metformin can be combined with six available treatment options: sulfonylurea (SU), thiazolidinedione (TZD), dipeptidyl peptidase 4 (DPP-4) inhibitor, sodium glucose transporter 2 (SGLT2) inhibitor, glucagon-like peptide 1 (GLP-1) receptor agonist, or basal insulin. If the A1C target is not achieved after 3 months of dual therapy, threedrug combination should be introduced. Following the failure of triple therapy, combination injectable treatment should be initiated. When initiating combination injectable therapy, metformin should be maintained in the therapeutic regimen. The decision about the maintenance of other oral agents is optional, depending on both drug characteristics and patients’ clinical profile. In patients with blood glucose >16.7 mmol/l or A1C >10%, or presenting with symptoms of hyperglycemia, initial insulin therapy should be considered [ 5 ].
Combination injectable therapy includes the addition of a single injection of rapid-acting insulin at the largest meal, or a GLP-1 receptor agonist to basal insulin, or the introduction of two daily injections of premixed insulins. When choosing the treatment regimen, it is advisable to take into consideration the advantages and disadvantages of each approach. Basal insulin and GLP-1 receptor agonists combination might be the preferred option because of lower levels of hypoglycemia and weight loss, but potential gastrointestinal side-effects and greater cost need to be considered. When choosing between rapid-acting insulin in addition to basal and premixed formulation, patient preferences and flexibility for adjustment of therapy
should be taken into account. Rapid-acting, basal insulin and premixed insulin analogs have more optimal pharmacodynamics profiles in comparison with human formulations, but are extremely costly. In patients with A1c above target on premixed insulin twice daily, switching to premixed analog insulin three times daily should be considered. In a patient with A1C above target on basal insulin and one single injection of rapid-acting insulin before the largest meal, the second or third injections of rapid-acting insulin before meals should be added. In general, when the A1c target is not being met, switching patients from one regimen to another is needed. SUs are widely used glucose-lowering agents with high efficacy in decreasing A1c and low cost. They should be avoiding when hypoglycemia and weight gain are of concern, and their cardiovascular (CV) safety is still controversial. TZD are highly efficacious in reducing A1c, with no hypoglycemia risk and low cost. They are associated with weight gain, edema and risk of heart failure (HF). Pioglitazone has proven CV benefits and beneficial effect in NASH. The advent of incretin-based therapies has been a huge step forward as a pathophysiological way of treating type 2 DM. With these agents, glucoregulation can be achieved without hypoglycemia risk and weight gain. DPP-4 inhibitors and GLP-receptor agonist differ in efficacy with regard to A1c decrease, effect on weight, and gastrointestinal (GI) side-effects. DPP-4 inhibitors are of intermediate efficacy, have no hypoglycemia risk, the effect on weight is neutral, and side-effects are rare. GLP-1 receptor agonists are highly efficacious in reducing A1c and weight gain and have low hypoglycemia risk, but might be associated with GI side-effects; and a certain percentage of patients do not respond to the treatment. The cost of both DPP-4 inhibitors and GLP-receptor agonists is high. The results of CV outcome studies have shown neutral effect of DPP-4 inhibitors and GLP-1 receptor agonist lixisenatide on major CV events in comparison with placebo. Some DPP-4 inhibitors have been associated with increased risk of HF. Recently, SGLT2 inhibitors have been introduced into clinical practice. Their mechanism of action is insulin-independent. SGLT2 inhibitors act by blocking glucose reabsorption at the level of proximal renal tubules. They show intermediate efficacy in decreasing A1c, have no hypoglycemia risk, and induce weight loss and lowering of blood pressure, but might be associated with dehydration and urinary or genital tract infections. Recently, two cardiovascular outcome trials (CVOTs) have shown beneficial effects of empagliflozin and liraglutide in patients with type 2 DM with CV disease or at high risk for CV disease. In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), empagliflozin versus placebo and standard care reduced the composite outcome of MI, stroke, and CV death by 14% (absolute rate 10.5% vs 12.1% in the placebo group) and CV by 38% (absolute rate 3.7% vs 5.9%) in patients with type 2 DM and existing CV disease. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial showed that liraglutide, a GLP-1 receptor agonist, versus placebo and standard care, reduced the composite primary outcome (MI, stroke, or cardiovascular death) by 13.0% in patients with type 2 DM at high risk for CV disease or with CV disease when compared with the placebo group (14.9%) after a median follow-up of 3.8 years. Based on this results, ADA/ EASD guidelines recommend that in type 2 DM patients with long-standing DM and established atherosclerotic CV disease, empagliflozin or liraglutide should be considered as a part of the therapeutic regimen [5, 6].
L. S. Duvnjak and S. V. Rebrina
Type 1 DM
Insulin is the cornerstone of type 1 DM treatment. Patients are usually treated with multiple daily injections of prandial and basal insulin, or insulin analogs. They should be properly educated about the significance of frequent daily blood glucose monitoring and insulin dosing adjustment, taking into account blood glucose levels, carbohydrate intake, and daily physical activity. Continuous subcutaneous insulin infusion represents an option in type 1 DM patients who can’t achieve optimal glucoregulation, mainly due to frequent hypoglycemia episodes [5, 6].
Role of Pacemakers and the Autonomic Neural System
Introduction
The autonomic nervous system (ANS) plays a key role in the function of the gastrointestinal (GI) system. It is composed of three interdependent parts: sympathetic, parasympathetic, and enteric nervous system (ENS). Sympathetic and parasympathetic parts form the extrinsic and ENS the intrinsic part of autonomic neural control of the GI system. The complex process of food intake and digestion is additionally orchestrated by the interstitial cells of Cajal.
Enteric Nervous System
The enteric nervous system (ENS) is a complex part of ANS with functional independence but multiple connections with other parts of the autonomic and central nervous system. Because of its functional and organizational complex structure and also its importance, it is often called the “little brain”. The ENS can operate autonomously, independently of the extrinsic control.
ENS consists of approximately 200–600 million sensory, motor and interneurons forming neuronal networks (plexuses) throughout the entire GI system, biliary tract, and pancreas. Neurons are located in two major plexuses, the myenteric and submucosal plexuses. The myenteric plexus (Auerbach’s plexus) is situated between the longitudinal and circular smooth muscle layers, and controls smooth muscle motor patterns (primarily regulates motility). The other plexus is the submucosal (Meissner’s plexus) situated in the submucosa between circular smooth muscle layer and the mucosal epithelium, and regulates secretion, absorption, and local blood flow.
Excitatory and inhibitory motor neurons of the ENS regulate smooth muscle activity, but also several populations of interneurons, and also primary sensory neurons that do not project to the central nervous system (CNS). Those sensory neurons can detect local mechanical, chemical, and thermal stimuli within the GI tract, and
then generate or modulate gastrointestinal activity independently of any central control. It means that most of the operations in the gut are independent of the input from the CNS.
