In-Depth Review

Acid-Base Disturbances in Gastrointestinal Disease

F. John Gennari and Wolfgang J. Weise
Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont

Disruption of normal gastrointestinal function as a result of infection, hereditary or acquired diseases, or complications of
surgical procedures uncovers its important role in acid-base homeostasis. Metabolic acidosis or alkalosis may occur, depend-
ing on the nature and volume of the unregulated losses that occur. Investigation into the specific pathophysiology of
gastrointestinal disorders has provided important new insights into the normal physiology of ion transport along the gut and
has also provided new avenues for treatment. This review provides a brief overview of normal ion transport along the gut and
then discusses the pathophysiology and treatment of the metabolic acid-base disorders that occur when normal gut function
is disrupted.
Clin J Am Soc Nephrol 3: 1861–1868, 2008. doi: 10.2215/CJN.02450508

T
he gastrointestinal tract is a slumbering giant with re-
gard to acid-base homeostasis. Large amounts of H⫹
and HCO3⫺ traverse the specialized epithelia of the
various components of the gut every day, but under normal
conditions, only a small amount of alkali (approximately 30 to
40 mmol) is lost in the stool (1,2). In contrast to the kidney, acid
and alkali transport in the gut is adjusted for efficient absorp-
tion of dietary constituents rather than for acid-base homeosta-
sis. The small amount of alkali lost as a byproduct of these
transport events is easily regenerated by renal net acid excre-
tion, which is regulated by the kidney to maintain body alkali
stores. Disruption of normal gut function, however, uncovers
its power to overwhelm acid-base homeostasis. Acid-base dis-
orders can vary from severe acidosis to severe alkalosis, de-
pending on the site along the gastrointestinal tract affected and
the nature of the losses that ensue. These disruptions in acid-
base equilibrium are associated with disorders of potassium
balance, often leading to either hypo- or hyperkalemia. Major
sodium and chloride losses also occur, sometimes causing life-
threatening volume depletion and almost always contributing
to the acid-base abnormalities.
Normal Physiology of Gut Fluid and
Electrolyte Transport
During the course of each day, secretion as well as absorption
of fluid and electrolytes occurs along the gastrointestinal tract.
Normally 7 to 8 L of fluid is secreted each day, far exceeding
dietary consumption, and almost all of these secretions, as well
as any ingested fluid, are absorbed by the end of the colon (1).
The gastrointestinal tract is divided into sequential segments,
each with a distinct group of ion transporters and channels that
interact with one another to determine the electrolyte content
and volume of the fluid in the gut lumen. With the exception of
the stomach and the exocrine pancreas, secretion of fluid and
electrolytes occurs primarily in a subset of cells in the epithelial
crypts with unique ion transport properties. Throughout the
gut, fluid and electrolyte transport (both absorption and secre-
tion) is driven primarily by Na⫹/K⫹-ATPase transport activity
across the basolateral membrane of epithelial cells. Several key
apical membrane electrolyte transporters participate, including
Cl⫺/HCO3⫺ and Na⫹/H⫹ ion exchangers and the cystic fibro-
sis transmembrane conductance regulator (CFTR) Cl⫺ channel,
all of which are present in many segments of the gut, and
H⫹/K⫹-ATPases, which are confined to the stomach and colon
(Figure 1). Disruption of function or abnormal stimulation of
these ion transporters underlies a variety of gastrointestinal
disorders that are associated with acid-base and electrolyte
disorders. A full description of the ion transport processes that
participate in normal gut function is beyond the scope of this
review, and reader is referred to other sources for more detail (1).
Mouth and Throat
Secretion of salivary fluid occurs via the parotid and salivary
glands, ultimately producing a hypotonic alkaline solution
when stimulated by activation of muscarinic receptors. Acinar
cells secrete fluid that is similar in composition to serum, and
then the secreted fluid is modified by Na⫹ and Cl⫺ absorption
and HCO3⫺ secretion. The apical membrane transport proteins
that alter the composition under conditions of stimulation re-
main to be defined, but HCO3⫺ secretion may occur via an
anion channel, possibly the CFTR Cl⫺ channel (3). When stim-
ulated, up to 1 L/d fluid is produced (Table 1). This alkaline
secretion likely serves to protect the mucosa of the mouth,
throat, and esophagus and has little impact on serum [HCO3⫺].
It is more than counterbalanced by gastric acid secretion in the
stomach.

