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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 . Metabolic or 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 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

he gastrointestinal tract is a slumbering giant with re- the stomach and the exocrine pancreas, of fluid and ϩ gard to acid-base homeostasis. Large amounts of H occurs primarily in a subset of cells in the epithelial Ϫ and HCO traverse the specialized epithelia of the crypts with unique ion transport properties. Throughout the T 3 various components of the gut every day, but under normal gut, fluid and transport (both absorption and secre- ϩ ϩ conditions, only a small amount of alkali (approximately 30 to tion) is driven primarily by Na /K -ATPase transport activity 40 mmol) is lost in the stool (1,2). In contrast to the , acid across the basolateral membrane of epithelial cells. Several key and alkali transport in the gut is adjusted for efficient absorp- apical membrane electrolyte transporters participate, including Ϫ Ϫ ϩ ϩ tion of dietary constituents rather than for acid-base homeosta- Cl /HCO3 and Na /H ion exchangers and the cystic fibro- Ϫ sis. The small amount of alkali lost as a byproduct of these sis transmembrane conductance regulator (CFTR) Cl channel, transport events is easily regenerated by renal net acid excre- all of which are present in many segments of the gut, and ϩ ϩ tion, which is regulated by the kidney to maintain body alkali H /K -ATPases, which are confined to the stomach and colon stores. Disruption of normal gut function, however, uncovers (Figure 1). Disruption of function or abnormal stimulation of its power to overwhelm acid-base homeostasis. Acid-base dis- these ion transporters underlies a variety of gastrointestinal orders can vary from severe acidosis to severe alkalosis, de- disorders that are associated with acid-base and electrolyte pending on the site along the gastrointestinal tract affected and disorders. A full description of the ion transport processes that the nature of the losses that ensue. These disruptions in acid- participate in normal gut function is beyond the scope of this base equilibrium are associated with disorders of review, and reader is referred to other sources for more detail (1). balance, often leading to either hypo- or . Major and losses also occur, sometimes causing life- Mouth and Throat threatening volume depletion and almost always contributing Secretion of salivary fluid occurs via the parotid and salivary to the acid-base abnormalities. glands, ultimately producing a hypotonic alkaline solution when stimulated by activation of muscarinic receptors. Acinar Normal Physiology of Gut Fluid and cells secrete fluid that is similar in composition to serum, and ϩ Ϫ Electrolyte Transport then the secreted fluid is modified by Na and Cl absorption Ϫ During the course of each day, secretion as well as absorption and HCO3 secretion. The apical membrane transport proteins of fluid and electrolytes occurs along the gastrointestinal tract. that alter the composition under conditions of stimulation re- Ϫ Normally 7 to8Loffluid is secreted each day, far exceeding main to be defined, but HCO3 secretion may occur via an Ϫ dietary consumption, and almost all of these , as well anion channel, possibly the CFTR Cl channel (3). When stim- as any ingested fluid, are absorbed by the end of the colon (1). ulated, up to 1 L/d fluid is produced (Table 1). This alkaline The gastrointestinal tract is divided into sequential segments, secretion likely serves to protect the mucosa of the mouth, Ϫ each with a distinct group of ion transporters and channels that throat, and esophagus and has little impact on serum [HCO3 ]. interact with one another to determine the electrolyte content It is more than counterbalanced by secretion in the and volume of the fluid in the gut lumen. With the exception of 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: [email protected] 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 ϩ ϩ 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 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

ϩ Salivary glands 0.20 to 1.00 Alkaline when stimulated, ͓K ͔ 20 to 30 mmol/L ϩ Stomach 0.50 to 2.00 Highly Acid when stimulated, ͓K ͔ approximately 10 mmol/L Biliary tree 1.00 Alkaline when stimulated ϩ Pancreas 1.00 to 2.00 Highly alkaline when stimulated, ͓K ͔ 5 to 10 mmol/L ϩ Jejunum/ileum 1.00 to 2.00 Alkaline, ͓K ͔ 5 to 10 mmol/L ϩ Ϫ Colon Ͻ0.15 Low pH, ͓Na ͔ and ͓Cl ͔Ͻ30 mmol/L, ϩ ͓K ͔ 55 to 75 mmol/L

aFluid volume delivered beyond indicated portion of the gastrointestinal tract.

