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Malabsorption Syndromes Department of pediatrics.

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1 Malabsorption Syndromes Department of pediatrics

2 Background Malabsorption syndromes encompass a number of different clinical entities that result in chronic diarrhea, abdominal distention, and failure to thrive. Clinical malabsorption can be broken down into several distinct conditions, both congenital and acquired, that affect one or more of the different steps in the intestinal hydrolysis and subsequent transport of nutrients.

3 Pathophysiology Carbohydrate, fat, or protein malabsorption is caused by a disorder in the intestinal processes of digestion, transport, or both of these nutrients across the intestinal mucosa into the systemic circulation. Either a congenital abnormality in the digestive or absorptive processes or, more commonly, a secondarily acquired disorder of such processes may result in malabsorption.

4 Carbohydrates Of the carbohydrates most commonly present in the diet (starches, sucrose, lactose), only starches require preliminary luminal digestion by salivary and, more importantly, pancreatic amylases. However, note that the development of pancreatic amylase is slow and is not complete until the second semester of life. The final products of amylase digestion include maltose, maltotriose, and higher residues of glucose polymers. The final hydrolysis of disaccharides and oligosaccharides occurs at the brush border of the enterocytes, where sucrase-isomaltase breaks down maltose, isomaltose (to glucose), and sucrose (to glucose and fructose); glucoamylase releases glucose from glucose polymers; and lactase splits lactose into glucose and galactose. Subsequent entry of the final monosaccharides (glucose, galactose, fructose) into the enterocytes through the brush border occurs via carrier molecules. Glucose and galactose share the same carrier, named SGLT-1, which transports 1 molecule of the monosaccharide and 1 sodium (Na) molecule in a secondarily active transport, energized by sodium- and potassium-activated adenosine triphosphatase (NaK ATPase. On the other hand, fructose uses a carrier that allows its entry only down a concentration gradient (facilitated diffusion).

5 Disorders of these processes can be congenital (cystic fibrosis and Shwachman-Diamond syndrome, which cause amylase deficiency; the extremely rare congenital lactase deficiency; glucose-galactose malabsorption; sucrase-isomaltase deficiency; adult-type hypolactasia) or acquired (the most common being lactose intolerance, typically secondary to a damage of the mucosa, such as a viral enteritis or conditions that cause mucosal atrophy, such as celiac disease).

6 Protein Proteins are first digested in the stomach, where pepsinogens, which are activated to pepsins by a pH of less than 4, hydrolyze them in large molecular weight peptides. Upon entering the duodenum, the pancreatic proteases (activated by trypsin, which has a proenzyme trypsinogen that is activated by the brush border–bound enterokinase) further split them into low molecular weight peptides and free amino acids.

7 Interestingly, the final breakdown products of intraluminal digestion of protein are composed of low molecular weight peptides (2-6 amino acid residues) in 70% of cases and of only free amino acids in 30% of cases. Subsequently, brush border–bound peptidases further hydrolyze peptides to release a mixture of free amino acids and small peptides (2-3 amino acid residues). Finally, free amino acids are taken up by enterocytes through specific Na-linked carrier systems (5 carriers with selective affinities for groups of amino acids are described), while the small peptides are translocated into the absorptive epithelial cells by a system with a broad specificity. Of interest, in the first few months of life, the latter system is much more active than those that transport amino acids and is thought to play a bigger physiological role.

8 Congenital disorders of protein digestion include conditions such as cystic fibrosis, Shwachman- Diamond syndrome, and enterokinase deficiency, which cause inadequate intraluminal digestion. No congenital defects have been described in any of the brush border–bound peptidases or in the peptide carrier. Acquired disorders of protein digestion and/or absorption are nonspecific (ie, they also affect the absorption of carbohydrates and lipids) and are found in conditions that result in damage to the absorptive intestinal surface, such as extensive viral enteritis, milk protein allergy enteropathy, and celiac disease.

9 Lipids A lingual lipase is responsible for the first partial hydrolysis of triglycerides; this enzyme becomes active in persons with low gastric pH levels and is active even in premature infants. However, the largest part of triglyceride digestion is accomplished in the duodenojejunal lumen because of a complex of pancreatic enzymes, the most important of which is the lipase-colipase complex. Like amylase, these enzymes also develop slowly, and this accounts for the known low capacity of babies to absorb lipids, termed physiologic steatorrhea of the newborn. Additionally, adequate concentrations of intraluminal conjugated bile salts are needed to form micelles, and the secretion of bile acids may also be partially inadequate in very young patients.

