Cardura
Jason Warren Freeman, M.D.
- Medical Director, Stroke Program, Sibley Memorial Hospital
https://www.hopkinsmedicine.org/profiles/results/directory/profile/3784557/jason-freeman
Spatial coding-association of wave frequencies with different areas of the membrane heart attack flac torrent order cardura 2mg line. Absence of the consensual reflex upon stimulating the left eye suggests damage to the left retina and/or to the left optic nerve arteria esfenopalatina purchase generic cardura from india. To dilate: a sympathetic agonist (a) or something that blocks muscarinic receptors (b) pulse pressure femoral artery generic cardura 2 mg. Circular muscles form a ring on the inner part of the iris blood pressure vitamins buy cardura 4 mg cheap, surrounding the pupil blood pressure over 60 order cardura cheap. The radial muscles extend from the outer edge of the iris to the circular muscles heart attack under 40 buy cardura 4mg line. When the radial muscles contract, they pull on the relaxed circular muscles and expand the diameter of the pupil (dilation). Chromaffin cells are modified postganglionic neurons, so they have nicotinic receptors. The axon contains voltage-gated channels, with separate channels for Na+ and K+ [p. This means that nicotine also excites sympathetic neurons, such as those that increase heart rate. The olfactory epithelium, located high in the nasal cavity, contains termini of olfactory neurons, which can bind to odorant molecules. Ascending pathways for pain go to the limbic system (emotional distress) and hypothalamus (nausea and vomiting). The transplanted cells were obtained from the olfactory bulb, where stem cells are present 33. The free nerve endings of nociceptors are sensitive to chemical, mechanical, and thermal stimuli. In bright light, retinal diffuses to the pigment epithelium (bleaching), where it is inactivated before returning to the rods and binding to opsin. Accommodation-through the relaxation and contraction of ciliary muscles and ligaments called zonules. Connections between the sympathetic ganglia allow rapid communication within the sympathetic branch. Antagonistic control: pupil of eye, heart (rate), bronchioles, digestive tract, endocrine and exocrine pancreas, urinary bladder. Examples: biceps/triceps in the upper arm; hamstring (flexor)/quadriceps (extensor) in the upper leg; tibialis anterior (flexor)/gastrocnemius (extensor) for foot movement at the ankle. Ends of the A bands are darkest because that is where thick and thin filaments overlap. T-tubules allow action potentials to travel from the surface of the muscle fiber to its interior. The banding pattern of organized filaments in the sarcomere forms striations in the muscle. A neuromuscular junction consists of axon terminals from one somatic motor neuron, the synaptic cleft, and the motor end plate on the muscle fiber. Visceral nervous system because it controls internal organs (viscera) and functions such as heart rate and digestion. Sympathetic neurons exit the spinal cord in the thoracic and lumbar regions; ganglia are close to the spinal cord. Parasympathetic exit from the brain stem or sacral region; ganglia on or close to their targets. Diffuse away from the synapse, broken down by enzymes in the synapse, taken back into the presynaptic neuron, or bind to a membrane receptor. Caffeine can prolong the activity of acetylcholine at synapses, which may enhance alertness. The crossbridges do not all unlink at one time, so while some myosin heads are free and swiveling, others are still tightly bound. The events of the latent period include creation of the muscle action potential, release of Ca2+ from the sarcoplasmic reticulum, and diffusion of Ca2+ to the contractile filaments. Creatine is the substrate, and kinase tells you that this enzyme phosphorylates the substrate. Increasing extracellular K+ causes the cell to depolarize and become less negative. Because creatine kinase catalyzes the reaction in both directions, the relative concentrations of the reactants and products determine the direction of the reaction. Multi-unit smooth muscle increases force by recruiting additional muscle fibers; single-unit smooth muscle increases force by increasing Ca2+ entry. If the muscle insertion point is farther from the joint, the leverage is better and a contraction creates more rotational force. The nervous system increases the force of contraction by recruiting additional motor units. Increased motor neuron firing rate causes summation in a muscle fiber, which increases the force of contraction. A marathoner probably has more slow-twitch muscle fibers, and a sprinter probably has more fast-twitch muscle fibers. Pacemaker potentials always reach threshold and create regular rhythms of contraction. Slow wave potentials are variable in magnitude and may not reach threshold each time. Increased frequency of action potentials in the neuron increases neurotransmitter release. Many Ca2+ channels open with depolarization; therefore, hyperpolarization decreases the likelihood that these channels open. Fatigue-a reversible state in which a muscle can no longer generate or sustain the expected force. May involve changes in ion concentrations, depletion of nutrients, or excitation-contraction coupling. The body uses different types of motor units and recruits different numbers of motor units. Small movements use motor units with fewer muscle fibers; gross movements use motor units with more fibers. These muscles exert opposite effects such as flexion and extension at a defined joint, thereby allowing movement. Fast-twitch glycolytic fibers-largest, rely primarily on anaerobic glycolysis, least fatigue-resistant. Slow-twitch-develop tension more slowly, maintain tension longer, the most fatigue-resistant, depend primarily on oxidative phosphorylation, more mitochondria, greater vascularity, large amounts of myoglobin, smallest in diameter. Pacemaker potentials-repetitive depolarizations to threshold in some smooth muscle and cardiac muscle. The neuronal channel for Na+ entry is a voltage-gated Na+ channel, but the muscle channel for Na+ entry is the acetylcholine-gated monovalent cation channel. Myosin heads swivel towards the M-line, simultaneously sliding the actin filaments along with them. Assuming these athletes are lean, differences in weight are correlated with muscle strength, so heavier athletes should have stronger muscles. More important factors are the relative endurance and strength required for a given sport. Any given muscle will have a combination of three fiber types, with the exact ratios depending upon genetics and specific type of athletic training. Leg muscles-fasttwitch glycolytic fibers, to generate strength, and fast-twitch oxidative, for endurance. The arm and shoulder muscles-fast-twitch glycolytic, because shooting requires fast and precise contraction. Leg muscles-fast-twitch oxidative, for moving across the ice, and fast-twitch glycolytic, for powering jumps. Two neuron-neuron synapses in the spinal cord and the autonomic ganglion, and one neuron-target synapse. Voluntary movements, such as playing the piano, and rhythmic movements, such as walking, must involve the brain. Reflex movements are involuntary; the initiation, modulation, and termination of rhythmic movements are voluntary. Alpha-gamma coactivation allows muscle spindles to continue functioning when the muscle contracts. When the muscle contracts, the ends of the spindles also contract to maintain stretch on the central portion of the spindle. Parts of the brain include the brain stem, cerebellum, basal ganglia, thalamus, cerebral cortex (visual cortex, association areas, motor cortex). Other functions include regulating drives such as sex, rage, aggression, and hunger, and reflexes including urination, defecation, and blushing. Heart, blood vessels, respiratory muscles, smooth muscle, and glands are some of the target organs involved. Tetanus toxin triggers prolonged contractions in skeletal muscles, or spastic paralysis. Botulinum toxin blocks secretion of acetylcholine from somatic motor neurons, so skeletal muscles cannot contract, which is flaccid paralysis. Sensor (sensory receptor), input signal (sensory afferent neuron), integrating center (central nervous system), output signal (autonomic or somatic motor neuron), targets (muscles, glands, some adipose tissue). Upon hyperpolarization, the membrane potential becomes more negative and moves farther from threshold. When you pick up a weight, alpha and gamma neurons, spindle afferents, and Golgi tendon organ afferents are all active. A crossed extensor reflex is a postural reflex initiated by withdrawal from a painful stimulus; the extensor muscles contract, but the corresponding flexors are inhibited. The bottom tube has the greater flow because it has the larger pressure gradient (50 mm Hg versus 40 mm Hg for the top tube). Tube C has the highest flow because it has the largest radius of the four tubes (less resistance) and the shorter length (less resistance). If the canals are identical in size and therefore in cross-sectional area A, the canal with the higher velocity of flow v has the higher flow rate Q. Connective tissue is not excitable and is therefore