Published online ahead of print. Publication date available at www.cjasn.org. Stomach

Digestion of many of the foods that we eat requires secre-
Correspondence: Dr. F. John Gennari, 2319 Rehab, UHC Campus, Fletcher Allen
Health Care, Burlington, VT 05401. Phone: 802-847-2534; Fax: 802-847-8736; E- tion of an acid solution into the lumen of the stomach.
mail: fgennari@uvm.edu Secretion of this solution involves several linked transport

Copyright © 2008 by the American Society of Nephrology ISSN: 1555-9041/306 –1861

1862 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 1861–1868, 2008

Figure 1. Key apical membrane ion transporters and channels in various segments of the gastrointestinal tract. The driving force
for most absorption and secretion across the apical membrane is the basolateral Na⫹/K⫹-ATPase shown. All other basolateral ion
transporters and channels are deliberately omitted. CFTR, cystic fibrosis transmembrane conductance regulator; DRA, down-
regulated in adenoma gene product; SCFA, short-chain fatty acids.

Table 1. Volume and nature of the fluid leaving various segments of the gastrointestinal tract
Gut Segment Range of Volume (L/d)a Nature of Fluid

Salivary glands 0.20 to 1.00 Alkaline when stimulated, 关K⫹兴 20 to 30

mmol/L
Stomach 0.50 to 2.00 Highly Acid when stimulated, 关K⫹兴
approximately 10 mmol/L
Biliary tree 1.00 Alkaline when stimulated
Pancreas 1.00 to 2.00 Highly alkaline when stimulated, 关K⫹兴 5
to 10 mmol/L
Jejunum/ileum 1.00 to 2.00 Alkaline, 关K⫹兴 5 to 10 mmol/L
Colon ⬍0.15 Low pH, 关Na⫹兴 and 关Cl⫺兴 ⬍30 mmol/L,
关K⫹兴 55 to 75 mmol/L
a
Fluid volume delivered beyond indicated portion of the gastrointestinal tract.

