A 15 year old girl presents to the physician's office with a three year history of intermittent diarrhea. Further history reveals a past history of anemia, anorexia, and minor abdominal pain. Her weight has been the same for 3 years now. Her mother has attributed this to her having a "rough time in school". Her mother also questions whether the symptoms could be related to a recent move from their home state of Minnesota. She has not yet reached menarche. A diet history suggests a normal diet with adequate iron intake. Her family history is negative for malabsorption and inflammatory bowel disease.
Exam: VS T 37.5, P98, R 18, BP 110/70. Ht 145 cm (57 inches), wt 35 kg (78 pounds), both less than the 5% percentile. She is alert, active and cooperative. She is thin and small for age but not cachectic. HEENT: Her conjunctivae are pale. Her teeth are pitted and discolored. Her neck is supple without adenopathy. Her heart and lungs are normal. Her abdomen is slightly protuberant and hyperresonant. Bowel sounds are slightly hyperactive. Tanner stage 4 for both breasts and pubic hair. Examination of both hands reveal mild pallor and flat fingernails. She is able to ambulate and no neurologic deficits are noted.
Because of her small size and amenorrhea, a bone age reveals a 3 year delay and suggests osteopenia. A stool examination is negative for blood and reducing sugars. The 72-hour fecal fat study shows a moderate increase in fat content. A CBC shows a mild anemia. Her reticulocyte count is low and her iron studies indicate the presence of iron deficiency. An ESR is normal, making the possibility of inflammatory bowel disease less likely. Her small size, the steatorrhea and the iron deficiency all suggest the possibility of some type of GI malabsorption condition. An upper GI study with small bowel follow-through is normal. A chloride sweat test for cystic fibrosis is normal. A lactose breath hydrogen test showed an elevation in hydrogen of 40 ppm, suggesting carbohydrate malabsorption. An upper GI endoscopy shows no visible abnormalities; specifically, no ulcers or hemorrhage. Biopsies from the duodenal and proximal jejunal area reveal severe villus atrophy consisting of a flat mucosa with deep crypts and no evidence of Giardia lamblia. A serologic human anti-tissue transglutaminase ELISA test came back positive for autoantibodies suggesting the diagnosis of celiac disease.
She is started on a strict gluten-free diet. She responds dramatically and upon follow-up is now reporting an increased appetite and improved mood. She has remained symptom free for about a year now. She has also noticed a resurgence in her growth and has reported menarche that started about a month ago.
Gluten-sensitive enteropathy, also known as sprue, celiac sprue and celiac disease, is one of the many causes of malabsorption. Malabsorption is a clinical term for the entire spectrum of conditions occurring during digestion and absorption of ingested nutrients by the gastrointestinal tract. Perturbations in the digestion and absorption of food nutrients can occur either in the luminal phase, the mucosal phase, or the transport phase of the ingested food. Classifying the many entities of malabsorption in this manner makes it easier to understand their exact mechanisms. Causes of malabsorption can be explained by the way the disease process interferes with the normal digestive and absorptive mechanisms.
Malabsorption encompasses conditions that go from a single nutrient malabsorption (e.g., lactose intolerance) to pan malabsorption (e.g., cystic fibrosis and celiac sprue). Celiac sprue is a disease that predominantly affects people of European descent (rare in people of African and Asian ethnicity), and currently has a frequency of 1 in 5000 in the US (although this frequency is debated and some feel that this frequency may be much higher). Celiac disease is manifested variably by malabsorption to different types of nutrients. While presenting symptoms such as diarrhea and weight loss are common, the specific cause of malabsorption should be established using physiological evaluations. In celiac sprue, suggestive screening investigations include steatorrhea that denotes fat malabsorption, decreased d-xylose absorption found in carbohydrate malabsorption, and serological markers such as antigliadin antibodies or the new ELISA test for anti-tissue transglutaminase. The treatment of the underlying disease is often dependent on the establishment of definitive cause for the malabsorption. In the case described, gluten-sensitivity is the underlying cause. Were it not for the logical steps followed by the clinician, the quite dramatic resolution of symptoms brought about by denying the patient food devoid of gluten would not have happened if the exact etiology was missed.