unable to conduct action potentials. It is possible to conclude that myocardial cells require extracellular Ca2+ for contraction but skeletal muscle cells do not. If all Ca2+ channels in the muscle cell membrane are blocked, there will be no contraction. If only some are blocked, the force of contraction will be smaller than the force created with all channels open. Na+ influx causes neuronal depolarization, and K+ efflux causes neuronal repolarization. The refractory period represents the time required for the Na+ channel gates to reset (activation gate closes, inactivation gate opens). If cardiac Na+ channels are completely blocked with lidocaine, the cell will not depolarize and therefore will not contract. The Ca2+ channels in autorhythmic cells are not the same as those in contractile cells. The Ca2+ channels in contractile cells are slower and do not open until the membrane has depolarized fully. If tetrodotoxin is applied, nothing will happen because there are no voltage-gated Na+ channels in the cell. Cutting the vagus nerve increased heart rate, so parasympathetic fibers in the nerve must slow heart rate. It also slows down the speed at which those action potentials are conducted, allowing atrial contraction to end before ventricular contraction begins. The fastest pacemaker sets the heart rate, so the heart rate increases to 120 beats/min. Atrial pressure increases because pressure on the mitral valve pushes the valve back into the atrium, decreasing atrial volume. Atrial pressure decreases during the initial part of ventricular systole as the atrium relaxes. Atrial pressure begins to decrease at point D, when the mitral valve opens and blood flows down into the ventricles. Ventricular pressure shoots up when the ventricles contract on a fixed volume of blood. After 10 beats, the pulmonary circulation will have gained 10 mL of blood and the systemic circulation will have lost 10 mL. Phase 2 (the plateau) of the contractile cell action potential has no equivalent in the autorhythmic cell action potential. The heart rate is either 75 beats/min or 80 beats/min, depending on how you calculate it. If you use the data from one R peak to the next, the time interval between the two peaks is 0. There are 4 beats in the 3 sec after the first R wave, so 4 beats/3 sec * 60 sec/min = 80 bpm. In 4, there are no recognizable waves at all, indicating that the depolarizations are not following the normal conduction path.
Neither striated ducts nor myoepithelial cells are present in the exocrine pancreas heart attack fever order cardura in united states online. Intercalated ducts converge to form interlobular ducts lined by a simple columnar epithelium blood pressure 80 over 50 4mg cardura mastercard. Secretin and cholecystokinin regulate the function of the pancreatic acinus and intercalated duct atrial fibrillation treatment purchase 2 mg cardura free shipping. Cholecystokinin and acetylcholine trigger the release of inactive forms of trypsin blood pressure stages best 4mg cardura, chymotrypsin arrhythmia when lying down order cardura with a mastercard, and carboxylpeptidases produced by the pancreatic acinar cells pulse pressure for athletes cheapest cardura. Secretin stimulates the secretion of water, sodium, and bicarbonate ions by centroacinar cells and epithelial cells of the intercalated duct. Acute pancreatitis is the result of pancreatic tissue autodigestion by the premature activation of pancreatic enzymes, in particular trypsin. This condition usually follows trauma, heavy meals or excessive alcohol ingestion or biliary tract disease. The clinical features of acute pancreatitis are severe abdominal pain, nausea, and vomiting. Acute pancreatitis can give rise to complications, such as abscess formation and cysts. Cystic fibrosis is an inherited disease affecting mucus-secreting tissues of the respiratory, 17. Each acinus is drained sequentially by: (1) An intercalated duct, lined by low squamous-to-cuboidal simple epithelium. Striated ducts converge toward interlobular ducts found between lobules in the interlobular septa. Lobar ducts join the main duct, which displays a stratified squamous epithelium near its opening in the oral cavity. Submandibular glands produce 70% of the saliva; the parotid glands contribute 25%. The main products in saliva are: (1) Lysozyme, which attacks the walls of bacteria. Essential concepts 555 Concept mapping Digestive Glands Digestive glands Salivary glands Parotid gland Submandibular gland Sublingual gland Pancreas Hepatic lobule Hepatocyte plates Bile canaliculi Hepatic sinusoids Liver Portal space Hepatic artery/arteriole Portal venule Secretory portion Serous acinus Myoepithelial cells Long intercalated duct Short striated duct Mixed acinus Myoepithelial cells Short intercalated duct Long striated duct Mucous acinus Myoepithelial cells Poorly developed intercalated and striated ducts Serous acinus Centroacinar cells Myoepithelial cells absent Bile duct Lymphatic vessel Central venule Endothelial cells Kupffer cells Excretory duct Intercalated duct Striated duct absent Space of Disse Space of Mall Perisinusoidal cell Canal of Hering (cholangiole) digestive, reproductive, and integumentary systems. Chronic pancreatitis in cystic fibrosis is characterized by a loss of acini, dilation of the pancreatic excretory ducts, and extensive fibrosis (increase in connective tissue). Activation of the oncogene K-ras and inactivation of tumor suppressor genes, including p53, are molecular characteristics of the tumor. The close association of the pancreas with large blood vessels, the extensive and diffuse abdominal drainage to lymph nodes, and the frequent spread of carcinoma cells to the liver via the portal vein are factors contributing to the ineffectiveness of surgical removal of pancreatic tumors. This category includes serous cystoadenomas (with cysts containing a clear fluid) and mucinous cystoadenomas (with cysts filled with a mucoid product). Gastrinomas, insulinomas, and glucagonomas are examples of endocrine tumors showing cytoplasmic secretory granules. This tumors belong to the category of syndromic functioning tumors (associated with a syndrome). Blood is supplied by two vessels: (1) the portal vein supplies 75% to 80% of the afferent deoxygenated blood volume from the digestive tract, spleen, and pancreas. Blood from the portal vein and hepatic artery mixes in the hepatic sinusoid of the liver lobules. Sinusoidal blood converges to the central venule (or vein), and is drained sequentially by the sublobular vein, collecting vein, and hepatic vein into the inferior vena cava. Bile, the exocrine product of the liver, is collected by the intrahepatic bile duct, and drained by the right and left hepatic ducts. Bile is stored in the gallbladder and released in the descending second part of the duodenum through the common bile duct. The hepatic lobule consists of anastomosing plates of hepatocytes limiting blood sinusoidal spaces lined by endothelial cells and Kupffer cells. The space of Disse is interposed between the sinusoidal space and the hepatocytes. Perisinusoidal cells of Ito (the storage site of retinoids) are present in the space of Disse. A limiting plate of hepatocytes is the boundary between the hepatocyte parenchyma and the connective tissue stroma. Bile is transported through bile canaliculi into the canal of Hering (or cholangiole), and then into the bile duct in the portal triad space. The hepatocyte has a basolateral domain with abundant microvilli extending into the space of Disse. Excess of fluid in the space of Disse, not absorbed by the hepatocytes, is drained into the lymphatic circulation through the space of Mall located adjacent to the limiting plate. The basolateral domain participates in the absorption of blood-borne substances (for example, bilirubin, peptide and steroid hormones, vitamin B12, and substances to be detoxified), and the secretion of plasma proteins (for example, albumin, fibrinogen, prothrombin, coagulation factors, and complement proteins). The apical domain borders the bile canaliculus, a trenchlike depression lined by microvilli and sealed by tight junctions. Long-term consumption of ethanol results in fatty liver, a reversible process if alcohol ingestion is discontinued. If alcohol consumption continues, hepatocyte injury can lead to cirrhosis (collagen proliferation of fibrosis of the liver) and hepatocellular carcinoma (malignant transformation of hepatocytes). Perisinusoidal cells remain in a quiescent, nonproliferative state, but can proliferate when activated by Kupffer cells and hepatocytes. Activation occurs after partial hepatectomy, focal hepatic lesions, and in different conditions that lead to fibrosis. Hepatitis is an inflammatory condition of the liver determined predominantly by viruses but also by bacteria (of intestinal origin or hema- togenous) and parasites (amebiasis and schistosomiasis). Immunity determined by one type of virus does not protect against infection caused by other viruses. Chronic hepatitis is defined by the presence of fibrosis, together with hepatocyte necrosis and inflammatory lymphocytic activity. Disruption of the limiting plate (zone I of liver acinus), progression of