Factor VII deficiency
pH 7.4 PCO2
A. Pathophysiology of Bone Local Mechanisms
Plate5.22PathophysiologyofBoneI
143 CO2 HCO3 H+
Pagets disease
Hematopoetic progenitor cells
RANKL
Calcitonin
Type I collagen Apoptosis
Osteogenesis imperfecta
Hypo-phosphatasia
Osteoclasts Osteoblasts
M-CSF
Pyknodysostosis
Cathepsin K Mesenchymal
progenitor cells
Osteopetrosis BMP
Degradation PTH
P Pyrophosphate
CA II
Cl
Apoptosis Cleidocranial
dystrophy
CBFA1
FGF
Osteochondrodysplasia IGF
PTHrP Calcitriol
Chondrocytes
pH decrease bone formation bone degradation
low high
Estrogens
Mineralization Alkaline
phospatase Osteocalcin Osteopontin
Osteo-protegerin
Mechanic stress
Estrogens
PTH Glucocorticoids
Growth hormone
Insulin Growth factors:
TGFb, FGF, PDGF, IGF
Phosphate
Vitamin A
Bone
Cartilage
Glucocorticoids
resorption is stimulated by excessive concen-trations of vitamin A.
Disorders of bone metabolism may affect the bone matrix or the mineralization of bone.
In Pagetʼs disease the overactivity of clasts with subsequent stimulation of osteo-blasts leads to enhanced bone turnover with for-mation of structurally disorganized bone, which is particularly susceptible to deformities and fractures. Putative causes include enhanced sensitivity of osteoclast progenitor cells to 1,25 (OH)2D3or enhanced formation or activity of RANKL. Mutations of RANK lead to a similar clin-ical condition. Juvenile Pagetʼs disease results from a genetic defect of osteoprotegrin.
The very common osteoporosis results from a longstanding disequilibrium between bone formation and bone resorption, which decreas-es the bone density. Causdecreas-es include glucocorti-coid excess, estrogen deficiency (postmeno-pausal), insulin deficiency (diabetes mellitus), calcium-deficient diet, smoking, and inactivity (rigid cast, tetraplegia, microgravity). However, most often the cause remains unknown (pri-mary osteoporosis). Effects of osteoporosis in-clude skeletal pain even at rest and bone frac-tures (e.g., spine, lower arms, femoral neck). Hy-percalcemia may be present in extreme cases.
Depending on its cause, osteoporosis may be lo-calized (e.g., under a rigid cast) or generalized (e.g., due to excess glucocorticoids).
In osteomalacia and rickets the mineraliza-tion of the bone matrix (osteoid) or of the growth plate is disturbed. Before longitudinal growth is concluded and before epiphyseal fu-sion has occurred, the abnormality mostly leads to rickets (widening of the growth plates and distorted growth). Hereby hypophospha-temia fosters the survival of chondrocytes in the growth plates. After longitudinal growth has ceased the decreased mineralization of the newly formed osteoid (formed in the course of normal bone remodeling), leads to osteomala-cia. Both rickets and osteomalacia can be caused by a reduced formation of calcitriol, for example, in dietary depletion or intestinal mal-absorption of vitamin D coinciding with lack of ultraviolet light in liver insufficiency, estrogen deficiency (postmenopausal), or in chronic re-nal failure (→p. 120 ff.). Even without calcitriol deficiency, hypophosphatemia (phosphate dia-betes, Fanconiʼs syndrome;→p. 104, 120 ff.) or
chronic renal tubular acidosis can result in os-teomalacia.
The effects of rickets are retarded growth, bow-legs or knock-knees, vertebral column de-formities, prominence of the costochondral junctions (rachitic rosary) as well as thin and soft cranial, particularly occipital, bones (cra-niotabes). Osteomalacia leads to bone pain (pain on movement), translucent bands of de-mineralization in bone (pseudofractures or Looserʼs zones), and muscular weakness (Ca2+ deficiency).
The demineralization of bone may increase renal Ca2+and phosphate excretion and thus re-sult in urolithiasis. Bone resorption may further be stimulated by tumors (formation of PTHrP and osteoclast-activating factor OAF). In pri-mary hyperparathyroidism (by uncontrolled proliferation of PTH-producing cells;→p. 18) normal bone is replaced by fibrous tissue.
