книги студ / Color Atlas of Pathophysiology (S Silbernagl et al, Thieme 2000)

Hyperinsulinism, Hypoglycemia

tions of amino acids in blood are markedly raised (e.g., in hyperleucinemia). The insulin release stimulated by the amino acids is then too high for the particular glucose concentration and hypoglycemia results. In liver failure the reduced breakdown of amino acids can cause hypoglycemia (→A2). Abnormalities of carbohydrate metabolism (→p. 244), such as some glycogen storage diseases, fructose intolerance or galactosemia, can also bring about hypoglycemia.

In the dumping syndrome after a gastric resection, sugar taken orally reaches the gut without delay, abruptly stimulates the release of gastrointestinal hormones, and is quickly absorbed. The gastrointestinal hormones and the steeply rising glucose concentration lead to an excessive release of insulin, so that hypoglycemia occurs after an interval of one to two hours (→p.148).

In rare cases an excess of insulin is caused by an insulin-producing tumor (→A3).

Relative insulin excess can also occur with normal insulin release if the release and/or the action of the insulin-antagonistic hormones (glucocorticoids, epinephrine, glucagon, somatotropin) is impaired. This is especially so if the glucose reserves are low and gluconeogenesis from amino acids is limited, as in liver failure, after starvation or alcoholism, but also on increased glucose utilization, as during heavy work or in tumors (→A5).

The most important effect of absolute or relative insulin excess is hypoglycemia, which causes a voracious appetite and leads to massive sympathetic nervous stimulation with tachycardia, sweating, and tremors (→A6). The impaired energy supply of the nervous system, which requires glucose, can result in seizures and loss of consciousness. Ultimately, the brain may be irreversibly damaged.

Plate 9.19 Hyperinsulinism, Hypoglycemia

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peptidases and some toxins. Kallikrein promotes its own activation via stimulation of factor XIIa (→p. 60). It is broken down very quickly (in < 1 min) in blood by the action of kininases.

The effects of bradykinin resemble those of histamine, namely vasodilation, increased vascular permeability, fall in blood pressure, tachycardia, increased cardiac contractility, raised catecholamine release, and stimulation of bronchial, intestinal, and uterine contraction. In contrast to histamine, however, bradykinin causes pain at nerve endings. In the gut and glands it promotes secretion, while it acts as a diuretic in the kidneys. Bradykinin also plays a role in inflammations (especially pancreatitis), edemas (especially angioneurotic edema), and pain.

Serotonin. In addition to being formed in the central nervous system (→p. 350), serotonin (→B) is formed in the enterochromaffin cells of the gut, in thrombocytes, proximal tubular cells, and the bronchi. Its release is increased especially in tumors of the enterochromaffin cells (carcinoid).

Serotonin leads to contraction of the smooth muscles in the bronchi, small intestine, uterus, and blood vessels either directly, or via the release of other mediators (prostaglandins, catecholamines). The effects of these actions are, among others, diarrhea, bronchospasm, and a rise in blood pressure. Nevertheless, serotonin can also have a vasodilating effect. Its action on blood vessels can cause headache (migraine). Serotonin promotes the aggregation of thrombocytes; it causes pain, can increase the permeability of peripheral capillaries, and can produce edemas. The sudden flushes that occur with tumors of the enterochromaffin cells are probably due to other mediators (especially kinins, histamine). The cause of endocardial fibrosis associated with tumors of the enterochromaffin cells remains undetermined. As serotonin is broken down in the liver, the systemic symptoms of serotoninproducing intestinal tumors (such as bronchospasm) commonly occur only after they have metastasized to the liver.

9 Hormones

296

Eicosanoids

Eicosanoids are a large group of intracellular and intercellular mediators that are formed from arachidonic acid, a polyunsaturated fatty acid. They are rapidly inactivated in the blood and thus act mainly on their immediate environment.

Arachidonic acid is released from phospholipids of the cell membrane under the influence of the enzyme phospholipase A2 (→ A1). This enzyme is activated by cell swelling and by an increase of intracellular Ca2+ concentration. It is stimulated by a number of mediators, such as histamine, serotonin, bradykinin, and norepinephrine (via α-receptors). Phopholipase A2 is inhibited by glucocorticoids (via lipocortin) and epinephrine (via β-receptors).

