2.

Pathophysiology of Diarrhea and

Malabsorption
2.1. Introduction
Diarrhea may best be defined as doctors Roux and Ryle did in 1924: Diarrhea is the too rapid
evacuation of too fluid stools." ormal stoolin! varies from three bo"el movements per "ee# to
three bo"el movements per day. $atients may report diarrhea "hen their o"n normal pattern of
bo"el movements is altered. %oosenin! of the stool occurs "hen daily fecal "ater output
increases by only &'()'m%. *n increase of fecal "ater excretion of 1''m% is sufficient to
increase daily stool "ei!ht by 2''!rams+24 hours, the upper limit of normal.
-he ma.or causes of diarrhea, outlined in -able 1 , may be classified into five broad cate!ories
related to their pathophysiolo!y:
1. /smotic diarrhea,
2. 0alabsorption +maldi!estion+fatty diarrhea 1steatorrhea2,
3. 4nflammatory diarrhea,
4. 5ecretory diarrhea, or
&. *ltered motility.
-his section "ill revie" the pathophysiolo!y of some of the more common and important causes
of diarrhea in these cate!ories. 4t should be remembered, thou!h, that these cate!ories are not
absolute and that in any one individual disease or syndrome one or more pathophysiolo!ic
processes may be the mechanism behind the development of diarrhea. 6or example, 7rohn8s
disease may cause diarrhea based on an inflammatory, malabsorptive, and secretory
pathophysiolo!y. 4n addition, some causes of malabsorption or maldi!estion may not necessarily
be associated "ith diarrhea.
Diarrhea may also be divided into acute diarrhea and chronic diarrhea . *cute diarrheal states
1diarrhea lastin! less than 4 "ee#s2 are most commonly due to infectious causes. 9o"ever, many
different medications or ischemia to the intestines can cause acute diarrhea. 7hronic diarrhea is
diarrhea "hich lasts for lon!er than 4 "ee#s.
-his section "ill not only discuss the pathophysiolo!y of diarrhea, but also the evaluation and
treatment of patients "ith diarrhea. -his section "ill /- focus on inflammatory bo"el disease
or infectious diarrhea, as these entities are covered else"here.
-able 1. 0a.or 7auses of Diarrhea
/smotic diarrhea :
/smotic laxative abuse
o 0!1/9222, 0!5/4, a25/4, %actulose, $olyethylene !lycol
7arbohydrate malabsorption
o %actose intolerance
0alabsorption+0aldi!estion+6atty Diarrhea
0alabsorption syndromes
o 0ucosal diseases of small intestine 1e.!. 7eliac sprue2
o 5hort bo"el syndrome 1after multiple sur!ical resections2
o 5mall bo"el bacterial over!ro"th
0esenteric ischemia
0aldi!estion
o $ancreatic insufficiency 1chronic pancreatitis, cystic fibrosis2
o Reduced luminal bile acid
4nflammatory diarrhea
4nflammatory bo"el disease
o :lcerative colitis
o 7rohn8s disease
o %ymphocytic or colla!enous colitis
o :lcerative .e.unoileitis 1rare complication of celiac sprue2
4nfections
o 4nvasive bacterial infection 17lostridium difficile, ;.7oli '1&<:9< and others2
o $henolphthalein, anthra=uinones, bisacodyl, senna, aloe, ricinoleic acid 1castor
oil2, dioctyl sodium sulfosuccinate
4schemic 7olitis
Radiation enterocolitis
eoplasia: colon carcinoma, lymphoma
5ecretory diarrhea
on(osmotic laxative use
o $henolphthalein, anthra=uinones, bisacodyl, senna, aloe, ricinoleic acid 1castor
oil2, dioctyl sodium sulfosuccinate
7on!ential chloridorrhea
4nfectious diarrhea: liberation of bacterial toxins
4leal bile acid malabsorption
>asculitis
Dru!s
euroendocrine tumors
o ?astrinoma
o >4$oma
o 5omatostatinomas
o 0astocytosis
o 7arcinoid syndrome
o 0edullary carcinoma of thyroid
eoplasia: villous adenoma, colon cancer, lymphoma
4diopathic secretory diarrhea
Disordered motility
$ost(va!otomy
$ost(sympathectomy
Diabetic neuropathy
9yperthyroidism
*ddison8s disease 1adrenal insufficiency2
4rritable bo"el syndrome
2.2. Osmotic Diarrhea
;xcess amounts of poorly absorbed substances that remain in the intestinal lumen may cause
osmotic diarrhea. %ar!e amounts of these substances 1e.!. lactose, lactulose, ma!nesium2 contain
osmotically active solutes "hich obli!ate retention of "ater in the lumen of the intestine by
virtue of their osmotic effects.