Despite its independence, the ENS is connected to the brain by afferent and efferent pathways. Afferent (sensory) pathways are mostly part of the vagus nerve and send stimuli resulting in sensations such as pain, stretch, fullness, and nausea. Efferent sympathetic and parasympathetic pathways modulate motility, secretion, and circulation, and help to coordinate different parts of the GI system in their complex functions.
The main excitatory neurotransmitter of ENS is acetylcholine, followed by neurokinin and substance P. Inhibitory neurotransmission occurs through nitric oxide (NO2) as a main inhibitory neurotransmitter, but neuropeptide Y and vasoactive intestinal peptide have also been found. The distribution of excitatory and inhibitory neurons throughout the GI tract in not equal [7].
Extrinsic Neural Control
The extrinsic nervous system modulates the function of the ENS through parasympathetic pathways (through vagus and sacral nerves) and sympathetic neural pathways (through thoracolumbar nerves).
The parasympathetic pathways project to the enteric neurons in the myenteric plexuses, providing ways for direct efferent central control, mostly excitatory for the muscles and inhibitory for the sphincters. In addition, vagus provides viscera with additional sensory innervation, creating direct connection of the GI tract with the CNS.
Prevertebral sympathetic neurons inhibit the activity of excitatory motor neurons in the myenteric plexus and of secretomotor neurons in the submucosal plexuses. In turn, a population of myenteric neurons (the intestinofugal neurons) project from the intestinal myenteric plexuses back to these same prevertebral sympathetic neurons. Thus, they create a long-range peripheral sympathetic–enteric neural control circuit.
Enteric neurons are restricted to the myenteric and submucosal layers, but glia cells and neuronal fibers of extrinsic system are distributed throughout the gut wall, including the lamina propria and mucosa [7].
Interstitial Cells of Cajal (ICC)
Neuromuscular junctions are another specificity in the GI system. Between enteric motor nerve terminals and the smooth muscle fibers there are “mediators” called interstitial cells of Cajal (ICC). These non-neuronal, non-glial cells have an important role in the reception and transduction of cholinergic excitatory and nitrergic
L. S. Duvnjak and S. V. Rebrina
inhibitory stimuli. Because of their capability of regulating the neuromuscular responses, ICC are also known as gut “pacemakers”. Described for the first time in 1893 by Spanish Nobel Laureate physician and neuropathologist Santiago Ramon y Cajal as nerve-like cells located between the nerve endings and smooth muscle cells in the GI tract, he classified them as primitive neurons. Because of their localization they have been called interstitial. They can be considered as a specialized population of smooth muscle cells, with only a small number of contractile elements but a large number of mitochondria and sets of channels in their membrane. Development of ICC is dependent on a thyrosine kinase receptor (Kit). ICC are found throughout the GI tract from the esophagus to the internal anal sphincter. They can also be found in other organs, such as pancreas, bladder, penis, vagina, uterus, mammary glands, ureteropelvic junction, and blood vessels. ICC represent only about 5% of cells present in the smooth muscle layer of the GI tract but have very significant physiological roles in GI motility [8].
ICC have multiple functions in the GI tract:
1. generation of electrical slow waves transmitted then to the muscle layers
2. coordination of electrical activity and propagation of slow waves
3. transduction of motor neural inputs from the motor nerve terminals
4. controlling and setting the smooth muscle membrane potential gradient
5. mechanosensation (afferent neural signaling) to stretch the smooth muscles.
ICC can be divided according to several criteria:
1. localization within the muscle layers (intramuscular, myenteric, subserosal)
2. basic morphology (stellate and bipolar)
3. primary function (pacemakers and mechanoreception)
According to their anatomical locations within the tunica muscularis, at least three separate functional groups of interstitial cells of Cajal (ICC) exist. A network of ICC lying between the circular and longitudinal muscle layers at the level of the myenteric plexus (Auerbach’s plexus) are called ICC-MY. Those cells are multipolar, with branched processes connecting to each other and forming a network around the myenteric plexus throughout the stomach and the small and large intestine. They are electrical pacemakers generating slow waves which control the frequency of phasic contractions of the tunica muscularis, and provide an active propagation pathway through which pacemaker activity spreads, ensuring the coordinated spread of slow waves within the GI tract.
A second population of ICC, known as intramuscular ICC or ICC-IM, are found within the muscle layers of the esophagus, stomach, and large intestine, and are innervated by enteric motor nerves but also vagal afferent nerves. ICC-IM are bipolar and essential for transmission of neural information to the smooth muscle cells— both cholinergic excitatory and nitrergic inhibitory stimuli. Excitatory neurotransmission through substance P and neurokinin was also observed.
A third population of ICC are found within the septa that separate muscle bundles, and are termed ICC-SEP. These ICC are multipolar and found in the stomach, small intestine, colon, and recto-anal regions of the GI tract. Although ICC-SEP
have the potential to generate pacemaker activity, they are not normally the dominant pacemaker, but mostly conduct the pacemaker activity deep into and between muscle bundles [9, 10].
There are few hypotheses about the mechanism of slow-wave generation by ICC, including the role of chloride and/or potassium channels, but the most important changes are considered to be those in the intracellular calcium level [9].
ICC represent a mediator of neurotransmission between extrinsic neuronal pathways and ENS and between ENS and smooth muscles. Most of the functions of ICC have been observed and proven in animal models, and are still waiting for confirmation in humans.
Neural Control of the GI Function
Food intake and digestion are complex processes involving several different cell types, including smooth muscles, epithelia, and blood vessels. This complex process is enabled and controlled through intrinsic and extrinsic autonomic neuronal pathways, and orchestrated by the interstitial cells of Cajal.
The basic unit of neural control in the GI tract is a peristaltic reflex that arises in the myenteric plexus in response to changes in the luminal contents. It consists of sensitive neurons, interneurons, and excitatory and inhibitory motor neurons. Additionally, the interstitial cells of Cajal (ICC) coordinate the contractile responses.
The process of neural control begins by stimulating primary sensory afferent neurons whose bodies are situated in the submucosal and the myenteric plexus by pressure, stretching, or inflammation of the GI walls. At one site nerve endings are reaching mucosa, on the other hand they create synapses with interneurons of the ENS. Enteric motor neurons innervate target cells, which are: muscles, mucosal epithelium, secretory glands, and the blood and lymphatic structures. The stimulus is transferred to the target cells via three reflexes, which are: (1) a local enteric system within the GI wall, (2) extraspinal reflexes that start in the GI and extend through the prevertebral ganglia without reaching the central nervous system, and (3) reflexes spreading from the GI system to the CNS [ 11 , 12 ].