10 Disorders of these processes can be congenital (cystic fibrosis and Shwachman-Diamond syndrome, which cause lipase and colipase deficiency; the uncommon isolated deficiency of lipase and colipase; the extremely rare congenital primary bile acid malabsorption, which results in low bile acids concentrations) or acquired (secondary mostly to disorders of the liver and the biliary tract or to chronic pancreatitis). Clearly, any condition that results in the loss of small intestinal absorptive surface also causes steatorrhea.

11 Frequency If celiac disease in its entirety (ie, including the forms without overt malabsorption) is considered among the malabsorption syndromes, this condition should be considered the most common inherited malabsorption syndrome because the documented prevalence is close to 1%. Cystic fibrosis is the second most common malabsorption syndrome. Other congenital disorders are rare, with the exception of adult- type hypolactasia, which has a prevalence that varies greatly among different ethnic groups. Among acquired conditions, cow's (and soy) milk protein allergic enteropathy is very common. The prevalence of milk protein allergy, of which enteropathy is one of the presenting clinical symptoms, is estimated to be around 3%.

12 A transient and common form of malabsorption in infants results from acute-onset enteritis (mostly viral, specifically rotaviral), which causes transient lactose intolerance. Although toddler's (or unspecific) diarrhea accounts for approximately 7.5% of referrals to pediatric gastroenterologists, it should not be considered a malabsorption syndrome because, by definition, no digestive or absorptive processes are impaired. Secondary malabsorption syndromes that result from liver, pancreas, and intestinal diseases are uncommon. The manifestations vary according to the severity of each disease and the extent of intestinal mucosal injury.

13 Mortality/Morbidity Although the morbidity can be severe, and aside from the single entity of cystic fibrosis, common malabsorption syndromes carry low mortality rates. Neonates and young infants, especially those with signs of malnutrition, are particularly at risk. In many of the congenital syndromes, morbidity varies with the particular syndrome and may be associated with systemic manifestations of the disease.

14 Race Congenital sucrase-isomaltase deficiency is most common in Canadian Eskimos and natives of Greenland. Trehalase (a sugar found almost exclusively in mushrooms) deficiency is rare, except in natives of Greenland. Adult-onset lactase deficiency is most common in persons of Asian, African, and Mediterranean descent.

15 Sex Celiac disease is slightly more common in females. Autoimmune enteropathy is an X-linked disorder that only affects males in familial cases.

16 Age Neonates and young infants with malabsorption syndromes are at particularly high risk for chronic diarrhea and malnutrition. Symptoms of a congenital disease are usually apparent shortly after birth (the exception being adult-onset lactase deficiency, which appears only after age 6-8 y) or after a short hiatus once a particular substance is ingested in substantial amounts. Protein sensitivity syndromes to milk or soy protein usually present in infants younger than 3 months, but solid food protein sensitivity syndromes are also known to occur in older patients.

17 CLINICAL History Diet history: Obtain a complete history of the patient's diet, including the amount and type of fluids, solid foods, and formula ingested. Caregivers should keep a detailed journal of the patient's diet and symptoms for a minimum of 1 week. – The proper amount of fluid for most young children is around 100 mL/kg/d. Fluid intake that exceeds this amount may result in looser stools, which causes a referral for a suspected but nonexistent malabsorption. – Fat is important for slowing the movement of food through the intestine via hormonal mechanisms. Fat intake of less than 3 g/kg/d may contribute to toddler's diarrhea, especially in the setting of excessive free fluid and carbohydrate intake (eg, as occurs with large amounts of fruit juice intake). Thus, history is important in differentiating the common toddler's diarrhea from the rarer malabsorption syndromes.

18 – In the United States, juice is commonly introduced into the diet in the latter portion of the first year of life. Purple grape juice has a high osmolarity, which can cause osmotic diarrhea. The transport of fructose into enterocytes is not active and relatively inefficient. Apple and pear juice contain a high fructose-to- glucose ratio, and consumption of these juices can result in fructose malabsorption and diarrhea. Since sorbitol and fructose compete for the same intestinal transporter, ingesting them together may result in the malabsorption of these sugars.

