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    Bile Plasma At a neutral pH buy 850 mg glucophage free shipping, the bile acids are mostly ionized and are Concentration Concentration referred to as bile salts purchase 850 mg glucophage. Conjugated bile acids ionize more Constituent (mEq/L) (mEq/L) readily than the unconjugated bile acids and buy 850 mg glucophage overnight delivery, thus, usually Na 140–170 145 exist as salts of various cations (e. This property of bile salts is HCO 15–60 24 3 important because they play an integral role in the intes- tinal absorption of lipid. Therefore, it is important that bile salts are absorbed by the small intestine only after all of the the opening of the duct that carries biliary and pancreatic lipid has been absorbed. The major lipids in bile are phospholipids and choles- Thus, most of the hepatic bile is stored in the gallbladder terol. After the ingestion of a meal, CCK is re- phosphatidylcholine (lecithin). The phospholipid and cho- leased into the blood, causing contraction of the gallblad- lesterol concentrations of hepatic bile are 0. The concentrations of these lipids in the gallbladder bile are even higher because of the absorption of water by the gallbladder. Cholesterol in The Major Components of Bile Are bile is responsible for the formation of cholesterol gallstones. Electrolytes, Bile Salts, and Lipids The electrolyte composition of human bile collected from Total Bile Secretion Consists of Three the hepatic ducts is similar to that of blood plasma, except Components, One of Which Depends on the HCO3 concentration may be higher, resulting in an al- Bile Acids kaline pH (Table 27. During the conversion, hydroxyl groups The total bile flow is composed of the ductular secretion and and a carboxyl group are added to the steroid nucleus. The ductular secretion acids are classified as primary or secondary (Fig. These cells actively se- primary bile acids are synthesized by the hepatocytes and in- crete HCO3 into the lumen, resulting in the movement of clude cholic acid and chenodeoxycholic acid. When bile en- may contribute to ductular secretion of fluid is the presence ters the GI tract, bacteria present in the lumen act on the of a cAMP-dependent Cl channel that secretes Cl into the FIGURE 27. Bile acids are conjugated with the amino acids glycine and taurine in the liver. Total canalicular bile flow is composed of bile acid–dependent flow ATP ADP+Pi and bile acid–independent flow. Hepatocyte up- take of free and conjugated bile salts is Na -dependent and Bile Secretion Is Primarily Regulated by a mediated by bile salt–sodium symport (Fig. The Feedback Mechanism, With Secondary energy required is provided by the transmembrane Na Hormonal and Neural Controls gradient generated by the Na /K -ATPase. This mecha- nism is a type of secondary active transport because the en- The major determinant of bile acid synthesis and secretion ergy required for the active uptake of bile acid, or its con- by hepatocytes is the bile acid concentration in hepatic por- jugate, is not directly provided by ATP but by an ionic tal blood, which exerts a negative-feedback effect on the gradient. The free bile acids are reconjugated with taurine synthesis of bile acids from cholesterol. Hepatocytes also make new of bile acids in portal blood also determines bile acid–de- bile acids from cholesterol. Between meals, the portal blood concen- tocytes by a carrier located at the canalicular membrane. After a meal, there is increased delivery of bile salts in cyte and the canaliculus lumen. CCK is secreted by the intestinal mucosa when fatty Bilirubin is secreted by hepatocytes via an active process. CCK causes Although the secretion of cholesterol and phospholipid is contraction of the gallbladder, which, in turn, causes in- not well understood, it is closely coupled to bile salt secre- creased pressure in the bile ducts. The osmotic pressure generated as a result of the se- rises, the sphincterof Oddi relaxes (another effect of CCK), cretion of bile salts draws water into the canaliculus lumen and bile is delivered into the lumen. When the mucosa of the small intestine is exposed to acid in the chyme, it releases secretin into the blood.