As emphasized before, the causes of malabsorption can be best appreciated if they are classified into the specific phase of digestion and absorption that is disturbed.
1. The luminal phase is where dietary fats, proteins, and carbohydrates are hydrolyzed and stabilized by digestive enzymes and bile. Diseases often associated with this phase include:
. . . . . - Enterokinase and trypsinogen deficiencies that can lead to protein malabsorption.
. . . . . - Impaired micelle formation that can cause problems in fat stabilization and the resulting fat malabsorption due to deconjugation of bile salts in bacterial overgrowth.
. . . . . - Stasis of intestinal content due to a variety of factors (motor and anatomic abnormalities, small bowel contamination from enterocolonic fistulas) can cause bacterial overgrowth.
. . . . . - Bacterial overgrowth can also cause decreased luminal availability of substrates (carbohydrates, protein, vitamins).
2. The mucosal phase relies on the integrity of the brush border membrane of intestinal epithelial cells to transport digested products from the lumen into the cells.
. . . . . - Impaired brush border enzyme activity may lead to lactose intolerance and sucrase-isomaltase deficiency.
. . . . . - Impaired nutrient absorption can be inherited or acquired deficits. Inherited defects include glucose-galactose malabsorption, a-betalipoproteinemia, and Hartnup disease.
. . . . . - Acquired defects which are more common may be caused by decreased absorptive surface area (intestinal resection), damaged mucosa (celiac sprue, tropical sprue, giardiasis, Crohn's), or an infiltrating disease of the intestinal wall (lymphoma, amyloidosis).
. . . . . - Tropical sprue and Giardiasis are two mucosal phase abnormalities due to damaged intestinal mucosa. Tropical sprue, a syndrome characterized by diarrhea, weight loss, and malabsorption, occurs in residents or visitors to the tropics and the subtropics, usually in connection with certain geographical areas such as Southeast Asia and the Caribbean. The pathophysiology is poorly understood but is theorized to be caused by an acute intestinal infection that leads to jejunal mucosal injury. The disease is primarily a disease of adults but it is also described in children.
. . . . . - Giardiasis like celiac sprue has symptoms characteristic of panmalabsorption. The organism, Giardia lamblia is a protozoan that appears to alter intestinal epithelial structure and function leading to malabsorption. Giardiasis usually begins with ingestion of the cyst that eventually leads to trophozoites in the stomach and duodenum. High-risk groups include travelers, homosexual men, individuals with immunoglobulin deficiency states, and children, especially those who attend day care centers.
3. Transport (removal) phase malabsorption abnormalities may be caused by lymphatic obstruction or vascular insufficiency.
The signs and symptoms of malabsorption depend on the specific cause or etiology, and the specific nutrient deficiency that ensues. Age also plays a big factor. Malabsorption causes a far more acute and wide-ranging symptomatology in younger children than in the older child. Diarrhea is the most common symptomatic complaint which might lead to dehydration, especially in younger patients. In older children, weight loss and fatigue might be more pronounced. Some patients may try to compensate by increasing caloric consumption, making the diagnosis more difficult. Children in the pubertal ages may display disturbance in anthropometric growth (weight, height, weight by height) and pubertal development. Other symptomatology that follows from specific components of disturbed digestion and absorption include:
Steatorrhea: Most often due to fat malabsorption.
Flatulence and abdominal distention: Release of gas by bacterial fermentation of undigested or unabsorbed food particles.
Edema: Commonly from chronic protein malabsorption or loss of protein into the lumen.
Anemia: Depending on the cause, can be micro or macrocystic, such as Fe deficiency anemia secondary to celiac disease.
Bleeding disorders and ecchymosis: Usually a result of vitamin K malabsorption.
Bone defects: Can be due to vitamin D deficiency or calcium malabsorption.