19 Gastrointestinal tract symptoms: Gastrointestinal tract symptoms are common in patients with malabsorption syndromes, and symptoms range from mild abdominal gaseous distention to severe abdominal pain and vomiting. Chronic or recurrent diarrhea is by far the most common symptom. – Abdominal distention and watery diarrhea, with or without mild abdominal pain, associated with skin irritation in the perianal area due to acidic stools are characteristic of carbohydrate malabsorption syndromes. – Periodic nausea, abdominal distention and pain, and diarrhea are common in patients with chronic Giardia infections.

20 – Vomiting, with moderate-to-severe abdominal pain and bloody stools, is characteristic of protein sensitivity syndromes or other causes of intestinal injury (eg, inflammatory bowel disease). – Recurrent abdominal pain has been implicated as a symptom of dietary disorders, although psychological variables that relate to an elevated anxiety level have clouded the certainty of this relationship. Malabsorption syndromes can definitely cause abdominal pain or irritability (particularly seen in celiac disease). – Failure to identify the cause of malabsorption can result in the misdiagnosis of a physiologic syndrome as a behavioral disorder. Some dietary items may cause symptoms only when they are taken alone or with other specific dietary items. – Poor appetite is common in food sensitivity syndromes. The child becomes conditioned to refuse foods that cause inflammatory reactions of the intestine. However, this is not typically obvious in celiac disease. Malabsorption syndromes not associated with inflammatory reactions typically cause an increase in appetite (eg, cystic fibrosis) unless the associated abdominal gaseous distention hampers intake and induces early satiety.

21 Stool characteristics – Patients with Toddler's diarrhea often have loose stools with undigested food particles. This should not be taken to imply the presence of true malabsorption. – Frequent loose watery stools may indicate carbohydrate intolerance. – Pasty or loose foul-smelling stools indicate fat malabsorption, also termed steatorrhea. This symptom is commonly seen in Giardia infections, enterokinase deficiency, hepatic and pancreatic dysfunction, and protein sensitivity syndromes. – Bloody stools are seen in patients with protein sensitivity syndromes and not in disaccharidase and pancreatic enzyme deficiencies or in patients with giardiasis.

22 Other symptoms – Systemic symptoms, including weakness, fatigue, and failure to thrive, are systemic consequences of chronically poor nutrient absorption. Malabsorption of carbohydrates, fats, or proteins can cause failure to thrive, while folate and B-12 malabsorption result in macrocytic anemia. – Patients with abetalipoproteinemia develop retinitis pigmentosa and ataxia because of chronic fat-soluble vitamin malabsorption and deficiency (vitamins A and E).

23 Physical In the absence of gastrointestinal tract symptoms, malabsorption syndromes should be considered during the workup for failure to thrive, malnutrition, poor weight gain, or delayed puberty. Signs of malnutrition discovered during physical examination, such as reduced muscle and fat mass, atrophic tongue changes, or enlarged liver or spleen, have been reported in children with chronic malabsorption. Malabsorption syndromes should be suspected in infants with weight loss or little weight gain since birth and in infants with low weight and weight-for-height percentiles. By definition, toddler's diarrhea does not cause failure to thrive, unless anxious parents intervene by imposing unnecessary dietary restrictions that result in lower caloric intake. Dehydration caused by a diarrhea that is induced by a malabsorption syndrome is not common, but, when it occurs, dehydration can cause serious morbidity and mortality. Assess each patient for signs, symptoms, and severity of dehydration. Lethargy, depressed consciousness, sunken anterior fontanel, dry mucous membranes, sunken eyes, poor skin turgor, and delayed capillary refill are all signs of dehydration. A significant increase in peristaltic activity can be detected audibly and with tactile palpation. This is associated with decreased intestinal transient time.

24 Large numbers of stools result in a constant wet diaper in young children. Failure to properly dry the buttocks and perianal area results in erythema, skin irritation, and skin breakdown, with evidence of bleeding seen in the diaper or in stool. Protein sensitivity may be associated with an eczematous rash.