    Epinephrine and NE produce catecholamine levels triggers some of the same metabolic widespread effects on the cardiovascular system 500mg glucophage with amex, muscular adjustments that occur more slowly during fasting order 500 mg glucophage amex. During system purchase 850mg glucophage visa, and carbohydrate and lipid metabolism in liver, fasting, these adjustments are triggered mainly in response muscle, and adipose tissues. In response to a sudden rise in to the gradual rise in the ratio of glucagon to insulin in the catecholamines in the blood, the heart rate accelerates, blood. The ratio also rises during profound hypoglycemia, coronary blood vessels dilate, and blood flow to the skele- reinforcing the actions of the catecholamines on tal muscles is increased as a result of vasodilation (but vaso- glycogenolysis, gluconeogenesis, and lipolysis. Smooth muscles in the air- cholamines released during hypoglycemia are thought to ways of the lungs, gastrointestinal tract, and urinary be partly responsible for the rise in the glucagon-to-insulin bladder relax. Muscles in the hair follicles contract, causing ratio by directly influencing the secretion of these hor- piloerection. Catecholamines stimulate the se- action to the sudden release of catecholamines is known as cretion of glucagon by the alpha cells and inhibit the se- the fight-or-flight response (see Chapter 6). These catecholamine-mediated responses to hypoglycemia are Catecholamines and the Metabolic Response to Hypo- summarized in Table 34. Catecholamines secreted by the adrenal medulla and NE released from sympathetic postganglionic nerve terminals are key agents in the body’s defense against hypoglycemia. Catecholamine release usually Catecholamine-Mediated Responses starts when the blood glucose concentration falls to the TABLE 34. A fur- ther decline in blood glucose concentration into the hy- Liver Stimulation of glycogenolysis poglycemic range produces marked catecholamine release. Stimulation of gluconeogenesis Hypoglycemia can result from a variety of situations, such Skeletal muscle Simulation of glycogenolysis as insulin overdosing, catecholamine antagonists, or drugs Adipose tissue Simulation of glycogenolysis that block fatty acid oxidation. Hypoglycemia is always a Stimulation of triglyceride lipolysis Pancreatic islets Inhibition of insulin secretion by beta cells dangerous condition because the CNS will die of ATP Stimulation of glucagon secretion by alpha cells deprivation in extended cases. The length of time pro- CHAPTER 34 The Adrenal Gland 621 REVIEW QUESTIONS DIRECTIONS: Each of the numbered (F) Defects in aldosterone synthase (C) Cholesterol side-chain cleavage items or incomplete statements in this 4. What is the mechanism through which enzyme section is followed by answers or by catecholamines stabilize blood glucose (D) 11 -Hydroxylase completions of the statement. Select the concentration in response to (E) 3-Hydroxy-3-methylglutaryl CoA ONE lettered answer or completion that is hypoglycemia? Which of the following sources of muscle weakness and fatigue, anorexia, and cholesterol is most important for (B) Catecholamines inhibit weight loss associated with sustaining adrenal steroidogenesis glycogenolysis in the liver gastrointestinal symptoms (nausea, when it occurs at a high rate for a long (C) Catecholamines stimulate the vomiting). A patient receiving long-term (D) Congenital adrenal hyperplasia (E) Cholesterol from the endoplasmic glucocorticoid therapy plans to (E) Hypopituitarism reticulum undergo hip replacement surgery. A 7-year-old boy comes to the (A) Glucocorticoids should be glucocorticoids accelerate pediatric endocrine unit for evaluation decreased to prevent serious gluconeogenesis during fasting? Review of his hypoglycemia during recovery (A) Glucocorticoids stimulate the growth charts indicates substantial (B) Glucocorticoids should be secretion of insulin, which activates weight gain over the previous 3 years increased to stimulate immune function gluconeogenic enzymes in the liver but little increase in height. To and prevent possible infection (B) Glucocorticoids inhibit the use of differentiate between the development (C) Glucocorticoids should be glucose by skeletal muscle of obesity and Cushing’s disease, blood decreased to minimize potential (C) Glucocorticoids maintain the and urine samples are taken. Which of interactions with anesthetics vascular response to norepinephrine the following would be most (D) Glucocorticoids should be (D) Glucocorticoids inhibit diagnostic of Cushing’s disease? Adrenocorticotropin serum cortisol, and decreased serum to result in a decreased rate of (ACTH)- and non-ACTH-mediated insulin aldosterone release? J Clin Endocrinol serum cortisol, and decreased urinary the kidney Metab 1999;84:1729–1736. Congenital adrenal hyperplasia is most concentration at the macula densa DHEA. Baillieres Clin Endocrinol likely a result of (E) An increase in renal sympathetic Metab 1998;12:67–81. Genotyping is a (B) Addison’s disease zona glomerulosa valuable diagnostic complement to (C) Defects in ACTH secretion 7. The rate-limiting step in the synthesis neonatal screening for congenital adre- (D) Defects in corticosteroid-binding of cortisol is catalyzed by nal hyperplasia due to steroid 21-hy- globulin (A) 21-Hydroxylase droxylase deficiency. J Clin Endocrinol (E) Cushing’s disease (B) 3 -Hydroxysteroid dehydrogenase Metab 1999;84:1505–1509.