Arachidonic acid can be transformed to leukotrienes via the enzyme lipoxygenase and to prostacyclin (prostglandin G [PGG2]) via the enzyme cyclo-oxygenase. Substances that can be formed from PGG2 include thromboxan A2 (TXA2) and the prostaglandins F2α (PGF2α), E2 (PGE2), and I2 (PGI2 = prostacyclin) (→ A3). The enzyme cyclo-oxygenase is inhibited by non-steroidal anti-inflammatory drugs (NSAIDs), for example, acetylsalicylic acid (aspirin). Inflammations and tissue damage cause activation of both cyclo-oxygenase and lipoxygenase, and thus increase the formation of eicosanoids.

The leukotrienes (→ A2) cause the contraction of the smooth muscles in the bronchi, blood vessels, gut, and uterus. They are responsible for lasting bronchoconstriction in asthma; their action on the gut can cause diarrhea and their effects on the uterus can bring about abortion of the fetus. Leukotrienes indirectly increase vascular permeability and thus bring about edemas. They also promote adhesions and chemotaxis and stimulate the release of histamine, oxygen radicals, and lysosomal enzymes as well as of insulin.

TXA2 is formed largely in thrombocytes and is essential for blood clotting. An excess of TXA2 favors the formation of thrombi. Administration of small doses of the cyclo-oxygenase inhibitor acetylsalicylic acid can thus reduce the risk of myocardial infarction because of its effect of reducing thrombocyte aggregation.

PGF2α stimulates the release of a series of

hormones and the contraction of the smooth muscles of blood vessels, gut, bronchi, and uterus.

PGE2 inhibits the release of hormones and lipolysis, stimulates the contraction of smooth muscles of the gut and uterus; however, it inhibits the contraction of the vascular and bronchial muscles. Cyclo-oxygenase inhibitors can thus cause asthma in an atopic individual (socalled analgesic asthma). The vascular effect can cause persistence of the ductus arteriosus. Conversely, the administration of cyclo-oxy- genase inhibitors during the last trimester can cause the premature closure of the ductus arteriosus. PGE2 increases glomerular filtration rate. It raises vascular permeability and thus promotes the development of edemas.

PGE2 and PGI2 aid in the demineralization of the bones (osteolysis). They stimulate the renal formation of renin and, by inhibiting the tubular reabsorption of Na+ and water, they produce natriuresis and diuresis. They raise the target level of temperature regulation (fever) and cause pain. The effects of the prostaglandins contribute to a large extent to the symptoms of infection.

PGE2 has an essential, protective role in the stomach by inhibiting the secretion of HCl and pepsin while promoting the secretion of HCO3– and mucus, which has a protective effect. It also causes vascular dilation. A reduction in PGE2 formation by cyclo-ogygenase inhibitors favors the development of gastric ulcers.

PGE2 also has a protective effect on the renal medulla. Via dilation of the vasa recta it improves O2 and substrate availability, and decreases the expenditure of energy by inhibiting NaCl reabsorption.

PGE2 is also of great importance in Bartter’s syndrome, which is due to mutations of the Na+-K+-2 Cl– cotransporter, the luminal K+ channels, or the basolateral Cl– channels in the loop of Henle. An excessive local formation of PGE2 is the consequence of the resulting transport defect. The inhibitory action of PGE2 on Na+ transport in more distal nephron segments adds to NaCl loss and its vasodilator action causes a profound drop in blood pressure. The affected children can be kept alive only with inhibitors of cyclo-oxygenase.

A. Eicosanoids

?

permeability

HCl/pepsin secretion

Edema

GFR

Silbernagl/Lang, Color Atlas of Pathophysiology © 2000 Thieme

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Plate 9.21 Eicosanoids

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which may be localized (e.g., individual muscles) or generalized (e.g., the entire musculature). Such damage can result in overactivity (e.g., involuntary muscle cramps or inadequate activity of sensory receptors with faulty sensory perceptions), or functional deficits (muscle paralysis or sensory deficits). Even when the sensory receptors are intact, sensory perception, especially via the eyes and ears, may be impaired if the transmission apparatus is defective.

An interruption of peripheral nerve conduction (→A2) impairs the signals that are propagated in this nerve, but different types of fibers (e.g., myelinated and nonmyelinated) may be affected differently. The result of complete disruption of nerve conduction is flaccid paralysis, loss of sensation and of autonomic regulation in the innervation area of the affected nerve. Analogously, lesions of a spinal nerve affect the corresponding dermatome. Diagnosis of nerve lesions thus requires an exact knowledge of the innervation area of individual nerves and dermatomes (cf. anatomy textbooks).