;lectrolyte absorption 1a
@
, A
@
, 7l
(
, 97/3
(
2 is unaffected by these osmotically(active substances
therefore stool "ater contains very little unabsorbed sodium and potassium. -his is the basis for
the measurement and calculation of the fecal osmotic !ap , a dia!nostic test in the evaluation of
patients "ith chronic diarrhea.
-he fecal osmotic !ap estimates the difference bet"een luminal osmolality and the osmolality of
luminal contents contributed by fecal electrolytes. %uminal osmolality is approximately e=ual to
body fluid osmolality 129' mosm+#! 92/2 since the colon cannot maintain an osmotic !radient
a!ainst plasma. 6urthermore, fecal osmolality may be measured directly but this measurement
should /- be used in the calculation of the fecal osmotic !ap: fecal osmolality be!ins to rise
almost immediately as it sits in the collection container. -his rise is due to monosaccharide
conversion by bacterial fermentation to several osmotically active or!anic acids. -he osmolality
of luminal contents contributed by fecal electrolytes is calculated by multiplyin! the sum of the
a@ and A@ concentrations measured in a stool sample by 2 1to account for the anions that
accompany these cations2. -herefore:
6ecal osmotic !ap B 29' mosm+#! 92/ C 2 1Da
@
E @ DA
@
E2 mmol+%
4n patients "ith pure osmotic diarrhea the fecal osmotic !ap should be lar!e 1F 12& mosm+#!
92/2. 4n patients "ith secretory diarrhea 1see -able 12 the osmotic !ap should be small 1G&'
mosm+#! 92/2.
0easurement of the p9 of feces may also be helpful in assessin! osmotic diarrhea. 7arbohydrate
induced diarrhea, such as lactase deficiency, typically has a lo" p9 "hereas ma!nesium induced
diarrhea has a hi!h p9.
-he hydro!en breath test 1also occasionally utiliHed in the assessment of bacterial over!ro"th
syndrome, discussed belo"2 may be used to detect lactose intolerance. * oral dose of lactose is
administered and, in patients "ith lactase deficiency, excess 92 is produced by colonic bacterial
fermentation of the unabsorbed carbohydrate. 92 diffuses into the !eneral circulation and is
liberated in expired air. 4n !eneral, a rise of over 2' ppm 1parts per million2 in exhaled hydro!en
at 3() hours after in!estion of the substrate is abnormal.
4mportant examples of osmotic diarrhea include lactose malabsorption and in!estion of excess
ma!nesium as in ma!nesium hydroxide. %actose intolerance is due to con!enital or, more
commonly, ac=uired deficiency in the brush border disaccharidase lactase. -his leads to
malabsorption of lactose C the su!ar contained in dairy products. %actose remains in the
intestinal lumen and acts as a stron! osmotic substance. -his leads to symptoms of flatulence,
bloatin!, and diarrhea. %actase deficiency is particularly common in *sians, *frican(*mericans,
ative *mericans, Ie"s, 9ispanics, 5outhern ;uropeans, and 0editerraneans. /ver one(half of
the "orldJs population is affected. %actose intolerance is treated by avoidance of lactose
containin! foods and+or supplementin! oral inta#e of dairy products "ith li=uid or tablet form of
the lactase enHyme.
2.3. Malabsorption, Maldigestion, and Fatty Diarrhea
*bnormalities of absorption may have several pathophysiolo!ic mechanisms as outlined belo".
*lthou!h all three ma.or nutrients 1fat, carbohydrate, and protein2 may be malabsorbed, clinical
symptoms usually only develop "ith carbohydrate and fat malabsorption. 5ome disorders that
cause fat, carbohydrate, and protein malabsorption may not cause diarrhea. -he student is
directed to the revie" section on normal physiolo!y of di!estion and absorption prior to studyin!
this section.
