Gastroenterology__cont._.doc Олена Костянтинівна Редько

2015

Ключові терміни: 3 Зміст

Ключові терміни: 3 Inflammatory Bowel Disease 3 Conditions 6 Biliary Atresia 10 Gastroesophageal Reflux 14 Ключові терміни: 4

Inflammatory Bowel Disease Malabsorption Conditions Biliary Atresia Gastroesophageal Reflux

Ключові терміни: Biliary atresia, Gastroesophageal (GE) reflux, Gluten-sensitive enteropathy, Inflammatory bowel disease, Malabsorption, Questions, The signs and symptoms of malabsorption, sprue, celiac sprue and celiac disease

Inflammatory Bowel Disease

This is a 16 year old female who presents with fever and diarrhea. Further questioning finds that she has had similar episodes in the past few years, but none as severe as the current episode. She does not weigh herself regularly so weight loss could not be confirmed. However, she does admit that her clothes feel somewhat looser than last year. Her menstrual periods are regular. Her last menstrual period began two weeks ago. Exam: VS T 37.0, P 85, RR 18, BP 100/65, oxygen saturation 100% in room air. Height is at the 50th percentile. Weight is at the 5th percentile. She is a thin appearing female in no acute distress. HEENT exam is significant for slightly tacky oral mucous membranes. Her eyes are not sunken. Neck is supple without lymphadenopathy. Her heart has a regular rhythm, but slight tachycardia with no murmurs. Her lungs are clear with good aeration. Her abdomen appears scaphoid. There are mildly hyperactive bowel sounds with diffuse vague abdominal pain without any point tenderness. No masses or organomegaly are noted. Her extremities are cool to at the distal limbs, but warm and dry otherwise. Her pulses are good with brisk capillary refill. No rashes are noted. Her breasts and genitalia are Tanner stage 3-4. Rectal exam demonstrates non-specific discomfort without masses or severe tenderness. Her anus is normal externally. Her stool is guaiac positive. A CBC shows mild microcytic, hypochromic anemia and thrombocytopenia. Wright's stain of the stool for fecal leukocytes is positive for WBCs, but no eosinophils. Stool, blood and urine cultures are obtained.

Inflammatory bowel disease (IBD) is a term that is used to describe chronic inflammatory diseases of the gut. It usually refers to Crohn's disease and ulcerative colitis. Crohn's disease (CD) is also known as regional enteritis. The disease is described as discontinuous (regional) areas of transmural inflammation that affect any part of the GI tract (mouth to anus). Ulcerative colitis (UC) is described as a process that results in diffuse superficial colonic ulceration. Although there are some discrepancies over previous misdiagnoses of IBD as infectious gastroenteritis, most experts agree that the incidence of UC has increased over the first half of the 1900s. Since then, the prevalence of UC has plateaued, while Crohn's disease has increased during the 1950s-1980s. The incidence of UC, as compared to CD is similar worldwide. Both have an increased prevalence in the Northern regions of the world. The two diseases are prevalent in North America, northwestern Europe, and in the United Kingdom. This is in comparison to the decreased rates in Southern Europe, South Africa, and Australia. IBD is rare in Asia, Africa, and South America. UC and CD are both diseases of late adolescence and early adulthood. However, there have been documented cases of IBD diagnosed in infancy and childhood. The incidence of UC is equal in the male and female gender. Crohn's disease is more common in females than males by 20-30%, but in the younger pediatric age groups, males have a greater incidence. Caucasians, especially Ashkenazi Jewish, have a greater risk than other ethnicities. Although the precise mechanism of IBD is still unknown, there is a general consensus that it is multifactorial. There is currently no known infectious agent that has been identified/isolated, which reproducibly causes IBD. Still, infection may be a "triggering event" for an acute episode of IBD. Viruses and Mycobacterium paratuberculosis are some of the organisms that have been studied. Ключові терміни: 5 Genetics is a likely contributor in the pathogenesis of IBD. In CD, monozygotic twins have a concordance rate of 44%, while just 4% in dizygotic twins. UC has less of a genetic preponderance as monozygotic twins have a concordance rate of 6% to 25%. There are multiple studies attempting to isolate the gene(s) involved in this disease that are beyond the scope of this chapter. Dietary components have also been studied. No toxin or antigen has been isolated. In a retrospective study, CD has been associated with "westernization" of the diet or an increased of intake of animal proteins, total fat and animal fat. Some interesting modulating factors are the protective effects of breastfeeding against CD and against UC. Cigarette smoking increases the risk for CD while it decreases the risk for UC. The big picture is that multiple events have an additive effect that results in an abnormal mucosal immune response, which leads to intestinal inflammation. If this inflammatory response is not well regulated, then chronic IBD develops.

Common Comparative Aspects of CD and UC:

Description Crohn's Disease Ulcerative Colitis

Location Mouth to anus Colon only

1. % ileocolic 2. % 3. % colonic

Abdominal mass common rare Perianal disease common rare Strictures common unusual Fistula common unusual Risk of cancer increased slightly increased greatly Histology Transmural inflammation Mucosal inflammation Skip areas Diffuse involvement Aphthoid lesions Crypt abscesses Fissuring ulceration Crypt distortion Granuloma Fibrosis Microscopic Edema, increase in Active UC: Neutrophils in the mononuclear cells in the mucosa, goblet cell mucus depletion, lamina propria. Again, and clumps of neutrophils in crypt the hallmark is transmural lumens. extension into the bowel wall and adventitia. Clinical Presentation Abdominal pain Bloody, mucusy diarrhea Anemia Lower abdominal cramps (less common) Weight loss Abdominal tenderness Falling off growth curve Vomiting Delayed puberty Fever Perianal lesions Weight loss Finger clubbing