25 Causes Carbohydrate malabsorption: Starch molecules are primarily digested by salivary and pancreatic amylase, but glucoamylase in the intestinal brush boarder also assists in digestion. – Pancreatic insufficiency impedes the digestion of large starch molecules. – Absence or reduction of the brush border disaccharidases causes selective carbohydrate malabsorption. – Transient reduction of these enzymes is common after an infection in the intestine, particularly a viral infection, because intestinal villi and microvilli may be damaged.

26 Causes – Glucoamylase and maltase are most resistant to the depleting effects of mucosal injury that result from infection, while lactase is the most sensitive because of its predominant distribution near the tips of the villi. – Lack of sucrase and isomaltase is, by far, the most frequent congenital enzyme deficiency. This enzyme deficiency is inherited in an autosomal recessive manner. – Congenital lactase deficiency is exceedingly rare, but adult-type lactase deficiency is very common in some ethnic groups. – Glucose and galactose are actively transported from the intestinal lumen into the cytoplasm of the enterocyte, while fructose (carrier mediated) and mannose are passively transported. – A congenital deficiency in the glucose galactose transporter (SGLT-1) is inherited in an autosomal recessive manner. – Take care when diagnosing lactose or another complex carbohydrate intolerance because many complex carbohydrates are broken down into glucose.

27 Causes – Both bacterial overgrowth of normal flora and growth of abnormal flora alter the intraluminal metabolism of carbohydrates. Bacteria ferment carbohydrates into smaller osmotically active molecules and organic acids. Increased osmolarity causes fluid from systemic circulation to enter the intestinal lumen, resulting in diarrhea. Organic acids stimulate motility and may directly injure the intestinal mucosa. Fermentation eliminates the reducing substances and lowers the pH of the stool. The production of lactate and short-chain fatty acids in the human colon can result in systemic acidosis. In particular, a syndrome of D-lactic acidosis may develop when specific bacteria that are capable of producing this uncommon and poorly cleared D isomer of lactate exist in the intestinal flora. – Bile acids are usually recycled by enterohepatic circulation. Many factors can prevent this recirculation. Bacterial overgrowth of normal flora and growth of abnormal flora are the most common causes of altered intraluminal metabolism of bile acids. Anaerobes and Staphylococcus aureus deconjugate bile acids, which impedes their active reabsorption by the terminal ileum into the portal circulation for reuptake by the liver. A congenital deficiency in the sodium–bile acid cotransporter results in primary bile acid malabsorption. The resulting diminished transport of bile acids from the intestinal lumen allows intestinal flora to deconjugate bile acids. – Deconjugated bile acids directly inhibit the carbohydrate transporters, reduce intraluminal pH levels, and damage the enterocyte. They may also directly stimulate the colon to secrete fluid, contributing to diarrhea.

28 Fat malabsorption – Increased delivery of fat to the colon results in diarrhea and soft, pasty, foul-smelling stools. However, the gas causes stools to float. Consequences include the malabsorption of fat-soluble vitamins A, D, E, and K and insufficient energy intake due to the high energy value of dietary lipids. – Digestion of fat begins in the stomach with gastric lipase; however, the major source of lipase is the pancreas. – Exocrine pancreatic insufficiency is the principal condition that results in severe fat malabsorption. Pancreatitis, pancreatic cancer, pancreatic resection, cystic fibrosis, Shwachman- Diamond syndrome, Johnson-Blizzard syndrome, and Pearson syndrome can all result in pancreatic insufficiency. Significant obstructive biliary or cholestatic liver disease or extensive intestinal mucosal disease, such as occurs in celiac disease, may also result in severe steatorrhea.

29 – Impaired bile production or secretion is seen in liver or biliary tract disease. Inflammation or resection of the ileum impedes enterohepatic circulation, which results in a reduced bile acid pool. Bacterial overgrowth in the small bowel deconjugates bile acids, thereby inactivating their ability to help lipids form a micelle. These syndromes result in moderate lipid malabsorption. – Abetalipoproteinemia is a rare disorder with autosomal recessive inheritance. Absence of the lipoproteins results in cytoplasmic lipid accumulation in the enterocyte. Lymphatic transport of long-chain fats is impaired in patients with abetalipoproteinemia, lymphangiectasia, and protein-losing enteropathy, resulting in moderate fat malabsorption.