Disorders of bone formation and resorption may result from rare genetic defects, as in mu-tations of type I collagen (osteogenesis imper-fecta) or inactivating mutations of CBFA1 (clei-docranial dysplasia). A defect of the alkaline phosphatase (hypophosphatasia) impairs the bone mineralization. The osteoclast function is compromised by defects of the H+pump sub-unit TC1RG1, the Cl−channel ClCN7, the car-bonic anhydrase II, or the RANK (osteopetrosis).
Bone resorption is further impaired at a genetic defect of the protease cathepsin K (pyknodysos-tosis, the likely disease of Toulouse-Lautrec).
Genetic defects of the Ca2+-sensing receptor (CaSR) lead to the familiary benign hypercalce-mia, activating mutations of the PTH receptor to Jansenʼs disease (hypercalcemia, hypophos-phatemia, skeletal malformations, dwarfism).
Genetic defects affecting PTH release (hypo-parathyroidism) or the PTH effect (pseudo-hypoparathyroidism, e.g., by a defective G pro-tein) similarly lead to hypercalcemia and par-tially to bone malformations. Hereditary PTH deficiency may further result in calcification and subsequent damage of basal ganglia. A ge-netic defect of the 1α-hydroxylase leads to pseudo-vitamin D-deficiency rickets, a heredi-tary increase of calcitriol sensitivity to the hypercalcemia of Williamsʼ syndrome.
A wide variety of distinct, rare, genetic de-fects (e.g., of FGF3) lead to defective cartilage formation (osteochondrodysplasia).
144
"
5Kidney,SaltandWaterBalance
Plate5.23PathophysiologyofBoneII
145 HPO42, Ca2+
Osteomalacia
Normal
Osteoporosis Estrogens Dehydrocholesterol
UV light Diet
Demineralization Osteoid breakdown
Glucocorticoids
Lacking mechanical stress
Tumors PTH
Bone pain, spine deformation, fractures, muscle weakness
Skeletal pain, vertebral prolapse, fractures of ulna, radius or neck of femur
Photos from: Siegenthaler, W. et al. Innere Medizin. Stuttgart: Thieme; 1992 (see plate A.) 25-(OH)-D3
Urolithiasis
Insulin Diabetes mellitus Hypocalcemia
Calcitriol Renal failure
Liver failure
Genetic defects
PTHrP, OAF Hypercalcemia
Phosphate
Jansens disease Hypopara-thyroidism
Sarcoidosis, tuberkulosis, lymphoma Williams syndrome
Macrophage
Vitamin D3
Ca2+ receptor B. Pathophysiology of Bone
6 Stomach, Intestines, Liver S. Silbernagl Function of the Gastrointestinal Tract
To cover the material and energy demands of the organism food must be swallowed, pro-cessed and broken down (digestion) as well as taken up (absorption) by the intestine. Solid foods are chewed by the teeth, each bite being mixed with saliva from the salivary glands. Sa-liva contains mucin, a lubricant, and antibodies as well asα-amylase to digest polysaccharides.
It is the task of the esophagus to rapidly trans-port the food from the throat to the stomach.
The lower esophageal sphincter briefly opens, but otherwise prevents reflux of the potential-ly harmful gastric juice. The proximal stomach primarily serves to store food taken up during a meal. Its muscle tone determines the supply to the distal stomach, where the food is processed (broken up further and emulsified). Proteins are denatured and broken down by the gastric acid and pepsins, and lipases begin fat diges-tion. The distal stomach also has the task of ap-portioning chyme. In addition, the stomach se-cretes the intrinsic factor that is essential for the absorption of cobalamines (vitamin B12).
The breakdown of food particles is complet-ed in the small intestine by means of enzymes from the pancreas and the mucosa of the small intestine. The HCO3– ions of the pancreatic juice are needed to neutralize the acidic chyme.