fibrosis into the portal spaces, nodular regeneration of hepatocytes, and proliferation of bile ductules (cholangiolar proliferation) are indications of a possible progression to cirrhosis. Bile participates in the excretion of cholesterol, phospholipids, bile salts, conjugated bilirubin, and electrolytes. Fat absorption in the intestinal lumen depends on the fat-emulsifying function of bile salts. Bile transports IgA to the intestinal mucosa (enterohepatic circulation), and inhibits bacterial growth in the small intestine. Bilirubin is the end product of heme catabolism: (1) About 85% of bilirubin originates from senescent red blood cells destroyed in the spleen by macrophages. Glucuronide separates from bilirubin in the small intestine and bilirubin is converted by intestinal bacteria into urobilinogen, which is excreted. Hyperbilirubinemia, an increase in the concentration of bilirubin circulating in blood, can occur when bilirubin cannot be conjugated in the hepatocyte (Crigler-Najjar disease). A defect in the transport of conjugated bilirubin to the bile canaliculus is the cause of the Dubin-Johnson syndrome. The wall of the gallbladder consists of a mucosa with folds and deep clefts, lined by a simple columnar epithelium. Neuroendocrine System the neuroendocrine system combines functions of the nervous system and the endocrine system aimed at the regulation of several physiologic processes. A key component of the neuroendocrine system is the hypothalamus, a site where neurons, acting as neurosecretory cells, release their neuropeptides into blood vessels to reach the adjacent hypophysis so they can collectively communicate with their target organs and tissues and receive information through feedback loops. Furthermore, the hypothalamus regulates the activities of the parasympathetic and sympathetic nervous system, including cardiovascular responses and glucose metabolism. This chapter addresses the structure and function of the hypophysis and the pineal gland. Both are endocrine glands located behind the blood-brain barrier, but their secretory products are released outside the blood-brain barrier in a cyclic, rhythmic, or pulsatile manner. The pars tuberalis envelops, like a partial or total collar, the infundibular stem or stalk, a neural component. Regions of the hypophysis (pituitary gland) the hypothalamus is divided into two symmetric halves by the third ventricle. It is limited rostrally by the optic chiasma, caudally by the mamillary bodies, laterally by the optic tracts, and dorsolaterally by the thalamus. Pars nervosa Adenohypophysis Pars tuberalis Pars distalis (anterior lobe) Pars distalis Hypothalamus Paraventricular nucleus Supraoptic nucleus Mamillary body Neurohypophysis Infundibulum Median eminence Infundibular process Pars nervosa (neural lobe) Pars intermedia Major subdivisions of the hypophysis the adenohypophysis is formed by three major subdivisions: (1) the pars distalis, or anterior lobe, the main glandular epithelial component; (2) the pars tuberalis, a collar-like nonsecretory tissue enveloping the infundibulum of the neurohypophysis; and (3) the pars intermedia, a narrow wedge forming a cap around the pars nervosa (neural lobe). The neurohypophysis consists of two parts: the pars nervosa, or neural Pars intermedia Immunostaining of lobe, and the infundibulum. The infundibulum is formed by two structures: (1) axonal neurofilaments the median eminence, a funnel-shaped extension of the hypothalamus; and (2) the infundibular process. Development of the hypophysis Infundibulum 1 Diencephalon 4 2 Infundibulum Stomodeum Notochord 1 A diverticulum, called the infundibulum, develops in the floor of the diencephalon and grows toward the stomodeum. There are two subtypes of craniopharyngiomas: (1) Adamantinomatous craniopharyngioma, common in children, and (2) papillary craniopharyngioma, frequent in adults. The neurohypophysis develops from an infundibular downgrowth from the floor of the diencephalon. However, the connecting stem of the neurohypophysis remains as the core of the infundibular stem, or stalk. Cells of the anterior surface of the pouch give rise to the pars distalis (the bulk of the gland). Superior extensions of the pouch surround the infundibular stem, forming the pars tuberalis. Hypothalamohypophyseal portal circulation the hypothalamus and the hypophysis form an integrated neuroendocrine network known as the hypothalamohypophyseal system. The hypothalamic adenohypophyseal system, connecting the hypothalamus to the anterior hypophysis. The hypothalamic neurohypophyseal system, linking the hypothalamus to the posterior hypophysis. Blood supply to the hypophysis Hypothalamus Hypothalamohypophysiotropic nuclei Hypothalamohypophyseal portal system Internal carotid artery 1 Adenohypophysis Neurohypophysis Paraventricular nucleus 2 3 Mamillary body Branch of the internal carotid artery Superior hypophyseal artery 2 Supraoptic nucleus Optic chiasma 5 4 6 Trabecular artery Primary capillary plexus in the upper infundibulum Portal veins 4 1 the trabecular artery connects the superior and inferior hypophyseal arteries 3 Secondary capillary plexus in the pars distalis Basophil Acidophil Inferior hypophyseal artery Branch of the cavernous carotid artery (internal carotid artery) Hypophyseal vein (to dural sinuses) Axon terminal 5 Capillary plexus of Hypophyseal vein (to dural sinuses) Adenohypophysis Neurohypophysis the pars nervosa Blood supply to the hypophysis the superior hypophyseal artery forms a primary capillary plexus in the infundibulum (formed by the median eminence and infundibular stem). The primary capillary plexus receives releasing and inhibitory hormones from the neuroendocrine hypothalamohypophysiotropic nuclei. Portal veins supply blood to the secondary capillary plexus, with which basophils and acidophils are associated. By this mechanism, hypothalamic releasing and inhibitory peptides act directly on cells of the pars distalis (anterior hypophysis) to regulate their endocrine function. The primary and secondary capillary plexuses linked by the portal veins form the hypothalamohypophyseal portal system. The inferior hypophyseal artery supplies the pars nervosa, forming a capillary plexus, which collects vasopressin (antidiuretic hormone) and oxytocin produced by neuroendocrine cells of the supraoptic and paraventricular nuclei, respectively. The superior and inferior hypophyseal arteries are connected by the trabecular artery, whose capillaries bypass the portal circulation of the adenohypophysis (see 6). The hypothalamus, corresponding to the floor of the diencephalon and forming part of the walls of the third ventricle, consists of at least twelve clusters of neurons, called nuclei, some of which secrete hormones. The neurosecretory cells of the hypothalamus exert positive and negative effects on the hypophysis through neuropeptides (called releasing and inhibitory hormones or factors), have a very short response time to neurotransmitters (fractions of a second), and send axons into the neurohypophysis. In contrast, the effects of hormones derived from the epithelial cells of the anterior hypophysis have a longer response time (minutes or hours) and can persist for as long as a day or even a month. Capillaries arising from the primary capillary plexus project down the infundibulum and pars tuberalis to form the portal veins. Identification of basophil, acidophil, and chromophobe cells in the anterior hypophysis Hematoxylin-eosin staining (H&E) the anterior hypophysis consists of clusters of epithelial cells adjacent to fenestrated capillaries. With hematoxylin and eosin (H&E), the cytoplasm of basophils stains blue-purple (glycoproteins) and acidophils stain light pink (proteins). Basophil Fenestrated capillary Acidophil Trichrome stain (aniline blue, orange G, and azocarmine) With the trichrome stain, the cytoplasm of basophils stains blue-purple and acidophils orange. Basophil Chromophobe Acidophil Red blood cells Plastic section stained with basic fuchsin and hematoxylin the polygonal shape of the epithelial cells of the anterior hypophysis is well defined in this preparation. The cytoplasm of basophils stains dark pink, acidophils stain light pink, and chromophobe cells are unstained. The use of specific antibodies against hormones produced in the anterior hypophysis has enabled (1) the precise identification of all hormone-producing cells of the anterior hypophysis; (2) the identification of hormone-producing adenomas; and (3) the elucidation of the negative and positive feedback pathways regulating the secretion of hypophyseal hormones. The transport of hypothalamic releasing and inhibitory neuropeptides from the primary capillary plexus to the hormone-producing epithelial cells of the anterior hypophysis. The functional integration of the hypothalamus with the anterior hypophysis, provided by the portal veins. A third capillary plexus, derived from the inferior hypophyseal artery, supplies the neurohypophysis. This third capillary plexus collects secretions from neurosecretory cells present in the hypothalamus. The secretory products (vasopressin [antidiuretic hormone] and oxytocin) are transported along the axons into the neurohypophysis.