Neurological manifestations: Electrolyte disturbance or specific vitamin malabsorption such as B12 neuropathy.
A malabsorption condition usually contains a specific physical manifestation (e.g., growth, weight, and pubertal disturbance). Growth and developmental charts are extremely helpful in diagnosis. A physical examination should look into the possibility of finding specific signs of individual nutrient malabsorption to aid in the organization of symptoms.
General: Orthostatic hypotension, weight loss, muscle wasting, loss of subcutaneous fat, pallor, ecchymosis.
HEENT: Alopecia or thinning hair, pale conjunctiva, aphthous ulcers, cheilosis, glossitis, dental hypoplasia, abdominal distention, tympanic abdomen, hyperactive bowel sounds, ascites.
Hands: Koilonychias (flattened or spoon shaped nails), pale skin.
Neurologic: Motor weakness, peripheral neuropathy, ataxia, Chvostek or Trousseau's sign due to hypocalcemia or hypomagnesemia, numbness, paresthesias.
Musculoskeletal: Mono or polyarthropathy, back pain, muscle weakness.
After the initial examination, a physician may have a reasonable idea of a diagnosis. Often, laboratory investigations are needed to confirm the cause.
Stool analysis: Quantitative stool fat analysis for 72 hours, consistency, pH (due to acidic stools in the presence of fermented sugars and reducing sugars in carbohydrate malabsorption), stool bile acids (increased in bacterial overgrowth syndromes), presence of large serum proteins (such as alpha-1-antitrypsin, may indicate a protein-losing enteropathy, ova and parasites (for Giardia), testing for chronic intestinal infections (such as C. difficile or Cryptosporidium), consistency, fecal leukocytes (such as in inflammatory bowel disease), and occult blood.
Screening Lab Tests: CBC (for anemia), blood smear (for abnormal blood morphologies that may indicate vitamin B-12 deficiency, amyloid, or a-betalipoproteinemia), urinalysis (urine may reveal unusually high concentration of malabsorbed substance since, in many cases, the kidney and the gut use the same transporter such as in glucose transporter deficiencies where urinary glucose will be elevated while the serum level is normal), total protein (decreased in protein malabsorption), albumin (decrease may indicate severe malnutrition or pancreatic insufficiency), liver function tests (in liver and biliary diseases), calcium and phosphorus levels (to determine vitamin D deficiency which might be present in gross steatorrhea), serum immunoglobulins (for autoimmune enteropathies), sweat test (for cystic fibrosis), and radiographic bone age (especially in pediatric patients).
Other lab studies to be considered include: Schilling test (for B12 deficiency), urinary 4-hydroxy phenylacetic acid (shown to be elevated in the urine of children with bacterial overgrowth syndrome; enteric bacteria that posses L-amino acid decarboxylase produce 4-hydroxyphenylacetic acid from dietary tyrosine), fat-soluble vitamin assays for fat malabsorption, LDL cholesterol (may be lower than normal with bile and malabsorption), ESR and C-reactive protein (may be elevated in inflammatory bowel disease), serum bile acids (congenital deficiency in the sodium-bile cotransporter results in primary bile acid malabsorption, which may appear as diminished reabsorption of bile acids in the kidney), GI motility studies (can be as simple as an upper GI contrast study or as complex as the performance of antroduodenal motility studies, depending on the need, which can recognize damage or abnormalities present in the gut due to inflammatory and infective processes), breath hydrogen analysis and, d-xylose absorption study (to specify carbohydrate malabsorptions), carbohydrate oral tolerance test (for specific carbohydrate digestion and absorption dysfunctions). IgG and IgA antigliadin and IgA antiendomysial antibodies are present in gluten-sensitive enteropathy. The presence human antitissue transglutaminase ELISA has a reported sensitivity of 96-100% and specificity of 99-100% and now appears to be the new criterion standard for screening of sprue.