A significant part of the information is transmitted from the gut to the brain. The vagus (tenth cranial nerve or CN X) is a key component in sending the information, and therefore a majority of vagal fibers are afferent. They carry signals from the viscera to the CNS. Some afferent signals from the gut cause discomfort, such as nausea and pain, but most do not reach consciousness.
The sympathetic (noradrenergic) fibers within the wall of the GI tract originate from cell bodies located within the prevertebral sympathetic ganglia. The celiac–mesenteric ganglia provide fibers to the stomach, small intestine, and, to some extent, the proximal large intestine. The inferior mesenteric ganglia provide fibers to the large intestine, and the remaining noradrenergic fibers to the rectum originate from the pelvic ganglia. The noradrenergic innervation from these prevertebral gan-
L. S. Duvnjak and S. V. Rebrina
glia supplies an extensive network of fibers to the smooth muscle wall, ganglia of the myenteric and submucosal plexus, and arteries of the GI tract. For the sympathetic part, brain regions containing premotor neurons are medulla oblongata, pons, and hypothalamus. For the parasympathetic part, premotor neurons occur mainly in the brainstem and hypothalamus. Most autonomic pathways are not under direct conscious control, but multiple areas such as prefrontal cortex, basal ganglia, anterior cingulate, and insula cortex; visual centers as well as amygdala have connections with autonomic control centers of the hypothalamus and brainstem. These areas share information with the limbic regions where emotional responses to sensory input from the outside as well as signals of the inside are processed. In addition, reverse connections from the brainstem and hypothalamus into those areas are responsible for our experience of well-being [7].
Diabetic Gastroenteropathy
Diabetic autonomic neuropathy (DAN), with changes in parasympathetic and sympathetic pathways, was traditionally considered to be the main underlying mechanism of gastrointestinal manifestations of diabetes. More recently, other causes have been identified: dysfunction of enteric nervous system, deficiency and malfunction of the ICC, smooth muscles myopathy, and changes in enteric microbiota [13].
DAN is the most neglected, yet one of the most serious complications of diabetes. It is a form of peripheral neuropathy, including damage of parasympathetic and sympathetic nerves as well as neuron networks of the ENS. It can be found in both type 1 and type 2 diabetes.
DAN can affect any organ of the body. Gastrointestinal system (GI) involvement has many specificities because of its specific autonomic nervous innervation.
Pathogenesis of Diabetic Gastroenteropathy
The etiology of diabetic neuropathy and also gastroenteropathy is complex and still completely unclear. Hyperglycemia leads to a number of metabolic, neurotrophic, vascular, and immunological changes that result in progressive damage of neurons.
Simplified pathogenesis of diabetic neuropathy includes: – increased activity of aldose reductase, resulting in an accumulation of sorbitol and fructose, and imbalance in the ratio of nicotinamide adenine dinucleotide phosphate and nicotinamide adenine dinucleotide – an increase in oxidative stress with the formation of ROS (reactive oxygen species)
– the creation of products of glycoxygenation through hexosamine pathway, glycation of intracellular and extracellular proteins with the formation of AGE products (advanced glycation end-product)
– inadequate activation of protein kinase C pathway – increased cytokine release
– autoimmunity
– deficit of neurotrophic factors.
All these pathogenic mechanisms may act independently or interdependently and thus lead to the development of diabetic neuropathy by direct damage to the nerve cells or indirectly through damage of vasa nervorum.
Pathophysiological changes result in degeneration of neuron cell body (soma), axonal degeneration with the loss of nerve fibers, demyelination and impairment of nerve fiber regenerability. This creates an imbalance between degeneration and regeneration of nerve fibers at the expense of the degenerate ones.
The pathogenic process can encompass all parts of the autonomic nervous system—sympathetic, parasympathetic, and enteric. All parts are not affected at the same time and not even with the same strength. Most sensitive are neurons with the longest axons. This may explain earlier affection of parasympathetic than of sympathetic nerves in the course of DAN. Even the different subpopulations of one system, e.g., enteric neurons, respond differently to diabetes. Some exhibit degeneration, some undergo changes in neurotransmitter content without degeneration, while some are unaffected. It is also interesting that the neurons with the same neurotransmitter in different parts of the GI system are affected differently. Some data suggest that inhibitory neurons are more severely affected than the excitatory neurons. Histopathological changes of glia cells are also observed. Degenerative changes and/or loss of ICC have also been observed in patients with diabetic gastroenteropathy. Furthermore, ICC lose their connections with enteric neurons, which results in decreased electrical activity of the muscle layers. Also, there is growing evidence that the underlying mechanisms in the pathogenesis of diabetic complications include certain genetic and epigenetic modifications, nutritional factors, and sedentary lifestyle [14, 15].
Those multifactorial etiopathogenetic changes may explain very heterogeneous clinical signs and symptoms of diabetic gastroenteropathy.
Gut Hormones
The gut was historically considered as an alimentary organ. Over recent decades, following the identification of multiple gut-derived hormones, it has been recognized as the largest endocrine organ in our body [16].
Gut hormones are peptides secreted from enteroendocrine cells (EEC) and neurons in the gastrointestinal (GI) tract. The expression of more than 30 hormone genes in the GI tract, along with multiple phenotypes of individual genes, is associated with
L. S. Duvnjak and S. V. Rebrina
the release of more than 100 different peptides. Hormone genes are also widely present in extra intestinal organs and neurons that may produce different active compounds of the same prohormone. Peptides released from various cells act locally via autocrine and paracrine mechanisms, on distant organs via endocrine mechanisms, and as neurotransmitters in the central and peripheral nervous systems [16, 17].
Many types of EEC are distributed throughout the GI tract, from the gastric cardia down to the distal colon and rectum. They show regional specificity due to physiologic effects of secreted peptides or receptor location, and are usually characterized by the secreted peptide. EEC are stimulated by different macronutrients such as carbohydrates, fats, or proteins. Released gut peptides are involved in the control of the main GI processes such as gut secretion, nutrient absorption, GI motility, and growth. In addition, they contribute to the maintenance of the metabolic homeostasis and food intake by mediating signaling pathways within the gut–brain axis. Within this axis, peptides show direct effects on the endocrine pancreas, act at the level of hypothalamus and brainstem, or activate vagal afferents of the peripheral nervous systems [16–18].
Gut–Brain Axis
The term “gut–brain axis” defines a close connection between GI hormones and the brain, in particular the hypothalamus and the brain stem, that plays an important role in the control of food intake and energy homeostasis. Hypothalamic nuclei involved in feeding behaviors and satiety include the arcuate nucleus of the hypothalamus (ARC), the dorsomedial (DMH), and the ventromedial hypothalamic nucleus (VMH). Hormones released from the stomach (ghrelin), small intestine (peptide tyrosine tyrosine—PYY), pancreas (insulin), and adipose tissue (leptin) bind to the receptors on orexigenic or anorexigenic neurons in the ARC. The majority of hormones, including glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), pancreatic polypeptide (PP), and oxyntomodulin (OXM or OXY) exert an anorexigenic effect in the brain. Ghrelin is so far the only known orexigenic hormone.