ϩ proteins in the parietal cells that line the stomach (Figure 1) falls to as low as 1.0 (H ϭ 100 mmol/L) and volume ϩ ϩ (1). Of these, the gastric H /K -ATPase is essential for acid increases to as high as 7 ml/min. The surge in acid secretion Ϫ secretion; pharmacologic blockade of this transporter effec- transiently increases serum [HCO3 ] by 1 to 2 mmol/L, a tively blocks acidification of the gastric contents. Hydrogen change referred to as the alkaline tide, once used as a test of ϩ ion secretion by this transporter is facilitated by K recycling acid secretion. The increase is transient, because the process across the apical membrane via a selective cation channel. of acid secretion itself sets in motion countervailing alkali Ϫ Chloride is secreted by an as-yet-unidentified Cl channel, secretion by the exocrine pancreas into the duodenum. Gas- yielding hydrochloric acid under conditions of stimulation. tric secretion is usually 1 to 2 L/d (Table 1). Under basal conditions, the secreted fluid is primarily NaCl. The pH and volume of gastric secretions is regulated primar- Duodenum ily by gastrin, so maximal volume and acid secretion occurs Regardless of the pH and tonicity of the gut contents that only after a meal. At such times, the pH of the gastric fluid enter the duodenum, this segment of the gut restores isotonicity Clin J Am Soc Nephrol 3: 1861–1868, 2008 Acid-Base Disorders in GI Disease 1863

Ϫ ϩ Ϫ through water and solute absorption, and the pH rises to 7.0. and Cl from the gut lumen and secrete H and HCO3 into it. Ϫ Acid is neutralized by HCO3 addition in pancreatic and bili- The latter two combine, forming H2CO3, which dehydrates Ϫ Ϫ ary secretions as well as by direct secretion in Brunner’s glands to form CO2 in the intestinal lumen. The Cl /HCO3 ex- along the duodenum (1). The specific ion transporters involved changer in the small intestine is the “downregulated in ade- Ϫ in duodenal HCO3 secretion remain to be defined. noma” (DRA) gene product, also named CLD (for chloride Ϫ Ϫ diarrhea) (9). By the end of the ileum, Cl /HCO3 exchange Pancreas predominates, resulting in an alkaline solution (Table 1). Chlo- Entry of the acid gastric secretions into the duodenum signals ride secretion occurs in specialized cells in the intestinal crypts Ϫ Ϫ the pancreas to secrete its highly alkaline solution ([HCO3 ] via a series of apical Cl ion channels, one of which is the CFTR Ϫ approximately 70 to 120 mmol/L) into the gut. The anion channel, recycling Cl into the lumen (Figure 1). In contrast to transporter primarily responsible for this process is an apical the colon, the small intestinal secretory cells do not have an Ϫ Ϫ ϩ membrane Cl /HCO3 exchanger (Figure 1). The activity of apical K channel. Potassium movement across the membrane Ϫ this ion exchanger is regulated by the CFTR Cl channel, which is accounted for by passive diffusion and , with Ϫ recycles Cl across the apical membrane (1,4). Under maximal absorption predominating (10). These absorptive and secretory Ϫ stimulation, some secreted HCO3 seems to enter the lumen processes leave the fluid that enters the colon slightly hypo- Ϫ Ϫ Ϫ directly via the CFTR channel as well as by Cl /HCO3 ex- tonic with a [HCO3 ] of approximately 30 mmol/L and with a Ϫ ϩ change (5). Pancreatic HCO3 secretion is stimulated by the [K ] of 5 to 10 mmol/L (Table 1). secretin, which is secreted when acidic fluid (pH Ͻ Ϫ 4.0) enters the duodenum. Thus, HCO3 secretion occurs only as a counterbalance to acid secretion in the stomach and Colon only when this acidic fluid is passed into the duodenum. At In the colon, the fluid volume of the stool is normally re- Ͻ ϩ Ϫ other times, the secretion is primarily isotonic NaCl. Pancreatic duced to 50 ml/d, and the concentrations of Na and Cl are Ͻ secretion amounts to 1 to 2 L/d (Table 1). reduced to 30 mmol/L (Table 1). absorption is accomplished by the same linked transporters described for ϩ Biliary Secretion the