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

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Cystic fibrosis (CF) is a genetic syndrome in which the epithelial secretion, for example, in the lungs, pancreas, liver, genital tract, intestine, nasal mucosa, and sweat glands are affected. Among Caucasians CF is the most frequent lethal (after a mean of 40 years) gene defect (1 per 2 500 births).

The defect is autosomal recessive (→ A1) and affects the epithelial transport protein CFTR (cystic fibrosis transmembrane conductance regulator). CFTR in healthy people consists of 1480 amino acids that form 12 transmembrane domains, two nucleotidebinding domains (NBD1, NBD2), and a regulator domain. At the latter, CFTR is regulated by a cAMP-dependent protein kinase A (→ A2; CFTR is shown opened up frontally). CFTR is probably a chloride channel that opens when the intracellular cAMP concentration is raised and, in addition, ATP is bound to NBD1 (and split?). Furthermore, intact but not defective CFTR inhibits certain Na+ channels (type ENaC). The fact that more of them open in CF results in increased absorption of Na+and water, for example, at the bronchial epithelium, from the mucus secreted into the lumen, so that the latter is thickened (see below).

Patients with cystic fibrosis have various mutations of CFTR, but the serious forms are most frequently caused by two defects on the NBD1 (→ A3): either the amino acid 508, phenylalanine (= F; mutation F508), is missing, or glycine (= G) in position 551 is replaced by aspartate (= D) (mutation G551 D).

CFTR is incorporated into the apical (luminal) cell membrane of many epithelial cells. CFTR has an important function in the excretory ducts of the pancreas, in that it is involved in secretion of a liquid rich in NaHCO3. HCO3– is exchanged for Cl– in these cells via an antiport carrier (→ A4). The opening of CFTR—for example, by secretin, which increases intracellular cAMP concentration— allows the Cl– that has entered the cell to be recycled, so that chloride is again available for the secretion of HCO3–, followed by Na+ and water. If the concentration of cAMP de-

In patients with CF, CFTR does not open up even when cAMP concentration is high. As a result, especially when acinar secretion is stimulated, the small pancreatic ducts contain a protein-rich, viscous secretion that occludes the transporting ducts and thus leads to chronic pancreatitis with its consequences (e.g., malabsorption due to lack of pancreatic enzymes and HCO3– in the duodenum;

→p.160).

Among other effects, abnormal CFTR af-

fects the intestinal epithelium so that neonatal meconium becomes viscous and sticky and thus cannot, as usual, pass out of the ileum after birth (meconium ileus).

As in the pancreas, the bile ducts may become obstructed and neonatal jaundice may thus be prolonged. The CFTR defect in the male genital organs may cause infertility (obstruction of the vas deferens); in the female genital organs it causes decreased fertility. The consequences of abnormal secretion in the nasal mucosa are polyps and chronic inflammation of the nasal sinuses. In the sweat glands the defect increases sweat secretion that during fever or high ambient temperature can lead to hypovolemia and even circulatory shock. In addition, electrolyte concentration is increased in sweat and the concentration of Na+ is higher than that of Cl– (the reverse of normal), a fact that is used in the diagnosis of CF (sweat test).

Morbidity and life-threatening complications of CF are mainly due to its effects on the bronchial epithelium. Its superficial mucus is normally thinned by fluid secretion. The CTFR defect causes (in addition to increased mucus secretion) the reabsorption instead of secretion of fluid. This results in a highly viscous and protein-rich layer of mucus that not only hinders breathing, but also forms a fertile soil for infections, especially with Pseudomonas aeruginosa and Staphylococcus aureus. Chronic bronchitis, pneumonia, bronchiectasis, and secondary cardiovascular disorders are the result.

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Gallstone Disease (Cholelithiasis)

which precipitate as calcium salts. Black stones, mainly formed by the first three of the above mechanisms, contain in addition to other compounds, calcium carbonate and phosphate, these latter presumed to be formed by the gallbladder’s decreased capacity to acidify.

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D. Role of Gall Bladder in Cholelithiasis

Plate 6.17 Cholelithiasis II

6 Stomach, Intestines, Liver

Bilirubin, largely originating from hemoglobin breakdown (ca. 230 mg/d), is taken up by the liver cells and coupled by glucuronyl transferase to form bilirubin-monoglucuro- nide and bilirubin-diglucuronide. This wa- ter-soluble conjugated (direct reacting) bilirubin is secreted into the bile canaliculi and 85% is excreted in the stool. The remaining 15% is deglucuronated and absorbed in the intestine for enterohepatic recirculation.

The normal plasma concentration of bilirubin is maximally 17 µmol/L (1 mg/dL). If it rises to more than 30 µmol/L, the sclera become yellow; if the concentration rises further, the skin turns yellow as well (jaundice [icterus]). Several forms can be distinguished:

Prehepatic jaundice is the result of increased bilirubin production, for example, in hemolysis (hemolytic anemia, toxins), inadequate erythropoiesis (e.g., megaloblastic anemia), massive transfusion (transfused erythrocytes are short-lived), or absorption of large hematomas. In all these conditions unconjugated (indirect reacting) bilirubin in plasma is increased.

Intrahepatic jaundice is caused by a specific defect of bilirubin uptake in the liver cells (Gilbert syndrome Meulengracht), conjugation (neonatal jaundice, Crigler–Najjar syndrome), or secretion of bilirubin in the bile canaliculi (Dubin–Johnson syndrome, Rotor syndrome).

In the first two defects it is mainly the unconjugatedplasma bilirubin that is increased; in the secretion type it is the conjugated bilirubin that is increased. All three steps may be affected in liver diseases and disorders, for example, in viral hepatitis, alcohol abuse, drug side effects (e.g., isoniazid, phenytoin, halothane), liver congestion (e.g., right heart failure), sepsis (endotoxins), or poisoning (e.g., the Amanita phalloides mushroom).