1. %uminal $hase
1. Reduced nutrient availability
1. 7ofactor deficiency
2. utrient consumption
2. 4mpaired fat solubiliHation
1. Reduced bile salt
2. 4mpaired bile salt secretion
3. Kile salt inactivation
4. 4mpaired 77A release
&. 4ncreased bile salt losses
3. Defective nutrient hydrolysis
1. %ipase
2. ;nHyme deficiency
3. 4mproper mixin! or rapid transit
2. 0ucosal $hase
1. ;xtensive mucosal loss
2. Diffuse mucosal disease
3. ;nterocyte defects
1. 0icrovillous inclusion disease
2. Krush border hydrolase deficiency
3. -ransport defects
4. ;pithelial processin!
3. -ransport $hase
1. >acular
2. %ymphatic
utrients may be malabsorbed due to defects in di!estion durin! the luminal phase of nutrient
absorption.
4ntralumenal maldi!estion may occur at several levels:
1. Reduced nutrient availability:
1. $atients "ho lac# intrinsic factor, the cofactor necessary for vitamin K12
absorption, due to autoimmune atrophic !astritis 1atrophic !astritis due to an
autoimmune process "here antibodies tar!et the 9
@
(*-$ase on parietal cells
causin! parietal cell lossL parietal cells produce intrinsic factor in addition to 97l2
leadin! to pernicious anemia. $atients are unable to absorb K12.
2. Kacterial over!ro"th syndrome 1discussed belo"2 leads to nutrient consumption
by bacteria.
2. 4mpaired fat solubiliHation
1. Reduced bile salt synthesis due to severe liver disease 1cirrhosis2 and impaired
bile salt secretion due to chronic cholestasis 1intrinsic liver disease "hich causes
bile duct dama!e or extrahepatic bile duct obstruction2: bile salts are thus not
available to form micelles to aid in fat solubiliHation for absorption.
2. Kile salts may be inactivated in the intestinal lumen by over!ro"th of bacteria in
the small bo"el bacterial over!ro"th syndrome . -he normal concentration of
bacteria in the proximal small intestine is less than 1'
4
cfus+ml 1colony formin!
units per ml2. 4n patients "ith conditions that predispose to intestinal stasis either
by anatomic or motility abnormalities 1see $redisposin! conditions favorin!
bacterial over!ro"th table belo"2 or in patients "ith abnormal connections
bet"een loops of proximal and distal bo"el, bacteria may over!ro" in the
proximal small intestine. -hese excess bacteria decon.u!ate bile salts leavin!
them uncon.u!ated and unable to participate in micelle formation. -his leads to
malabsorption of fat and symptoms of abdominal pain, diarrhea, and bloatin!. 4t
may also lead to malabsorption of the fat soluble vitamins *, D, ;, A. 7linically,
vitamin A deficiency is detected by measurin! the prothrombin time 1$-2 in
blood. 4f prolon!ed this may su!!est vitamin A deficiency as several of the
proteins in the coa!ulation cascade rely on vitamin A for their formation.
-able 2. $redisposin! 7onditions 6avorin! Kacterial /ver!ro"th
4ntestinal 5tasis
*natomic
4ntestinal strictures 1secondary to 7rohns disease, radiation, or mali!nancy, for example2
5mall intestinal diverticulosis 1seen in scleroderma
5ur!ical procedures creatin! blind loops 1end(side entero(enteric anastomoses, Killroth 44 anastomoses, .e.uno(ileal
bypass2
0otility disorders
5cleroderma
Diabetes mellitus 1diabetic autonomic neuropathy2
4diopathic intestinal pseudoobrstruction
*bnormal connections bet"een proximal and distal bo"el
Resection of ileocecal valve
6istulas 1!astrocolic, .e.unocolic due to 7rohns, peptic ulcer disease, cancer2
1. Dia!nosis of bacterial over!ro"th
1. Direct aspiration of luminal contents at the time of endoscopy 1not routinely
performed2 and cultured
2. 9ydro!en breath tests. * substrate 1a carbohydrate such as !lucose, lactulose,
lactose, or fructose2 is administered and then expired air is then analyHed for
hydro!en 1922 content. *n earlyM pea# 13'()' minutes after in!estion2 in the 92
concentration in expired air is detected if the substrate is metaboliHed by
excessive small intestinal bacteria. * lateM pea# 12(3 hours after in!estion2 is
typically seen "hen malabsorbed substrate reaches the colon and is metaboliHed
by normally present colonic bacteria.