proteins in the parietal cells that line the stomach (Figure 1)
(1). Of these, the gastric H⫹/K⫹-ATPase is essential for acid
secretion; pharmacologic blockade of this transporter effec-
tively blocks acidification of the gastric contents. Hydrogen
ion secretion by this transporter is facilitated by K⫹ recycling
across the apical membrane via a selective cation channel.
Chloride is secreted by an as-yet-unidentified Cl⫺ channel,
yielding hydrochloric acid under conditions of stimulation.
Under basal conditions, the secreted fluid is primarily NaCl.
The pH and volume of gastric secretions is regulated primar-
ily by gastrin, so maximal volume and acid secretion occurs
only after a meal. At such times, the pH of the gastric fluid
falls to as low as 1.0 (H⫹ ⫽ 100 mmol/L) and volume
increases to as high as 7 ml/min. The surge in acid secretion
transiently increases serum [HCO3⫺] by 1 to 2 mmol/L, a
change referred to as the alkaline tide, once used as a test of
acid secretion. The increase is transient, because the process
of acid secretion itself sets in motion countervailing alkali
secretion by the exocrine pancreas into the duodenum. Gas-
tric secretion is usually 1 to 2 L/d (Table 1).
Duodenum
Regardless of the pH and tonicity of the gut contents that
enter the duodenum, this segment of the gut restores isotonicity
Clin J Am Soc Nephrol 3: 1861–1868, 2008
through water and solute absorption, and the pH rises to 7.0.
Acid is neutralized by HCO3⫺ addition in pancreatic and bili-
ary secretions as well as by direct secretion in Brunner’s glands
along the duodenum (1). The specific ion transporters involved
in duodenal HCO3⫺ secretion remain to be defined.
Pancreas
Entry of the acid gastric secretions into the duodenum signals
the pancreas to secrete its highly alkaline solution ([HCO3⫺]
approximately 70 to 120 mmol/L) into the gut. The anion
transporter primarily responsible for this process is an apical
membrane Cl⫺/HCO3⫺ exchanger (Figure 1). The activity of
this ion exchanger is regulated by the CFTR Cl⫺ channel, which
recycles Cl⫺ across the apical membrane (1,4). Under maximal
stimulation, some secreted HCO3⫺ seems to enter the lumen
directly via the CFTR channel as well as by Cl⫺/HCO3⫺ ex-
change (5). Pancreatic HCO3⫺ secretion is stimulated by the
hormone secretin, which is secreted when acidic fluid (pH
⬍4.0) enters the duodenum. Thus, HCO3⫺ secretion occurs
only as a counterbalance to acid secretion in the stomach and
only when this acidic fluid is passed into the duodenum. At
other times, the secretion is primarily isotonic NaCl. Pancreatic
secretion amounts to 1 to 2 L/d (Table 1).
Biliary Secretion
Although the pancreas is by far the major source of the
HCO3⫺ added to the duodenal contents, stimulation of biliary
secretion by the hormones secretin and cholecystokinin also
produces an alkaline solution that contains HCO3⫺ in a con-
centration higher than in plasma (approximately 40 to 60
mmol/L) (6). This secretion is typically approximately 1 L/d.
Jejunum and Ileum
This segment of the bowel both absorbs and secretes fluid,
but absorption normally predominates, reducing the total gut
fluid content to approximately 1 L/d by the time it enters the
colon (Table 1). Absorption is driven by sodium and chloride
uptake (driving water uptake) and occurs via two linked trans-
porters, the Na⫹/H⫹ exchanger and the Cl⫺/HCO3⫺ ex-
changer (Figure 1) (7,8). These two transporters take up Na⫹
Table 2. Ranges of volume and electrolyte composition in vomitus, diarrhea fluid, and ileostomy drainagea
State Volume (L/d) 关Na⫹兴 (mmol/L)
Normal stool ⬍0.15 20 to 30
Vomitus/NG drainage 0.00 to 3.00 20 to 100
Inflammatory diarrhea 1.00 to 3.00 50 to 100
Secretory diarrhea 1.00 to 20.00 40 to 140
Congenital chloridorrhea 1.00 to 5.00 30 to 80
Villous adenoma 1.00 to 3.00 70 to 150
Ileostomy drainage
new 1.00 to 1.50 115 to 140
adapted 0.50 to 1.00 40 to 90
a
Data primarily from reference (1).
b
Approximately 30 mmol/d organic anions are lost in the stool, causing a deficit in potential alkali for the body (see text).
c
No data available.
Acid-Base Disorders in GI Disease 1863
and Cl⫺ from the gut lumen and secrete H⫹ and HCO3⫺ into it.
The latter two ions combine, forming H2CO3, which dehydrates
to form CO2 in the intestinal lumen. The Cl⫺/HCO3⫺ ex-
changer in the small intestine is the “downregulated in ade-
noma” (DRA) gene product, also named CLD (for chloride
diarrhea) (9). By the end of the ileum, Cl⫺/HCO3⫺ exchange
predominates, resulting in an alkaline solution (Table 1). Chlo-
ride secretion occurs in specialized cells in the intestinal crypts
via a series of apical Cl⫺ ion channels, one of which is the CFTR
channel, recycling Cl⫺ into the lumen (Figure 1). In contrast to
the colon, the small intestinal secretory cells do not have an
apical K⫹ channel. Potassium movement across the membrane
is accounted for by passive diffusion and solvent drag, with
absorption predominating (10). These absorptive and secretory
processes leave the fluid that enters the colon slightly hypo-
tonic with a [HCO3⫺] of approximately 30 mmol/L and with a
[K⫹] of 5 to 10 mmol/L (Table 1).
Colon
In the colon, the fluid volume of the stool is normally re-
duced to ⬍50 ml/d, and the concentrations of Na⫹ and Cl⫺ are
reduced to ⬍30 mmol/L (Table 1). Sodium chloride absorption
is accomplished by the same linked transporters described for
the small intestine, but, in addition, Na⫹ is absorbed via an
apical membrane Na⫹ channel regulated by aldosterone (Fig-
ure 1) (11,12). The HCO3⫺ secreted in the colon by the Cl⫺/
HCO3⫺ exchanger is consumed (along with much of the
HCO3⫺ delivered from the ileum) in buffering organic acids
produced by colonic bacteria. Some of the organic anions pro-
duced by this reaction are absorbed via a linked HCO3⫺ ex-
change transporter (1) (Figure 1), but the remainder are ex-
creted and make up the 30 to 40 mmol/d of potential alkali lost
in the stool despite the absence of measurable HCO3⫺ in the
stool (Table 2). The colonic absorptive epithelial cells also have
a unique apical membrane H⫹/K⫹-ATPase that absorbs K⫹
and secretes H⫹ into the gut lumen (13,14), but the role of this
transporter is unclear because significant net K⫹ secretion oc-
curs in the colon, raising [K⫹] in stool water to as high as 75
mmol/L. Secretory cells in the colon contain the same apical
关K⫹兴 (mmol/L) 关Cl⫺兴 (mmol/L) 关HCO3⫺兴 (mmol/L)
55 to 75 15 to 25 0b
10 to 15 120 to 160 0
15 to 20 50 to 100 10
15 to 40 25 to 105 20 to 75
15 to 60 120 to 150 ⬍5
15 to 80 50 to 150 Unknownc
5 to 15 95 to 125 30
5 20 15 to 30
1864 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 1861–1868, 2008