This interaction results in the release of orexigenic neuropeptides, neuropeptide Y (NPY) and agouti-related peptide (AgRP) or the anorexigenic neuropeptides, pro-opiomelanocortin, (POMC: yielding the neurotransmitter α-MSH), and cocaine and amphetamine-regulated transcript (CART). These neuropeptides reach the secondary neurons in other areas of the hypothalamus, such as the paraventricular nucleus (PVN), to modulate the sensation of hunger and satiety. Additional satiety signals from the liver and GI tract reach the nucleus of the nucleus solitary tract (NTS) through the vagus nerve. Projections from the NTS to the thalamus mediate the perception of gastrointestinal fullness and satiety [19] (Fig. 1.2).
Fig. 1.2 Gut-brain axis. ARC nucleus arcuatus, nucleus of the hypothalamus, NTS nucleus tractus solitarius, PVN paraventricular nuclei, LH lateral hypothalamus, GLP-1 glucagon like peptide 1, CCK cholecystokinin, PP pancreatic polypeptide, PYY peptide Y
ARC orexigenic neurons
BRAIN
PVN LH HYPOTHALAMUS
ARC anorexigenic neurons
NTS
nerve
GLP-1 CCK, PP PYY
GUT HORMONES
Gut Hormones
Anatomically, nutrient-induced secretion of gut hormones starts in the stomach where gastrin and ghrelin are released.
Gastrin
Gastrin is a peptide hormone synthesized in the G-cells of the antrum region of the stomach. It has a major role in the control of gastric acid secretion. Released upon stimulation by food (mainly protein), it causes the secretion of gastric juice, which ceases when the luminal pH becomes less than 3.
The characterization of the peptide structure allowed the discovery of its effect on promoting proliferation and growth of the gastric antrum and possible association with cancer development. It also increases the motility of the stomach and to a lesser degree of the upper small intestine and the gallbladder. Gastrin exerts its actions through the same receptors as cholecystokinin (CCK-1 and CCK-2), which are found mainly on parietal and enterochromaffin cells of the gastric body [17, 19].
VAGUS
GHRELIN
L. S. Duvnjak and S. V. Rebrina
Ghrelin
Ghrelin is a 28-amino-acid peptide produced mainly by the stomach. Other sources of ghrelin include hypothalamus, pituitary gland, and several peripheral organs. It was initially discovered as a natural ligand for the growth hormone secretagogue receptor (GHS-R) that potently stimulates growth hormone (GH) secretion. Ghrelin is recognized as the only orexigenic gut peptide, the secretion of which increases during fasting and conditions leading to negative energy balance, while nutrition intake suppresses it. It has an important role in the control of food intake and energy balance as one of the communication pathways between the body and the brain. Ghrelin acts directly through GHS-R, expressed in the ARC, by stimulating the release of orexigenic peptides (neuropeptide Y—NPY and agouti-related peptide—AgRP) or by activating ghrelin receptors in vagal afferent neurons. Beyond controlling food intake, ghrelin stimulates gastric motility, increases lipid storage, and inhibits insulin secretion by stimulating GH release. These effects are potentially promising as treatment strategies in obesity, gastroparesis, and diabetes. However, the wide distribution of both ghrelin and GHSR1a receptors in various tissues, suggesting different biological functions, calls for caution for possible side-effects. A selective GHSR agonist, relamorelin, is currently in a clinical phase 2b trial for the management of diabetic gastroparesis. Based on animal data studies, GHSR1a antagonism was recognized as a potential treatment strategy for T2DM. Despite its ability to promote weight gain, antagonism of ghrelin signaling showed modest anti-obesity effects in both animal and human studies [20, 21].
The small intestine secretes a variety of hormones that contribute to metabolic homeostasis.
Cholecystokinin
Cholecystokinin, is a peptide secreted by the endocrine I cells in the proximal part of small intestine. It has a major role in gallbladder contraction and pancreatic enzyme secretion. CCK level increase is triggered by the presence of food in the duodenum, and ceases following the absorption of the digested food. Beyond involvement in the digestive process, CCK induces the delay of gastric emptying, stimulates insulin secretion, and regulates food intake. It was the first hormone shown to be involved in satiety signals via direct effect on hypothalamus or via afferent vagal nerve. CCK effects are mediated through CCK-1 receptors expressed along the GIT, and CCK-2 receptors in the brainstem, hypothalamus, and brain areas involved in reward and memory. Studies with CCK receptor agonist have failed to demonstrate beneficial effect on weight loss in humans [ 18 , 19 ].
Secretin
Secretin is a 27 amino-acid peptide secreted from the enteroendocrine S cells of the small intestine. It has a major role in neutralizing the acidic chyme in the intestine by stimulation of pancreatic fluid and bicarbonate secretion. Secretin secretion is stimulated by acidification of the duodenum and ceases after its neutralization. Other functions include inhibition of gastric acid release and intestinal motility. It exerts its action through a receptor that belongs to the family of G protein-coupled receptors (GPCRs). Members of GPCRs are glucagon, calcitonin, parathyroid hormone, pituitary adenylyl cyclase-activating peptide (PACAP), and vasoactive intestinal polypeptide. In addition to the small intestine, other sources of secretin include the hypothalamus, cortex, cerebellum, and brainstem [17–19].
Pancreatic Polypeptide Family
Pancreatic polypeptide family includes pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY). These 36 amino acid peptides share a common chemical structure, but are distributed in different locations of the GI tract and nervous system and regulate different physiological functions.
NPY is found in the central and peripheral nervous system, mainly in sympathetic neurons and acts as a neurotransmitter.
PP is secreted by endocrine PP cells in the pancreas. PP release is stimulated by food ingestion mediated by humoral signals as ghrelin, and by increase in adrenergic activity. PP is responsible for delaying of gastric emptying, inhibition of gallbladder contraction, and attenuation of pancreatic exocrine secretions within the so called “ileal brake”. The latter refers to the slowing of nutrients transit through the gut.
PP also acts on the level of area postrema, hypothalamus, and vagus to induce an anorexigenic response. Its level has been found to be decreased in obese subjects following food intake [18, 22].
PYY
PYY is co-secreted with GLP-1 by the enteroendocrine L intestinal cells, mainly in the ileum and colon, in response to food ingestion, and is also found in the nerves of the enteric system. The contribution of PYY to the regulation of energy homeostasis is of importance. It might have a role in reducing food intake by inhibiting the activity of neurons NPY/AgRP and stimulating POMC/CART in the ARC of the hypothalamus. PYY also inhibits gastric emptying and gastric acid and pancreatic exocrine secretion [17, 22].