Barium radiographic studies (upper GI series) can be useful in assessing anatomy and function. Endoscopy performed by a gastroenterologist permits direct visualization of the mucosal surface. During the endoscopy procedure, mucosal biopsies can provide histological information, identification of infective organisms and functional assays of the biopsied tissue for specific enzymes.
Medical management of underlines two basic principles: 1) Treatment of the etiology of malabsorption. 2) Correction of nutritional deficiencies.
Treatment of malabsorption is as varied as the etiologies that cause them. The intestine appear to repair itself slowly, thus treatment may require a longer course. Since many of the conditions that are caused by malabsorption, respond well to specific remedies, the need to make an accurate diagnosis becomes even more important. Most treatments highlight the dramatic effect of correcting the underlying defects of digestion and absorption. An example would be the gluten-free diet instituted in patients with gluten sensitivity. The effects of strict adherence to this diet include the full reversal of the disease process. Treatment of diarrhea with oral gentamicin or an appropriate broad-spectrum antibiotics that includes anaerobic coverage (e.g., metronidazole) reverses bacterial overgrowth and chronic infections, resulting in a rapid improvement in the patient's function. Specific malabsorption syndromes that include enzyme deficiency or imbalance can be successfully managed with oral supplements. The use of lactase supplements or non-lactose containing milk substitutes is beneficial in lactose intolerance. Pancreatic lipase can be replaced with oral supplements to improve fat digestion.
Efficient absorption of essential nutrients will not occur if the diarrhea is still present. Usually, the complete withdrawal of the offending substance can correct diarrhea. Care should be taken to avoid the iatrogenic elimination of necessary nutrients. For example, in celiac disease, gluten withdrawal is often enough to correct the symptoms. Carbohydrates and other foodstuff not continuing gluten can continue to be consumed.
Correction of nutritional deficiencies is the other important treatment goal. Dietary modifications and supplementation are especially useful if one considers the slow self-repair process of the severely damaged intestines. Dietary changes should be individually tailored to the individual and the underlying cause of malabsorption, but in general, a high protein, low fat diet is recommended. Decreased fat intake also reduces steatorrhea. The dietary modifications closely parallel the essence of withdrawing certain offending food products in the diet and promoting adequate calorie intake. Vitamin, mineral, and trace element deficiencies should be sought and corrected. Supplementation of nutrients whose absorption and digestion mechanisms were disturbed is essential. Anemia should be treated with appropriate supplements and specific deficiencies corrected by oral (or parenteral) supplementation. Fat-soluble vitamins may be required for a patient with severe steatorrhea.
1. What are the three phases of digestion and absorption discussed in this chapter?
2. Dietary fats, proteins, and carbohydrates are hydrolyzed and stabilized by digestive enzymes and bile in which phase?
3. Identify the phase in which digested food is moved from the lumen into the cells.
4. True/False: The symptoms of malabsorption are worse in older children compared to younger children.
5. True/False: Diarrhea is the most common presenting symptom of malabsorption in younger children.
6. True/False: Withdrawal of gluten-containing food from a patient with celiac disease is often enough to reverse the symptoms of malabsorption.
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2. Yang VW. Malabsorption. eMedicine Journal 2001 September;2(9).
3. Frye RE. Malabsorption Syndromes. eMedicine Journal 2001 September;S(11).
4. Talusan-Soriano K, Lake A. Malabsorption in Children. Pediatr Rev 1996;17(4):135-142.
5. Busschots GV. Sprue. eMedicine Journal 2002 January;3(1).
6. Godkin A, Jewell D. The pathogenesis of Celiac Disease. Gastroenterology 1998;115(1):206-210.
7. Bai J. Malabsorption Syndromes. Digestion 1998;59(5):530-546.
8. Lindley KJ, Macdonald S. Malabsorption in Children. Practitioner 2001;245(1620):169-170.
Answers to questions
1. Luminal phase, mucosal phase, and transport (removal) phase.
2. Luminal phase.
3. Mucosal phase.
4. False. Younger patients often display a more acute and wider-ranging symptomatology than older children.