Cl⫺ channel as in the small intestine, but, in addition, they
contain several apical K⫹ channels. In colon secretory cells, Cl⫺
channel function is partially dependent on K⫹ secretion (15).
Potassium secretion via these apical channels is stimulated by
aldosterone, and this secretion is responsible for the increase in
stool [K⫹] (16). Because of the small volume of stool water
normally excreted, net daily K⫹ loss in the stool is only 10 to 15
mmol/d, but the quantity lost can easily increase if stool water
volume increases.
Acid-Base and Electrolyte Disorders
Vomiting and Nasogastric Drainage
Gastric fluid typically contains 120 to 160 mmol/L Cl⫺, bal-
anced by K⫹, Na⫹, and H⫹ (Tables 2 and 3). Under basal
conditions, the cation is primarily Na⫹, and, when stimulated,
the cation is primarily H⫹, the latter rising to as high as 100
mmol/L (1). Potassium concentration remains at approxi-
mately 10 mmol/L in both settings. Loss of this Cl⫺-rich solu-
tion through either vomiting or nasogastric drainage causes
major Cl⫺ losses, with variable H⫹ loss as well. Any H⫹ loss
abruptly increases serum [HCO3⫺] while simultaneously abro-
gating the signal to the pancreas to secrete HCO3⫺ into the
duodenum. The result is metabolic alkalosis, initiated by the
H⫹ loss but sustained by disproportionate loss of Cl⫺, a chain
of events that leads to greater depletion of body Cl⫺ stores than
of other electrolytes (17). The abrupt increase in serum
[HCO3⫺] leads to some HCO3⫺ loss in the urine initially, but
this anion rapidly disappears, and urine pH falls despite a
sustained increase in serum [HCO3⫺]. Initial loss of Na⫹ is also
rapidly followed by a rise in K⫹ excretion, leading to secondary
K⫹ depletion and hypokalemia. In the new steady state, alka-
losis and hypokalemia are sustained until gastrointestinal Cl⫺
losses are stopped and body stores are repleted (17–19). The
renal mechanisms that lead to a sustained increase in renal H⫹
secretion remain incompletely defined but likely involve stim-
ulation of H⫹ secretion in the collecting duct (20). Although
extracellular fluid volume and K⫹ depletion normally contrib-
ute to sustaining the alkalosis, these events are neither neces-
sary nor sufficient (19,21–23). Loss of H⫹ in the gastric contents
also contributes to the alkalosis, but a similar pattern can be
seen with Cl⫺ loss without accompanying loss of H⫹ (e.g., with
diuretic agents that block Cl⫺ reabsorption in the loop and
early distal tubule). The metabolic alkalosis induced by naso-
gastric drainage or vomiting can be severe. With continued
losses, serum [HCO3⫺] may rise to as high as 80 mmol/L with
a concomitant fall in serum [Cl⫺] (24). In fact, in patients with
serum [HCO3⫺] ⬎45 mmol/L, gastric losses are virtually al-
ways the precipitating cause. A characteristic feature of the
urine electrolytes in the metabolic alkalosis caused by gastric
losses is a [Cl⫺] ⬍10 mmol/L, a finding that can aid in the
diagnosis of surreptitious vomiting. Treatment with isotonic
saline and/or KCl corrects the disorder, and reversal of the
initial cause of the upper gastrointestinal losses prevents its
recurrence (Table 4). If continued losses cannot be prevented,
then pharmacologic inhibition of the gastric H⫹/K⫹-ATPase
will ameliorate this form of metabolic alkalosis (25), but
whether it can prevent the disorder remains to be determined.
Diarrhea
For acid-base and electrolyte abnormalities to occur in diar-
rhea states, the volume of fluid lost must be sufficiently large to
overcome the kidney’s ability to adjust excretion to maintain
acid-base equilibrium. When losses are sufficiently large, the
disorder that develops is determined by the specific electrolyte