In posthepatic jaundice the extrahepatic bile ducts are blocked, in particular by gallstones (→ p.164ff.), tumors (e.g., carcinoma of the head of the pancreas), or in cholangitis or pancreatitis (→ p.158). In these conditions

Cholestasis (→ A,B), i.e., blockage of bile flow, is due to either intrahepatic disorders, for example, cystic fibrosis (→ p.162), granulomatosis, drug side effects (e.g., allopurinol, sulfonamides), high estrogen concentration (pregnancy, contraceptive pill), graft versus host–reaction after transplantation, or, secondarily, extrahepatic bile duct occlusion

(see above).

In cholestasis the bile canaliculi are enlarged, the fluidity of the canalicular cell membrane is decreased (cholesterol embedding, bile salt effect), their brush border is deformed (or totally absent) and the function of the cytoskeleton, including canalicular motility, is disrupted. In addition, one of the two ATP-driven bile salt carriers, which are meant for the canalicular membrane, is falsely incorporated in the basolateral membrane in cholestasis. In turn, retained bile salts increase the permeability of the tight junctions and reduce mitochondrial ATP synthesis. However, it is difficult to define which of these abnormalities is the cause and which the consequence of cholestasis. Some drugs (e.g., cyclosporin A) have a cholestatic action by inhibiting the bile salt carrier, and estradiol, because it inhibits Na+-K+-ATPase and reduces membrane fluidity.

Most of the consequences of cholestasis (→ B) are a result of retention of bile components: bilirubin leads to jaundice (in neonates there is a danger of kernicterus), cholesterol to cholesterol deposition in skin folds and tendons, as well as in the cell membranes of liver, kidneys, and erythrocytes (echinocytes, akanthocytes). The distressing pruritus (itching) is thought to be caused by retained endorphins and/or bile salts. The absence of bile in the intestine results in fatty stools and malabsorption (→ p.152ff.). Finally, infection of accumulated bile leads to cholangitis, which has its own cholestatic effect.

6 Stomach, Intestines, Liver

Venous blood from stomach, intestines, spleen, pancreas, and gallbladder passes via the portal vein to the liver where, in the sinusoids after mixture with oxygen-rich blood of the hepatic artery, it comes into close contact with the hepatocytes (→ A1). About 15% of cardiac output flows through the liver, yet its resistance to flow is so low that the normal portal vein pressure is only 4 –8 mmHg.

If the cross-sectional area of the liver’s vascular bed is restricted, portal vein pressure rises and portal hypertension develops. Its causes can be an increased resistance in the following vascular areas, although strict separation into three forms of intrahepatic obstructions is not always present or possible:

Prehepatic: portal vein thrombosis (→ A2);

Posthepatic: right heart failure, constrictive pericarditis, etc. (→ A2 and p. 228);

Intrahepatic (→ A1):

–presinusoidal: chronic hepatitis, primary biliary cirrhosis, granuloma in schistosomiasis, tuberculosis, leukemia, etc.

–sinusoidal: acute hepatitis, damage from alcohol (fatty liver, cirrhosis), toxins, amyloidosis, etc.

-postsinusoidal: venous occlusive disease of the venules and small veins; Budd–

Chiari syndrome (obstruction of the large hepatic veins).

Enlargement of the hepatocytes (fat deposition, cell swelling, hyperplasia) and increased production of extracellular matrix (→ p.172) both contribute to sinusoidal obstruction. As the extracellular matrix also impairs the exchange of substances and gases between sinusoids and hepatocytes, cell swelling is further increased. Amyloid depositions can have a similar obstructive effect. Finally, in acute hepatitis and acute liver necrosis the sinusoidal space can also be obstructed by cell debris.

Consequences of portal hypertension. Wherever the site of obstruction, an increased portal vein pressure will lead to disorders in the preceding organs (malabsorp-

from abdominal organs via vascular channels that bypass the liver. These portal bypass circuits (→ A3) use collateral vessels that are normally thin-walled but are now greatly dilated (formation of varices; “haemorrhoids” of the rectal venous plexus; caput medusae at the paraumbilical veins). The enlarged esophageal veins are particularly in danger of rupturing. This fact, especially together with thrombocytopenia (see above) and a deficiency in clotting factors (reduced synthesis in a damaged liver), can lead to massive bleeding that can be acutely life-threatening.

The vasodilators liberated in portal hypertension (glucagon, VIP, substance P, prostacyclins, NO, etc.) also lead to a fall in systemic blood pressure. This will cause a compensatory rise in cardiac output, resulting in hyperperfusion of the abdominal organs and the collateral (bypass) circuits.

Liver function is usually unimpaired in prehepatic and presinusoidal obstruction, because blood supply is assured through a compensatory increase in flow from the hepatic artery. Still, in sinusoidal, postsinusoidal, and posthepatic obstruction liver damage is usually the cause and then in part also the result of the obstruction. As a consequence, drainage of protein-rich hepatic lymph is impaired and the increased portal pressure, sometimes in synergy with a reduction in the plasma’s osmotic pressure due to liver damage (hypoalbuminemia), pushes a protein-rich fluid into the abdominal cavity, i.e., ascites develops. This causes secondary hyperaldosteronism (→ p.174) that results in an increase in extracellular volume.

As blood from the intestine bypasses the liver, toxic substances (NH3, biogenic amines, short-chain fatty acids, etc.) that are normally extracted from portal blood by the liver cells reach the central nervous system, among other organs, so that portalsystemic (“hepatic”) encephalopathy develops (→ p.174).