Crohn's Disease commonly presents with crampy abdominal pain, recurrent fever, weight loss, and diarrhea. Abdominal pain is diffuse and more severe than in UC and often worse in the lower right quadrant. Rectal bleeding is seen in about a third of the cases. Weight loss, poor weight gain, anorexia, and delayed growth occur in 40% of cases. This growth abnormality may present as short stature and/or delay in sexual maturation. Perianal disease may be the presenting complaint. Further examination may show a fistula, skin tags, or recurrent abscesses. Ulcerative colitis presents with bloody stools, abdominal pain, and tenesmus. 100% of cases present with bloody mucinous stool. Mild disease is defined as less than 6 stools per day, no fever, no anemia, and no hypoalbuminemia. Moderate disease is described as more than 6 stools per day, fever, anemia, and hypoalbuminemia. 90% of cases present with mild to moderate disease. Severe disease exhibits high fever, abdominal tenderness, distention, tachycardia, leukocytosis, hemorrhage, severe anemia, and more than eight stools per day. Rare complications that may arise include toxic megacolon and intestinal perforation. Extraintestinal complications of IBD may involve the joints (arthralgias are more common than arthritis), integument (erythema nodosum and pyoderma gangrenosum), eyes (episcleritis, uveitis, and rarely, orbital myositis), hepatobiliary system (sclerosing cholangitis, chronic active hepatitis), Malabsorption Conditions 6 (pancreatitis), renal system (nephrolithiasis, hydronephrosis), coagulation system (hypercoagulability), and bone (decreased bone density). The diagnosis is based on clinical presentation, radiologic findings, with mucosal biopsy, and exclusion of other causes. Since corticosteroids will likely be used for treatment, stool cultures are done to rule out infectious causes. The stool may need to be evaluated for tuberculosis and schistosomiasis. Double-contrast barium enema may show diminished colonic haustrations in UC. In CD, it may identify nodularity, skip areas, a string sign, and fistula formation. is superior to evaluate the large bowel because of its increased sensitivity and biopsy capability for histologic assessment. Hematologic findings may exhibit anemia and thrombocytopenia. Further studies may show specific nutritional deficiencies including iron deficiency, hypoalbuminemia, and elevated transaminases. There have been recent advances in serologic testing, which in addition to screening for IBD, can differentiate between CD and UC. Anti-neutrophil cytoplasmic antibodies (ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) are laboratory tests that are used to serve this purpose. ANCAs are immunoglobulin IgG antibodies that are directed against neutrophil cytoplasmic components. Initially ANCAs had been studied in Wegener's granulomatosis and necrotizing vasculitis. By utilizing immunofluorescence studies, UC can be identified as it demonstrates perinuclear staining (pANCA). The test is specific in separating IBD from infectious colitis and other GI disorders. Unfortunately, the sensitivity is only 50-65%. ASCAs are IgG and IgA antibodies that bind to mannose sequences in the cell wall of S. cerevisiae strain Sul. The specificity and sensitivity of this test is also suboptimal. It is positive in 55-60% of people with CD and 5- 10% of those with other GI disorders. Its low sensitivity and specificity have kept these studies from replacing definitive radiologic and endoscopic studies. The tests are also limited in the cases where they are most needed. In CD limited to the colon, the pANCA may also be positive. ASCA is also less likely to be positive in CD limited to the colon. Thus, the dilemma remains in which the clinician attempts to distinguish UC from CD involving the colon only. Sulfasalazine is the usual treatment for mild to moderate UC and Crohn's disease of the colon. Sulfasalazine is not effective in small bowel CD. In moderate to severe UC and Crohn's disease of the small bowel, corticosteroids are used. Care must be taken to rule out bacterial causes of diarrhea prior to starting systemic corticosteroid therapy. Severe UC is treated with hyperalimentation, high dose corticosteroids, sulfasalazine, and cyclosporine. Corticosteroids may result in growth retardation. Metronidazole is used to treat perirectal fistulae in patients with CD. Metronidazole is used for both active disease, as well as prevention of recurrence. Azathioprine and 6-mercaptopurine are immunomodulating drugs which are used to reduce inflammation of the intestines, so that the corticosteroid doses can be reduced. Cyclosporine and tacrolimus inhibit cell-mediated immunity. Anti-TNF-alpha is a newer intervention that may be beneficial. Surgical resection is indicated when there are intractable symptoms despite medical therapy, intestinal complications, intra-abdominal abscesses, bowel-bladder fistula, perforation, and/or hemorrhage. Surgical resection does not necessarily result in a cure. In some patients, elective is performed to reduce or eliminate the risk of colon cancer. Crohn's disease may be subdivided into 3 categories: 1) The fistulizing type may form fistulas that are entero-enteric (between bowel segments), bowel-bladder, enterocutaneous (bowel to skin), perianal fistulas, and/or intra-abdominal abscess. 2) Patients with fibrostenosing disease have persistent abdominal pain and radiologic findings consistent with stenoses of the small or . 3) The inflammatory category includes patients who do not fit either of the two diseases or had been in one category and now fit in another. As listed above, growth impairment may occur either secondary to the illness or to therapy. Death in CD is rare in children. Adults with Crohn's colitis may have the same risk for cancer as do patients with UC. The overall risk for colorectal cancer is 8% after twenty years of disease. This risk is increased in those affected by perianal disease. Most patients undergo resection of the affected segment within 20 years, which decreases the overall incidence of carcinoma. Ulcerative colitis is also divided into 3 categories, which include mild, moderate and severe disease. One large study noted 70% of children entering remission by three months despite their initial severity level. The greater the severity of the disease, the greater was the likelihood of undergoing a colectomy. Nine percent and 25% those with moderate to severe disease underwent colectomy by 1 and 5 years, respectively. After 10 years of disease, the risk for colorectal cancer increases. About 12% of those with disease for 10 to 25 years will have colorectal cancer. Since there is such a high risk, regular colonoscopic surveillance is recommended, which identifies colorectal cancer at a potentially curable stage 65% of the time. However, these biannual examinations that start at 7-10 years of disease were not found to be cost effective. A more sensitive, specific and reliable screening test is currently being sought. Questions

1. 1. What portion(s) of the GI tract are affected by CD versus UC? 2. 2. Which IBD has a greater association with cancer? Malabsorption Conditions 7 3. 3. What are the common histologic findings in CD and UC? 4. 4. Name three extraintestinal findings in IBD? 5. 5. Describe the three types of CD and UC.

Answers to questions

1. 1. CD affects the gut anywhere between the mouth to the anus, while UC affects the colon. 2. UC has a greater risk for cancer. CD only slightly increases the risk for cancer. 3. CD: Transmural inflammation, skip areas, aphthoid lesions, fissuring ulceration, granuloma, fibrosis. UC: Mucosal inflammation, diffuse involvement, crypt abscesses, crypt distortion. 4. Joints: arthralgias are more common than arthritis. Integument: erythema nodosum and pyoderma gangrenosum. Eyes: episcleritis, uveitis, and rarely, orbital myositis. Hepatobiliary system: sclerosing cholangitis, chronic active hepatitis. Pancreas: pancreatitis. Renal system: nephrolithiasis, hydronephrosis. Coagulation system: hypercoagulability. Bone: decreased bone density. 5. Crohn's disease may be subdivided into 3 categories: 1) The fistulizing type, 2) Patients with fibrostenosing disease, and 3) The inflammatory category. Ulcerative colitis is divided into three categories: mild, moderate, severe.