2. -reatment of bacterial over!ro"th:
1. 7orrection of predisposin! factor if possible 1i.e., correction of sur!ical
abnormality or treatment of underlyin! disease2
2. 7orrection of nutritional deficiencies
3. *ntibiotics
1. 4ncreased bile salt losses
5ur!ical resection of or extensive inflammatory disease in the terminal ileum 1as seen in
7rohn8s disease2 may lead to malabsorption of bile acids. -he loss of bile acids in the
stool leads to relative bile salt deficiency resultin! in impaired fat solubiliHation.
1. Defective nutrient hydrolysis
1. Nollin!er ;llison syndrome C excess 97l 1acid2 production may inactivate !astric
lipase and proteolytic pancreatic exocrine enHymes.
2. $ancreatic enHyme deficiency C due to chronic pancreatitis or a mali!nancy
obstructin! the outflo" of pancreatic .uices into the duodenum.
3. 4mproper mixin! C due to sur!ical resection such as post(!astrectomy 1Killroth 4
or Killroth 44 anastomoses for example2
4. Rapid intestinal transit ( diabetic neuropathy or hyperthyroidism 1disordered
motility2
0alabsorption : 0ucosal abnormalities:
0any diseases may interrupt the mucosal inte!rity and thus the absorptive surface of the
intestine leadin! to malabsorption. -he small bo"el mucosa may be dama!ed due to prior
radiation treatment, vascular insufficiency, or from inflammatory or infectious conditions. *s
mentioned above, inflammatory diseases such as 7rohn8s disease disrupt the mucosa leadin! to
malabsorption. 7eliac sprue is a diffuse mucosal disease of the small bo"el "hich leads to
villous atrophy and subse=uent nutrient malabsorption.
7eliac sprue or !luten sensitive enteropathy is a chronic disease "ith a characteristic althou!h
not specific mucosal lesion of the small intestine "hich impairs nutrient absorption and "ith
removal of all "heat !liadins 1the toxic alcohol(soluble !luten fractions2 from the diet there is
resolution of the mucosal abnormality and improvement in nutrient absorption.
$atholo!y: 5mall intestinal villous atrophy and increases in lamina propria lymphocytes.
;pidemiolo!y: Ohites 1hi!hest incidence in orthern ;uropeans, particularly 4reland2
althou!h celiac sprue has been documented in *sians from 4ndia and $a#istan.
7linical presentation: >aried C often dependin! on extent and de!ree of villous atrophy.
7lassically, crampy abdominal pain, diarrhea, flatulence, bloatin!, "ei!ht loss,
steatorrhea. *lso: 4ron deficiency anemia, osteoporosis 1vitamin D malabsorption2,
peripheral neuropathy 1K12 deficiency2, easy bruisin! 1vitamin A malabsorption2, edema
1malabsorption of protein2.
Dia!nosis :
o Kiopsy of small intestine durin! upper endoscopy for patholo!ic evaluation
o 5erolo!y:
*nti(!liadin antibodies 14!* and 4!?2
*nti(endomysial antibodies 14!*2 C these 4!* antibodies are reactive "ith
the linin! of visceral smooth muscle 1i.e., the endomysium2. 5ensitivity
and specificity is very hi!h "ith these antibodies compared to anti(!liadin
in the detection of celiac sprue. 4t is unclear if these antibodies play a role
in the patho!enesis of celiac sprue.
4t "as recently 1199<(199P2 discovered that tissue trans!lutaminase is the
anti!en reco!niHed by endomysial antibodies. -here is no" an ;%45* that
can be used to measure tissue trans!lutaminase antibodies "ith hi!h
specificity and sensitivity.
-reatment :
o -he mainstay of treatment for celiac sprue is a !luten free diet. -his diet is
incredibly restrictive necessitatin! the evaluation by a dedicated nutritionist.
?liadins 1the alcohol soluble fraction of !luten C the ma.or "heat stora!e protein2
and prolamins 1alcohol soluble fractions of rye, barley, and oat stora!e proteins2
of rye, barley, and possibly oats are toxic to celiac sprue patients. 6or more details
on the !luten free diet the 7eliac 5prue association "ebsite is particularly helpful:
http:++""".csaceliacs.or!+basics.html .