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    Cellularity may Signal intensity of GRE sequences is also dependent also be increased in patients suffering from chronic bac- upon magnetic susceptibility generic glucophage 500mg mastercard, allowing for differentiating terial infectious spondylitis (Fig buy 500 mg glucophage with mastercard. In these cases order 500 mg glucophage free shipping, tumor infiltration with and without trabecular destruc- MR imaging signal intensity alterations are probably due tion. This situation can be found in tumor infiltration of to reactive bone marrow stimulation. The subtraction placed by non-neoplastic stimulated, bone marrow cells, of fat and water signal on opposed GRE sequences pro- which are necessary for the production of white blood vides a perfect background with low signal intensity to cells in chronic infection. Stäbler Imaging Diffuse Bone Marrow Abnormalities When there are diffuse abnormalities of the bone marrow signal in hematologic neoplasias and myeloproliferative diseases but no focal disease is present, a pathologic sig- nal intensity of the bone marrow can be overlooked. In this situation, a homogenous diffuse decrease of signal intensity over all vertebral bodies on T1-weighted spin- echo images results from a homogenous replacement of fat cells by cellular marrow or an accumulation of iron in the bone marrow in hemolytic disorders. In the presence of diffuse neoplastic bone marrow in- filtration or bone marrow stimulation, low homogenous SI on T1-weighted images is seen, in addition to increased SI on STIR-images. The percentage enhancement following Gadolinium injection is increased (Fig. On the STIR-image multiple metastasis are outlined with high signal intensity. The lo- cation of the metastasis, which is of risk for a neuro- logic complication by com- pressing the spinal cord, is easily recognized a b Fig. Diffuse neoplastic bone marrow infitration in a patient enhanced T1-weighted image (a). On unenhanced T1-weighted image a diffuse quency selective fat suppression creates a low intensity back- low SI is present in all vertebrae (a). Gadolinium enhancement is ground to highlight the enhancing metastasis (b) heavily increased indicating the diffuse tumor infiltration (b) Bone Marrow Disorders 79 Multiple Myeloma The “salt-and-pepper” pattern is characterized by an irregular bone marrow structure with irregular areas of Multiple myeloma is characterized by bone marrow infil- high and low signal intensity on T1-weighted spin-echo tration with neoplastic plasma cells. Hyperintense areas cretory and Bence Jones plasmacytoma, these cells pro- on T1-weighted spin-echo images represent focal fat de- duce monoclonal immunglobulins, recognizable in serum posits, whereas hypointense areas correlate with electrophoresis. The “salt-and-pepper” pattern correlates up to ten years in cases of smoldering myeloma. Bone marrow biopsy is essential for diagnosis of mul- When minimal plasma cell infiltration is present, this tiple myeloma and gives direct proof for atypical plasma is usually accompanied by a normal or even increased cells. Because of the small size of the biopsy sample, amount of marrow fat cells. In malignant tumors with dif- however, the result is not always representative of the en- fuse bone marrow infiltration, there is rapid displacement tire bone marrow, especially in cases of nodular involve- of fat cells by tumor cells. At the beginning of interstitial ment, in which the correlation of bone marrow biopsy tumor infiltration in multiple myeloma, monoclonal plas- and MRI is low. Laboratory parameters, such as serum- ma cells arrange themselves in such a way as to not dis- paraprotein, β2-microglobulin and the labeling index, are place the fat cells. Apparently, these cells produce factors indirect criteria, but correlate well with tumor mass and which inhibit normal hematopoesis, thus increasing the survival times. Therefore, despite tumor cell in- plasmacytoma, these parameters may be negative. When filtration and replacement of hematopoetic cells, bone “solitary” plasmacytoma is present, MR imaging can de- marrow fat may be normal or even increased without sig- tect or exclude additional marrow abnormalities. As long as there is no crit- ical shift in the water to fat ratio of the bone marrow, myeloma remains undetected in MR imaging. Differentiation of acute osteoporotic In diffuse plasma cell infiltration, no contrast to unin- and tumor-related vertebral fractures volved bone marrow is present. Patients with a diffuse infiltration pattern in multiple myeloma are generally in On T1- and T2-weighted spin echo as well as STIR im- stage II or III disease which is prognostically unfavor- ages and following contrast enhancement, acute benign able.