Cost of cardura. Senior male doctor measuring patients blood pressure.
The vertebral bones are predominantly trabecular bone surrounded by a thin rim of compact bone hypertension 90 discount 4mg cardura free shipping. Therefore prehypertension 23 years old cheap cardura 2mg on-line, they may be crushed or may wedge anteriorly arrhythmia etiology discount cardura 4mg mastercard, resulting in pain and in a reduction in height arteria retinae discount 4 mg cardura mastercard. Bisphosphonate drugs decrease fracture by inhibiting bone resorption and increasing bone mass blood pressure jumping around cheap 2 mg cardura overnight delivery. Denosumab mimics the function of osteoprotegerin and decreases bone resorption blood pressure medication memory loss discount cardura 4 mg, as determined by measuring in urine and serum of bone-collagen degradation products and increased bone mineral density at 1 year. Osteopetrosis (Greek osteon, bone; petra, stone; osis, condition) is a clinical syndrome caused by a failure of osteoclasts to remodel bone. For comparison, osteosclerosis is an increase in bone mass due to enhanced osteoblastic activity. Severe anemia and infections are related to bone marrow failure due to the occlusion of marrow spaces. Compression of cranial nerves determines hearing and vision loss and paralysis of facial muscles. Multiple bone factures and scoliosis (abnormal curvature of the spine) are characteristic. Because of its relatively benign clinical condition, many patients are asymptomatic and the condition is only detected by coincidental radiographic examination. Osteomalacia (Greek osteon, bone; malakia, softness) is a disease characterized by a progressive softening and bending of the bones. Softening occurs because of a defect in the mineralization of the osteoid due to lack of vitamin D or renal tubular dysfunction (see Chapter 14, Urinary System). In the young, a defect in mineralization of cartilage in the growth plate (see Chapter 5, Osteogenesis), causes a defect called rickets (juvenile osteomalacia). Osteomalacia can result from a deficiency of vitamin D (for example, intestinal malabsorption) or heritable disorders of vitamin D activation (for example, renal 1 -hydroxylase deficiency in which calciferol is not converted to the active form of vitamin D, calcitriol; see vitamin D in Chapter 19, Endocrine System). Although bone fractures are a common characteristic in patients with osteomalacia and osteoporosis, note that there is defective osteogenesis in osteomalacia in contrast to bone weakening of a previous normal osteogenesis process in patients with osteoporosis. Essential concepts Connective Tissue An extension of the adult connective tissue classification is based on which fibers predominate. Elastic connective tissue, found in the form of sheets or laminae in the wall of the aorta, is rich in elastic fibers. The fibroblast synthesizes the precursor molecules of various types of collagens and elastin and proteoglycans. Procollagen, the initial collagen precursor which contains hydroxyproline and hydroxylysine, is secreted by fibroblasts in the form of a triple helix flanked by nonhelical domains. Procollagen peptidase cleaves the nonhelical domains and procollagen becomes tropocollagen. Tropocollagen molecules self-assemble in a staggered array in the presence of lysyl oxidase to form a cross-banded collagen fibril. Osteoblasts, chondroblasts, odontoblasts and smooth muscle cells can also synthesize collagens. Defects in the processing of procollagen and tropocollagen and the assembly of collagen fibrils give rise to variations of the Ehlers-Danlos syndrome, characterized by hyperelasticity of the skin and hypermobility of the joints. Elastin, the precursor of elastic fibers, is also synthesized and processed sequentially. Fibroblasts or smooth muscle cells secrete desmosine- and isodesmosine-containing proelastin, which is partially cleaved to give rise to tropoelastin. Tropoelastin, fibrillins and fibulin 1 assemble into elastic fibers that aggregate to form bundles of elastic fibers. A defect in fibrillin 1 affects the assembly of mature elastic fibers, a characteristic of Marfan syndrome. Their function in connective tissue is the turnover of fibers and extracellular matrix and, most important, the presentation of antigens to lymphocytes as an essential step of immune and inflammatory reactions. The functions of connective tissue include the storage of metabolites, immune and inflammatory responses and tissue repair after injury. Connective tissue consists of thee basic components: cells, fibers and extracellular matrix (called ground substance). The proportion of these three components contributes to the classification of connective tissue. Connective tissue can be classified into three major groups: (1) Embryonic connective tissue. The embryonic connective tissue, or mesenchyme, consists predominantly of extracellular matrix. The adult connective tissue can be subclassified as: (1) Loose or areolar connective tissue (more cells than fibers, found in the mesentery or lamina propria of mucosae). Finally, tumor cells can produce chemokine molecules on their surface that facilitate their transendothelial migration to metastasize. There are two types of adipose tissue: (1) White fat, the major reserve of long-term energy. Mesenchymal stem cells give rise to white fat preadipocytes and common myoblast/ brown fat preadipocyte precursors. White fat can transdifferentiate into brown fat-like adipocytes following cold exposure and -adrenergic signaling. Lipoprotein lipase is transferred to endothelial cells in the adjacent blood vessels to enable the passage of fatty acids and triglycerides into the adipocytes. Fat can accumulate in a single lipid-strorage droplet (unilocular) or multiple small lipid droplets (multilocular). The granules contain vasoactive mediators (histamine, heparin, and chemotactic mediators), chymases and other proteases. Like most vasoactive agents, they induce an increase in vascular permeability leading to edema. Mast cells and basophils circulating in blood derive from the same progenitor in the bone marrow. Mast cells play a role in allergic hypersensitivity reactions associated with asthma, hay fever, and eczema. Three characteristics define the structure of a plasma cell: a well-developed rough endoplasmic reticulum, an extensive Golgi apparatus, and a prominent nucleolus. These features define the plasma cell as an actively protein-producing cell, whose main product are immunoglobulins. The extracellular matrix is a combination of collagens, noncollagenous glycoproteins, and proteoglycans. Each proteoglycan consists of a core