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“There is a carpet on the floor, a rarity in Germany, and Liszt generally walks about, and smokes, talks and calls upon one or other of us to play. From time to time he will sit down and play himself where a passage does not suit him and when he is in good spirits he makes little jests all the time. His playing was a complete revelation to me and has given me an entirely new insight into music. You can not conceive, without hearing him, how poetic he is, or the thousand nuances which he can throw into the simplest thing. He is equally great on all sides. From the zephyr to the tempest the whole scale is equally at his command.
“But Liszt is not at all like a master and can not be treated as one. He is a monarch, and when he extends his royal scepter you can sit down and play to him. You never can ask him to play anything for you no matter how much you are dying to hear it. You can not even offer to play yourself. You lay your notes on the table so he can see that you want to play, and sit down. He takes a turn up and down the room, looks at the music, and if the piece interests him, he will call upon you.
“Yesterday I had prepared for him his ‘Au Bord d’une Source.’ I was nervous and played badly. He was not to be put out, however, but acted as if he thought I had played charmingly, and then he sat down and played the whole piece himself, oh, so exquisitely! It made me feel like a wood-chopper. The notes just seemed to ripple off his fingers’ ends with scarce any perceptible motion. As he neared the close I remarked that the funny little expression came over his face which he always has when he means to surprise you, and he suddenly took an unexpected chord and extemporized a poetical little end, quite different from the written one. Do you wonder that people go distracted over him?”
A talented pupil of Henselt’s arrived and played for Liszt with great success. Miss Fay says: “She played with the greatest aplomb, although her touch had a certain roughness about it to my ear. But all playing sounds barren by the side of Liszt, for his is the living, breathing impersonation of poetry, passion, grace, wit, coquetry, daring, tenderness and every other fascinating attribute that you can think of.
“I’m ready to hang myself half the time when I’ve been to him. Oh! he is the most phenomenal being in every respect! All that you’ve heard of him would never give you an idea of him. In short, he represents the whole scale of human emotions. He is a many-sided person and reflects back the light in all colors, no matter how you look at him. His pupils adore him, as in fact every one else does, but it is impossible to do otherwise with a person whose genius flashes out of him all the time so, and whose character is so winning.
“One day this week, when we were with Liszt, he was in such high spirits that it was as if he had suddenly become twenty years younger. A student from the Stuttgart Conservatory, played a Liszt concerto. His name is V. Liszt kept up a little running fire of satire all the time he was playing, but in a good-natured way. Everything that he says is so striking. In one place where V. was playing the melody rather feebly Liszt suddenly took his place at the piano, and said: ‘When I play, I always play for the people in the gallery so that those persons who pay only five groschen for their seats may also hear something.’ Then he began and I wish you could have heard him. The sound didn’t seem very loud, but it was penetrating and farreaching. When he had finished he raised one hand in the air, and you seemed to see all the people in the gallery drinking in the sound. That is the way Liszt teaches you. He presents an idea to you and it takes fast hold of your mind, and it sticks there. Music is such a real, visible thing to him that he always has a symbol, instantly, in the material world to express his idea.
“How he can bear to hear us play, I can not imagine. I assure you, no matter how beautifully we play any piece, the minute Liszt plays it, you would scarcely recognize it. His touch and his peculiar use of the pedals are the secrets of his playing, and then he seems to dive down into the most hidden thoughts of the composer, and fetch them to the surface, so they gleam out at you, one by one, like stars.
“The more I see and hear Liszt the more I am lost in amazement. I can neither eat nor sleep on those days that I go to him. I often think of what Tausig said once: ‘Oh! compared with Liszt, we other artists are all blockheads!’ I did not believe it at the time, but I’ve seen the truth of it.
“Liszt does such bewitching little things. The other day, for instance, Fraulein Gaul was playing something to him, and in it were two runs, and after each run two staccato chords. She did them most beautifully and struck the chords immediately after.
“‘No, no,’ said Liszt, ‘after you make a run you must wait a minute before you strike the chords as if in admiration of your own performance. You must pause, as if to say, ‘now nicely I did that.’ Then he sat down and made a run himself, waited a second, and then struck the two chords in the treble, saying as he did so, ‘Bra-vo,’ and then he played again, struck the other chord, and said again, ‘Bra-vo,’ and positively, it was as if the piano had softly applauded! That is the way he plays everything. It seems as if the piano were speaking with a human tongue.
“You can not conceive anything like Liszt’s playing of Beethoven. When he plays a sonata it is as if the composition rose from the dead and stood transfigured before you. You ask yourself, ‘did I ever play that?’”
Once Miss Fay asked the master to tell her how he produced a certain effect in one of his great passages. He smiled and then immediately played the whole passage. “‘Oh! I’ve invented a great many things,’ he said, indifferently, ‘this for instance,’ and he began playing a double roll of octaves in chromatics in the bass of the piano. It was very grand and made the room reverberate.
‘Magnificent,’ said I. ‘Did you ever hear me do a storm?’ said he. ‘No.’ ‘Ah! you ought to hear me do a storm, storms are my forte.’ Then to himself between his teeth, while a weird look came into his eyes as if he could indeed rule the blast—‘Then crash the trees.’
How ardently I wished he would play a storm, but he did not. Alas, that we poor mortals here below should share so often the fate of Moses and have only a glimpse of the Promised Land, and that without the consolation of being Moses!
“Liszt sometimes strikes wrong notes when he plays, but it does not trouble him in the least, on the contrary he rather enjoys it when he comes down squarely wrong, as it affords him an opportunity of displaying his genius and giving things such a turn that the false note
will appear simply a key leading to new and unexpected beauties. An accident of this kind happened to him in one of the Sunday matinees when the room was full of distinguished people and of his pupils. He was rolling up the piano in arpeggios in a very grand manner indeed, when he struck a semi-tone short of the high note upon which he had intended to end. I caught my breath and wondered whether he was going to leave us like that, in mid air, as it were, and the harmony unresolved or whether he would be reduced to the humiliation of correcting himself like ordinary mortals and taking the right chord. A half smile came over his face, as much as to say, ‘don’t fancy that this little thing disturbs me,’ and he instantly went meandering down the piano in harmony with the false note he had struck, and then rolled deliberately up in a second grand sweep, this time striking true. I never saw a more delicious piece of cleverness. It was so quick-witted and so exactly characteristic of Liszt. Instead of giving you a chance to say ‘He has made a mistake,’ he forces you to say, ‘He has shown how to get out of a mistake.’