Fat digestion in addition requires bile salts sup-plied in bile. The products of digestion (saccharides, amino acids, dipeptides, mono-glycerides, and free fatty acids) as well as wa-ter, minerals, and vitamins are absorbed in the small intestine.
Together with the bile secreted by the liver, excretory products (e.g., bilirubin) reach the stool. The liver has numerous additional meta-bolic functions: it is the obligatory intermedi-ate station for almost all substances absorbed from the small intestine, and it is able to detox-ify numerous foreign substances and metabolic end-products and to bring about their excre-tion.
The large intestine is the last station for wa-ter and ion absorption. It is colonized by bacte-ria (intestinal flora) with physiological func-tions. The large intestine, especially the caecum and rectum, are also storage places for the
fe-ces, so that defecation is necessary relatively rarely, despite frequent food intake.
The two plexuses in the wall of the esopha-gus, stomach, and intestine serve to control motility and secretion, with superregional re-flexes and modulating influences of the central nervous system transmitted via the autono-nomic nervous system and visceral–afferent nerve tracts. In addition, the gastrointestinal tract secretes numerous peptide hormones and transmitters that participate in controlling and regulating the gastrointestinal tract and its ac-cessory glands.
There are many nonspecific and specific mechanisms which defend against pathogenic organisms on the inner surface (ca. 100 m2) of the gastrointestinal tract. Beginning at the mouth, components in saliva, such as mucins, immunoglobulin A (IgA), and lysozyme, inhibit microorganisms invading. Hydrochloric acid and pepsins have a bactericidal effect, and Pey-erʼs patches in the gastrointestinal tract are its own immunocompetent lymph tissue. Special M cells (“membranous cells”) of the mucosa provide luminal antigens with access to Peyerʼs patches, which can respond with release of IgA (oral immunization or, as an abnormal process, allergization). IgA is combined in the intestinal epithelium with the secretory component which protects the secreted IgA against diges-tive enzymes. The intestinal defense mecha-nisms recognize the physiological intestinal flora, which are thus protected against the im-mune response. Macrophages in the intestinal wall and in the sinusoids of the liver (Kupffer cells) form a further barrier against invading pathogenic organisms.
146
Plate6.1FunctionoftheGastrointestinalTract
147 Mouth
Tasting, chewing, forming food bolus
Saliva Lubrication, rinsing,
digesting Esophagus
Transport
Proximal stomach Storage
Distal stomach Preparation, digestion, apportioning Liver
Bile (excretion, fat digestion), metabolism, detoxication
Gallbladder Storage of bile
Pancreas (exokrine) Digestive enzymes, HCO3 as H+ buffer
Cecum Storage
Rectum Storage, excretion Small intestine Digestion, absorption A. Function of Organs of the Gastrointestinal Tract
Esophagus
The musculature in the upper third of the esophageal wall is partly made up of striated muscle, partly of smooth muscle. On swallow-ing (deglutition) the upper esophageal sphinc-ter opens reflexly and a (primary) peristaltic re-flex wave moves the bolus of food in the esoph-agus. Here the dilation by the bolus initiates further (secondary) peristaltic waves that con-tinue until the bolus has reached the stomach.
The lower esophageal sphincter is opened by a vagovagal reflex at the beginning of the swal-lowing action. This receptive relaxation reflex is mediated by the inhibitory noncholinergic nonadrenergic (NCNA) neurones of the myen-teric plexus (→A).
Esophageal motility, for example, the pro-gression of the peristaltic wave, is usually test-ed by pressure measurements in the various segments of the esophagus (→A 1, 2). The rest-ing pressure within the lower esophageal sphincter is ca. 20–25 mmHg. During receptive relaxation the pressure falls to the few mmHg that prevail in the proximal stomach (→A 3), indicating opening of the sphincter.