protein attached to a linear hyaluronan molecule by a linker protein. Attached to the core protein are numerous glycosaminoglycan chains (keratan sulfate, dermatan sulfate and chondroitin sulfate). Malignant cells originated in a lining epithelium (carcinoma) or a glandular epithelium (adenocarcinoma) can break down the basement membrane and invade the underlying connective tissue. The histologic sequence of epithelial tumor invasion starts with dysplasia (increased cell proliferation and incomplete cell maturation), followed by carcinoma in situ (loss of epithelial normal organization within the limits of the basement membrane), microinvasive carcinoma (decreased expression of cadherins and breakdown of the basement membrane) and invasive carcinoma. Cessation in the expression of cadherins weakens the cohesive nature of the epithelial tumor. The production of proteinases allows the tumor cells to invade and attach to components of the connective tissue. Then, tumor cells produce autocrine motility factors, to enable tumor cell motility; vascular permeability Essential concepts 157 deposits can increase by inhibition of lipase activity (antilipolytic effect) determined by insulin and prostaglandins. Phosphorylated perilipin changes its conformation and enables lipolysis by lipases. Leptin, a peptide produced by adipocytes, regulates appetite, energy balance, and feeding. Leptin-deficient mice are obese and infertile, conditions that are reversible when leptin is administered to the mutants. Like a typical connective tissue member, cartilage consists of cells, fibers, and extracellular matrix. Cartilage lacks blood vessels and is surrounded by the perichondrium (except in fibrocartilage and articular hyaline cartilage, which lack a perichondrium). The perichondrium consists of two layers: an outermost fibrous layer, consisting of elongated fibroblastlike cells and blood vessels, and the innermost chondrogenic cell layer. Chondrogenesis (cartilage growth) takes place by two mechanisms: (1) Interstitial growth (within the cartilage). During interstitial growth, centers of chondrogenesis, consisting of chondroblasts located in lacunae and surrounded by a territorial matrix, divide by mitosis without leaving the lacunae and form isogenous groups. During appositional growth, the cells of the perichondrial chondrogenic layer differentiate into chondroblasts following activation of the gene encoding the transcription factor Sox9. A lack of Sox9 gene expression causes campomelic dysplasia characterized by bowing and angulation of long bones, hypoplasia of the pelvis and scapula, and abnormalities of the vertebral column. Macroscopically, a mature long bone consists of a shaft or diaphysis, and two epiphyses at the endings of the diaphysis. During bone growth, a cartilaginous growth plate is present at the epiphysismetaphysis interface. The diaphysis is surrounded by a cylinder of compact bone housing the bone marrow. The epiphyses consist of spongy or cancellous bone covered by a thin layer of compact bone. The periosteum covers the outer surface of the bone (except the articular surfaces and the tendon and ligament insertion sites). Microscopically, there is: (1) Lamellar bone, with a regular alignment of collagen fibers, typical of mature bone. Blood vessels are present in the central canal, which is surrounded by concentric lamellae. Each lamella contains lacunae and radiating canaliculi occupied by osteocytes and their cell processes. Osteoblasts synthesize type I collagen, noncollagenous proteins, and proteoglycans. These are the components of the bone matrix or osteoid deposited during bone formation. In mature bone, the bone matrix consists of about 35% organic components and about 65% inorganic components (calcium phosphate with the crystalline characteristics of hydroxyapatite). Osteopontin contributes to the development of the sealing zone during osteoclast bone resorption activity. Preosteoblasts differentiate into postmitotic osteoblasts expressing the transcription factors Runx2 and Osterix (Osx). Note that the osteoblast differentiation process requires the participation of three transcription factors: Sox9, Runx2, and Osx. Runx2-deficient mice have a skeleton consisting of cartilage and lack osteoclasts. In humans, cleidocranial dysplasia, characterized by hypoplastic clavicles and delayed ossification of sutures of certain skull bones, is associated with defective expression of the Runx2 gene. The function of osteoclasts is regulated by calcitonin, produced by C cells located in the thyroid gland. The free domain has a sealing zone, a tight belt consisting of v 3 integrin with its intracellular domain linked to F-actin and the extracellular domain attached to osteopontin on the bone surface. The osteoclast is a multinucleated cell resulting from the fusion of several monocytes during osteoclastogenesis. You should be aware that the bone marrow contains megakaryocytes that may be confused with the osteoclasts. Osteoclasts are intimately associated to bone and are multinucleated; megakaryocytes are surrounded by hematopoietic cells and their nucleus is multilobed. Bone removal occurs in two phases: First, the mineral component is mobilized in an acidic environment (~pH 4. Because of the significant H+ transport, a parallel bicarbonate-chloride ion transport mechanism is required to maintain intracellular electroneutrality. The osteoclast precursor is a member of the monocyte-macrophage lineage present in the adjacent bone marrow. Osteoblasts recruit monocytes and differentiate them into osteoclasts, the cell in charge of bone remodeling and mobilization of calcium. Osteoclastogenesis consists of several phases under strict control by the osteoblast. Osteoporosis is the loss of bone mass leading to bone fragility and susceptibility to fractures. The major factor in osteoporosis is the deficiency of the sex steroid estrogen that occurs in postmenopausal women. Osteopetrosis is a clinical syndrome caused by a failure of osteoclasts to remodel bone. Osteomalacia is characterized by a progressive softening and bending of the bones. Softening occurs because of a defect in the mineralization of the osteoid due to lack of vitamin D or renal tubular dysfunction. Osteogenesis Bone, including associated ligaments, tendons and articular cartilage, withstand the forces of compression, tension and shear stress. In addition to a description of the two major processes of ossification, this chapter addresses pathologic conditions, such as the sequence of bone fracture healing, metabolic and hereditary disorders and rheumatoid arthritis, within an integrated histologic and clinical context.