“Another day I heard him pass from one piece into another by making the finale of the first one play the part of prelude to the second. So exquisitely were the two woven together that you could hardly tell where the one left off and the other began. Ah, me! such a facile grace! Nobody will ever equal him with those rolling basses and those flowing trebles. And then his Adagios! When you hear him in one of those you feel that his playing has got to that point where it is purified from all earthly dross and is an exhalation of the soul that mounts straight to heaven.”
This little book contains many more beautiful passages but we are reluctantly forced to desist. One charming trait of Liszt is related, however, which we can not pass over in closing. Miss Fay says:
“Gottschal, organist in Weimar, told me that one time when Tausig was ‘hard up’ for money, he sold the score of Liszt’s ‘Faust’ for five thalers, to a servant, along with a great pile of his own notes. Gottschal, hearing of it, went to the man and purchased them. Then he went to Liszt and told him that he had the score. As it happened, the publisher had written for it that very day and Liszt was turning the house upside down, looking for it everywhere. He was in an awful
state of mind because his score was nowhere to be found. ‘A whole year’s labor lost,’ he cried, and he was in such a rage that when Gottschal asked him for the third time what he was looking for, he turned and stamped his foot at him and said: ‘You confounded fellow, can’t you leave me in peace and not torment me with your stupid questions?’ Gottschal knew perfectly well what was wanting but he wished to have a little fun out of the matter. At last he took pity on Liszt and said: ‘Herr Doctor, I know what you have lost! It is the score to your Faust.’ ‘O,’ said Liszt, changing his tone immediately, ‘do you know anything of it?’ ‘Of course, I do,’ said Gottschal, and proceeded to unfold Master Tausig’s performance and how he had rescued the precious music. Liszt was transported with joy that it was found and cried out: ‘We are saved, Gottschal has rescued us,’ and then Gottschal said that Liszt embraced him in his transport, and could not say or do enough to make up for his having been so rude to him. Well, you would have supposed that it was now all up with Master Tausig, but not at all. A few days after was Tausig’s birth-day. Madame C. took Gottschal aside and begged him to drop the subject of the note-stealing, for Liszt doted so on his Carl that he wished to forget it. Sure enough, Liszt kissed Carl and congratulated him on his birth-day and consoled himself with his same old observation: ‘You’ll either turn out a great blockhead, my little Carl, or a great master.’”
“O, thou amiable grand master Liszt!”
Thus closes our notice of this genial book. Since the “soulful fantasies” of Bettina about Beethoven, nothing comparable with it from a lady’s hand has appeared.
In closing, we append, with the master’s own approval, as the facsimile in our own little work shows, a list of his principal scholars. We preface it with a sentiment of the master, which shows how much that remark of Beethoven’s to Bettina about music was to him—“The elevated types of the moral sense also constitute its foundations,” or truth and the will combined. It reads:
“It belongs to the higher mission of art, not only to exhibit and celebrate in song the heroic spirit but to inspire it. Hence the artist
should feel it, preserve it and diffuse it like a sacred flame.”
APPENDIX.
A LETTER FROM LISZT’S FATHER.
The Harmonicon, an English musical journal, of June, 1824, contains the following interesting letter, addressed to its editor by Liszt’s father:
P , 1824.
S :—The expressions which you frequently employed in speaking of my son have been so flattering, that I can not but be sensible of your kindness, and therefore take this opportunity of testifying my gratitude. I must say, that I by no means anticipated the high degree of success with which he was honored by the public of Paris, and above all, was not prepared for the comparison, by no means advantageous, which they were pleased to draw between the rising talents of my son, and those of our great Mozart. I recognize in this amiable exaggeration that spirit of French politeness, the boast of which I have all my life been accustomed to hear, and my son will think himself most happy, if hereafter he shall have the good fortune to share some degree of celebrity with the masters of the German school, though he must remain at a very humble distance from him whom it glories in placing at its head.
You must however allow me, Sir, to make a few observations upon the following expression that occurred in one of your journals: “The parents of young Liszt are poor, and he supports them by the product of his talents.”
Fortune, it is true, has not loaded me with her favors, yet I have no reason to complain of her neglect. For the space of twenty-three years I have been in the service of Prince
Esterhazy, where I filled the situation of steward of part of his sheep-farms. The immense income of this prince, and the noble and generous manner in which he acts toward those who have the good fortune to belong to any of his establishments, have long since placed me in that aurea mediocritas so happily described by the Latin poet.
Having observed in my only son, from a very early age, a decided predilection for music, and having from my youth cultivated the art as an amateur, I myself, for the space of three years, superintended his first musical education with that constancy and perseverance which form one of the characteristic traits of our nation. I afterward placed him for eighteen months under the instruction of Messrs. Salieri and Czerny, from the first of whom he received lessons in harmony and counter-point, and from the second, instruction on the piano-forte, and to both of whom he is indebted for their kind care and attention. I am happy to be thus able publicly to render them the homage of my grateful acknowledgments.
I came to Paris with the permission of the prince, and by the advice of my friends, in order to perfect my son’s talents, by affording him an opportunity of hearing the numerous artists whom this capital contains, and of cultivating the French language, of which he has already some general idea; a language which justly lays claim to the title of being that of Europe. At the same time, I have not neglected to take advantage of the eagerness testified by the Parisians to hear his performance, in order to indemnify myself for the expenses necessarily attendant upon a long journey, and the removal of my whole family.
Accept my best acknowledgments, and believe me, etc.,
A L
Accompanying this letter is the following editorial comment:
“The young Francis Liszt, with his father, arrived in London last month, and has exhibited his talents to many people of rank, and to some of the most distinguished professors of this metropolis, who all agree in considering him as a performer that would be ranked very high, even were he arrived at full manhood, and therefore a most surprising instance of precocious talent at so early an age as twelve. He executes the most difficult of the modern piano-forte music without the smallest apparent effort, and plays at sight things that very few masters would venture upon, until they had given to them a little private study. But his extemporaneous performances are the most remarkable. Upon any subject that is proposed to him he improvises with the fancy and method of a deliberating composer, and with the correctness of an experienced contrapuntist. His hand is not unusually large, but is amazingly strong, and his touch has all the vigor of maturity. He has reached the usual growth of boys of his age, and possesses an open, intelligent and agreeable countenance, with a frankness, but at the same time a propriety of manner, that indicates a good temper and a correct understanding.”
LISZT’S ONE OPERA.