Malabsorption Conditions

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 Malabsorption Conditions 8 during digestion and absorption of ingested nutrients by the . 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 . 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 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. Malabsorption Conditions 9 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), 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 Biliary Atresia 10 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.

Questions

1. 1. What are the three phases of digestion and absorption discussed in this chapter? 2. 2. Dietary fats, proteins, and carbohydrates are hydrolyzed and stabilized by digestive enzymes and bile in which phase? 3. 3. Identify the phase in which digested food is moved from the lumen into the cells. 4. 4. True/False: The symptoms of malabsorption are worse in older children compared to younger children. 5. 5. True/False: Diarrhea is the most common presenting symptom of malabsorption in younger children. 6. 6. True/False: Withdrawal of gluten-containing food from a patient with celiac disease is often enough to reverse the symptoms of malabsorption.

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. 5. True. 6. True. Biliary Atresia 11

Biliary Atresia

This is a 4 week old female who presents to the office with parental reports of increasing jaundice over the last week. Her parents report that 2 weeks ago, she began to have yellowing of her eyes with subsequent yellowing of her skin when she was diagnosed with physiologic jaundice. After persistent jaundice for 5 days, her parents changed her from breast-feeding to a commercial formula. Since the jaundice appears to be worsening, her parents decided to bring her in for re-evaluation. Her stools have been pale in color for the past 10 days along with darker urine. She was born by spontaneous vaginal delivery to a G2P1 A+ mother at 39 weeks with Apgar scores of 9 and 9 and 1 and 5 minutes. There were no complications noted at birth, the nursery, or at discharge home. The patient was not jaundiced at discharge or when seen at initial office visits. Her highest bilirubin previously was 12.0 and her blood type is A+. Exam: VS Normal. Weight and height are at the 60th percentile. She is awake, alert, in no acute distress and is easily comforted by her mother during the exam. Her skin is jaundiced, most notably in the cephalic and truncal areas, with scleral icterus. Her liver is slightly enlarged without nodularity. No splenomegaly is noted. The remainder of her exam is normal. Laboratory examinations reveal a total bilirubin of 15 mg/dL, direct bilirubin of 12.3 mg/dL, ALT 45 U/L, AST 52 U/L, and an alkaline phosphatase of 2007 U/L. The patient undergoes a DISIDA scan after 5 days of phenobarbital therapy. The scan showed normal uptake by the liver but no excretion of the isotope (i.e., no bile flow) into the bowel even after 24 hours. She is referred to the surgical service for evaluation. She is then scheduled for a with intraoperative cholangiogram, wedge and possible Kasai procedure.