/ther aspects of treatment include nutrient supplementation: iron, K12, calcium,
vitamin D, vitamin A.
$atho!enesis of celiac sprue :
o ?enetic factors: F9&Q of patients carry 9%*(DR2 or CDRPL 1'Q of first de!ree
relatives have celiac sprue
o ;nvironmental a!ent C !liadin component of !luten
o *utoimmune response to !liadin and prolamin peptide fra!ments.
o Diarrhea caused by malabsorbed substances includin! electrolytes, protein, and
fat
o $resumed pathophysiolo!y: ?liadin is absorbed into the lamina pro 7on!enital
defects of ion absorptive processes pria and presented to - cells by anti!en
presentin! cells in con.unction "ith 9%*(DR2 or DRP. -issue trans!lutaminase
deamidates !liadin peptides "hich !enerates acidic, ne!atively char!ed residues
"hich binds the - cell receptor more stron!ly. -his leads to a more pronounced -
cell response. -hese activated lymphocytes !enerate a cyto#ine response 1-6(S,
interleu#in(4, interferon(T2, "hich lead to dama!ed villi and inflammation.
o 5ee illustration in ;n!l I 0ed 2''2L 34): 1P'(1PP
7eliac 5prue : associated diseases: Dermatitis herpetiformis, pruritic blisterin! s#in
eruption associated "ith 4!* deposits in s#in
o 5mall intestinal lymphoma 1increased ris# of lymphoma in patients "ith celiac
sprue: ris# may be lessened "ith adherence to !luten free diet2
$ost(absorptive+-ransport $hase *bnormalities Resultin! in 0alabsorption
Defective chylomicron synthesis in a(beta lipoproteinemia
5ubmucosal infiltration in the intestinal "all due to lymphoma or amyloidosis
%ymphatic obstruction in intestinal lymphan!iectasia
2.. Inflammatory Diarrhea
Diarrheal diseases that fit into this cate!ory are discussed in detail in the section on inflammatory
bo"el diseases and in the infectious disease section on infectious diarrhea. Kriefly, in addition to
mucosal disruption resultin! in enterocyte dama!e and abnormal absorption of nutrients and
electrolytes, inflammatory processes may result in dischar!e of mucus, proteins, and blood into
the intestinal lumen.
2.!. "ecretory Diarrhea
5ecretory diarrhea is caused by abnormal ion transport in intestinal epithelial cells usually
resultin! in decreased absorption of electrolytes. -he ma.or solutes in the intestinal lumen of
patients "ith secretory diarrhea are a
@
, A
@
, 7l
(
, and 97/3
(
therefore electrolytes account for
most of the luminal osmolality. 7onse=uently, the fecal osmotic !ap U29' C 21Da
@
E @ DA
@
E2V is
small, usually less than &' mosm+#! 92/. 4n addition, because this type of diarrhea is due to
abnormalities in ion transport, the diarrhea usually persists despite fastin!. 9o"ever, reliance on
this clinical history point 1i.e., diarrhea "hich continues despite fastin!2 can be troublesome:
most patients "ith secretory diarrhea 1defined as a small fecal osmotic !ap2 still absorb most of
the 9(1'% of fluid enterin! the .e.unum each day C they .ust do not absorb almost all of it as in
normal circumstances. -herefore, one may ar!ue that the term secretory diarrhea is a misnomer
and should really be called non(osmoticM diarrhea.
-here are four main cate!ories of disease resultin! in secretory diarrhea:
1. 7on!enital defects of ion absorptive processes
1. 7on!enital chloridorrhea results from defective or absent 7l
(
+97/3
(
exchan!er in
the ileum and colon. -his results in excess 7l( loss in the stool and metabolic
al#alosis.
2. 7on!enitally defective or absent a
@
+9
@
exchan!er leads to excess a
@
in the
stool and metabolic acidosis
2. 4ntestinal resection
1. Decreased absorptive surface for not only nutrients but also electrolytes and fluid
2. 7ombined malabsorption and secretory component
3. Diffuse mucosal disease "ith destruction of enterocytes or reduction in enterocyte
function
1. 5imilar pathophysiolo!y to intestinal resection C also may cause nutrient
malabsorption in addition to electrolyte malabsorption 1defective ion transport2
4. *bnormal mediators: result in chan!es in intracellular si!nalin! path"ays
1. 7han!es in c*0$ 1cyclic adenosine monophosphate2, c?0$ 1cyclic !uanosine
monophosphate2, calcium, and+or protein #inases. -hese chan!es lead to a
decrease in a@ absorption or an increase in 7l( secretion.