A German correspondent of the Harmonicon sent that paper the following account of the performance of Liszt’s Opera, “Don Sancho,” on Oct. 18, 1825, at the Academie Royale de Musique, Paris:
“The extraordinary youth, the composer of this opera, has but just entered his thirteenth year. He has been acknowledged by some of the first connoisseurs of Germany and France to merit a place among the principal pianists of Europe; nay, some have gone so far as to say that he yields the palm to Hummel only, whose immense talent as an improvisatore undoubtedly stands as yet alone and unrivaled. But the youthful Liszt is also a
composer and gifted with the talent of improvisation in a high degree. Aware of this, and wishing early—we trust not too soon—to develop his talents, the admirers of the youthful compatriot of Mozart desired him to try his strength on a wider field; they procured a poem adapted, as they supposed, to his powers. He has for some time been diligently engaged upon it, and the present is the result of his labors. * * * *
“The subject of the opera is taken from a tale of Florian, entitled ‘Don Sancho,’ one of the feeblest of all this author’s works. It is a kind of allegory, in which Love appears in person, armed with his bow and arrows. The little god is the lord and master of an almost inaccessible castle, the gate of which can be entered only by two and two at a time. The drawbridge is never let down, save to a knight accompanied by his lady. Elvira, persecuted by one whom she detests, and who is attempted to be forced upon her as a husband, disguises herself as a knight, and finding a favorable moment for escape, sallies forth alone from the castle of the King, her father. In the midst of a forest she meets with Don Sancho, who, being in quest of adventures, is desirous of entering into conversation with the unknown. Piqued at being answered only in monosyllables, he finds means to excite a quarrel. A combat ensues. Elvira, as every child could have foreseen, is vanquished. She sinks to the earth and her helmet falling off discovers the features of a beauteous female. The victor is on his knees before his lovely foe; Elvira no longer merits that title. She also is in love with Don Sancho at first sight. But a fearful storm comes on, and they hasten to the Castle of Love (Le Chateau d’ Amour) which is seen in the distance. On the way they are encountered by Rostubalde—for such is the name of the odious rival—who wishes to prevent their entrance into the castle. Don Sancho rushes upon him but is wounded; Elvira avenges the wound of her lover by the death of Rostubalde. At length the two lovers are at the gates of
the castle. The winged god appears upon one of the towers. ‘Open to us,’ cries Elvira, ‘we are two faithful ones who love, and will love forever.’ At this magic word ‘ever,’ the gates fly open. Cupid with a single touch heals the wound of Don Sancho. Elvira returns with him to the court of the good-natured King, her father, who asks not a word of explanation relative to the absence of his blooming daughter from her home, but hastens to unite the two lovers.
“In the outline here given of this dull and insipid pastoral, will, with a very few exceptions, be found the general story of the opera in question. The principal change is that of the person of Rostubalde into an enchanter, of the name of Alidor; but even this resource, such as it is, the authors have turned but to little account. In a word, we consider our young artist as dragged to the earth by the dead weight of this mass, which he has attempted in vain to leaven by his genius.
“But we must now speak of the music. The overture contains many happy motives, and passages of great beauty and effect. If it fails in being strongly characteristic, we should impute the fault in a great measure to the subject. An overture should be the preface to the work, but what must be the preface to a work without interest! Among the airs, the most admired was that of the Magician, and above all, two romances, one sung by Don Sancho and the other by the Page. Many of the orchestral parts are treated with a vigor and intelligence which would do honor to composers long disciplined in their art.
“Upon a cool and dispassionate view of the whole composition, we must remark, that the young Liszt ought to view this, his first dramatic work, only in the light of an experiment on the extent of his powers. Mozart was only twelve years of age when he composed his ‘Finta Semplice’ for the theater of Vienna. The distance is immense indeed between that essay and his ‘Don
Giovanni’; but the question is whether he would ever have created the latter wondrous opera, if his first steps in the career of excellence had been inhumanly arrested.”
BIHARY.
A review of Liszt’s “Bohemiens” which appeared in the London Athenæum of 1859 gives the following interesting sketch of Bihary, the gypsy virtuoso:
“Next we come to John Bihary, who seems to have been ‘the highest expression’ of the gypsy virtuoso,—a brilliant player, courted at all the courts and royally repaid for his playing:—a man as impudent as an Italian tenore of the worst class. Bihary lived in our own time, for he gave a performance before Maria Louisa in 1814, and there made himself so remarkable by his undisguised admiration of one of the Imperial Princesses present, that his hostess found it necessary to rebuke his audacious eyes. The violinist was called up and was asked if he was a married man. His answer was ‘Yes;’ and that his wife was with him in Vienna. On this he was bidden to present her forthwith. Bihary’s wife was sent for on the spot. A striking looking and still young woman, magnificently attired in the gypsy dress, was brought. On receiving her, the Empress said to Bihary, that since heaven had given him so beautiful and faithful a helpmate, he was inexcusable in being so sensitive to the beauty of any princess, recommended to him more propriety for the future, and after paying marked compliments to Eve (Bihary’s wife), caused fifty ducats to be given to her, and sent the pair home in one of the court carriages. A second anecdote concerning Bihary is little less characteristic of manners. About the year 1824 a carriage accident disabled him for life. With true gypsy improvidence he had laid by nothing for a rainy day, and could hardly toil through the least important part in the band of which he had been the king. In this fallen estate it
chanced that he fell in at a tavern with some Hungarian noblemen, who had known him in his days of court splendor and insolence. He was prevailed on to play slowly one or two of the very easy pieces of national music which he had yet power to master. His arm was soon tired. On his stopping, one of his princely auditors bound it up in bank-notes. Bihary died in 1827.”
THE HUNGARIAN GYPSY MUSIC.
“The Hungarian gypsy merely plays Hungarian; he sings little or not at all; and what is his principal instrument, and at the same time the principal instrument of the Hungarian popular music? It is the dulcimer or cimbalo. This instrument, consisting of a triangular wooden frame, with a bottom and sounding board, over which wires by twos or threes are stretched upon bridges, which are struck with two wooden hammers, covered on the upper part with cloth or leather, is peculiarly fitted to infuse into the little gypsy orchestra that palpitating, feverish, tremulous essence, by which the performance of a Magyar nota gains so much. With this are associated the string quartet, together with the contra-basso and also quite willingly the clarinet. On the contrary all other instruments, as oböes, flutes, fagotti, horns, trumpets, etc., are entirely excluded from a Hungarian gypsy orchestra.
