Maldigestion of fat

Abnormal micellar formation i

Fat malabsorption

Vitamin K deficiency Vitamin D deficiency

Fat malabsorption

Weight loss



Obstruction of lymphatic vessels




Weight loss

The symptom of constipation may signify different things in individual cases, depending on what is considered to be "normal": too little, too hard or rare a stool, difficult defecation, or the sensation of incomplete emptying. Constipation is often harmless, but it can be a sign of numerous diseases.

The causes of constipation are:

♦ Low-fiber diet, as intestinal motility depends on the volume of intestinal contents.

ev The larger the volume the greater the motili-=. ty.

¡5 ♦ Reflex and/or psychogenic disorders.

a These include: 1) anal fissure that is painful <u and reflexly raises the tone of the anal In sphincter, thus increasing the pain, and so j£ on; 2) so-called anismus (outlet obstruction), ra i.e., contraction (rather than the normal re-^ laxation) of the pelvic floor when the rectum K is stretched. Such a "false" reflex is commonly id found in women who were abused as children, but also in patients with Parkinson's disease; 3) paralytic ileus (acute pseudoobstruction) that may be caused reflexly by operations (particularly in the abdomen), trauma, or peritonitis, and may persist in the colon for several days.

♦ Functional disorders of transport, whether of neurogenic, myogenic, reflex (see above), medicinal (e.g., opiates), or ischemic cause (e.g., trauma or arteriosclerosis of the mesenteric arteries). Functional intestinal obstruction is called pseudo-obstruction.

♦ Neurogenic causes. Congenital absence of ganglion cells near the anus (aganglionosis in Hirschsprung's disease), resulting in persisting spasm of the affected segment due to failure of receptive relaxation (^ A, bottom right) and absence of anorectal inhibitory reflexes (internal anal sphincter fails to open when rectum fills). In Chagas' disease the causative organism (Trypanosoma cruci) de-nervates the intestinal ganglia, thus producing dilation of the colon (megacolon; see below). In addition, systemic nervous diseases (Parkinson's disease, diabetic polyneuropa-thy, viral neuritis, tabes dorsalis, multiple sclerosis) or nerve and spinal cord lesions

156 that, among other effects, interrupt intestinal distance reflexes, can cause pseudo-obstruction.

♦ Myogenic causes. Muscular dystrophies, scleroderma (see also Plate 6.3), dermato-myositis, and systemic lupus erythematosus.

♦ Mechanical obstruction in the intestinal lumen (e.g., foreign bodies, roundworms [Ascaris], gallstones), in the intestinal wall (e.g., tumor, diverticulum, stenosis, stricture, hematoma, infection) or from outside (e.g., pregnancy, adhesion, hernia, volvulus, tumor, cyst). The result is mechanical intestinal occlusion (obstruction).

♦ Finally, in some patients constipation (alternating with diarrhea) may occur without any of the above causes being identified. Emotional or physical stress is often the precipitating factor in what is called irritable colon.

Effects of obstruction and pseudoobstruction. Complete occlusion leads to a proximal accumulation of gases and fluid and dilates the intestine, which initially contracts painfully every few minutes. Especially if the proximal small intestine is affected, the advancing dilation impairs blood flow, causes vomiting and results in dehydration (hypo-volemia). This can progress rapidly because increased amounts of fluid can be secreted in the intestine. As well as dilation, bacteria ascending from the large to the small intestine also cause this; their endotoxins result in the liberation of VIP, PG12, and PGF2. Inflammation caused by bacteria along with edema formation in the intestinal wall and peritonitis as well as possibly resulting ischemia (see above) can quickly become life-threatening. 1f the (pseudo-)obstruction is located far toward the anus, megacolon may develop (^ A). It may occur acutely in case of fulminant colitis, volvulus, or without recognizable cause (Ogilvie syndrome). Distinction between this and paralytic ileus (see above) is largely made from the patient's history.

|— A. Causes and Consequences of Constipation and (Pseudo-)Obstruction

|— A. Causes and Consequences of Constipation and (Pseudo-)Obstruction

Obstruction Pseudo-obstruction
Photo: Sleisenger, Fortran. Gastrointestinal Disease. 5th ed. Philadelphia: WBSaunders; 1993; Vol. 1: 892