Table 3. Acid-base and electrolyte abnormalities associated with gastrointestinal disorders

Extracellular
Gastrointestinal Disorder Acid-Base Disorder Potassium Fluid Volume

Vomiting, nasogastric drainage Metabolic alkalosis Low Low

Diarrhea states
cholera Metabolic acidosis Low Very low
other infectious Metabolic acidosis Low Very low
autoimmune No significant disordera Normala Normala
congenital chloridorrhea Metabolic alkalosis Low Low
Villous adenoma of colon No significant disorder Normal or low Normal or low
Metabolic alkalosis or
metabolic acidosis
Laxative abuse No significant disorderb Low Normal or low
Pancreatic/biliary drainage Metabolic acidosis Normal or high Low
when losses high and
sustained
Ileostomy drainage Metabolic acidosis High Low
Metabolic alkalosis Normal Low
Short bowel Metabolic acidosisc Normal Normal
a
Unless diarrhea is severe, then metabolic acidosis, volume depletion, and hypokalemia.
b
May have minor increase in serum 关HCO3⫺兴.
c
d-Lactic acidosis.
Clin J Am Soc Nephrol 3: 1861–1868, 2008 Acid-Base Disorders in GI Disease 1865

Table 4. Treatment of gastrointestinal disorders that disrupt acid-base and electrolyte homeostasis
Unproven and Potential
Gastrointestinal Disorder Treatment Future Treatments

Vomiting Isotonic saline Proton pump inhibitors

Nasogastric drainage KCl, Reverse underlying cause
Cholera Oral electrolyte solutions, Isotonic saline, Blockade of CFTR Cl⫺ channel,
NaHCO3, KHCO3 Ca2⫹ receptor agonists
Infectious diarrhea Oral electrolyte solutions, Isotonic saline, Blockade of CFTR Cl⫺ channel,
NaHCO3, KHCO3 Ca2⫹ receptor agonists
Congenital chloridorrhea Oral NaCl and KCl supplements Proton pump inhibitors
Increased ileostomy drainage Isotonic saline, NaHCO3 when serum
关HCO3⫺兴 is low
Short bowel syndrome Limit carbohydrate intake