From age 30 on pulse pressure practice buy cardura paypal, resorption begins to exceed deposition blood pressure headache symptoms discount cardura 4 mg without a prescription, with concurrent loss of bone from the skeleton pulse blood pressure calculator buy cardura with visa. A nonendocrine factor that plays an important role in bone mass is mechanical stress on the bone blood pressure 130/80 purchase 4 mg cardura otc. High-impact exercise heart attack vs heart failure order cardura visa, such as running wide pulse pressure icd 9 buy cardura 4mg line, helps build bone but non-weight-bearing exercise such as swimming will not. Osteocytes apparently act as mechanosensors and are able to transduce mechanical stimuli into intracellular signals to lay down bone. In an interesting twist, early evidence suggests that the primary cilia of osteocytes [p. Calcium entering the cytoplasm initiates exocytosis of synaptic and secretory vesicles, contraction in muscle fibers, or altered activity of enzymes and transporters. Ca21 is part of the intercellular cement that holds cells together at tight junctions. Although Ca2+ is essential for blood coagulation, body Ca2+ concentrations never decrease to the point at which coagulation is inhibited. However, removal of Ca2+ from a blood sample will prevent the specimen from clotting in the test tube. This function of Ca 2+ has not been introduced before in this text, but it is the function that is most obvious in Ca2+-related disorders. In its most extreme form, hypocalcemia causes sustained contraction (tetany) of the respiratory muscles, resulting in asphyxiation. Transcellular absorption is hormonally regulated; paracellular absorption is unregulated. Output, or Ca2+ loss from the body, occurs primarily through the kidneys, with a small amount excreted in feces. Ionized Ca2+ is freely filtered at the glomerulus and then reabsorbed along the length of the nephron. Hormonally regulated reabsorption takes place only in the distal nephron and uses transporters similar to those found in the intestine. What does hypercalcemia do to neuronal membrane potential, and why does that effect depress neuromuscular excitability Calcium homeostasis follows the principle of mass balance: Total body calcium = intake - output 1. In the plasma, nearly half the Ca 2+ is bound to plasma proteins and other molecules. In addition, Ca2+ is concentrated inside mitochondria and the sarcoplasmic reticulum. Electrochemical gradients favor movement of Ca2+ into the cytosol when Ca2+ channels open. Bone is the largest Ca2+ reservoir in the body, with most bone Ca2+ in the form of hydroxyapatite crystals. Bone Ca2+ forms a reservoir that can be tapped to maintain plasma Ca2+ homeostasis. Usually only a small fraction of bone Ca2+ is ionized and readily exchangeable, and this pool remains in equilibrium with Ca2+ in the interstitial fluid. Only about one-third of ingested Ca2+ is absorbed, and unlike organic nutrients, Ca2+ absorption is hormonally regulated. Many people do not eat enough Ca2+containing foods, however, and intake may not match output. Intestinal calcium absorption is apparently both transcellular and paracellular (between the cells). Once inside the cell, Ca2+ binds to a protein called calbindin that helps keep free intracellular [Ca2+] low. This is necessary because of the role of free Ca2+ as an intracellular signal molecule. Of these, parathyroid hormone and calcitriol are the most important in adult humans. The parathyroid glands, which secrete parathyroid hormone para-, alongside of, were discovered in the 1890s by physiologists studying the role of the thyroid gland. These scientists noticed that if they removed all of the thyroid gland from dogs and cats, the animals died in a few days. In contrast, rabbits died only if the little parathyroid "glandules" alongside the thyroid were removed. The scientists then looked for parathyroid glands in dogs and cats and found them tucked away behind the larger thyroid gland. If the parathyroid glands were left behind when the thyroid was surgically removed, the animals lived. The scientists concluded that the parathyroid glands contained a substance that was essential for life, although the thyroid gland did not. The absence of parathyroid hormones causes hypocalcemic tetany and respiratory paralysis, as mentioned in the section on functions of calcium. Parathyroid hormone raises plasma Ca2+ in three ways: Parathyroid hormone Four small parathyroid glands lie on the Calcium Balance 771 fiG. Increased bone resorption by osteoclasts takes about 12 hours to become measurable. These paracrine factors are receiving intense scrutiny as potential pharmacological agents. As we mentioned previously, regulated Ca2+ reabsorption takes place in the distal nephron. If the concentrations exceed that level, calcium phosphate crystals form and precipitate out of solution. High concentrations of calcium phosphate in the urine are one cause of kidney stones. The body makes calcitriol from vitamin D that has been obtained through diet or made in the skin by the action of sunlight on precursors made from acetyl CoA. People who live above 37 degrees of latitude north or below 37 degrees south do not get enough sunlight to make adequate vitamin D except in the summer, and they should consider taking vitamin supplements. Vitamin D is modified in two steps-first in the liver, then in the kidneys-to make vitamin D3 or calcitriol. Calcitriol is the primary hormone responsible for enhancing Ca2+ uptake from the small intestine. In addition, calcitriol facilitates renal reabsorption of Ca2+ and helps mobilize Ca2+ out of bone. This action ensures maximal absorption of Ca2+ from the diet at a time when metabolic demands for calcium are high. Experiments in animals have shown that calcitonin decreases bone resorption and increases renal calcium excretion. Calcitonin apparently plays only a minor role in daily calcium balance in adult humans. Patients whose thyroid glands have been removed show no disturbance in calcium balance, and people with thyroid tumors that secrete large amounts of calcitonin also show no ill effects. However, phosphates have other significant physiological roles, including energy transfer and storage in highenergy phosphate bonds, and activation or deactivation of enzymes, transporters, and ion channels through phosphorylation and dephosphorylation. Enhances kidney excretion Signal transduction pathways appear to vary during cell cycle Experimentally decreases plasma Ca2+ but has little apparent physiological effect in adult humans. Osteoporosis Is a Disease of Bone Loss One of the best-known pathologies of bone function is osteoporosis, a metabolic disorder in which bone resorption exceeds bone deposition. Most bone resorption takes place in spongy trabecular bone, particularly in the vertebrae, hips, and wrists. Osteoporosis is most common in women after menopause, when estrogen concentrations fall. Bone loss and small fractures and compression in the spinal column lead to kyphosis hump-back, the stooped, hunchback appearance that is characteristic of advanced osteoporosis in the elderly. Risk factors include small, thin body type; postmenopausal age; smoking; and low dietary Ca2+ intake. The most effective drugs for preventing or treating osteoporosis act more directly on bone metabolism. Currently clinical studies are investigating whether some combination of bisphosphonates and teriparatide is more effective in combating osteoporosis than either drug alone. To avoid osteoporosis in later years, young women need to maintain adequate dietary calcium intake and perform weightbearing exercises, such as running or aerobics, which increase bone density. Loss of bone mass begins by age 30, long before people think they are at risk, and many women suffer from low bone mass (osteopenia) before they are aware of a problem. He goes on a low-calcium diet, avoiding milk, cheese, and other dairy products, but several months later he returns to the emergency room with another painful kidney stone. Spinks sends him to an endocrinologist, who recommends surgical removal of the overactive parathyroid glands. He must have his plasma Ca2+ levels checked regularly for the rest of his life to ensure Question Q1: What role does Ca2+ play in the normal functioning of muscles and neurons Integration and Analysis Muscle weakness in hyperparathyroidism is the opposite of what you would predict from knowing the role of Ca2+ in muscles and neurons. Hypercalcemia Q2: What is the technical term for "elevated levels of calcium in the blood" Filtration at the glomerulus is a selective process that excludes blood cells and most plasma proteins [p. A significant amount of plasma Ca2+ is bound to plasma proteins and therefore cannot filter. Each hormone has stimuli that initiate its secretion, and feedback signals that modulate its release. Molecular interactions and communication across membranes are also essential to hormone activity. In many instances, such as calcium and phosphate homeostasis, the principle of mass balance is the focus of homeostatic regulation. Cortisol is a typical steroid hormone in its synthesis, secretion, transport, and action. It promotes gluconeogenesis, breakdown of skeletal muscle proteins and adipose tissue, Ca2+ excretion, and suppression of the immune system. Basic components of endocrine pathways include hormone receptors, feedback loops, and cellular responses. Hypercortisolism usually results from a tumor or therapeutic administration of the hormone. The thyroid follicle has a hollow center filled with colloid containing thyroglobulin and enzymes. Tetraiodothyronine (thyroxine, T4) is converted in target tissues to the more active hormone triiodothyronine (T3). Thyroid hormones are not essential for life, but they influence metabolic rate as well as protein, carbohydrate, and fat metabolism. Long bone growth occurs at epiphyseal plates, where chondrocytes produce cartilage. Calcium acts as an intracellular signal for second messenger pathways, exocytosis, and muscle contraction. Calcitonin from the thyroid gland plays only a minor role in daily calcium balance in adult humans. Normal growth requires growth hormone, thyroid hormones, insulin, and sex hormones at puberty. The adrenal cortex secretes hormones, and the adrenal medulla secretes hormones. For (a) cortisol, (b) growth hormone, (c) parathyroid hormone, and (d) T3 and T4: Draw the full control pathway and show feedback where appropriate. Make a table showing the effects of cortisol, thyroid hormones, growth hormone, insulin, and glucagon on protein, carbohydrate, and lipid metabolism. Explain why the deficiency of parathyroid hormone causes hypocalcemic tetany and respiratory paralysis. Draw an osteoclast and diagram this process, including enzymes and the appropriate transporters on each membrane. How many different transporters can you think of that could be used to reabsorb bicarbonate Boston is located at 42 degrees north latitude, and weak sunlight in winter there does not allow skin synthesis of vitamin D. A lady with a history of smoking and a poor appetite fractures her hand and leg as the result of a fall. As part of the treatment, a doctor initiates a therapy that includes bisphosphonate and teriparatide. One diagnostic test to determine the cause of hypercortisolism is a dexamethasone suppression test. The following table shows the results from two patients given a dexamethasone suppression test. When blood test results came back last week, someone in the office spilled a cup of coffee on them, smearing the patient names and some of the numbers. Your tentative diagnoses, based on physical findings and symptoms, for those three patients are: Mr. The following graph shows the results of a study done in Boston that compared blood vitamin D levels during summer and winter. On graph A, plot the effect of plasma parathyroid hormone concentration on plasma Ca2+ concentration. On graph B, plot the effect of plasma Ca2+ concentration on plasma parathyroid hormone concentration. Although, at first sight, the immune system may appear to be autonomous, it is connected by innumerable structural and functional bridges with the nervous system and the endocrine system, so as to constitute a multisystem. Cell infected with poxvirus (650x) 777 778 chaPter 24 the Immune System " aughter is the best medicine.