2. 0ediators
3. /ther mediators: bacterial toxins
4. /ther mediators: non(osmotic laxatives 1see -able 12
&. 0ore mediators: fatty acids C byproducts of fat malabsorption "hich reach colon
and stimulate colonic secretion.
). 0ore mediators: bile acids C bile acids not absorbed in ileum due to ileal resection
or severe ileal disease 1such as in 7rohn8s disease2 can also act as a cathartic in
the colon and stimulate secretion of fluid and electrolytes.
<. 6inal mediators: circulatin! a!ents released by neuroendocrine tumors 1rare2. 15ee
-able 32
-able 3. euroendocrine -umors and 5ecretory Diarrhea
7ondition 0ediator 0echanism of Diarrhea /ther 0anifestations
Nollin!er(;llison syndrome ?astrin *cid inactivation of pancreatic
enHymes and bile salts
4ntestinal fluid and electrolyte
secretion
*cid(induced dama!e to intestinal
5evere peptic ulcer disease
;rosive esopha!itis
-umor in pancreas or duodenum
mucosa
4ncreased motility
7arcinoid syndrome 5erotonin, substance $,
Krady#inin, 0otilin,
$rosta!landins
4ncreased motility
4ntestinal fluid and electrolyte
secretion
6lushin!
OheeHin!
Ri!ht(sides heart failure
9ypotension
0edullary 7arcinoma of the -hyroid 7alcitonin,
$rosta!landins
4ntestinal fluid and electrolyte
secretion
4ncreased motility
-hyroid module or enlar!ement
$ancreatic 7holera >4$ 1>asocactive
intestinal peptide2
4ntestinal fluid and electrolyte
secretion
9ypo#alemia
*chlorhydria
6lushin!
9ypotension
?luca!onoma ?luca!on 4ntestinal fluid and electrolyte
secretion
ecrolytic erythema mi!rans
1rash2
Diabetes
*nemia
7heilitis+!lossitis
-umor in pancreas
5omatostatinoma 5omatostatin Decreased intestinal nutrient Diabetes
absorption
5teaorrhea due to decrease
pancreatic secretion
Dyspepsia
7holelithiasis
$ancreatic tumor
5ystemic 0astocytosis 9istamine 4ntestinal fluid and electrolyte
secretion
?astric hypersecretion
>illous atrophy
6lushin!
ausea+vomitin!
*bdominal pain
Dermato!raphism
2.#. Disordered Motility
7onditions "hich cause altered !astric, small intestinal, or colonic motor activity may cause
diarrhea by limitin! the time for the normal di!estive and absorptive processes to ta#e place.
-hat is, food boluses are propelled rapidly throu!h the intestinal lumen decreasin! the contact
time at absorptive epithelial cells.
$atients "ith autonomic diabetic neuropathy or hyperthyroidism may have altered intestinal
motility leadin! to diarrhea. $atients "ho have had a va!otomy and+or partial !astrectomy are
also prone to altered motility. *bnormal motility also li#ely contributes to diarrhea in patients
"ith the irritable bo"el syndrome.
4rritable bo"el syndrome 14K52, one of the most common syndromes identified in
!astroenterolo!y clinics, is felt to be due to hei!htened visceral sensation and altered intestinal
motility. -ypically, symptoms include intermittent, non(localiHin! abdominal pain "ith an altered
bo"el pattern. -hat is, patients alternate from bein! constipated to havin! diarrhea. -his is often
associated "ith a sensation of incomplete evacuation after bo"el movements or the passa!e of
mucus in the stool. 4K5 does not cause blood in the stool, fevers, nocturnal symptoms of
diarrhea, or "ei!ht loss. -here are set criteria for the dia!nosis of 4K5 based on the clinical
history alone and most !astroenterolo!ists may suspect and can dia!nose 4K5 "ithout dia!nostic
testin!, but endoscopic procedures, blood "or#, or !astrointestinal x(rays are often performed to
rule out other diseases. -reatment is usually symptomatic 1anti(diarrheals, anti(spasmodics, fiber
supplementation, avoidance of laxatives2.