30 Protein malabsorption – Protein malabsorption is a fairly common result of exocrine pancreatic enzyme deficiency, as occurs in patients with cystic fibrosis. – Protein malabsorption that results from congenital enterokinase deficiency is well described but rare. – Creatorrhea, loss of protein in the stool (ie, protein- losing enteropathy), is often caused by the leakage of protein from the serum due to inflammation of the mucosa, as in Crohn disease, celiac disease, and protein sensitivity syndromes. Congenital lymphangiectasia, a developmental disorder in which dilation and dysfunction of intestinal lymphatics occurs, often in association with limb edema (Milroy disease), may present with severe protein-losing enteropathy without mucosal injury.

31 Vitamin malabsorption – Malabsorption of vitamin B-12 and folate is associated with tropical spruce, a disorder that is acquired after travel to tropical areas. – Vitamin B-12 is absorbed in the ileum, and absorption requires an intrinsic factor made in the gastric parietal cell. Intrinsic factor deficiency that results from atrophic gastritis or absence (from resection) or disease of the terminal ileum (the predominant site of active B-12) results in vitamin B-12 malabsorption.

32 DIFFERENTIALS Congenital Microvillus Atrophy Constitutional Growth Delay Crohn Disease Cystic Fibrosis Diarrhea Failure to Thrive Gastroenteritis Giardiasis Growth Failure Irritable Bowel Syndrome Lactose Intolerance Congenital Microvillus Atrophy Constitutional Growth Delay Crohn Disease Cystic Fibrosis Diarrhea Failure to Thrive Gastroenteritis Giardiasis Growth Failure Irritable Bowel Syndrome Lactose Intolerance

33 Other Problems to be Considered Enterokinase deficiency Hypobetalipoproteinemia Pancreatic enzyme deficiencies Pancreatic insufficiency

34 WORKUP Lab Studies Stool analysis – The presence of reducing substances indicates that carbohydrates have not been properly absorbed. One common mistake, especially with the use of superabsorbent diapers, is to test the solid portion of the stool instead of the liquid portion. Furthermore, in stools that are not fresh, bacterial hydrolysis, removal of the reducing substances, and artifactual reduction of pH occur. – Acidic stool has a pH level of less than 5.5. This indicates carbohydrate malabsorption, even in the absence of reducing substances. – Normally, stool bile acids should not be detected. If bile acid malabsorption is suspected, quantitative conjugated and unconjugated bile acids may be measured in stool, although this test is not routinely available and is not used in routine clinical practice. – The level of quantitative stool fat and the amount of fat intake should be measured and monitored for 3 days. Normal fat absorption depends on age (lower in the neonate) and improves throughout the first year of life to the reference range levels of 95% or higher. Moderate fat malabsorption ranges from 60-80%. Fat absorption of less than 50% indicates severe malabsorption.

35 – The presence of large serum proteins in the stool, such as a 1 -antitrypsin, indicates leakage of serum protein and serves as a screening test for protein- losing enteropathy. – Examination of the stool for ova and parasites or testing for the stool antigen may reveal the presence of Giardia species, a known cause of acquired malabsorption syndromes in children who are usually older than 2 years. – Testing for other chronic intestinal infections that cause malabsorption, such as Clostridium difficile (assays for toxins A and B) or Cryptosporidium species (modified acid-fast examination of stool), may be performed.

36 Urinalysis – Urine examination may reveal an unusually high concentration of the malabsorbed substance, since, in many cases, the kidney and the gut use the same transporter. – In glucose-galactose malabsorption, the urinary glucose level is typically elevated when the serum glucose level is within reference range because of congenital malfunction of SGLT-1. – Levels of urinary 4-hydroxyphenylacetic acid have been demonstrated to be elevated in the urine of children with bacterial overgrowth syndrome.

37 Other laboratory studies – A CBC count may reveal megaloblastic anemia in patients with folate and vitamin B-12 malabsorption or neutropenia in patients with Shwachman-Diamond syndrome (associated with pancreatic insufficiency). In patients with abetalipoproteinemia, blood smears may reveal acanthocytosis. – Total serum protein and albumin levels may be lower than reference range in syndromes in which protein is lost or is not absorbed, particularly in protein-losing enteropathy and pancreatic insufficiency or enterokinase deficiency, respectively. – With fat malabsorption or ileal resection, fat-soluble vitamin levels in the serum are lower than reference range. – With bile acid malabsorption, levels of the low-density lipoprotein (LDL) cholesterol may be lower than reference range.