content of the losses (26). Table 2 shows the approximate
changes in stool volume and electrolyte content that occur with
inflammatory and secretory diarrheas. Table 2 focuses on Na⫹,
K⫹, and HCO3⫺, but it should be emphasized that these fluid
losses are typically isotonic and also contain other cations and
anions. Concentration ranges rather than average values are
shown in Table 2, because wide ranges in values have been
found to occur (1). A full description of the electrolyte content
is beyond the scope of this review.
In inflammatory diarrheas (e.g., ulcerative colitis, Crohn dis-
ease), stool volume is typically ⬍3 L/d, and alkali and salt
losses are usually manageable. Adjustments in intake and renal
regulatory mechanisms maintain normal acid-base and volume
equilibrium. With larger losses, any form of diarrhea will lead
to a significant fall in extracellular fluid volume, reducing GFR
and limiting the ability of the kidney to help correct the abnor-
malities. This pattern of events most commonly occurs with
secretory diarrheas, and the typical presentation is hypoten-
sion, acute renal failure, hyperchloremic metabolic acidosis,
and hypokalemia. When diarrhea is severe, lactic acidosis may
supervene as a result of tissue hypoperfusion (27). The patho-
physiology and treatment of specific diarrhea states are dis-
cussed next.
Cholera. The diarrhea in cholera is caused by the bacte-
rium Vibrio cholera. This intestinal pathogen produces a toxin
that increases cAMP levels by permanently activating adenylyl
cyclase in intestinal crypt cells, producing a sustained activa-
tion of the apical membrane CFTR Cl⫺ channel and thereby
leading to excessive Cl⫺ secretion into the ileum and colon
(28,29). The increase in Cl⫺ secretion in turn stimulates the
apical Cl⫺/HCO3⫺ exchanger, increasing stool [HCO3⫺]. The
increase in anion secretion results in increased paracellular Na⫹
and water entry, resulting in high-volume diarrhea that con-
tains a large amount of HCO3⫺, as well as Na⫹, Cl⫺, and K⫹
(Table 2). The clinical presentation is severe volume depletion,
hyperchloremic metabolic acidosis, and hypokalemia. Oral hy-
potonic electrolyte solutions are effective first-line therapy for
this disorder and have been shown to reduce mortality signif-
icantly (Table 4) (1,30,31). Oral intake of 75 to 100 ml/kg body
wt is recommended (1). When oral rehydration fails to keep up
with losses, vigorous intravenous volume repletion with added
potassium and bicarbonate can be life-saving. The CFTR chan-
nel is central to the pathophysiology of this disorder, because
blockade of the channel by a specific inhibitor completely pre-
vents the effect of cholera toxin on rat intestinal fluid secretion
(32). The hope is that a clinically useful inhibitor of the CFTR
channel could eventually become an adjunct to the manage-
ment of cholera (27), but no suitable inhibitor has yet been
developed. A second approach shown to be effective in exper-
imental animals is activation of the calcium-sensing receptor,
which hastens breakdown of cAMP and thereby decreases the
stimulation of secretory channels in intestinal epithelial cells
(33).
Other Bacterial Diarrheas. Enteropathic Escherichia coli
and other bacteria and viruses can cause diarrhea, producing
metabolic acidosis and hypokalemia when severe enough (par-
ticularly in young children and infants). The pathophysiology
of these diarrhea states is less well defined, but both increased
secretion and absorption seem to contribute. Enterotoxin ob-
tained from pathogenic E. coli activates guanylyl cyclase, which
increases cyclic GMP levels, stimulating Cl⫺ secretion in intes-
tinal epithelial cells (34). Experimental studies also suggested
that inflammation downregulates both the intestinal Cl⫺/
HCO3⫺ exchanger and Na⫹/K⫹-ATPase and also increases gut
water permeability nonspecifically (35,36). Replacement of the
fluid and electrolytes that are lost in these infectious diarrheas
with either hypotonic oral solutions or intravenous solutions,
along with appropriate antibiotic therapy, remains the center-
piece of treatment (Table 4) (27).
Autoimmune Diarrhea. The diarrheas that occur with ul-
cerative colitis and Crohn and celiac diseases all are associated
with T cell–mediated gut inflammation. Animal studies have
shown that T cell activation increases gut permeability and
downregulates Na⫹/K⫹-ATPase activity, changes that could
be responsible for the increase in stool volume seen in these
disorders (36). Reflecting that stool volume is only moderately