Alcoholism is the major cause of chronic pancreatitis blood pressure headache cardura 2mg on-line, leading to a permanent loss of pancreatic endocrine and exocrine functions arrhythmia medscape cardura 2mg free shipping. Cystic fibrosis is an inherited blood pressure chart toddler cardura 2mg cheap, autosomal recessive disease affecting the function of mucus-secreting tissues of the respiratory (see Chapter 13 blood pressure medication numbness 2 mg cardura, Respiratory System) blood pressure chart man order 4mg cardura otc, intestinal hypertension jnc 7 ppt buy cardura with visa, and reproductive systems; the sweat glands of the skin (see Chapter 11, Integumentary System); and the exocrine pancreas in children and young adults. A thick sticky mucus obstructs the duct passages of the airways, pancreatic and biliary ducts, and intestine, followed by bacterial infections and damage of the functional tissues. Some affected babies have meconium ileus, a blockage of the intestine that occurs soon after birth. A large number of patients (85%) have chronic pancreatitis characterized by a loss of acini and dilation of the pancreatic excretory ducts into cysts surrounded by extensive fibrosis (hence the designation cystic fibrosis of the pancreas). Insufficient exocrine pancreatic secretions cause the malabsorption of fat and protein, reflected by bulky and fatty stools (steatorrhea). Portal space and the bile ducts 1 Bile canaliculus Hepatocyte plate Hepatocytes are arranged in plates, one cell thick. Hepatocyte plates branch or anastomose, leaving a space between them containing venous sinusoids. In histologic sections, rows of hepatocytes, representing sections of plates, converge at the central vein. Bile duct Portal venule Hepatic arteriole Limiting plate the limiting plate of hepatocytes surrounds the portal space. Branches of vessels and biliary ductules perforate the limiting plate to enter or exit the hepatic lobule. Hepatic venous sinusoid (fenestrated) extend toward the central vein of the hepatic lobule Bile excretory pathway A branch of the hepatic arteriole supplies the wall of the bile duct 1 At least two faces of a hepatocyte contain a trench forming a bile canaliculus. At the periphery of the hepatic lobule, bile canaliculi empty into a thin periportal bile ductule, known as 2 the canal of Hering (or cholangiole) lined by cuboidal/squamous epithelial cells. The terminal ductule leaves the lobule through the limiting plate and enters the 3 portal bile duct in the portal space. The disease is detected by the demonstration of increased concentration of NaCl in sweat. Liver the liver, the largest gland in the human body, consists of four poorly defined lobes. The portal vein (75% to 80% of the afferent blood volume) transports blood from the digestive tract, spleen, and pancreas. The hepatic artery, a branch of the celiac trunk, supplies 20% to 25% of oxygenated blood to the liver by the interlobar artery and interlobular artery pathway before reaching the portal space. Blood from branches of the portal vein and the hepatic artery mixes in the sinusoids of the liver lobules, as we discuss in detail later. Central venules converge to form the sublobular veins, and blood returns to the inferior vena cava following the collecting veins and hepatic veins pathway. The right and left hepatic bile ducts leave the liver and merge to form the hepatic duct. General organization of the hepatic lobule the structural and functional unit of the liver is the hepatic lobule. A central venule (or vein) in the core of the hepatic lobule collects the sinusoidal blood transporting a mixture of blood supplied by branches of the portal vein and the hepatic artery. Histologic and functional classification of the hepatic lobule 2 Portal lobule 1 Hepatic lobule (classic) Portal triad Branches of the portal vein Bile duct Branch of the portal vein 1 Hepatic lobule (classic) Bile duct Branch of the hepatic artery Central venule 2 Portal lobule A branch of the hepatic artery the classic hexagonal lobule contains a central venule and components of the portal triad at the angles. The center of the portal lobule is the bile duct collecting the bile from all canaliculi. I In zone I (periportal), hepatocytes actively synthesize glycogen and plasma proteins. Bile produced in the hepatocytes is secreted into narrow intercellular spaces, the bile canaliculi, located between the apposed surfaces of adjacent hepatocytes. Organization of the hepatic lobule 1 the perisinusoidal space of Disse separates the basolateral domain of the hepatocyte from blood circulating in the hepatic sinusoid. Sinusoid feeding into the central venule Hepatic lobule Hepatic sinusoid 1 Space of Disse Central venule Hepatocyte plates are formed by single rows of hepatocytes. Endothelial cell 2 the space of Mall, found at the periphery of the hepatic lobule, is continuous with the space of Disse. Lymphatic vessels surround the blood vessels and bile ductules in the portal space. Kupffer cell Perisinusoidal cell Hepatocyte plate 2 Bile canaliculus 3 Canal of Hering Space of Mall Lymphatic vessel Portal venule Hepatic arteriole Bile duct Portal space Limiting plate 3 the canal of Hering (or cholangiole) is the terminal point of the network of bile canalicular trenches found on the hepatocyte surfaces. The canal of Hering is located at the periphery of the hepatic lobule (periportal site), is lined by a squamous-to-cuboidal simple epithelium, and connects with the bile ductules in the portal space after perforating the limiting plate. The connective tissue of the portal space provides support to the portal triad formed by branches of the hepatic artery (arteriole), portal vein (venule), and bile duct (ductule). In addition, lymphatic vessels and nerve fibers are present in the portal space (also designated portal canal, portal area, or portal tract). The portal lobule concept, based on the bile drainage pathway from adjacent lobules toward the same bile duct. The liver acinus concept, based on the gradient distribution of oxygen along the venous sinusoids of adjacent lobules. Components of the portal triad, constituting a branch of the portal vein and hepatic artery and a bile duct, are usually found at the angles of the hexagon. This geometric organization is poorly defined in humans because the limiting perilobular connective tissue is not abundant. However, recognition of the components of the portal triad is helpful in determining the boundaries of the human hepatic lobule. In the portal lobule, the portal triad is the central axis, draining bile from the surrounding hepatic parenchyma. In the liver acinus, the boundaries are determined by a terminal branch of the hepatic artery. Although pathologic changes in the liver are usually described in relation to the classic lobule, the liver acinus concept is convenient for understanding liver regeneration patterns, liver metabolic activities, and the development of cirrhosis. Hepatocyte the hepatocyte is the functional exocrine and endocrine cell of the hepatic lobule. Hepatocytes form anastomosing one-cell-thick plates limiting the sinusoidal spaces. Endoplasmic reticulum in hepatocytes the rough endoplasmic reticulum in hepatocytes is involved in the synthesis of plasma proteins: albumin, coagulation factors (fibrinogen and prothrombin in particular), and binding proteins for hormones and growth factors in blood circulation. Glycogen Lipid droplet the smooth endoplasmic reticulum in hepatocytes is