Biliary atresia (BA) is a serious cause of infantile cholestasis and the most common cause of orthotopic in children. BA was originally thought of as the progressive fibrosis and obliteration of the extrahepatic biliary system. However, it is now known that the intrahepatic bile ducts are also affected by the disease process. The incidence of BA is not well known with individual studies reporting an incidence ranging from 1 in 8,000 live births to 1 in 25,000. There are 2 types of BA that are currently recognized and described: a fetal or embryonic type and a perinatal type. The fetal type occurs in 15-35% of cases and is characterized by an earlier onset of cholestasis. There is an association between the fetal type and other congenital anomalies such as situsinversus, polysplenia, cardiac malformations, and other manifestations. There also tends to be a lack of remnants at the porta hepatis with the fetal form of BA. The more common form of BA is the perinatal form which occurs in 65-85% of cases and is not associated with congenital anomalies. As the names imply, the initiating event of the two types are theorized to occur at different times in development with probably very different etiologies. Research has focused on the possible etiology of the perinatal form with causes including viral infections, auto-immune disease, and immune mediated damage. The viruses that are under question include CMV, reovirus, rotavirus, HPV, and retroviruses. Theories of the etiology of the fetal type of BA center around a possible morphogenesis defect, known as the ductal plate malformation, due to defective gene expression leading to the associated congenital anomalies. While there are possible candidates for the defective gene there has been no definitive identification. Therefore the etiology of both forms of BA remains unknown at this point. The signs and symptoms of biliary atresia will be dependent upon the time of presentation. Usually, the patient is born at term with a normal birth weight. Jaundice can be present at birth or it can present as late as 3 to 5 weeks of life. Other than jaundice, another common complaint is acholic stools, which are highly suggestive of cholestasis. There can be some pigment in the stool due to sloughing of cells that contain pigments. However, this pigment is only present superficially with the core of the stool remaining pale. Since the bile pigments are no longer released into the stool, they will be deposited in the urine leading to darker urine. On physical exam the patient will usually have an enlarged firm liver (normal averaging 4.5-5 cm at 1 week and 6-7 cm during early adolescence). The presence of splenomegaly is variable and more common with later presentations as part of the constellation of . Patients may also present with the findings associated with the fetal form of BA including polysplenia, situsinversus, and Biliary Atresia 12 cardiac malformations. The undiagnosed infant with BA will present with a much different picture. This is due to the progressive nature of the disease. Later presentations are associated with the progression of the disease to biliary cirrhosis and the development of portal hypertension with failure to thrive. The clinical picture at this point will be dominated with findings suggestive of cirrhosis and portal hypertension such as jaundice, hepatosplenomegaly, a nodular liver, varices, ascites, and hepatic vascular bruits. Laboratory examination will show an elevated total bilirubin with an increased direct (conjugated) portion. The serum aminotransferases levels will tend to be normal or mildly elevated. Alkaline phosphatase will be highly elevated reaching levels higher then 5 times normal. Early in the disease process there are usually no changes in coagulation studies. There are many conditions that can cause cholestasis in the neonate and lead to jaundice. These include hepatitis (viral and other causes), sepsis, endocrinopathies, metabolic derangements, and nutritional hepatotoxicities. The most common disorders in decreasing incidence are idiopathic neonatal hepatitis, BA, alpha-1-antitrypsin deficiency, and persistent intrahepatic cholestasis disorders. The greatest challenge is the differentiation of BA from idiopathic neonatal hepatitis and the intrahepatic cholestasis disorders. Idiopathic neonatal hepatitis is not the same entity as neonatal viral hepatitis. As its name implies, the cause is unknown. There have been diseases that are now described that were once under the heading of idiopathic neonatal hepatitis such as alpha-1-antitrypsin deficiency. These patients tend to present with low birth weight, early onset of jaundice, and usually have pigmented stools. Associated malformations are usually not found with this disease and if present should prompt the search for an alternate diagnosis. Laboratory findings include elevations in the serum aminotransferases and bilirubin. Alkaline phosphatase can be elevated but is not always. Coagulation studies may also be abnormal. A diagnosis of idiopathic neonatal hepatitis should only made when other causes of cholestasis (including BA and alpha-1-antitrypsin deficiency) are ruled out. Histologic findings include disruption of the lobular architecture with hepatocellular swelling, focal necrosis, and the presence of multi-nucleated giant cells. However, the presence of hepatocellular swelling giant cells can also be seen in BA. The largest portion of the workup for idiopathic neonatal hepatitis is to rule out any metabolic, infectious, genetic, or other described conditions. Under the heading of persistent intrahepatic cholestasis disorders is intrahepatic bile duct paucity which includes both non-syndromic bile duct paucity and syndromic forms such as Alagille syndrome. These are characterized by the absence or marked decrease in the number of intrahepatic interlobular bile ducts, with normal sized arteries and portal veins in the triad. Intrahepatic bile duct paucity was previously referred to as "intrahepatic bile duct atresia" or "intrahepatic biliary atresia". This was a misleading term that is no longer used since by definition BA is the fibrosis and obliteration of the extrahepatic biliary system, not the intrahepatic system. These diseases are diagnosed by the presence of cholestasis and bile duct paucity on liver biopsy. The non-syndromic form describes a common pathology with various etiologies, which are still poorly understood. With the syndromic forms there are characteristic findings associated with the bile duct paucity. For example in Alagille syndrome, or arteriohepatic dysplasia, there are characteristic facies along with ocular, cardiovascular, vertebral, and kidney pathology. Efforts must be made to diagnose BA early since the success of intervention is dependent upon the time frame. When a child presents with jaundice, the first step is to evaluate the total and fractionated bilirubin in each patient with jaundice. If the elevation is isolated to the unconjugated (indirect) fraction of bilirubin then significant liver pathology is unlikely. However, if the elevation is in the conjugated (direct) fraction or it is 20% or greater of an elevated total bilirubin then cholestasis more likely. If the presence of cholestasis is established, then the etiology must be found in a timely fashion. Panels of testing can quickly rule out or diagnose entities such as hypothyroidism, galactosemia, tyrosinemia, alpha-1- antitrypsin deficiency, and infectious diseases. Once these items are ruled out, the challenge is to differentiate between idiopathic neonatal hepatitis and BA. Non-invasive testing for biliary atresia currently relies on the use of hepatobiliary with the use of 99mTc-iminodiacetic acid compounds or HIDA scans. The newer iminodiacetic compounds have greater concentrations in the bile then the original compounds. HIDA scans using older compounds will not visualize the biliary tract if the bilirubin is high, so the currently favored compound is 99m Tc-disofenin or DISIDA. Images consistent with BA will show normal uptake by the liver with no excretion into the bowel even after 24 hours. The specificity of the DISIDA scan can be increased by pretreatment with phenobarbital (5mg/kg/24h PO for 5 days prior to study) to increase the excretion of the disofenin. If the DISIDA scan demonstrates bile flow from the liver to the duodenum (i.e., the biliary tree is visualized), then BA is ruled out and the work-up can stop. Patients who demonstrate an obstructive pattern on DISIDA will have BA in 80-85% of cases; however, neonatal hepatitis is still possible since it can cause severe cholestasis. In patients with idiopathic neonatal hepatitis, there is slow uptake of the compound with excretion into the bowel; however, in some instances, the cholestasis is so sluggish, it cannot be reliably distinguished from BA. DISIDA scanning is less reliable with higher levels of serum bilirubin, however bowel activity is still observed with hyperbilirubinemia as high as 20-30 mg/dL. If there is poor Biliary Atresia 13 uptake by the liver without bowel activity it is indicative of severe hepatocyte damage that could be caused by either BA or idiopathic neonatal hepatitis. Another method for the diagnosis of BA is the use of ultrasound guided liver biopsy. While there are no pathognomonic histological changes, the biopsy is reported to provide a diagnosis of BA ranging from 70% to 97%. Findings include edema of the portal tracts, tortuous proliferation of bile ductules, fibrosis, along with intracellular and canalicular cholestasis. There is also a mixed infiltration of neutrophils and lymphocytes with a mild non-specific cholangitis. Of note is that there can also be ballooning of the hepatocytes and multinucleated giant cell formation. This can cause some overlap between the histological picture presented by BA and by idiopathic neonatal hepatitis. If the biopsy shows absence or reduction in the amount of interlobular bile ducts at the portal triad, with an intact biliary tree on scintigraphy, then a diagnosis of intrahepatic bile duct paucity (formerly known as intrahepatic biliary atresia) is established and true or extrahepatic BA is ruled out. Also of note is that there should be no dilation of the intrahepatic bile ducts in BA as can happen with some other forms of extrahepatic cholestasis. The gold standard for the diagnosis of BA is the laparotomy with intraoperative . If an intact extrahepatic biliary system is not visible, then extrahepatic biliary atresia is evident. If an intact biliary tree is visible, then an intraoperative cholangiogram is done, in which the surgeon cannulates the bile duct and injects contrast to determine if the biliary ducts are patent. Non-patency indicates sclerosed ducts and extrahepatic biliary atresia. A patent biliary system visualized on the intraoperative cholangiogram rules out extrahepatic biliary atresia. At this point, a wedge liver biopsy is obtained. This biopsy is examined for the presence of intrahepatic bile ducts. If the intrahepatic bile ducts are obliterated or reduced in number, then bile duct paucity (formerly called intrahepatic biliary atresia), is present. An intact and patent extrahepatic biliary tree rules out extrahepatic biliary atresia and the presence of normal intrahepatic bile ducts rules out bile duct paucity. This diagnostic algorithm is summarized below. Diagnostic algorithm of biliary atresia:

1. 1) Direct hyperbilirubinemia prompts evaluation and lab work-up. 2. 2) Look for evidence of bile excretion (DISIDA scan, pigmented stools): Any evidence of bile excretion, rules out BA. If cholestasis is present (i.e., no bile excretion is demonstrated), then proceed to next the step. 3. 3) Laparotomy:

a) Look for a visible biliary tree: If absent, then extrahepatic BA is present. If present, then proceed to next step. b) Perform an intraoperative cholangiogram: If non-patent, then extrahepatic BA is present. If cholangiogram demonstrates patents ducts, then proceed to next step. c) Perform a wedge liver biopsy: If intrahepatic bile ducts are obliterated or reduced in number, then bile duct paucity (formerly known as intrahepatic BA), is present. The biopsy can also be used to find an alternate diagnosis. If bile ducts are patent and present, then BA is not present, in which case the biopsy is likely to demonstrate an alternate diagnosis such as neonatal hepatitis.