Most pancreatic enzymes are activated by enteropeptidase only when they reach the intestinal lumen. The activation of trypsino-gen to trypsin is a key feature in this, because trypsin activates other enzymes. If it is activated in the acinar cells, the pancreatic trypsin inhibitor-protein is responsible for trypsin not being effective there. However, if this protective mechanism does not keep up with the trypsin activation, or trypsin be-ev comes active in the lumen of the pancreatic duct, self-digestion of the pancreas occurs, es i.e., acute pancreatitis. a Even though there is a history of high alco-<u hol consumption and gallstones in 80% of In cases, the pathogenetic mechanism is not h, quite clear. The following possibilities are ac being discussed as playing a part, either in ^ combination or separately depending on the K case:

id ♦ Increased pressure in the pancreatic duct

(flow resistance and/or flow too high) can play a part in the development of acute pancreatitis (^ A1). Occlusion of the duct after the merging of the bile duct (e.g., by a gallstone;^ A2) also leads to reflux of bile into the pancreas, where it damages the duct epithelium and accelerates fat digestion.

♦ While it is unclear, in relation to the above points, how trypsin is activated, if duodeno-pancreatic reflux occurs (e.g., when the duodenum is obstructed distally), the enzymes activated in the duodenum pass back into the pancreas (^ A3).

♦ Alcohol, acetylsalicylic acid, histamine, etc. increase the permeability of the pancreatic duct epithelium, so that larger molecules can pass through it. Enzymes secreted by the acinar cells thus diffuse into periductal interstitial tissue and damage it (^ A4). In addition, alcohol in the duct system seems to precipitate proteins, causing a rise in upstream pressure (^ A4).

♦ Research on animal models with acute pancreatitis indicates that under some circumstances pancreatic enzymes may also be activated intracellularly. The process of sorting out lysosomal enzymes and H+-ATPase,

158 on the one hand, and the pancreatic proenzymes to be secreted, on the other, as nor mally occurs in the Golgi apparatus, seems to be disturbed (^A5). Thus, the proenzymes together with the lysosomal proteases will be incorporated into the same vesicles, so that trypsin will be activated there. Trace amounts are enough for this, because trypsin can activate itself autocatalytically.

Trypsin activates other enzymes (phos-pholipase A2, elastase, etc.), clotting factors (prothrombin to thrombin), tissue hormones (bradykinin and kallidin are activated via kallikrein), and cytotoxic proteins (complement system). In the pancreas (^A6; P in the computed tomogram) there is at first generalized cell swelling (pancreatic edema; ^ A7, P + E). Activated elastase, in particular, causes vessel arrosion with bleeding (hemor-rhagic pancreatitis) and ischemic zones in the organ. These ischemic areas are further enlarged by the formation of thrombi brought about by thrombin activation, the result being necrosis. The endocrine islet cells are also destroyed, causing insulin deficiency and thus hyperglycemia. Fat necrosis develops around the pancreas with accompanying soap formation, a process that uses up Ca2+ (Ca2+ sequestration) and also causes hypocalcemia (see below). Mg2+ ions in the plasma binding to the liberated fatty acids cause hypomagnesemia (^ p. 126). All this damage can spread to neighboring retroperi-toneal organs, i.e., spleen, mesentery, omen-tum, duodenum, etc.

As the activated enzymes appear in plasma, where their presence is of diagnostic significance, hypoalbuminemia develops with resulting hypocalcemia, as well as systemic vasodilation and plasma exudation (triggered by bradykinin and kallidin), ultimately ending in circulatory shock. Phospholipase A2 and free fatty acids (due to increased li-polysis) in plasma destroy the surfactant on the alveolar epithelium, causing arterial hyp-oxia. Finally, the kidneys will also be damaged (danger of anuria).

i— A. Causes and Consequences of Acute Pancreatitis


Phospholipase A2 Elastase

Extracellular and/or intracelluar trypsin activation *

Activation of: Complement Prothrombin Kallikrein

Cell toxicity Thrombin ^dS™' kallidin

Thrombosis ^od^™ and plasma exudation

Phospholipase A2 Elastase

Cell toxicity Thrombin ^dS™' kallidin

Systemic damage

V v Shock Hypoxia Anuria

V v Shock Hypoxia Anuria

CTs from: Sleisenger, Fortran. Gastrointestinal Disease. 5th ed. Philadelphia: WBSaunders; 1993; Vol.2: 1641 (Supplied by E.T. Steward, M.D.)