increased, acid-base and/or electrolyte disorders rarely occur
in these patients. In one study of patients with Crohn disease
with varying intestinal involvement, serum [HCO3⫺] and [K⫹]
both were in the normal range in all patients (37). Although the
1866 Clinical Journal of the American Society of Nephrology
authors concluded that mild to moderate metabolic alkalosis is
present in patients with more extensive involvement, review of
their data indicates that mean arterial [HCO3⫺], 26 mmol/L,
was within the normal range even in these patients and was
only 2 mmol/L higher than in patients with lesser involvement.
Congenital Chloridorrhea. In this disorder, high-volume
watery diarrhea begins at birth (38,39). The disorder is caused
by a loss of function mutation in the downregulated in ade-
noma (DRA or CLD) gene, leading to an absence of any func-
tioning gut Cl⫺/HCO3⫺ exchange (40,41). As a result of the
absence of Cl⫺ absorption and HCO3⫺ secretion, the diarrhea
fluid contains primarily Na⫹, Cl⫺, and K⫹ (Table 2). As dis-
cussed previously, gastrointestinal losses with [Cl⫺] that essen-
tially equal or exceed [Na⫹] ⫹ [K⫹] lead to disproportionate
Cl⫺ depletion, producing metabolic alkalosis through effects on
renal acid and K⫹ excretion. Concomitant NH4⫹ losses in the
diarrhea fluid may also contribute to the development of met-
abolic alkalosis (2), but the disorder is sustained unless the Cl⫺
losses can be replaced (Table 4). Management of the continued
fluid and electrolyte losses is obviously a difficult problem, so
patients with this disease usually have sustained metabolic
alkalosis and are chronically volume depleted. In a single case
report, inhibition of the gastric H⫹/K⫹-ATPase, using omepra-
zole, reduced stool volume dramatically in a patient with con-
genital chloridorrhea, providing a promising new tool for man-
aging this disorder (42).
Villous Adenoma. Little is known about the ion transport
pathways that are stimulated or inhibited by these rare tumors,
but they produce a copious secretion with Na⫹ and Cl⫺ con-
centrations approaching those of serum (Table 2) (43). The
usual rate of fluid secretion by these tumors is ⬍3 L/d; there-
fore, it is not surprising that they only occasionally are associ-
ated with significant acid-base disorders. Both metabolic acido-
sis and metabolic alkalosis have been reported to occur (43).
Laxative Abuse
Long-term laxative ingestion with the intent to increase stool
volume causes increased and unregulated losses of K⫹ (44,45).
If this excess loss is not counterbalanced by a concomitant
increase in dietary K⫹ intake, then body K⫹ stores will become
depleted, a change that causes hypokalemia and some H⫹ shift
into cells, raising extracellular fluid [HCO3⫺] (18). The increase
in [HCO3⫺] may be sustained by the effect of K⫹ depletion to
increase renal NH4⫹ production and excretion. The major clin-
ical feature of laxative abuse is hypokalemia; clinically signifi-
cant metabolic alkalosis, if present, is usually mild in the ab-
sence of concomitant bulimia (44,45). If laxative abuse induces
excessive diarrheal losses, then metabolic acidosis can of course
occur, as with any severe diarrhea (45).
Biliary and Pancreatic Drainage
Pancreatic and biliary drainage most often occurs after sur-
gery, and usually the volume is low, so, despite loss of a
HCO3⫺-rich fluid, significant metabolic acidosis does not occur.
In the rare setting in which drainage volume exceeds 1 to 2 L/d,
however, metabolic acidosis will develop and be maintained by
concomitant volume depletion (2).
Clin J Am Soc Nephrol 3: 1861–1868, 2008
Ileostomy Drainage
Patients with well-functioning ileostomies have daily fluid
losses of 0.5 to 1.0 L and adapt to these obligatory losses
through subtle changes in salt and water intake, as well as
changes in urine volume and electrolyte and acid excretion
(46 – 48). When ileostomy drainage abruptly increases, the re-
sultant salt and water losses can easily produce symptomatic
volume depletion. In this setting, either metabolic acidosis or
metabolic alkalosis may occur (46,48 –51). The development of
metabolic acidosis is not surprising because ileostomy fluid
[HCO3⫺] is usually higher than in plasma (Table 2), causing
disproportionate alkali loss. Metabolic acidosis is almost al-
ways accompanied by hyperkalemia, reflecting that K⫹ is not
secreted in the ileum and therefore the losses contain little K⫹
(Table 2). In addition, renal K⫹ excretion is impaired by the