38 – With inflammatory bowel diseases, the erythrocyte sedimentation rate, C-reactive protein level, or both are commonly elevated. – In patients with liver or biliary disease, the results of liver function tests may be higher than reference range levels. These tests include assays for alanine aminotransferase (ALT), aspartate aminotransferase (AST) (in hepatitis), g-glutamyltransferase (GGT), alkaline phosphatase, and bilirubin (in cholestatic liver disease). – Immunoglobulin G (IgG) and immunoglobulin A (IgA) antigliadin and IgA antiendomysial antibodies, or especially tissue transglutaminase antibodies, are useful in the diagnosis of gluten-sensitive enteropathy. – Enterocyte, smooth muscle, thyroid, and islet cell serum antibodies are revealed in patients with autoimmune enteropathy.

39 Imaging Studies Although upper gastrointestinal radiography with small bowel follow-through demonstrates a pattern of thickened folds and increased fluid content in the jejunal loops in celiac disease and conditions characterized by protein-losing enteropathies, this test is no longer used because it is unspecific and not sensitive enough, especially when compared with other diagnostic tests.

40 Procedures Substance tolerance test – Attempt to isolate the substance that is causing the malabsorption. Resolution of diarrhea after the suspected substance is removed from the diet and resumption of the diarrhea when the substance is reintroduced are specific signs that the particular substance is not adequately absorbed. – If diarrhea does not resolve when the particular substance is removed from the diet, this does not necessarily indicate intolerance to the substance. – Malabsorption of certain nutrients can result in secondary intestinal damage and secondary malabsorption, which may no longer be related to the malabsorbed substance. Thus, this technique has low sensitivity until mucosal injury has had a chance to heal. – Challenging the patient with the suspected malabsorbed substance once the diarrhea has resolved provides a more sensitive test.

41 Carbohydrate malabsorption tolerance test – Carbohydrate malabsorption results in bacterial fermentation. This biochemical process releases hydrogen gas that is absorbed into the blood and excreted by the lungs. – Under normal conditions, fermenting bacteria reside in the large intestine. When the bacteria in the large intestine ferment the carbohydrate load, an increase in the level of exhaled hydrogen is detected. – The amount of carbohydrate administered is typically 2 g/kg, with a maximum dose of 50 g. When testing for lactose tolerance, using a more physiologic amount (eg, g) may be preferable. – An increase in the exhaled hydrogen concentration following ingestion of an oral carbohydrate load (>20 ppm) indicates carbohydrate malabsorption. Bacterial overgrowth in the small intestine results in an additional early rise in the exhaled hydrogen concentration. – Antibiotic administration within the 2 weeks prior to the test may cause false-negative results in this test.

42 D-xylose absorption test – Another time-honored test for carbohydrate malabsorption is the D-xylose absorption test. Xylose is a pentose that is passively absorbed by the jejunal mucosa. – A standard dose of 5 g or, alternatively, 14.5 g/m 2 (maximum dose of 25 g) of D-xylose is orally administered as a 10% solution in water. The test result is positive in the following instances: Children who weigh less than 30 kg - Serum level at 1 hour after ingestion is less than 25 mg/dL. Children who weigh more than 30 kg - The 5-hour urinary excretion is less than 15%. A positive test result suggests malabsorption due to proximal small bowel mucosal lesion (enteropathy). Beware of false-positive results (eg, from delayed gastric emptying, small bowel bacterial overgrowth, accelerated transit time).

43 Mucosal biopsy – This test is fundamental in obtaining a definitive diagnosis in many circumstances, such as common celiac disease. Almost all pediatric gastroenterology centers obtain biopsies of the duodenal mucosa during an upper endoscopy. – Moderate villous atrophy may be seen in protein-sensitive enteropathies, Giardia infection, or bile acid malabsorption. – Histologic examination of the biopsy tissue may reveal the mucosal inclusions seen in abetalipoproteinemia, eosinophilic gastroenteritis, Wolman disease, or congenital microvillous atrophy, for which electron microscopy is needed. – Functional assays of the biopsy tissue assess carbohydrate disaccharidase enzymes.