The lower esophageal sphincter is usually closed, just like its upper counterpart. This bar-rier against reflux of the harmful gastric juice (pepsin and HCl) is strengthened when the sphincter pressure is raised (→B), for example, by the action of acetylcholine liberated from the ganglion cells of the myenteric plexus, or by adrenergic agonists, by hormones, such as gas-trin (reflux protection during digestive gastric motility), motilin (reflux protection during in-terdigestive motility), somatostatin, and sub-stance P, by paracrine action (histamine, PGF2α), by protein-rich food, or by high intra-abdominal pressure (contraction of intra-abdominal muscles, obesity, ascites). This pressure would tear open the sphincter but for the fact that part of the 3–4 cm long lower esophageal sphincter lies within the abdominal space. As a consequence, the sphincter pressure is creased (from outside) in proportion to the in-crease in intra-abdominal pressure. Further-more, parts of the diaphragm surround the lower esophageal sphincter (left and right crux) in a scissor-like manner, so that the sphincter is automatically clamped when the diaphragm contracts. An intact
phrenico-esophageal ligament (→E 1) and a relatively acute angle of His between the end of the esophagus and the stomach are also important in providing reflux protection during swallow-ing.
Factors that lower sphincter pressure will promote reflux. Among these are vasoactive in-testinal polypeptide (VIP) and ATP, the trans-mitters of the inhibitory NCNA neurones as well as dopamine andβ-adrenergic agonists, hormones such as secretin, cholecystokinine (CCK), progesterone, and glucose–dependent insulinotropic peptide (GIP = formerly: gastric inhibitory polypeptide), paracrine substances (NO, PGI2, PGE2), a progesterone effect during pregnancy, food with a high fat content, and many others.
Sporadic reflux of gastric juice is an every-day physiological event, either from unexpect-ed pressure on a full stomach, or during swal-lowing (opening of sphincter for a few seconds;
→B 5, right), or during transient openings of the sphincter (→B 5, left) that last up to half a minute and are triggered by marked dilation of the stomach wall and not by the act of swal-lowing. These transient sphincter openings are probably part of the expulsion reflex through which swallowed air and CO2can be expelled from the stomach. The fact that significant re-flux occurs as a consequence can be concluded from the marked drop in pH in the distal esophagus (→B 4).
Three mechanisms are responsible for pro-tecting the esophageal mucosa after reflux:
◆Volume clearance, i.e. the rapid replacement of reflux volume into the stomach by the esophageal peristalsis reflex. Reflux volume of 15 mL, except for a small residual amount, nor-mally remains in the esophagus for only five to 10 seconds (→B 1).
◆pH clearance. Residual gastric juice, left be-hind by the volume clearance, has an un-changed, low pH. It only rises, step by step (→B 2), with each act of swallowing (→B 3), i.e., the swallowed saliva buffers the residual re-flux volume. pH clearance is dependent on the amount and buffering capacity of saliva.
◆The wall of the esophagus contains epitheli-um with barrier properties. Of its 25–30 cell layers (→E, right) it is particularly the stratum 148
"
6Stomach,Intestines,Liver
Plate6.2EsophagusI
149
10 20 30 s
40
0 40 0 40
0
mmHg
7 0 4
80
0 40 mmHg 120
mmHg 0
10
0 5 15
8
0 4
1
2
3
4 1
2
3 5
0 Esophagus
lumen
Lower sphincter
Stomach Swallowing
Migration of the peristaltic wave
Sphincter opening
Breathing Vagus n.
NCNA fibers inhibit:
opening Cholinergic fibers excite:
shortening Pharynx
Striated muscles Upper sphincter
Smooth muscles
Neuronal control of sphincter
(after S. Cohen)
Thoracic esophagus Acetylcholine, a-adrenergic
agonists, hormones, protein-rich food, histamine,
high intra-abdominal pressure, PGF2a, etc.
Increased pressure in esophageal sphincter
Inhibits reflux
Abdominal esophagus with lower sphincter
Transient sphincter opening
Pressure in lower sphincter pH
Swallowing Volume clearance
pH clearance
Esophageal pressure pH
Bolus volume (mL)
Acidbolus Swallowing
VIP, b-adrenergic agonists, hormones, dopamine, NO, PGI2, PGE2, chocolate,
acid gastric juice, fat, smoking, etc.
Decreased pressure in esophageal sphincter
Promotes reflux
1 min Diaphragm
(after Kahrilas and Gupta) (after Helm et al.)
1 min
in stomach pH in distal esophagus A. Motility of Esophagus