Depending on the anatomic type of BA which is present, it can be classified as either a correctable lesion (20% of cases) or a non-correctable lesion (80% of cases). A correctable lesion has fibrosis of the distal biliary tree with the proximal biliary tree and the intrahepatic bile ducts remaining patent. In these cases, excision of the fibrotic area and direct drainage into the bowel is possible. In the non-correctable lesions, the biliary system is fibrotic to the level of the porta hepatis. These patients need to undergo the Kasai procedure to establish bile flow. The Kasai procedure is the Roux-en-Y where the porta hepatis is attached to a loop of bowel after resection of the fibrotic biliary system. This procedure basically anastomoses the liver directly to the bowel so that in theory, bile can flow from the liver into the bowel. The reason that the procedure succeeds is that at the porta hepatis there are microscopic bile ductules that have proliferated which communicate with the intrahepatic system. Some groups use frozen section biopsy during the laparotomy to examine the tissue at the porta hepatis using the size of the vessels as a marker for the likelihood of successful re- establishment of bile flow. However, there have been variations in the size of vessels required and this theory is not universally accepted. The success of the Kasai procedure depends largely on 2 factors: age at procedure and experience of the center it is performed at. To obtain maximum benefit from the Kasai procedure it should be performed before the patient is 3 months old, ideally less then 2 months. This is the major reason why the diagnostic determination of whether BA exists, must be done expeditiously. Establishment of bile flow is achieved in 80% of the patients who are less then 2 months, 50% between 2 and 3 months, and less then 10% if older then 3 months. The decrease in the success rate of the Kasai procedure with advancing age is due to progressive damage to the liver from untreated BA (i.e., further back-up of bile flow inflicts additional damage to the existing intrahepatic ducts). The other factor is the experience of the center Gastroesophageal Reflux 14 performing the surgery. Outcomes of the procedure and post-procedure survival are improved when the hospital does more then 5 procedures a year. If the child is diagnosed at an age greater then 3 months, the Kasai procedure has a low probability of success. Performing a Kasai procedure after this age is thus controversial, versus proceeding straight to liver transplantation, which is the treatment for a failed Kasai procedure. It is the general consensus that a patient should undergo the Kasai procedure even if they present at ages greater then 3 months if it is possible that bile flow can be established. While a post Kasai transplant is technically more difficult, there was no reported change in survival after transplantation in patients who underwent primary transplantation versus those who had a failed Kasai procedure prior to transplantation. The use of the Kasai procedure may not provide long term cure in the older BA patient but it may buy time for preparation for transplantation, finding a donor, and advancement of transplantation technology. Ascending cholangitis is the most common complication, occurring in 40-60% of Kasai procedures. The etiology for this is anatomic and bacterial. Bowel bacteria have access to the existing bile ducts and hepatic tissue. The normal anatomy of an intact bile duct prevents bowel contents from refluxing up toward the liver. In the Kasai procedure, the bowel contents containing digestive enzymes have direct access to the existing bile ducts and hepatic tissue causing the cholangitis. An anti-refluxing valve can be surgically created within the duodenal segment anastomosed to the liver, but such alterations in the Kasai procedure and various medical regimens have not proven successful. There does appear to be an increased risk in the patients with established bile flow, probably due to an intact pathway for ascending bacteria. Prophylactic antibiotics with trimethoprim-sulfamethoxazole is designed to reduce bowel bacterial counts. Repeated episodes of cholangitis can lead to extensive liver damage and cirrhosis. Another common complication of BA is portal hypertension, which occurs in 35-75% of patients. This occurs due to the progressive inflammation and fibrosis of the intrahepatic biliary system and/or repeated episodes of cholangitis leading to cirrhosis. The portal hypertension that develops will have the sequelae of other forms of portal hypertension such as varices, ascites, hypertensive gastropathy, hypersplenism, and encephalopathy. The most common presentation is esophageal variceal hemorrhage occurring in 30-60% of patients. Treatment relies on the same methods employed in adults for other forms of portal hypertension. BA is a chronic cholestatic disease if untreated can lead to complications as a result of the cholestasis. The end result is biliary/hepatic cirrhosis if BA is not treated with a life expectancy of 2 years. Mortality is a result of liver failure or portal hypertension. As mentioned before the chance of establishing bile flow in BA patients with the Kasai procedure is dependent upon the age that the patient undergoes surgical intervention. However, it should be noted that the establishment of bile flow does not necessarily mean long term cure since BA also involves intrahepatic inflammation that can lead to cirrhosis. After the Kasai procedure, the patient can be stratified into 1 of 3 prognostic groups at 4 to 6 weeks post operatively. The first group are the patients who produce adequate bile flow and are relieved of their jaundice. They will have long term survival and possibly not need liver transplantation. The second group has moderate bile flow but they remain jaundiced and will continue to survive post-Kasai, however they will eventually need liver transplantation later in life. The third group are those who do not establish bile flow. This is considered a failure of the Kasai procedure and they will need liver transplantation in order to survive. While the Kasai procedure establishes bile flow, it does not necessarily halt the intrahepatic inflammation and fibrosis. Patients who undergo the Kasai procedure can survive with their native liver in 20-30% of cases, but the remainder will eventually need liver transplantation. Overall survival rates of patients with BA post intervention in recent studies range from 70 to 85%. Ten year survival ranges from 33% in older studies to 68% in more recent studies. Survival with one's native liver at 5 years has been reported to be as high as 32% in recent studies and 27% at 10 years. Biliary atresia is no longer a fatal disease in all who are diagnosed with it. The early diagnosis and treatment of BA can lead to long term survival without the need for liver transplantation. However, the key is the early diagnosis of BA in order to ensure that surgery can be performed in a timely manner at a high level center to increase the likelihood of success. Despite this, there are still many children who are untreated at 3 months of age (as high as 14-19% in some studies). Efforts to introduce screening methods for BA have been attempted with poor results. The best method so far, is to maintain a high clinical suspicion in the jaundiced patient. Direct hyperbilirubinemia deserves a prompt and thorough evaluation. Questions

1. 1. True/False: A 2 week old infant presents with persistent jaundice to the office. No further work up is necessary since this is physiologic jaundice. 2. 2. A DISIDA scan report, for a patient in whom biliary atresia is suspected, comes back stating that there was poor uptake into the liver and no visualization of the isotope into the bowel. Can you diagnose biliary atresia in this patient? 3. 3. A liver biopsy shows hepatocellular ballooning and the presence of multinucleated giant cells. Is this consistent with biliary atresia? Gastroesophageal Reflux 15 4. 4. A patient presents to you with lightly colored stool; however, when the stool is broken up it is noticed that the center is clay colored. What is this indicative of? 5. 5. A 16 week old patient is diagnosed with biliary atresia, should he/she undergo a Kasai procedure if there are no contraindications or should the patient just wait for a liver transplant?