Lesions of the spinal cord (→A3) can cause loss of sensory perception and/or autonomic functions as well as flaccid or spastic paralysis. Conversely, abnormal stimulation of neurons can lead to inadequate sensations and functions. The affected areas approximately follow the distribution of the dermatomes.

Lesions in supraspinal structures (→A4) can also result in deficits or abnormal excitations that are circumscribed both as to function and to body region (e.g., in localized lesions in primary sensory cortical areas). However, more commonly they cause complex disorders of the sensory and motor systems and/ or autonomic regulation. Additionally, impairment of integrative cerebral functions such as memory, emotions, or cognition may occur in the course of a variety of diseases.

10 Neuromuscular and Sensory Systems

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Pathophysiology of Nerve Cells

In order to fulfill their function, neurons must be able to receive information from other cells and then pass it on to yet other cells. As a rule the information is received via membrane receptors that are activated by neurotransmitters. The activity of ionic channels is influenced directly or via intracellular mechanisms of transmission. Thus, in suitable target cells acetylcholine (ACh) opens nonspecific cation channels that will then allow the passage of Na+ and K+. This will lead to depolarization of the cell membrane and thus to opening of the voltage-gated Na+ and Ca2+ channels. Ca2+ ions then mediate the release of neurotransmitters by the target cell. In the long term, cell metabolism and gene expression of the target cell, and thus the formation of synapses and the synthesis and storage of neurotransmitters are also regulated.

Abnormalities can interfere with each element of this cascade (→A). For example, receptor density can be reduced by down-regu- lation. Also, certain mechanisms of intracellular transmission can be blocked. An example is the blocking of G proteins by, among others, pertussis toxin (→A1). Ionic channels can be blocked by drugs, or their activity changed by Ca2+, Mg2+, or H+. Furthermore, their effect on the membrane potential can be distorted by a change in ionic gradients, such as an increase or a decrease in the intracellular or, more importantly, extracellular K+ concentration. Both occur when Na+/K+-ATPase is inhibited, for example, due to energy deficiency. Axonal transport as well as formation, storage, release, and inactivation of neurotransmitters (→A2) can be impaired, for example, by genetic defects or drugs. Functional abnormalities can be reversible once the damage is no longer effective.

Lesions may also lead to irreversible destruction of neurons. In addition to cell death by direct damage to it (necrosis, e.g., due to energy deficiency or mechanical destruction), socalled programmed cell death (apoptosis) may also play a role in this (→A3 and p.12). Neurons cannot be renewed in adults. Thus, the destruction of neurons will cause an irreversible impairment of function, even if other neu-

rons can partly take over the function of the dead cell.

Deleterious substances must pass the blood–brain barrier if they are to reach the neurons of the central nervous system (CNS) (→B). An intact blood–brain barrier impedes the passage of most substances and prevents pathogens and immunocompetent cells entering (→p. 356). However, some toxins (e.g., pertussis and botulinus toxins) reach neurons in the spinal cord through retrograde axonal transport via peripheral nerves, and thus avoid the blood–brain barrier (→p. 356). Some viruses also reach the CNS in this way.

If an axon is transected (→C), the distal parts of the axon die (Waller degeneration).

Axons of central neurons as a rule do not grow outward again, rather the affected neuron dies by apoptosis. Causes include absence of the nerve growth factor (NGF), which is normally released by the innervated, postsynaptic cell and, via the axon, keeps the presynaptic cell alive. Interruption of the retrograde axonal transport in an otherwise intact axon also leads to death of the neuron. The proximal stump of the peripheral axon can grow out again (→C2). The proteins that are necessary for this to happen are formed within the cell body and are transported to the place of injury by axonal transport. A possible reason for survival of the affected cell is that macrophages migrating into the peripheral nerve, via the formation of interleukin 1, stimulate the Schwann cells to produce NGF. Macrophages are not, however, able to enter the CNS.

Transection of an axon not only causes death of the primarily damaged neuron (→C1), the absence of innervation often leads to death of the target cell (anterograde transneuronal degeneration) and sometimes also of cells that innervate the damaged cell (retrograde transneuronal degeneration).