44 Histologic Findings Biopsy of the small intestine remains the criterion standard for the diagnosis of celiac disease. The classic features include villous atrophy, infiltration of the epithelium by cytotoxic intraepithelial T lymphocytes, and crypt hyperplasia. However, the spectrum can range from intraepithelial lymphocytosis and crypt hyperplasia without villous atrophy to severe villous atrophy with crypt hypoplasia.

45 TREATMENT Medical Care Because the intestine heals slowly, chronic diarrhea may require a long course of treatment. Treating diarrhea with oral gentamicin or another suitable broad-spectrum antibiotic, particularly one with anaerobic coverage (eg, metronidazole), diminishes bacterial overgrowth. In children with chronic diarrhea secondary to bile acid malabsorption, the use of cholestyramine (Questran) to bind bile acids may help to reduce the duration and severity of the diarrhea. Any loss of pancreatic enzymes can be replaced with oral supplements. Immunosuppressive medications can be used to control autoimmune enteropathy and should be prescribed only by a specialist. Eliminate allergenic or malabsorbed substances. In patients with celiac disease, strict adherence to a diet completely devoid of wheat, barley, and rye is necessary

46 Surgical Care Most children with short gut syndrome are eventually weaned off parenteral nutrition and do not require surgery. However, in some children, disease is refractory to enteral feeding, and other children develop end-stage liver disease from the prolonged supplementation of parenteral nutrition. Consider liver, gut, or multivisceral transplantation in these children.

47 Consultations In children in whom a malabsorption syndrome is suspected to cause growth failure or is associated with high morbidity, prompt referral to a pediatric gastroenterologist is recommended.

48 Diet Carbohydrate intolerance – Initiate treatment in patients with severe acquired carbohydrate intolerance by eliminating all dietary carbohydrates until the diarrhea is resolved. Then, slowly reintroduce carbohydrates. – In infants, use a glucose polymer (Polycose)–based formula (eg, Pregestimil). In patients with the most severe carbohydrate intolerance, use MJ3232A, a casein-based formula that contains essential amino acids and medium-chain triglyceride (MCT) oil and no carbohydrates. If MJ3232A is used, parenteral dextrose must be supplied. – Once the diarrhea has resolved, slowly reintroduce fructose into the diet as the only enteral carbohydrate source.

49 – Begin with 14 g fructose/L formula, and gradually advance in 14-g increments to a maximum of 56 g fructose/L formula. Once this goal is reached, slowly replace fructose with Polycose until 56 g Polycose/L formula is tolerated. Once 56 g Polycose/L formula is tolerated, begin introducing Pregestimil, a lactose-free formula. – For older children, eliminate simple carbohydrates and lactose from the diet until the diarrhea is resolved. Simple sugars, including fruit juices, should be avoided for several weeks. – If after several weeks of a relatively carbohydrate-free diet symptoms return when carbohydrates are reintroduced, the child most likely has a congenital defect in carbohydrate transport or digestion.

50 Fat intolerance – MCT oil is used to treat patients with poor weight gain that results from fat malabsorption. MCT oil does not require traditional fat metabolism and, thus, is more easily absorbed directly into the enterocyte and is transported through the portal vein to the liver. – Fat-soluble vitamin supplements are required for patients with fat malabsorption or short gut syndrome. – Supplements in patients with fat malabsorption should also include linoleic and linolenic fatty acids. – Patients with short gut syndrome may not be able to effectively absorb formula until mucosal hyperplasia has increased the mucosal absorption area. During this period of adaptation, appropriate parenteral nutrition may be needed to maintain optimal nutritional status.

51 Alternative formulas – Currently, soy formulas are not considered effective for the prevention or treatment of nutritional allergies. Instead, use hydrolyzed protein formulas. – High-degree protein hydrolysate formulas are used to treat infants with a cow's milk allergy, but these formulas may contain residual epitopes capable of provoking a severe allergic reaction. In these infants, use formulas with crystalline amino acids (eg, Neocate, EleCare, EO28) as the protein source.