Answers to questions

1. 1. False. Persistent jaundice needs to be worked up before permanent damage is done by any number of pathological conditions, such as BA. Since there is little risk involved, the threshold to obtain a serum fractionated bilirubin should be low. If there is an elevation of conjugated bilirubin at 14 days of age or earlier, it is by definition neonatal cholestasis. 2. 2. No. With poor uptake into the liver you can only state that there is cholestasis. This may be transient cholestasis due to hepatitis, or it may be due to severe damage to the hepatocytes by several possible causes including biliary atresia. To make a diagnosis, there needs to be normal uptake in the liver with no movement into the bowel, even after 24 hours. Pretreatment with phenobarbital improves the yield on the DISIDA scan. 3. 3. Yes, this histopathology is consistent with the histopathology seen with biliary atresia. However, it is also consistent with idiopathic neonatal hepatitis and therefore a definitive diagnosis can not be made on this biopsy result alone. 4. 4. The presence of clay colored or acholic stools are indicative of cholestasis. The lack of bile flow into the bowel prevents the characteristic stool coloring. The superficial light coloring is due to the sloughing of pigmented cells during the transit in the bowel and does not affect the core of the stool. 5. 5. While there is little chance of long-term survival with the patient's native liver in someone who undergoes the Kasai procedure after 3 months of age, there is some benefit. The Kasai procedure can lead to extended survival time with the native liver, allowing the patient to stabilize baseline health. There is also a benefit in that there will be longer period of time to find a donor and prepare the patient for transplantation. However, each patient is different and some may be better served by primary liver transplantation.

Gastroesophageal Reflux

A one month old male is brought to your office by his first time parents with a complaint of constant irritability and spitting up. The 2.8 kg (6 pounds, 3 ounce) product of an uneventful full term pregnancy and delivery, he was discharged on the second day of life. He always seems to be hungry, and since his mother is certain that she is not producing enough milk, she has been following the breast feedings with formula for the last 2 weeks. He currently will feed at the breast for 10 minutes, then consume another 4 ounces by bottle. When left with his grandparents, he will finish an entire 8 ounce bottle in 5-10 minutes and they report he will cry if they try to cut him off at the recommended 4-5 ounces. The vomiting generally occurs immediately after feedings. It is not forceful, nor is it blood or bile-tinged. He fills 10 diapers with urine daily, and lately he has been having watery stools, which have further worried his grandparents. Despite all this, he weighed 3.5 kg (7 pounds, 11 ounces) at the two week checkup and he now weighs 4.3 kg (9 pounds, 8 ounces). Exam: VS are unremarkable. His physical examination is notable only for fussiness when laid supine on the table, with resolution when held upright or in the prone position. You witness effortless regurgitation of 2-5 ml of curdled formula every few minutes during the history and exam since his parents "topped him off" with formula in your waiting room before the appointment as he was beginning to fuss.