5lo" motility may also result in diarrhea: 5lo" intestinal transit may result in intestinal stasis
leadin! to bacterial over!ro"th 1discussed above2.
http://ocw.tufts.edu/Content/48/lecturenotes/571075
Pathophysiology
Diarrhea is the reversal of the normal net absorptive status of "ater and electrolyte absorption to
secretion. 5uch a deran!ement can be the result of either an osmotic force that acts in the lumen
to drive "ater into the !ut or the result of an active secretory state induced in the enterocytes. 4n
the former case, diarrhea is osmolar in nature, as is observed after the in!estion of nonabsorbable
su!ars such as lactulose or lactose in lactose malabsorbers. 4nstead, in the typical active secretory
state, enhanced anion secretion 1mostly by the crypt cell compartment2 is best exemplified by
enterotoxin(induced diarrhea.
4n osmotic diarrhea, stool output is proportional to the inta#e of the unabsorbable substrate and is
usually not massiveL diarrheal stools promptly re!ress "ith discontinuation of the offendin!
nutrient, and the stool ion !ap is hi!h, exceedin! 1'' m/sm+#!. 4n fact, the fecal osmolality in
this circumstance is accounted for not only by the electrolytes but also by the unabsorbed
nutrient1s2 and their de!radation products. -he ion !ap is obtained by subtractin! the
concentration of the electrolytes from total osmolality 1assumed to be 29' m/sm+#!2, accordin!
to the formula: ion !ap B 29' C D1a @ A2 W 2E.
4n secretory diarrhea, the epithelial cells8 ion transport processes are turned into a state of active
secretion. -he most common cause of acute(onset secretory diarrhea is a bacterial infection of
the !ut. 5everal mechanisms may be at "or#. *fter coloniHation, enteric patho!ens may adhere
to or invade the epitheliumL they may produce enterotoxins 1exotoxins that elicit secretion by
increasin! an intracellular second messen!er2 or cytotoxins. -hey may also tri!!er release of
cyto#ines attractin! inflammatory cells, "hich, in turn, contribute to the activated secretion by
inducin! the release of a!ents such as prosta!landins or platelet(activatin! factor. 6eatures of
secretory diarrhea include a hi!h pur!in! rate, a lac# of response to fastin!, and a normal stool
ion !ap 1ie, 1'' m/sm+#! or less2, indicatin! that nutrient absorption is intact.
http://emedicine.medscape.com/article/98598!o"er"iew#awaa$%$$aa
Pathophysiology of 'iarrhea
Diarrhea is an increase in the volume of stool or fre=uency of defecation. 4t is one of the
most common clinical si!ns of !astrointestinal disease, but also can reflect primary
disorders outside of the di!estive system. 7ertainly, disorders affectin! either the small
or lar!e bo"el can lead to diarrhea.
6or many people, diarrhea represents an occasional inconvenience or annoyance, yet at
least 2 million people in the "orld, mostly children, die from the conse=uences of
diarrhea each year.
-here are numerous causes of diarrhea, but in almost all cases, this disorder is a
manifestation of one of the four basic mechanisms described belo". 4t is also common
for more than one of the four mechanisms to be involved in the patho!enesis of a !iven
case.
Osmotic Diarrhea
*bsorption of "ater in the intestines is dependent on ade=uate absorption of solutes. 4f
excessive amounts of solutes are retained in the intestinal lumen, "ater "ill not be
absorbed and diarrhea "ill result. /smotic diarrhea typically results from one of t"o
situations:
Ingestion of a poorly absorbed substrate:
(he o)ending molecule is usually a
car$ohydrate or di"alent ion. Common e*amples include mannitol or
sor$itol+ epson salt ,-g./40 and some antacids ,-g/10.
Malabsorption: 2na$ility to a$sor$ certain car$ohydrates is the most
common de3cit in this category of diarrhea+ $ut it can result "irtually
any type of mala$sorption. 4 common e*ample of mala$sorption+
a5icting many adults humans and pets is lactose intolerance resulting
from a de3ciency in the $rush $order en6yme lactase. 2n such cases+ a
moderate 7uantity of lactose is consumed ,usually as mil80+ $ut the
intestinal epithelium is de3cient in lactase+ and lactose cannot $e
e)ecti"ely hydroly6ed into glucose and galactose for a$sorption. (he
osmotically!acti"e lactose is retained in the intestinal lumen+ where it
9holds9 water. (o add insult to in:ury+ the una$sor$ed lactose passes
into the large intestine where it is fermented $y colonic $acteria+
resulting in production of e*cessi"e gas.