“What does the gypsy produce with these instruments? Is his music, is the popular instrumental music any mere dance music? Essentially, perhaps; but ere the dancing mood begins, ere joy and appetite for pleasure hurry the Magyar ember into dance and play, and make him forget himself, he must first, in the slow, sustained tones of a Lassu (Adagio) in the minor, pour out his complainings, roll away the sighs which hold his soul imprisoned in a melancholy gloom. Not suddenly can his soul plunge into the fresh major tones of his national dances; nay, he often
clings to the dear minor mood after his sadness is supposed to have given place to idle joy and pleasure. The kind of music which we would here indicate is called in general Csardas. This signifies both the dance itself and the dance music; and as every Hungarian dance is preceded by an introductory Lassu, this also is included in the term. The Lassu, soaring beyond the possibility of being represented as a dance, is usually followed by a Frisded, or Allegretto, of a quicker movement, but usually kept also in the minor, yet shaped already to the dance, but only for the solo dance of men. If the Magyar ember allows himself to be drawn away from his sombre mood into a dance, it is at first only a solo dance; self-satisfied, he spins round in a circle and as yet covets not an object for his love; only when the third part in this psychological economy of the dance, with its quick, strong strokes, has hurried him completely out of himself, does he begin to know no moderation and no goal. His eye sparkles, his feet stamp, like those of an untamed horse. To think, it is good that a man do not remain alone, and to grasp at a maiden, are one act, and he begins with her that wild, unbridled dance, which is called Csardas in the narrower sense of the word, or by way of distinction, Friss (i. e., Allegro, Presto). Already in the Lassu, the dull brooding in which the soul of the Magyar ember swims, is crossed by some occasional gleams of enthusiasm; but in the Frisded the dark clouds of sadness begin first to break away, and the Friss tears away entirely the thin veil which yet lay on his soul and left him in a self-contented solitude. Now no repose is longer to be thought of; from melancholy it becomes impetuous passion; from pain unbounded pleasure; in short, his Me, delivered from itself, riots and storms away until his feet refuse their service.”—Neue Zeitschrift fuer Musik.
HEINE ON LISZT.
“That such a restless head, driven and perplexed by all the needs and doctrines of his time, feeling the necessity of troubling himself about all the necessities of humanity, and eagerly sticking his nose into all the pots in which the good God brews the future, that Franz Liszt can be no still piano-forte player for tranquil townsfolks and good-natured nightcaps is self-evident. When he sits down at the piano, and has stroked his hair back over his forehead several times, and begins to improvise, he often storms away right madly over the ivory keys, and there rings out a wilderness of heaven-high thoughts, amid which, here and there, the sweetest flowers diffuse their fragrance, so that one is at once troubled and beatified, but troubled most.
“I confess to you, much as I love Liszt, his music does not operate agreeably upon my mind; the more so that I am a Sunday child and also see the specters which others only hear; since, as you know, at every tone which the hand strikes upon the key-board the corresponding tone-figure rises in my mind; in short, since music becomes visible to my inward eye. My brain still reels at the recollection of the concert in which I last heard Liszt play. It was in a concert for the unfortunate Italians, in the hotel of that beautiful, noble and suffering princess who so beautifully represents her material and her spiritual fatherland, to wit, Italy and Heaven. * * * * (You surely have seen her in Paris, that ideal form which yet is but the prison in which the holiest angel soul has been imprisoned. * * But this prison is so beautiful that every one lingers before it as if enchanted, and gazes at it with astonishment.) * * It was in a concert for the benefit of the unhappy Italians when I last heard Liszt, last winter, play, I know not what, but I could swear he varied upon themes from the Apocalypse. At first I could not quite distinctly see them, the four mystical beasts; I only heard their voices, especially the roaring of the lion and the screaming of the eagle. The ox with the book in his hand I saw clearly enough. Best of all he played the Valley of Jehosaphat. There were lists as at a
tournament, and for spectators, the risen people, pale as the grave and trembling, crowded round the immense space. First galloped Satan into the lists, in black harness, on a milk-white steed. Slowly rode behind him, Death on his pale horse. At last Christ appeared, in golden armor, on a black horse, and with His holy lance He first thrust Satan to the ground, and then Death, and the spectators shouted.”
H H .
A LETTER FROM BERLIOZ TO LISZT.
The following is an extract from a letter written by Berlioz to Liszt in 1843, as it appears in the former’s “Musical Wandering through Germany:”
“Proudly you can exclaim, like Louis XIV, ‘I am the orchestra! I am the chorus! At my grand piano I sing, dream, rejoice, and it excels in its rapidity the nimblest bows. Like the orchestra, it has its whispering flutes and pealing horns, and without any preparation can, like that, breathe the evening breeze from its silvery clouds of magic chords and tender melodies. It requires no scenes, no decorations, no spacious stage; I need not weary myself with tedious rehearsals; I want neither a hundred, nor fifty, nor twenty assistants; I need not one, and can even do without music. A large hall, a grand piano, and I am master of a whole audience. Applause resounds through the room.’ When his memory awakens brilliant fantasies under his fingers, shouts of enthusiasm welcome them. Then he sings Schubert’s Ave Maria, or Beethoven’s Adelaide, and every heart bounds to meet him, every breath is hushed in agitated silence, in suppressed amazement. Then, high in air ascend the thundering strife and glittering finale of these mighty fireworks and the acclamations of the admiring public. Now, amid a shower of wreaths and blossoms, the priest
of harmony ascends his golden tripod, beautiful maidens approach, to kiss with tears the hem of his garment; to him belongs the sincere admiration of earnest minds, as well as the involuntary homage of the envious; to him bend noble forms, to him bow hearts who do not comprehend their own emotions.
“And the next day, having poured forth the inexhaustible treasure of his inspiration, he hastens away, leaving behind him a glittering train of glory and enthusiasm. It is a dream! One of those golden dreams which one has when he is named Liszt or Paganini.”
HESSE’S CRITICISM OF LISZT.
Hesse, the famous German organist, after hearing Liszt play at Breslau, in 1859, recalls his playing sixteen years previously in the same place. He writes to the Breslauer Zeitung:
“On the 9th of May, a grand concert was arranged in the Schiesswerder Hall, by Herr Doctor Leopold Damrosch, in honor of, and with the cooperation of, the CourtCapellmeister Herr Doctor F L . Liszt, the great, genial master of the piano-forte, who with his achievements on this instrument alarmed the world, gave eleven concerts here in Breslau in the year 1843, with ever increasing success. He electrified his hearers by such playing as no one had shown before. Whoever thought to give himself up to his playing with the calm and comfortable feeling that he would to the performances of Hummel and other masters, was greatly mistaken. Liszt transferred his moods to the piano. He screwed up the feelings of the hearer to a pitch of feverish excitement, but he allowed them also to subside occasionally. We were at that time so fortunate as to be daily in his presence and admire his magical play. His repertoire was multifarious; he played all masters.
“We will not waste words about his gigantic technique, his art of singing on the instrument, etc.; these are well-known things; thousands have heard him. But we can not forbear alluding to one composition; we mean his ‘Reminiscences from Don Juan,’ one of the most genial of piano pieces. We lament for any one who has not heard him play these reminiscences. The marble guest on horseback, the insinuating Don Juan with his La ci darem, the struggling and at last consenting Zerlina, the Champagne song, etc., all this did Liszt pass before our minds in such a way that we forgot Liszt, concert-hall and all; one awoke from the performance as from a blissful dream. Four times we heard this piece by him, and always with the same emotions.”