Gastroesophageal (GE) reflux is defined by the North American Society for Pediatric Gastroenterology Gastroesophageal Reflux 16 and Nutrition (NASPGN) as the "passage of gastric contents into the ". This is a normal physiologic process including regurgitation (the generally low pressure passage of gastric contents up to the mouth) as opposed to vomiting (the forceful expulsion of gastric contents via the mouth) as the latter is more often associated with obstruction or other significant abnormal alteration of gastric motility involving reversal of the usual gastric emptying phenomenon. Likewise, it is to be differentiated from rumination, which is the purposeful return of gastric contents to the mouth as a response to behavioral issues, most typically beginning in the second half of the first year of life and occurring in neglected infants and children in part as self-stimulatory behavior or as a means of getting attention from an otherwise markedly non-interactive (and usually clinically depressed) caretaker. GE reflux occurs at all ages, and its consideration is best divided between infantile reflux and reflux in the older toddler/child, as the presentations will differ due to responses available due to developmental stage. It can be a chronic and a recurrent problem. In infants, the more typical presentation is as above, which the NASPGN label "the happy spitter" who freely regurgitates, but more commonly than not, has no sign of respiratory compromise. With the relatively low acid secretory capability and the constant feeding of early infancy, there is less tendency to irritability suggestive of dyspepsia, though many (like the child in the example) will show some sign, and some will become markedly colicky. The attribution of the colicky behavior to reflux is supported by an increase in fussiness in positions where reflux would be promoted; such as supine or slumped in a mal- positioned baby seat, or at times when reflux can be expected; such as following an overfeeding as in our example. In toddlers and older children, overt regurgitation is less common as they spend more time upright and typically will have learned eating behaviors favoring solids and minimizing liquids which further help retain most of the feedings in the stomach. The retention is not complete, however, and they more typically present with symptoms or signs suggestive of distal esophageal irritation. Aside from complaints of epigastric pain (in the pre-verbal toddler often indicated as holding the epigastrium or refusing to eat further), they can include drooling (caused by reflex hypersalivation triggered by the acid sensors of the distal esophagus acting via the brainstem on the salivary glands), or pronounced eructation (i.e., belching, representing regurgitation of air co-swallowed with the saliva). The latter two are manifestations of the esophageal protective mechanisms, and can be seen in early infancy presentations, just as many toddlers will still regurgitate freely. In the older child and adolescent, hypersalivation is more commonly manifest as a sleeping behavior (as not all the saliva produced while recumbent is swallowed) and often is accompanied by sleep in specific positions of comfort, the most common of which are prone and left decubitus as these offer some positional advantage to mitigate reflux. These options are not available to the infant (particularly in the face of the American Academy of Pediatrics' "Back to Sleep" campaign against SIDS), often resulting in worsening colicky behavior, as noted in our example. Occasional patients will present with respiratory symptoms as their primary complaint with reflux laryngitis and the contribution of microaspiration of either regurgitated acid or oral secretions (from the hypersalivation) in the exacerbation of chronic asthma is gaining increasing recognition. Though more common as a presenting complaint among older children, it will occur in younger children as well, but is not the more common presentation for any age. A more worrisome presentation is frank aspiration or choking, resulting in pneumonia for the former and symptoms ranging from gagging and sleep interruption to apparent life threatening events (ALTE) for the latter. These more serious conditions require full regurgitation, and are also far less common than the non-respiratory symptoms which require reflux only part-way up the esophagus. The NASPGN have acquiesced to the AAP in dissuading prone sleeping position before 12 months of age, though proning may be used while "awake, particularly in the postprandial period". GE reflux, and more specifically secondary esophageal irritation (if not frank esophagitis), can result in voluntary reduction in intake in all ages, resulting in classic failure to thrive or frank weight loss. It can result in overt feeding refusal, though it more commonly is manifested as a selective intake, avoiding items which cause pain including acidic and spicy foods, and surprisingly commonly, items with adverse effect on the distal esophagus, including caffeine and chocolate if the examiner questions specifically. GE reflux must be differentiated from vomiting, as the latter hints at obstruction, and can also arise from metabolic processes (urea cycle defects and Reye syndrome) as well as disease in other organ systems (increased intracranial pressure, pancreatitis, urinary tract infection, or distention of any hollow viscus such as the or renal pelvis/ureters). It should also be differentiated from extra- abdominal causes such as post-tussive vomiting, or altered motility due to allergic enteritis or eosinophilic gastroenteritis. In the case above, a one month old with projectile vomiting would suggest pyloric stenosis, but in our case the vomitus is not forceful and has been present from the neonatal period. Projectile vomiting requires an intact lower esophageal sphincter (LES) function to develop adequate intragastric pressure. Since GE reflux is common at this age (>50%), projectile vomiting may not be present in infants with coexisting pyloric stenosis with GE reflux, which may delay the diagnosis of pyloric stenosis. Three mechanisms produce the majority of GE reflux: 1) Chronically decreased lower esophageal sphincter tone is most common at all ages and can be expected to improve over the first year of life. It is Gastroesophageal Reflux 17 characterized by symptoms which occur more commonly immediately after feedings and further reflect effects of posture or intra-abdominal pressure. 2) Delayed gastric emptying is common among adults due to progressive gastroparesis, particularly with diabetes mellitus, but is less common in children. Characteristically it will produce symptoms which continue for hours after feedings, reflecting the persistently full stomach. 3) Inappropriate LES relaxation is least common of the three, and typically produces more irregular timing of the symptoms, which tend to be more fleeting as the esophageal protective mechanisms are typically more effective in these youngsters than with the other two. The diagnosis of GE reflux is typically made by a detailed history and physical examination alone. Regurgitation reliably reported or observed with appropriate adjunct symptoms and signs is suggestive of uncomplicated GE reflux. A careful elucidation of a consistent constellation of symptoms can suggest reflux which is not visible (which is also sufficient to trigger the first lines of intervention). It is in situations where significant secondary disease is present (such as recurrent aspiration, stridor suggesting laryngeal irritation, or failure to thrive with or without frank feeding refusal), that subspecialist assistance should be sought at an early stage, even if overt regurgitation makes the diagnosis fairly certain. Efforts should be made to exclude the other items in the differential diagnosis above, but many can be excluded on the basis of a good history and physical examination of the relevant organ systems. Radiographic studies are not part of the usual initial workup since the absence of reflux on a short radiographic study cannot rule out GE reflux, and the manipulation inherent in the exam can itself trigger regurgitation. The main utility of the upper gastrointestinal contrast study is to search for structural anomalies such as malrotation as well as the much rarer webs and secondary strictures. These are often accompanied by signs of obstruction (though bilious vomiting may be absent if the obstruction is proximal to the mid-duodenum). The exception is the younger patient with signs of tracheomalacia, as the rare vascular ring, trapping both the esophagus and trachea in its grasp during in utero growth, deserves early intervention. Another exception is pyloric stenosis, for which ultrasound provides less invasive evaluation, permitting earlier access to surgery. The radionuclide gastric emptying study, likewise is not commonly part of an initial workup, as its prime utility is in assessing delayed gastric emptying. Unfortunately, age appropriate standards are not well established, prompting the use of this test in the more severe cases where surgery is already being contemplated (typically fundoplication). Scintigraphic imaging during the hour-long study can also identify reflux visually (but again cannot rule it out due to the short duration of the study) and 24 hour delayed imaging is cited as being of utility in searching for evidence of aspiration. pH probes offer a means of assessing the frequency and duration of acid reflux, and with the double- sensor probes, the differentiation between regurgitation and reflux only part-way up the esophagus can be made. Twenty-four hour studies are more reliable than those of shorter duration, since reflux varies with activity and sleep state. Their prime utility is in the patient with symptoms which are clear and disruptive who does not have a clear association with visible regurgitation. The classic example is the infant with repeated ALTEs who is found with curdled feedings. The main issue in such patients in establishing causality is determining whether the reflux came first, then the obstruction, then the apnea. It is more common that the apnea came first, then the agonal relaxation of the LES and regurgitation. In such situations, simultaneous multichannel recordings are essential, since the transition from one stage to the next may be only seconds apart, and on such studies many infants with obstructive apneic episodes and known GE reflux have the two occur at completely different times. Manometric studies have fallen on disfavor, as they do not address the issues of delayed gastric emptying or inappropriate relaxation of the LES.

For the average healthy infant with no threatening complications, the GE reflux can be approached first with basic mechanical measures:

1. 1) Regulate feedings: As in our illustration, overfilling of the stomach is to be discouraged, and in such a patient, I would recommend the bottle feedings be halted if there is ample evidence of sufficiency of breast feedings. This can be reinforced by following the urine output, with most parents being reassured when told that the fluid urinated had to have been absorbed, and the nutrients associated with that fluid can be expected to be absorbed as well. In the bottle-fed infant, the volume can be calculated, but I have found it easier to give the caretakers a means of identifying the volume that would fit in a minimally distended stomach as being roughly a quarter of the abdominal volume as measured between the ribs and the pelvic brim. This forestalls repeated questions of "how much can we feed now?" as the child grows. The feedings also need to be regularly spaced, to avoid overfilling with too closely spaced feedings. This is less of a problem in the exclusively breast-fed infant, but is not eliminated. For the demanding infant, use of suitable pacification (particularly a parental digit) can be helpful. The feedings also need to be evenly paced, to allow enough time for the infant to feel full and cut off the feeding before overfilling occurs. With the bottle-fed infant, thickening of the feedings is possible; in exclusive breast-feeding, the parental digit will again have to be used. 2. 2) Positioning: Maximizing the vertical distance between the mouth (or more particularly the Gastroesophageal Reflux 18 larynx) and the stomach helps minimize reflux and secondary esophageal irritation (i.e., colic). The literature does support prone positioning in this regard, but the cautions noted above regarding SIDS apply. It is worth mentioning to parents, however that infants choose their own sleeping positions once they are able to roll from supine to prone around 4 months of age to avoid many sleepless nights repeatedly rolling their infant back into the supine position only to flip back as soon as he or she is free to do so. Decubitus positioning provides some relief, as can positioning in a recliner (as long as the angle chosen does not cause slumping). There will be times when carrying the infant upright may offer the only relief (particularly after overfeeding). 3. 3) Thickening the feedings may be a consideration in the formula fed infant, and is far less practical in the breast-fed one. In many cases the greater utility of the thickening is in slowing the feeding rate than in any retention within the stomach. Rice cereal is preferred over the recently introduced formulas that thicken when exposed to acid (recall many young infants may not produce much acid). Typical recipes call for one-half to one tablespoon of rice cereal per ounce of formula, which also adds substantially to the overall caloric intake. Thickening to encourage retention in the stomach is of most use in those with evidence of chronic low LES tone (spitting which occurs predominantly shortly after the meal) and can be less than useful in those who have delayed gastric emptying (with spitting which continues for hours after a meal) as it may cause further delay in emptying. In such infants who are formula fed, one of the cheaper partially hydrolyzed formulas may provide the better option, as fluids empty from the stomach faster than curd. In that respect, breast feeding, with its thinner curd, tends to empty faster than most formulas.

In older toddlers and children:

1. 1) Regulate the feedings: Many with secondary esophageal irritation (if not frank esophagitis) will tend to complain of nausea and anorexia in the morning, and skip or minimize breakfast intake. They may or may not eat much lunch, particularly if the school is providing a spicy menu. They often eat more of their daily caloric intake throughout the afternoon and evening. Redistributing the intake to be more evenly spaced during the day will result in less nocturnal acid reflux and is of most utility in those complaining of symptoms after supper or nocturnal waking or morning nausea. Avoidance of after supper snacking can also help. 2. 2) Positioning is less of a problem once infants pass 6 months of age and can choose to be upright. For older children, the option of elevation of the head of the bed for sleep is often declined as more seem to prefer prone positioning. 3. 3) Avoid agents prone to adversely altering LES tone and functioning such as caffeine and nicotine.

In all age groups, a therapeutic trial to address acid can be of significant diagnostic utility. My personal preference is to use antacids, since this provides immediate pain relief (good reinforcement). Typical therapeutic courses with histamine-2 receptor blockers or proton pump inhibitors run 6-8 weeks with only partial resolution. In infants, the aluminum containing antacids should be avoided since aluminum absorption may cause osteodystrophy. A typical therapeutic trial yields suggestive results within 2 weeks, and can be helpful in determining whether an atypical (but non-threatening) symptom is acid-related. Beyond these basic steps, the evaluation and therapy diverge based on the dominant symptoms. If delayed gastric emptying is the issue, therapy centers on properistaltic agents and may include a more thorough evaluation of structure and gastric emptying. If pain or other inflammatory signs are dominant (i.e., reflux laryngitis), acid secretion suppression or blockade are the mainstay, and endoscopy (with biopsy) offers the best diagnostic discrimination. These measures typically prompt subspecialist assistance. Infantile reflux typically presents with overt regurgitation and dyspepsia (colic). These can be expected to improve markedly over the first year of life with the transition to a diet based more on solids than liquids and attainment of a more upright posture. Conversely, GE reflux in the older child tends to present as chronic or recurrent pain, with only secondary signs or symptoms of reflux and no overt regurgitation. It represents a chronic problem, the symptoms of which may run life-long, and if mechanical measures and intermittent acid neutralization do not provide adequate symptomatic relief, long-term medical therapy may be warranted. In either case, in the absence of life-threatening complications, surgical options are not a routine consideration, and generally are considered only in the face of failure of extended and aggressive medical management of significant levels of disease.

Questions 1. True/False: Gastroesophageal Reflux is a rare phenomenon in childhood. 2. For the vomiting infant: a. The parents can be reassured it is a process the child will outgrow as they get older. b. Thickening the feedings sometimes works. Gastroesophageal Reflux 19 c. Proper positioning may be helpful. d. Deserves further evaluation.

1. 3. A one month old second born female presents with worsening of her GE reflux. The regurgitation remains effortless, but is increasing in volume and seems more prominent an hour or so after meals. She has been more demanding of feedings and has had fewer wet diapers over the last few days and is losing weight. Her parents have felt "something moving" in her stomach in the hour after feedings over the last week. What is happening? 2. 4. True/False: A 4 year old with complaints of abdominal pain that disrupt school attendance warrants a two week trial of a proton pump inhibitor. 3. 5. True/False: A diagnosis of pain due to gastroesophageal reflux is likely to lead to a lifetime of expensive medication.

Answers to questions

1. 1. False. Though most episodes are asymptomatic, reflux is a routine physiologic phenomenon in everyone, at every age. It is gastroesophageal reflux DISEASE that is uncommon in most of childhood. 2. 2. d. Remember regurgitation is effortless, vomiting is forceful and is atypical for uncomplicated GE reflux. It can indicate obstruction or metabolic derangement, and represents a problem that requires an answer in as short a period of time as possible (even if the answer is a diagnosis of routine gastroenteritis). 3. 3. Consider pyloric stenosis, even if only a few of the classic symptoms and signs are present. Waiting for the diagnosis to become more obvious further delays surgical intervention and increases the risk of complications such as hypochloremic alkalosis and dehydration. See differential diagnosis above. 4. 4. This one is arguable, but my personal preference is to start treatment with antacids since it offers a means of immediate relief of any truly peptic pain episode, and younger children are better reinforced by immediacy of the response. Of course a good history and physical should come first to verify the pain does fit a "peptic" pattern, as constipation is more likely at this age. 5. 5. False. The vast majority of uncomplicated pain seems to respond to mechanical measures, avoidance of caffeine, nicotine, and the like, and intermittent antacid use. It is only when the pain episodes remain disruptive more than once weekly that it is generally warranted to proceed to chronic medical therapy, and then only at the minimal doses necessary unless other complications (e.g., Barrett's esophagus) occur.