* distin!uishin! feature of osmotic diarrhea is that it stops after the patient is fasted or
stops consumin! the poorly absorbed solute.
Secretory Diarrhea
%ar!e volumes of "ater are normally secreted into the small intestinal lumen, but a lar!e
ma.ority of this "ater is efficienty absorbed before reachin! the lar!e intestine. Diarrhea
occurs "hen secretion of "ater into the intestinal lumen
exceeds absorption.
0any millions of people have died of the secretory
diarrhea associated "ith cholera. -he responsible
or!anism, Vibrio cholerae, produces cholera toxin, "hich stron!ly activates adenylyl
cyclase, causin! a prolon!ed increase in intracellular concentration of cyclic *0$
"ithin crypt enterocytes. -his chan!e results in prolon!ed openin! of the chloride
channels that are instrumental in secretion of "ater from the crypts, allo"in!
uncontrolled secretion of "ater. *dditionally, cholera toxin affects the enteric nervous
system, resultin! in an independent stimulus of secretion.
;xposure to toxins from several other types of bacteria 1e.!. E. coli heat(labile toxin2
induce the same series of steps and massive secretory diarrhea that is often lethal unless
the person or animal is a!!ressively treated to maintain hydration.
4n addition to bacterial toxins, a lar!e number of other a!ents can induce secretory
diarrhea by turnin! on the intestinal secretory machinery, includin!:
some la*ati"es
hormones secreted $y certain types of tumors ,e.g. "asoacti"e
intestinal peptide0
a $road range of drugs ,e.g. some types of asthma medications+
antidepressants+ cardiac drugs0
certain metals+ organic to*ins+ and plant products ,e.g. arsenic+
insecticides+ mushroom to*ins+ ca)eine0
4n most cases, secretory diarrheas "ill not resolve durin! a 2(3 day fast.
Infammatory and Infectious Diarrhea
-he epithelium of the di!estive tube is protected from insult by a number of mechanisms
constitutin! the !astrointestinal barrier, but li#e many barriers, it can be breached.
Disruption of the epithelium of the intestine due to microbial or viral patho!ens is a very
common cause of diarrhea in all species. Destruction of the epithelium results not only
in exudation of serum and blood into the lumen but often is associated "ith "idespread
destruction of absorptive epithelium. 4n such cases, absorption of "ater occurs very
inefficiently and diarrhea results. ;xamples of patho!ens fre=uently associated "ith
infectious diarrhea include:
;acteria: Salmonella, E. coli,
Campylobacter
<iruses: rota"iruses+ corona"iruses+
par"o"iruses ,canine and feline0+ noro"irus
Proto6oa: coccidia species+ Cryptosporium+ Giardia
-he immune response to inflammatory conditions in the bo"el contributes substantively
to development of diarrhea. *ctivation of "hite blood cells leads them to secrete
inflammatory mediators and cyto#ines "hich can stimulate secretion, in effect imposin!
a secretory component on top of an inflammatory diarrhea. Reactive oxy!en species
from leu#ocytes can dama!e or #ill intestinal epithelial cells, "hich are replaced "ith
immature cells that typically are deficient in the brush border enyHmes and transporters
necessary for absorption of nutrients and "ater. 4n this "ay, components of an osmotic
1malabsorption2 diarrhea are added to the problem.
Diarrhea Associated with Deranged Motility
4n order for nutrients and "ater to be efficiently absorbed, the intestinal contents must be
ade=uately exposed to the mucosal epithelium and retained lon! enou!h to allo"
absorption. Disorders in motility than accelerate transit time could decrease absorption,
resultin! in diarrhea even if the absorptive process per se
"as proceedin! properly.
*lterations in intestinal motility 1usually increased
propulsion2 are observed in many types of diarrhea. Ohat
is not usally clear, and very difficult to demonstrate, is
"hether primary alterations in motility are actually the cause of diarrhea or simply an
effect.
http://www."i"o.colostate.edu/h$oo8s/pathphys/digestion/smallgut/diarrhea.html