Chronic pancreatitis is an inflammatory process that destroys the exocrine and endocrine tissues and leads to fibrosis of the organ. There are several forms of chronic pancreatitis:

♦ Chronic calcifying pancreatitis A, left) is the most common form (70-80%of cases), caused by chronic alcohol abuse (>80g/d over many years) and is characterized by irregularly distributed tissue lesions with intraductal protein plugs and stones as well as atrophy and stenosis of the ductal system. Three mechanisms play a role in its patho-genesis:

1. While normally, in parallel with the stimulation of the acini (enzyme-rich secretion), there is greater secretion in the ducts (HCO3-, water), it is reduced in chronic pancreatitis. As a result, protein concentration in the pancreatic juice is increased, especially when acinar secretion is stimulated. This leads to protein precipitation in the ductal lumens and protein plugs and deposits are thus formed.

2. Calcium salts are deposited on the precipitated protein, resulting in the formation of stones in the lumen of small ducts, and concentric calcium deposits on the walls of the larger ducts. The cause of all this may be that two components of pancreatic juice are diminished in chronic pancreatitis, namely those that normally prevent the precipitation of calcium salts from pancreatic juice. One of these components is citrate, which binds calcium complexly, the other is the 14 kDa protein, lithostatin (= pancreatic stone protein [PSP]), which holds calcium salts in solution during (physiological) hypersaturation.

3. Similar to acute pancreatitis (^ p. 158), intraductal activation of trypsin occurs. This not only contributes to the autodigestion of pancreatic tissue, but also activates other aggressive enzymes, such as elastase and phos-pholipase A2, in the ductal system and, in some circumstances, also interstitially. It is thought that the cause of the premature enzyme activation is that impaired drainage has increased intraductal pressure, resulting in epithelial lesions, together with raised proenzyme content (while the concentration of trypsin inhibitor-protein remains unchanged; ^ p. 158).

♦ The rarer chronic-obstructive pancreatitis

(^ A, right) is caused by occlusion of the main excretory duct(s) by tumors, scar stricture, or stenosis of the papilla, among others. There is no calcification, but the ductal system is markedly dilated upstream of the stenosis (^A; endoscopic retrograde pancreatography [ERP], in which contrast media are injected for radiological visualization). If the obstruction is removed in time, this form of chronic pancreatitis (in contrast to the calcifying form) is reversible.

♦ Other forms of chronic pancreatitis include the idiopathic, nonalcoholic form in malnourished juveniles in the tropics, and the form seen in hypercalcemia due to hyper-parathyroidism.

Acute exacerbation of chronic pancreatitis is usually difficult to distinguish from acute pancreatitis, especially when there is a history of high alcoholic intake. In both cases the premature activation of pancreatic enzymes is a prominent feature (see above and p. 158). It can lead, via pancreatic edema, to pancreatic hemorrhage and necrosis as well as to acute pseudocysts, abscess, and/or impairment of neighboring organs such as duodenum, antrum, choledochal duct, and colon.

The results of chronic pancreatitis are tissue atrophy, ductal stenosis, and periductal fibrosis with scarring. This gradually leads to loss of parenchyma, which will cause exocrine and later also endocrine pancreatic insufficiency. Intermittent or continuous pain, malabsorption (^ p. 152ff.), diarrhea (^ p.150), and weight loss as well as diabetes mellitus (^ p. 286ff.) and damage to neighboring organs (pancreatic ascites, portal and splenic vein thrombosis, obstructive jaundice, etc.) are associated with this.

i— A. Causes and Consequences of Chronic Pancreatitis


Occlusion of main pancreas duct

Pancreatic juice:

Secretion of Citrate concentration

HCOjT and fluid \ Lithostatin concentration ^

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