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    In several forms of mus- these diseases is Duchenne’s muscular dystrophy cular dystrophy cheap glucophage 850 mg visa, both laminin and dystrophin are lacking (DMD) (also called pseudohypertrophic MD) purchase 500 mg glucophage, which is an or defective cheap 500mg glucophage otc. X-linked hereditary disease affecting mostly male children A disease as common and devastating as DMD has long (1 of 3,500 live male births). The recent identifica- gressive muscular weakness during the growing years, be- tion of three animals—dog, cat, and mouse—in which ge- coming apparent by age 4. A characteristic enlargement of netically similar conditions occur promises to offer signifi- the affected muscles, especially the calf muscles, is due to cant new opportunities for study. The manifestation of the a gradual degeneration and necrosis of muscle fibers and defect is different in each of the three animals (and also dif- their replacement by fibrous and fatty tissue. The mdx most sufferers are no longer ambulatory, and death usu- mouse, although it lacks dystrophin, does not suffer the ally occurs by the late teens or early twenties. Re- rious defects are in skeletal muscle, but smooth and car- search is underway to identify dystrophin-related proteins diac muscle are affected as well, and many patients suffer that may help compensate for the major defect. A related (and cause of their rapid growth, are ideal for studying the nor- rarer) disease, Becker’s muscular dystrophy (BMD), mal expression and function of dystrophin. Progress has has similar symptoms but is less severe; BMD patients of- been made in transplanting normal muscle cells into mdx ten survive into adulthood. Some six other rarer forms of mice, where they have expressed the dystrophin protein. A Using the genetic technique of chromosome mapping gene expressing a truncated form of dystrophin, called (using linkage analysis and positional cloning), re- utrophin, has been inserted into mice using transgenic searchers have localized the gene responsible for both methods and has corrected the myopathy. DMD and BMD to the p21 region of the X chromosome, The mdx dog, which suffers a more severe and human- and the gene itself has been cloned. It is a large gene of like form of the disease, offers an opportunity to test new some 2. About shows prominent muscle fiber hypertrophy, a poorly un- one third of DMD cases are due to new mutations and the derstood phenomenon in the human disease. Taking ad- other two thirds to sex-linked transmission of the defective vantage of the differences among these models promises gene. The BMD gene is a less severely damaged allele of to shed light on many missing aspects of our understand- the DMD gene. The product of the DMD gene is dystrophin, a large pro- tein that is absent in the muscles of DMD patients. The function of dy- References strophin in normal muscle appears to be that of a Burkin DJ, Kaufman SJ. The alpha7beta1 integrin in mus- cytoskeletal component associated with the inside surface cle development and disease. The childhood muscular dystrophies: most important of these is laminin 2, a protein associated Making order out of chaos. A skeletal muscle fiber is surrounded on its outer sur- gitudinal elements terminate in a system of terminal cister- face by an electrically excitable cell membrane supported nae (or lateral sacs). These contain a protein, calsequestrin, by an external meshwork of fine fibrous material. Together that weakly binds calcium, and most of the stored calcium these layers form the cell’s surface coat, the sarcolemma. Although they traverse other set of membranes called the sarcoplasmic reticulum the muscle fiber, T tubules do not open into its interior. The SR many types of muscles, T tubules extend into the muscle is specially adapted for the uptake, storage, and release of fiber at the level of the Z line, while in others they penetrate calcium ions, which are critical in controlling the processes in the region of the junction between the A and I bands. Within each sarcomere, the association of a T tubule and the two terminal cisternae at its SR consists of two distinct portions. The longitudinal ele- sides is called a triad, a structure important in linking mem- ment forms a system of hollow sheets and tubes that are brane action potentials to muscle contraction.

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