small intestine, but, in addition, Na is absorbed via an ϩ Although the pancreas is by far the major source of the apical membrane Na channel regulated by (Fig- Ϫ Ϫ Ϫ HCO3 added to the duodenal contents, stimulation of biliary ure 1) (11,12). The HCO3 secreted in the colon by the Cl / Ϫ secretion by the secretin and cholecystokinin also HCO3 exchanger is consumed (along with much of the Ϫ Ϫ produces an alkaline solution that contains HCO3 in a con- HCO3 delivered from the ileum) in buffering organic acids centration higher than in plasma (approximately 40 to 60 produced by colonic bacteria. Some of the organic anions pro- Ϫ mmol/L) (6). This secretion is typically approximately 1 L/d. duced by this reaction are absorbed via a linked HCO3 ex- change transporter (1) (Figure 1), but the remainder are ex- Jejunum and Ileum creted and make up the 30 to 40 mmol/d of potential alkali lost Ϫ This segment of the bowel both absorbs and secretes fluid, in the stool despite the absence of measurable HCO3 in the but absorption normally predominates, reducing the total gut stool (Table 2). The colonic absorptive epithelial cells also have ϩ ϩ ϩ fluid content to approximately 1 L/d by the time it enters the a unique apical membrane H /K -ATPase that absorbs K ϩ colon (Table 1). Absorption is driven by sodium and chloride and secretes H into the gut lumen (13,14), but the role of this ϩ uptake (driving water uptake) and occurs via two linked trans- transporter is unclear because significant net K secretion oc- ϩ ϩ Ϫ Ϫ ϩ porters, the Na /H exchanger and the Cl /HCO3 ex- curs in the colon, raising [K ] in stool water to as high as 75 ϩ changer (Figure 1) (7,8). These two transporters take up Na mmol/L. Secretory cells in the colon contain the same apical

Table 2. Ranges of volume and electrolyte composition in vomitus, diarrhea fluid, and ileostomy drainagea ͓ ϩ͔ ͓ ϩ͔ ͓ Ϫ͔ ͓ Ϫ͔ State Volume (L/d) Na (mmol/L) K (mmol/L) Cl (mmol/L) HCO3 (mmol/L) Normal stool Ͻ0.15 20 to 30 55 to 75 15 to 25 0b Vomitus/NG drainage 0.00 to 3.00 20 to 100 10 to 15 120 to 160 0 Inflammatory diarrhea 1.00 to 3.00 50 to 100 15 to 20 50 to 100 10 Secretory diarrhea 1.00 to 20.00 40 to 140 15 to 40 25 to 105 20 to 75 Congenital chloridorrhea 1.00 to 5.00 30 to 80 15 to 60 120 to 150 Ͻ5 Villous adenoma 1.00 to 3.00 70 to 150 15 to 80 50 to 150 Unknownc Ileostomy drainage new 1.00 to 1.50 115 to 140 5 to 15 95 to 125 30 adapted 0.50 to 1.00 40 to 90 5 20 15 to 30

aData primarily from reference (1). bApproximately 30 mmol/d organic anions are lost in the stool, causing a deficit in potential alkali for the body (see text). cNo data available. 1864 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 1861–1868, 2008

Ϫ Cl channel as in the small intestine, but, in addition, they losses are stopped and body stores are repleted (17–19). The ϩ Ϫ ϩ contain several apical K channels. In colon secretory cells, Cl renal mechanisms that lead to a sustained increase in renal H ϩ channel function is partially dependent on K secretion (15). secretion remain incompletely defined but likely involve stim- ϩ Potassium secretion via these apical channels is stimulated by ulation of H secretion in the collecting duct (20). Although ϩ aldosterone, and this secretion is responsible for the increase in volume and K depletion normally contrib- ϩ stool [K ] (16). Because of the small volume of stool water ute to sustaining the alkalosis, these events are neither neces- ϩ ϩ normally excreted, net daily K loss in the stool is only 10 to 15 sary nor sufficient (19,21–23). Loss of H in the gastric contents mmol/d, but the quantity lost can easily increase if stool water also contributes to the alkalosis, but a similar pattern can be Ϫ ϩ volume increases. seen with Cl loss without accompanying loss of H (e.g., with Ϫ agents that block Cl reabsorption in the loop and Acid-Base and Electrolyte Disorders early distal tubule). The induced by naso- and Nasogastric Drainage gastric drainage or vomiting can be severe. With continued Ϫ Ϫ Gastric fluid typically contains 120 to 160 mmol/L Cl , bal- losses, serum [HCO3 ] may rise to as high as 80 mmol/L with ϩ ϩ ϩ Ϫ anced by K ,Na , and H (Tables 2 and 3). Under basal a concomitant fall in serum [Cl ] (24). In fact, in patients with ϩ Ϫ Ͼ conditions, the cation is primarily Na , and, when stimulated, serum [HCO3 ] 45 mmol/L, gastric losses are virtually al- ϩ the cation is primarily H , the latter rising to as high as 100 ways the precipitating cause. A characteristic feature of the mmol/L (1). Potassium concentration remains at approxi- electrolytes in the metabolic alkalosis caused by gastric Ϫ Ϫ mately 10 mmol/L in both settings. Loss of this Cl -rich solu- losses is a [Cl ] Ͻ10 mmol/L, a finding that can aid in the tion through either vomiting or nasogastric drainage causes diagnosis of surreptitious vomiting. Treatment with isotonic Ϫ ϩ ϩ major Cl losses, with variable H loss as well. Any H loss saline and/or KCl corrects the disorder, and reversal of the Ϫ abruptly increases serum [HCO3 ] while simultaneously abro- initial cause of the upper gastrointestinal losses prevents its Ϫ gating the signal to the pancreas to secrete HCO3 into the recurrence (Table 4). If continued losses cannot be prevented, ϩ ϩ duodenum. The result is metabolic alkalosis, initiated by the then pharmacologic inhibition of the gastric H /K -ATPase ϩ Ϫ H loss but sustained by disproportionate loss of Cl , a chain will ameliorate this form of metabolic alkalosis (25), but Ϫ of events that leads to greater depletion of body Cl stores than whether it can prevent the disorder remains to be determined. of other electrolytes (17). The abrupt increase in serum Ϫ Ϫ [HCO3 ] leads to some HCO3 loss in the urine initially, but Diarrhea this anion rapidly disappears, and urine pH falls despite a For acid-base and electrolyte abnormalities to occur in diar- Ϫ ϩ sustained increase in serum [HCO3 ]. Initial loss of Na is also rhea states, the volume of fluid lost must be sufficiently large to ϩ rapidly followed by a rise in K excretion, leading to secondary overcome the kidney’s ability to adjust excretion to maintain ϩ K depletion and . In the new steady state, alka- acid-base equilibrium. When losses are sufficiently large, the Ϫ losis and hypokalemia are sustained until gastrointestinal Cl 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 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 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

aUnless diarrhea is severe, then metabolic acidosis, volume depletion, and hypokalemia. b ͓ Ϫ͔ May have minor increase in serum HCO3 . cd-. 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 Ϫ Cholera Oral electrolyte solutions, Isotonic saline, Blockade of CFTR Cl channel, 2ϩ NaHCO3,KHCO3 Ca receptor agonists Ϫ Infectious diarrhea Oral electrolyte solutions, Isotonic saline, Blockade of CFTR Cl channel, 2ϩ NaHCO3,KHCO3 Ca receptor agonists Congenital chloridorrhea Oral NaCl and KCl supplements Proton pump inhibitors

Increased ileostomy drainage Isotonic saline, NaHCO3 when serum ͓ Ϫ͔ HCO3 is low Short bowel syndrome Limit carbohydrate intake

content of the losses (26). Table 2 shows the approximate with losses, vigorous intravenous volume repletion with added changes in stool volume and electrolyte content that occur with potassium and can be life-saving. The CFTR chan- ϩ inflammatory and secretory diarrheas. Table 2 focuses on Na , nel is central to the pathophysiology of this disorder, because ϩ Ϫ K , and HCO3 , but it should be emphasized that these fluid blockade of the channel by a specific inhibitor completely pre- losses are typically isotonic and also contain other cations and vents the effect of cholera toxin on rat intestinal fluid secretion anions. Concentration ranges rather than average values are (32). The hope is that a clinically useful inhibitor of the CFTR shown in Table 2, because wide ranges in values have been channel could eventually become an adjunct to the manage- found to occur (1). A full description of the electrolyte content ment of cholera (27), but no suitable inhibitor has yet been is beyond the scope of this review. developed. A second approach shown to be effective in exper- In inflammatory diarrheas (e.g., ulcerative colitis, Crohn dis- imental animals is activation of the -sensing receptor, ease), stool volume is typically Ͻ3 L/d, and alkali and salt which hastens breakdown of cAMP and thereby decreases the losses are usually manageable. Adjustments in intake and renal stimulation of secretory channels in intestinal epithelial cells regulatory mechanisms maintain normal acid-base and volume (33). equilibrium. With larger losses, any form of diarrhea will lead Other Bacterial Diarrheas. Enteropathic Escherichia coli to a significant fall in extracellular fluid volume, reducing GFR and other bacteria and viruses can cause diarrhea, producing and limiting the ability of the kidney to help correct the abnor- metabolic acidosis and hypokalemia when severe enough (par- malities. This pattern of events most commonly occurs with ticularly in young children and infants). The pathophysiology secretory diarrheas, and the typical presentation is hypoten- of these diarrhea states is less well defined, but both increased sion, acute renal failure, hyperchloremic metabolic acidosis, secretion and absorption seem to contribute. Enterotoxin ob- and hypokalemia. When diarrhea is severe, lactic acidosis may tained from pathogenic E. coli activates guanylyl cyclase, which Ϫ supervene as a result of hypoperfusion (27). The patho- increases cyclic GMP levels, stimulating Cl secretion in intes- physiology and treatment of specific diarrhea states are dis- tinal epithelial cells (34). Experimental studies also suggested Ϫ cussed next. that downregulates both the intestinal Cl / Ϫ ϩ ϩ Cholera. The diarrhea in cholera is caused by the bacte- HCO3 exchanger and Na /K -ATPase and also increases gut rium Vibrio cholera. This intestinal pathogen produces a toxin water permeability nonspecifically (35,36). Replacement of the that increases cAMP levels by permanently activating adenylyl fluid and electrolytes that are lost in these infectious diarrheas cyclase in intestinal crypt cells, producing a sustained activa- with either hypotonic oral solutions or intravenous solutions, Ϫ tion of the apical membrane CFTR Cl channel and thereby along with appropriate antibiotic therapy, remains the center- Ϫ leading to excessive Cl secretion into the ileum and colon piece of treatment (Table 4) (27). Ϫ (28,29). The increase in Cl secretion in turn stimulates the Autoimmune Diarrhea. The diarrheas that occur with ul- Ϫ Ϫ Ϫ apical Cl /HCO3 exchanger, increasing stool [HCO3 ]. The cerative colitis and Crohn and celiac diseases all are associated ϩ increase in anion secretion results in increased paracellular Na with T –mediated gut inflammation. Animal studies have and water entry, resulting in high-volume diarrhea that con- shown that T cell activation increases gut permeability and Ϫ ϩ Ϫ ϩ ϩ ϩ tains a large amount of HCO3 , as well as Na ,Cl , and K downregulates Na /K -ATPase activity, changes that could (Table 2). The clinical presentation is severe volume depletion, be responsible for the increase in stool volume seen in these hyperchloremic metabolic acidosis, and hypokalemia. Oral hy- disorders (36). Reflecting that stool volume is only moderately potonic electrolyte solutions are effective first-line therapy for increased, acid-base and/or electrolyte disorders rarely occur this disorder and have been shown to reduce mortality signif- in these patients. In one study of patients with Crohn disease Ϫ ϩ icantly (Table 4) (1,30,31). Oral intake of 75 to 100 ml/kg body with varying intestinal involvement, serum [HCO3 ] and [K ] wt is recommended (1). When oral rehydration fails to keep up both were in the normal range in all patients (37). Although the 1866 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 1861–1868, 2008 authors concluded that mild to moderate metabolic alkalosis is Ileostomy Drainage present in patients with more extensive involvement, review of Patients with well-functioning ileostomies have daily fluid Ϫ their data indicates that mean arterial [HCO3 ], 26 mmol/L, losses of 0.5 to 1.0 L and adapt to these obligatory losses was within the normal range even in these patients and was through subtle changes in salt and water intake, as well as only 2 mmol/L higher than in patients with lesser involvement. changes in urine volume and electrolyte and acid excretion Congenital Chloridorrhea. In this disorder, high-volume (46–48). When ileostomy drainage abruptly increases, the re- watery diarrhea begins at birth (38,39). The disorder is caused sultant salt and water losses can easily produce symptomatic by a loss of function mutation in the downregulated in ade- volume depletion. In this setting, either metabolic acidosis or noma (DRA or CLD) gene, leading to an absence of any func- metabolic alkalosis may occur (46,48–51). The development of Ϫ Ϫ tioning gut Cl /HCO3 exchange (40,41). As a result of the metabolic acidosis is not surprising because ileostomy fluid Ϫ Ϫ Ϫ absence of Cl absorption and HCO3 secretion, the diarrhea [HCO3 ] is usually higher than in plasma (Table 2), causing ϩ Ϫ ϩ fluid contains primarily Na ,Cl , and K (Table 2). As dis- disproportionate alkali loss. Metabolic acidosis is almost al- Ϫ ϩ cussed previously, gastrointestinal losses with [Cl ] that essen- ways accompanied by hyperkalemia, reflecting that K is not ϩ ϩ ϩ tially equal or exceed [Na ] ϩ [K ] lead to disproportionate secreted in the ileum and therefore the losses contain little K Ϫ ϩ Cl depletion, producing metabolic alkalosis through effects on (Table 2). In addition, renal K excretion is impaired by the ϩ ϩ renal acid and K excretion. Concomitant NH4 losses in the associated volume depletion. diarrhea fluid may also contribute to the development of met- Metabolic alkalosis is a more surprising outcome of increased Ϫ abolic alkalosis (2), but the disorder is sustained unless the Cl ileostomy drainage and seems to occur much less commonly. In Ϫ losses can be replaced (Table 4). Management of the continued a few cases, this disorder has been severe, with serum [HCO3 ] fluid and electrolyte losses is obviously a difficult problem, so Ͼ40 mmol/L (48,51). In these cases, the electrolyte content of Ϫ patients with this disease usually have sustained metabolic the losses has been characterized by Cl concentrations that are ϩ alkalosis and are chronically volume depleted. In a single case almost equal to [Na ], and both are higher than are normally ϩ ϩ Ϫ report, inhibition of the gastric H /K -ATPase, using omepra- seen in ileostomy fluid. Because disproportionate Cl loss is the zole, reduced stool volume dramatically in a patient with con- most common cause of metabolic alkalosis, this characteristic Ϫ genital chloridorrhea, providing a promising new tool for man- likely accounts for the disorder. The cause of the high [Cl ]in aging this disorder (42). the ileal drainage remains unclear but seems most likely due to Ϫ Villous Adenoma. Little is known about the ion transport impaired ileal Cl absorption (48). The alkalosis is sustained by pathways that are stimulated or inhibited by these rare tumors, the associated volume depletion, which impairs any changes in ϩ Ϫ but they produce a copious secretion with Na and Cl con- renal acid excretion that might ameliorate the disorder. In centrations approaching those of serum (Table 2) (43). The contrast to the patients with metabolic acidosis, hyperkalemia usual rate of fluid secretion by these tumors is Ͻ3 L/d; there- is not a feature of the cases with metabolic alkalosis even fore, it is not surprising that they only occasionally are associ- though renal function may be markedly impaired. The normal ϩ ϩ ated with significant acid-base disorders. Both metabolic acido- or slightly low serum [K ] likely reflects K losses in the urine ϩ sis and metabolic alkalosis have been reported to occur (43). in response to metabolic alkalosis as well as to transcellular K shifts. Laxative Abuse The fist line of treatment of either disorder is vigorous reple- Long-term laxative ingestion with the intent to increase stool tion of extracellular fluid volume with isotonic saline (Table 4). ϩ volume causes increased and unregulated losses of K (44,45). When acidosis is severe, treatment should also include replace- Ϫ ϩ If this excess loss is not counterbalanced by a concomitant ment of alkali stores with HCO3 .IfK depletion is present, ϩ ϩ increase in dietary K intake, then body K stores will become then appropriate potassium replacement should be undertaken ϩ depleted, a change that causes hypokalemia and some H shift as well. Ϫ into cells, raising extracellular fluid [HCO3 ] (18). The increase Ϫ ϩ in [HCO3 ] may be sustained by the effect of K depletion to Short Bowel Syndrome ϩ increase renal NH4 production and excretion. The major clin- In patients who have undergone jejunoileal bypass surgery ical feature of laxative abuse is hypokalemia; clinically signifi- for weight reduction or who have a shortened small intestine cant metabolic alkalosis, if present, is usually mild in the ab- connected to the colon for other reasons, undigested glucose sence of concomitant bulimia (44,45). If laxative abuse induces delivery to the colon is increased, providing a substrate for excessive diarrheal losses, then metabolic acidosis can of course bacteria that metabolize this sugar to (1,52). This occur, as with any severe diarrhea (45). bacterial metabolic process produces d- and l-lactic acid, both of which are readily absorbed into the circulation. Humans Biliary and Pancreatic Drainage have the enzyme machinery to metabolize l-lactic acid rapidly, Pancreatic and biliary drainage most often occurs after sur- but d-lactic acid is only slowly metabolized. Absorption of gery, and usually the volume is low, so, despite loss of a sufficient d-lactic acid results in a characteristic syndrome of Ϫ HCO3 -rich fluid, significant metabolic acidosis does not occur. mental confusion and metabolic acidosis with an increased In the rare setting in which drainage volume exceeds 1 to 2 L/d, . Because only l-lactate is measured in the usual however, metabolic acidosis will develop and be maintained by laboratory test for lactic acid, no elevation in lactate will be concomitant volume depletion (2). detected despite the increased anion gap acidosis. With mass Clin J Am Soc Nephrol 3: 1861–1868, 2008 Acid-Base Disorders in GI Disease 1867 spectrometry or chromatography methods that detect both d- potential and bicarbonate secretion in isolated interlobular and l-lactic acid, the elevated d-lactate levels will be evident ducts from guinea-pig pancreas. J Gen Physiol 120: 617–628, (2). The symptoms and acidosis clear spontaneously with time 2002 as the d-lactic acid is gradually removed from the circulation by 6. Spirli C, Granato A, Zsembery K, Anglani F, Okolicsanyi L, , but the syndrome will recur after eating another LaRusso NF, Crepaldi G, Strazzabosco M: Functional po- ϩ ϩ Ϫ Ϫ high-carbohydrate meal. Once recognized, the disorder is easily larity of Na /H and Cl /HCO3 exchangers in a rat cholangiocyte cell line. Am J Physiol 275: G1236–G1245, treated by limiting the carbohydrate content of the diet (Table 1998 4). Because of many problems with jejunoileal bypass, of which 7. Turnberg LA, Bieberdorf FA, Morawski SG, Fordtran JS: this disorder is only one, the operation is no longer performed Interrelationships of chloride, bicarbonate, sodium, and for weight loss. hydrogen transport in the human ileum. J Clin Invest 49: 557–567, 1970 Conclusions 8. 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