52 MEDICATION Drug Category: Antibiotics These agents are used to treat bacterial overgrowth. Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

53 Drug Name Gentamicin (Garamycin) Description Aminoglycoside antibiotic for gram-negative coverage. Used in combination both with an agent against gram-positive organisms and with an agent that covers anaerobes. Poor oral absorption allows gentamicin to target normal and abnormal gut flora while maintaining high intraintestinal bioavailability. Pediatric Dose 50 mg/kg/d PO divided qid for 5 d Contraindications Documented hypersensitivity Interactions Unknown with oral administration Pregnancy C - Safety for use during pregnancy has not been established. Precautions Unless renal failure exists, serum level monitoring is not required because only small amount of gentamicin is orally absorbed

54 Drug Category: Bile acid&;binding agents These agents are used in combination with antibiotics for bile acid malabsorption syndromes. Bacteria overgrowth may cause diarrhea by deconjugation and dehydroxylation of bile acids. Primary bile acid malabsorption may also occur.

55 Drug Name Cholestyramine (Questran) Description Binds bile acids, thus reducing damage to the intestinal mucosa. Also reduces induction of colonic fluid secretion. Forms a nonabsorbable complex with bile acids in the intestine, which in turn inhibits enterohepatic reuptake of intestinal bile salts. Pediatric Dose 2-4 g/d PO divided bid/qid for 8-10 d Contraindications Documented hypersensitivity; biliary obstruction; neonates with history of structural intestinal abnormalities, abdominal surgery, or necrotizing enterocolitis Interactions Inhibits absorption of numerous drugs including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, phenobarbital, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, penicillin G, and fat-soluble vitamins Pregnancy C - Safety for use during pregnancy has not been established. Precautions Caution if constipation exists; avoid aspartame-containing cholestyramine with phenylketonuria; cholestyramine products containing added carbohydrates (ie, fructose, sorbitol) for flavoring (eg, LoCholest) may exacerbate diarrhea and should be avoided

56 Drug Category: Digestive enzymes Pancreatic enzyme deficiency may occur because of steatorrhea secondary to malabsorption.

57 Drug Name Pancrelipase (Cotazym, Zymase, Ultrase, Pancrease, Creon) Description Assists in digestion of protein, starch, and fat. Contains lipase, protease, and amylase. Pediatric Dose Adjust dose according to severity of pancreatic enzyme deficiency and fat content of stools U/kg (based on lipase content) enteric-coated tab per meal; not to exceed 2500 IU/kg/dose, because colitis with strictures (fibrosing colonopathy) may occur at higher doses Contraindications Documented hypersensitivity; history of pork protein allergy Interactions Drugs that increase gastric pH (eg, H2 antagonists) may increase effects of pancreatic enzymes by inhibiting destruction of ingested pancreatic enzymes Pregnancy C - Safety for use during pregnancy has not been established. Precautions High doses may be associated with fibrosing colonopathy, which has been evident in patients with cystic fibrosis who developed ascending colon strictures; high degree of variability between enzyme products (do not interchange once stabilized)

58 FOLLOW-UP Further Inpatient Care If the patient shows any symptoms of dehydration or malnutrition, admit the patient to a medical care facility and immediately initiate treatment with parenteral fluid and nutrition supplements. Treatment for severe acquired carbohydrate malabsorption requires admission to a medical care facility for enteral nutrition with a low-carbohydrate formula and administration of parenteral dextrose.

59 Further Outpatient Care Strict follow-up monitoring with the primary care pediatrician is necessary to reevaluate diet therapy efficacy and compliance.

60 Prognosis Mucosal atrophy caused by infectious gastroenteritis, food-sensitivity enteropathies, or malnutrition can result in an 80% reduction of intestinal surface area. Once the causative agent is removed, the repair of the small bowel is usually rapid (4-6 days). In some patients, repair may be slow, and after 2 months, the villi surface area is 63% normal and the microvillous surface area is only 38% normal. Some malabsorption syndromes are transient, while others simply require a change in diet. Most disorders that cause secondary malabsorption are progressive and, because of systemic complications, result in a limited lifespan in patients. For example, patients with abetalipoproteinemia can die in early adulthood because of cardiac abnormalities, while patients with severe autoimmune enteropathies or microvillus inclusion disease have a very poor prognosis without intestinal transplantation. Outcome in patients with short gut syndrome is variable. The long-term prognosis depends primarily on the amount of time parenteral nutrition is required. The complications of parenteral nutrition and the lack of trophic stimulation of intestinal mucosal growth impede recovery. Delayed intestinal autonomy depends on the characteristics of the residual intestine length, presence of the ileocecal valve and colon, and motor function. Bacterial overgrowth compromises intestinal adaptation and increases the risk of liver disorders

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