associated volume depletion.
Metabolic alkalosis is a more surprising outcome of increased
ileostomy drainage and seems to occur much less commonly. In
a few cases, this disorder has been severe, with serum [HCO3⫺]
⬎40 mmol/L (48,51). In these cases, the electrolyte content of
the losses has been characterized by Cl⫺ concentrations that are
almost equal to [Na⫹], and both are higher than are normally
seen in ileostomy fluid. Because disproportionate Cl⫺ loss is the
most common cause of metabolic alkalosis, this characteristic
likely accounts for the disorder. The cause of the high [Cl⫺] in
the ileal drainage remains unclear but seems most likely due to
impaired ileal Cl⫺ absorption (48). The alkalosis is sustained by
the associated volume depletion, which impairs any changes in
renal acid excretion that might ameliorate the disorder. In
contrast to the patients with metabolic acidosis, hyperkalemia
is not a feature of the cases with metabolic alkalosis even
though renal function may be markedly impaired. The normal
or slightly low serum [K⫹] likely reflects K⫹ losses in the urine
in response to metabolic alkalosis as well as to transcellular K⫹
shifts.
The fist line of treatment of either disorder is vigorous reple-
tion of extracellular fluid volume with isotonic saline (Table 4).
When acidosis is severe, treatment should also include replace-
ment of alkali stores with HCO3⫺. If K⫹ depletion is present,
then appropriate potassium replacement should be undertaken
as well.
Short Bowel Syndrome
In patients who have undergone jejunoileal bypass surgery
for weight reduction or who have a shortened small intestine
connected to the colon for other reasons, undigested glucose
delivery to the colon is increased, providing a substrate for
bacteria that metabolize this sugar to lactic acid (1,52). This
bacterial metabolic process produces d- and l-lactic acid, both
of which are readily absorbed into the circulation. Humans
have the enzyme machinery to metabolize l-lactic acid rapidly,
but d-lactic acid is only slowly metabolized. Absorption of
sufficient d-lactic acid results in a characteristic syndrome of
mental confusion and metabolic acidosis with an increased
anion gap. Because only l-lactate is measured in the usual
laboratory test for lactic acid, no elevation in lactate will be
detected despite the increased anion gap acidosis. With mass
Clin J Am Soc Nephrol 3: 1861–1868, 2008
spectrometry or chromatography methods that detect both d-
and l-lactic acid, the elevated d-lactate levels will be evident
(2). The symptoms and acidosis clear spontaneously with time
as the d-lactic acid is gradually removed from the circulation by
metabolism, but the syndrome will recur after eating another
high-carbohydrate meal. Once recognized, the disorder is easily
treated by limiting the carbohydrate content of the diet (Table
4). Because of many problems with jejunoileal bypass, of which
this disorder is only one, the operation is no longer performed
for weight loss.
Conclusions
Disruption of normal bowel function as a result of infection,
inflammation, complications of surgical procedures, or hered-
itary and acquired transport abnormalities uncovers its critical
importance for acid-base, electrolyte, and fluid volume ho-
meostasis. The nature of the acid-base disorder that develops is
directly dependent on the electrolyte composition of the fluid
that is lost as well as by the magnitude of the losses. Regardless
of whether metabolic acidosis or alkalosis develops, the disor-
der is sustained only when the losses are large enough to
impair renal homeostatic mechanisms and maintenance of fluid
and electrolyte balance through increased oral intake. The
mainstay of the acute treatment for all sustained disorders of
acid-base equilibrium that are induced by abnormal gastroin-
testinal losses is vigorous extracellular fluid volume repletion,
with appropriate adjustments in the electrolyte composition of
the replacement fluids to reflect specific losses. The long-term
approach is to correct the underlying gastrointestinal disorder
if possible. Our hope is that advances in our understanding of
ion transport along the gut will provide new avenues for the
treatment of disorders that disrupt its function. Gastrointestinal
disorders provide an experiment in nature that has shed light
on the normal transport properties of the gut as well as uncov-
ered its importance in acid-base and electrolyte homeostasis.
Disclosures
None.
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