highly developed and is always associated with clusters of glycogen molecules forming typical rosette-like inclusions. Stored glycogen in hepatocytes represents a glucose reserve for the maintenance of sugar concentrations in blood. Rough endoplasmic reticulum Albumin, a major product of the hepatocyte, maintains plasma oncotic pressure. Complement proteins, synthesized by hepatocytes, participate in the destruction of pathogens. Smooth endoplasmic reticulum the smooth endoplasmic reticulum has an important function in detoxification. Enzymes necessary for the detoxification of drugs (barbiturates), steroids, alcohol, and other toxicants reside in the membrane of the smooth endoplasmic reticulum. Blood from the portal vein and hepatic artery flows into the sinusoids and is drained by the central venule (no apparent smooth muscle cell wall). Apical and basolateral domains of hepatocytes Hepatic sinusoids are lined by two cell types: (1) discontinuous endothelial cells and (2) phagocytic cells of Kupffer. Kupffer cell is a differentiated phagocytic cell derived from monocytes A hepatocyte has distinct domains: apical domains, represented by the bile poles, and extensive basolateral domains with microvilli extending into the space of Disse. Basolateral domain Apical domain Golgi apparatus Fenestrated endothelium Reticular fibers Space of Disse Nucleus Bile canaliculus Apical domain Peroxisome Rough endoplasmic reticulum Peroxisome A membrane-bound structure that contains oxidases and catalase. Bile canaliculus Lipid droplet Basolateral domain Nucleus Smooth endoplasmic reticulum and associated glycogen inclusions Rough endoplasmic reticulum Boundary of a hepatocyte Endothelial cell Endothelial cell lining a hepatic sinusoid. Endothelial cells have a fenestrated cytoplasm associated with a discontinuous basal lamina. Bile released into the canaliculus is drained by the canal of Hering, or cholangiole, an epithelial-lined ductule in the periportal space. The canal of Hering carries the bile to the bile ductules, one of the three components of the portal space. Space of Disse the space of Disse, between the sinusoid and the basolateral domain of hepatocytes, enables an exchange between blood and hepatocytes. Hepatocyte absorptive function is enhanced by the microvilli extending into the space of Disse. Hepatic sinusoids and bile canaliculi Lumen of a hepatic sinusoid A discontinuous basal lamina supports the fenestrated endothelial cell lining of a hepatic sinusoid. Fenestrated endothelial cell lining of a hepatic sinusoid Microvilli of the basolateral domain of a hepatocyte extending into the subendothelial space of Disse Rough endoplasmic reticulum Glycogen the bile canaliculus is a space limited by two or more hepatocytes. Tight junctions seal the intercellular space, thus preventing the leakage of bile. Alcohol is oxidized to acetaldehyde in the cytoplasm and acetaldehyde is converted to acetate in mitochondria. An excess of H+ and acetaldehyde causes mitochondrial damage, disrupts microtubules, and alters proteins that can induce autoimmune responses leading to hepatocyte injury. Reactive oxygen produces injury to hepatocytes by causing lipid peroxidation, resulting in cell membrane damage. Large fat deposits in the cytoplasm of hepatocytes are observed in fatty liver (steatosis) following long-term consumption of alcohol. Excess fluid in the space of Disse is collected in the space of Mall, located at the periphery of the hepatic lobule. Lymphatic vessels piercing the limiting plate drain the fluid of the space of Mall. Gap junctions on the lateral surfaces of adjacent hepatocytes enable intercellular functional coupling. Note that hepatocytes synthesize several plasma proteins required for blood clotting (see Chapter 6, Blood and Hematopoiesis). Perisinusoidal cell and chronic liver disease Perisinusoidal cell 1 Tumor necrosis factor ligand causes a slowdown and arrest of the flow of bile in bile ducts (cholestasis: Greek chole, bile; stasis, standing still). Persistent virus replication in hepatocytes causes chronic liver disease, which may progress to fibrogenesis, cirrhosis and finally hepatocellular carcinoma. Hepatitis B virus and hepatitis C virus replicate in hepatocytes and promote prolonged inflammation, fibrogenesis and hepatocyte regeneration resulting in chronic liver damage leading finally to hepatocellular carcinoma. Fibrogenesis follows a period of hepatitis during which hepatocytes are injured and destroyed, a process followed by regeneration. Liver fibrogenesis promotes chronic liver disease in response to continuing inflammation and regeneration. Fibrosis and inflammatory cells, mainly lymphocytes and macrophages, are seen in the distorted portal space. Regenerated hepatocyte nodule surrounded and infiltrated by connective tissue containing collagens and extracellular matrix material. The removal of iodine from the thyroid hormones triiodothyronine (T3) and thyroxine (T4). The detoxification of lipid-soluble drugs such as phenobarbital, during which the smooth endoplasmic reticulum is significantly developed. The Golgi apparatus contributes to glycosylation of secretory proteins and the sorting of lysosomal enzymes. Lysosomes degrade aged plasma glycoproteins internalized at the basolateral domain by a hepatic lectin membrane receptor, the asialoglycoprotein receptor, with binding affinity to terminal galactose after the removal of sialic acid. Lysosomes in hepatocytes store iron, which can exist as soluble ferritin and insoluble hemosiderin, the degradation product of ferritin. Peroxisomes is a hereditary disorder of copper metabolism in which excessive deposits of copper in liver and brain lysosomes produce chronic hepatitis and cirrhosis. Pathology: Alcoholism and fatty liver (alcoholic steatohepatitis) Peroxisomes are membrane-bound organelles with a high content of oxidases and catalases for the oxidation of fatty acids and production and breakdown of hydrogen peroxide. Because hydrogen peroxide is a toxic metabolite, the enzyme catalase degrades this product into oxygen and water. Peroxisomes derive from preexisting preperoxisomes budding off from the endoplasmic reticulum or by fission from pre-existing peroxisomes. Then, the organelle imports peroxisomal matrix proteins from the cytosol, targeted to peroxisomes by peroxisome targeting signals. Some of the peroxins are defective and associated with peroxisome biogenesis disorders, including Zellweger syndrome. The biogenesis of peroxisomes and their role in inherited disorders are outlined in Chapter 2, Epithelial Glands. Pathology: Liver iron-overload disorders After absorption in the stomach, most ethanol is transported to the liver, where it is metabolized to acetaldehyde and acetate in the hepatocytes. Long-term consumption of ethanol results in fatty liver (a reversible process if ethanol consumption is discontinued), steatohepatitis (fatty liver accompanied by an inflammatory reaction), cirrhosis (collagen proliferation or fibrosis), and hepatocellular carcinoma (malignant transformation of hepatocytes). Injury of hepatocytes results in programmed cell death, or apoptosis, caused by the activation of caspases (see Chapter 3, Cell Signaling). Pathology: Perisinusoidal cells Severe liver diseases can result from the excessive storage of iron and copper. Hereditary hemochromatosis is an example of a disease characterized by increased iron absorption and accumulation in lysosomal hepatocytes.
Additional information: