Carbohydrate Malabsorption and Disaccharidase Deficiencies

Clinically, congenital disaccharidase deficiency and carbohydrate malabsorption is an osmotic type of diarrhea caused by unabsorbed solute in the ileum. The normal rapid transit of the GI tract in children results in a more severe form of diarrhea than in adults. Histologically, the appearance of the small intestine in these cases is usually unremarkable. Therefore, the diagnosis is usually confined by determination of disacchariadase activity in homogenates of small bowel biopsy specimens or by breath testing.

Congenital disaccharidase and transporter deficiencies are rare; these disorders are much more likely to be secondary, resulting from diffuse mucosal damage due to infectious gastroenteritis, gluten-sensitive enteropathy, or other food allergies. Accelerated crypt shedding, which occurs in mucosal injury, may outpace expression of brush border enzymes and transporter proteins, leading to worsening of the diarrhea and malabsorption. This may be one reason why tacrolimus, which reduces the rate of T cell–driven crypt cell proliferation and shedding, has been found to be effective in conditions such as “tufting” enteropathy and AIE.^11,12

Lipid Trafficking Disorders

Fat absorption by enterocytes begins with emulsification and solubilization of cholesterol in the intestinal lumen by biliary lipids and salts. Most clinical disorders of fat malabsorption result from severe liver disease, pancreatic disease (e.g., cystic fibrosis), or extensive ileal resection (as in Crohn’s disease), with loss of the enterohepatic circulation of bile acids. Intestinal biopsies play a limited role in the diagnosis of these disorders. However, primary disorders involving abnormalities of fat transport within enterocytes, although uncommon, may result in a characteristic vacuolization of enterocytes in intestinal biopsy specimens.

Abetalipoproteinemia, hypolipoproteinemia, and chylomicron retention disease (Anderson disease) share many characteristics, including fat malabsorption, low levels of serum lipids, failure to thrive in childhood, neurologic and visual problems resulting from malabsorption of fat-soluble vitamins, and accumulation of lipid droplets in the enterocytes. These conditions are associated with disorders of apolipoproteins, which reside on the surface of chylomicrons. Apoliproproteins native to the intestine are apolipoprotein A-I (apo A-I), apo A-IV, and apo B, which has two forms, apo B-100 and apo B-48, both encoded by the same gene located on chromosome 2.¹⁷ Localization of apolipoproteins in the Golgi apparatus and along the microvilli of enterocytes has been demonstrated by immuno-electron microscopy.¹⁸

Abetalipoproteinemia

Abetalipoproteinemia is an autosomal recessive disorder characterized by absence of apo B-containing lipoproteins. The molecular basis is a mutation of MTTP, the gene that codes for microsomal triglyceride transfer protein, which is located on chromosome 4q22 (see Table 9.2).¹⁹ MTTP is responsible for the assembly of lipoprotein particles and for the proper folding of apo B, which prevents its premature degradation.²⁰ Because of the mutation, fatty acids within intestinal cells cannot be exported as chylomicrons. Patients develop diarrhea and fat malabsorption usually within the first few months of life, with acanthocytosis; deficiencies in fat-soluble vitamins then result in retinitis pigmentosa and neurologic symptoms. However, there is clinical heterogeneity because signs and symptoms may occasionally manifest in older individuals. Serum levels of cholesterol and triglycerides are typically low and, most importantly, do not rise after a fatty meal. Small bowel biopsies typically reveal preserved villi (Fig. 9.1, A), but characteristic multivacuolated, fat-filled enterocytes may be seen in specimens from fasting patients, which on electron microscopy are irregular in size and generally not membrane bound (see Fig. 9.1, B). In addition, lipid does not accumulate in the extracellular space. Hepatic biopsies typically reveal steatosis, with numerous non-membrane-bound lipid droplets within hepatocyte cytoplasm.²¹ Fibrosis evolving to cirrhosis has been reported in some patients.²²

Amino Acid Transport Disorders

Disorders of amino acid transport rarely cause prominent GI manifestations, except for lysinuric protein intolerance (LPI), which results from mutations in the SLCA7 gene. This gene codes for the light chain subunit of the heterodimer amino acid transporter at the basolateral membrane of intestinal and renal epithelial cells.²⁵ Clinically, LPI manifests with failure to thrive, vomiting, and diarrhea. Hepatosplenomegaly, hematologic anomalies, and neurologic involvement including hyperammonemic coma are recurrent clinical features. The urea cycle intermediates ornithine and arginine fail to exit from intestinal epithelium in LPI, resulting in a urea cycle dysfunction with hyperammonemia and alterations of mental status. Two major complications, pulmonary alveolar proteinosis and renal disease, are increasingly observed in patients with LPI.^26,27 The condition is recognized by the presence of markedly elevated urinary levels of lysine and other dibasic amino acids; DNA testing may be required for confirmation of the diagnosis. One 5-year-old boy who was reported to have chronic diarrhea and a “flat gut” on small intestinal biopsy was unsuccessfully treated with a gluten-free diet.²⁸ Other complications associated with this disorder include systemic lupus erythematosus, hemophagocytic lymphohistiocytosis,²⁹ and sudden infant death.³⁰

Electrolytes and Trace Elements

The biology of intestinal ion transport is a complex field. Disorders range from rare selective deficiencies to multisystem diseases such as cystic fibrosis. Defects that manifest primarily with severe diarrhea in infancy include congenital chloride diarrhea and congenital sodium diarrhea. Intestinal biopsy findings in these cases have been reported to be normal or to show only mild partial villus atrophy.³¹ Congenital chloride diarrhea is caused by mutations in the gene for solute-linked carrier family 26, member 3 (SLC26A3). It manifests as a life-threatening congenital diarrhea. Long-term manifestations include renal disease, spermatoceles, and male subfertility.³² Congenital sodium diarrhea results in hyponatremia and metabolic acidosis. The syndromic form of this disorder has been linked to mutations in SPINT2 and is also characterized by cloanal and anal atresia, hypertelorism, double kidney, cleft palate, and digital anomalies.¹³

Acrodermatitis enteropathica is an autosomal recessive disorder that is caused by a defect in intestinal absorption of zinc. Mutations in a candidate gene, ZIP4 (SLC39A4), result in defective epithelial transport in the intestine and kidney.¹³ There is a characteristic clinical syndrome of diarrhea combined with acral and orificial skin lesions. Rodin and Goldman found pancreatic islet hyperplasia, absence of the thymus and germinal centers, and plasmacytosis of the spleen and lymph nodes in autopsy studies.³³ Inclusion bodies in Paneth cells have been reported in patients with this disorder.^34,35 A decrease in villus height is observed in animal models of zinc deficiency and is corrected by zinc supplementation.³⁶ Interference with chylomicron development and function has been noted.³⁷ Severe zinc deficiency is also seen in other disorders, such as the Cronkhite-Canada syndrome.³⁸

Menkes disease is an X-linked disorder that results from a defect in intestinal absorption of copper. Affected patients present with characteristic hair shaft anomalies (pili torti), cerebral degeneration, hypopigmentation, abnormal bones, vomiting and diarrhea, and, occasionally, protein-losing enteropathy (PLE). The disorder maps to Xq12-q13 and is caused by mutations in the ATP7A gene, which encodes a copper-transporting P1B-type adenosine triphosphatase that is part of a family of membrane proteins responsible for cation transport across membranes.^39,40

Vitamins

Congenital vitamin B₁₂ transport disorders include congenital intrinsic factor deficiency, selective absence of intrinsic factor without any gastric anomaly, congenital pancreatic insufficiency of various causes, and congenital selective vitamin B₁₂ malabsorption—the latter an autosomal recessive disorder characterized by megaloblastic anemia, hepatosplenomegaly, vomiting, diarrhea and proteinuria. These disorders are caused by mutations in the gene CUBN, which encodes an ileal cell surface receptor protein known as cubilin.⁴¹ None of these disorders results in any characteristic histologic changes on intestinal biopsies.

A rare congenital disorder of intracellular vitamin B₁₂ metabolism belonging to the cobalamin C (CblC) family has also been described. Patients present with diarrhea, renal failure, and systemic thromboemboli in association with a striking gastric atrophy.⁴² PLE responsive to hydroxycobalamin treatment has been reported in one patient with this disorder,⁴³ presumably on the basis of the gastric anomaly.

Bile Acids

Heubi and colleagues⁴⁴ described a severe type of refractory diarrhea caused by a primary disorder of bile acid absorption; intestinal biopsy findings were normal. A defect in the gene coding for an ileal Na⁺-dependent bile acid transporter, SLC10A2, has been found in this disorder.⁴⁵ Bile acid–related diarrheal illnesses are much more commonly secondary to chronic pancreatic insufficiency⁴⁶ or to loss of ileal surface, as occurs with short gut syndrome resulting from necrotizing enterocolitis⁴⁷ or with extensive ileal resection in Crohn’s disease.^48,49

Pathology

Small bowel biopsy specimens in MVID are usually characterized by severe villus atrophy, mild or moderate crypt hyperplasia, and a variable degree of inflammation in the lamina propria, but without crypt destruction (Fig. 9.2, A). The diagnosis may be strongly suspected on paraffin-embedded sections by the absence of a distinct brush border using the periodic acid–Schiff (PAS) stain, and by the presence of PAS-positive diastase-resistant densities in the apex of enterocytes (see Fig. 9.2, B and C). Similar observations are seen on immunohistochemical staining for alkaline phosphatase and anti-CD10. More recently, similar results using antibodies directed against anti-Rab11a, a small GTPase protein on the surface of recycling endosomes, has provided further evidence that MVID is a disorder of apical plasma membrane recycling.⁵⁴ The pathognomonic ultrastructural features include absent or small stubby microvilli, vesicular structures located toward the apex of enterocytes containing microvilli, and granules containing dense amorphous material (Fig. 9.3). Microvillus inclusions have also been reported in the colon, gallbladder, and renal tubular epithelium in these patients.⁵⁵ A variety of ultrastructural features have also been noted in patients with this disorder, and finding the “typical” inclusions may require a prolonged search.⁵⁶

Atypical inclusions include the presence of numerous small electron-lucent vesicles and accumulation of osmiophilic vermiform structures.⁵⁷ Cases with these features have been previously reported as “MVID with atypical features” or as “microvillous dystrophy.”^58,59 Genetic analysis helps in defining whether the ultrastructural (and sometimes clinical) variability represent different entities or variations in the spectrum of manifestations of a single disorder, especially given the enormous prognostic and therapeutic implications.

Treatment

Patients with MVID are dependent on total parenteral nutrition (TPN). Medical therapy in these patients is generally ineffective, and improved survival may require small bowel transplantation.⁶⁰ An intriguing instance of apparent resolution of the disease with improvement of the mucosal features in a patient on long-term TPN has been reported.⁶¹

Congenital tufting enteropathy (CTE) was first described by Reifen and colleagues⁶² in patients presenting in the neonatal period with watery diarrhea. The prenatal history is usually uneventful. The disease appears to be inherited in an autosomal recessive fashion, as suggested by the finding of other affected siblings and frequent parental consanguinity. The incidence is estimated at 1 : 50,000 to 1 : 100,000 live births in Europe, and it is more frequent in patients of Arabic origin.⁶³ Cases of tufting enteropathy have been described in association with other malformations, including facial dysmorphism, micrognathia and anal imperforation,⁶⁴ and choanal atresia and hair abnormalities.⁶⁵ Superficial punctate keratitis and conjunctival erosions have been observed in about 50% of patients.⁶⁶ In addition, an association has been reported between CTE and autoimmune phenomena, including autoimmune anemia, thrombocytopenia,⁶⁷ and chronic arthritis.⁶⁸ Using single nucleotide polymorphism (SNP) analysis in an affected kindred, Sivagnanam and co-workers⁶⁹ identified the epithelial cell adhesion molecule gene (EPCAM), located on chromosome 2p21, as the causative gene. EpCAM belongs to a family of cell adhesion receptors, is associated with tight junction proteins, and is responsible for cell–cell interaction by recruiting actin filaments to sites of contact.⁷⁰

Pathology

The histologic hallmarks of CTE are severe villus atrophy with the formation of “tufts” of rounded, teardrop-shaped enterocytes that appear to shed into the lumen. There may be a mild increase in lamina propria inflammatory cells, but intraepithelial lymphocytes do not appear to be significantly increased. The brush border is normal by PAS staining, and electron microscopic findings are nonspecific. Dilated crypts have also been described. Epithelial abnormalities typically vary over time and may be subtle or absent in the first biopsy (Fig. 9.4). Abnormalities in immunohistochemical staining for basement membrane laminin and heparan sulfate proteoglycans,⁵⁵ ultrastructural irregularities of desmosomes, and abnormal distribution of α₂β₁ integrin⁷¹ have been observed in patients with this disorder. Immunohistochemistry of intestinal tissue reveals decreased expression of EpCAM, which may be helpful in diagnosis.⁷² Intestinal features resembling CTE have been observed in a knockout mouse model for transcription factor Elf3.⁷³

Enteroendocrine cell dysgenesis (ECD) is an autosomal recessive disorder associated with congenital absence of enteroendocrine cells in the small and large bowel secondary to mutations in the NEUROG3 gene, located on chromosome 10q21.3. This gene is required for differentiation of epithelial cells to an endocrine phenotype.⁷⁸ Affected patients exhibit a congenital diarrheal syndrome with profound malabsorption of all nutrients from birth. Patients also typically develop insulin-dependent diabetes, some during infancy and others later in childhood.^78,79 Pancreatic exocrine function is normal. Neurogenin-3 null mice lack enteroendocrine cells⁸⁰ and are also severely diabetic, because neurogenin-3 is required for pancreatic endocrine development.⁸¹

Pathology

Intestinal biopsies may be normal or may reveal villous atrophy, the severity of the changes perhaps related to different mutations in the NEUROG3 gene⁷⁹ (Fig. 9.5). The brush border is normal, and goblet and Paneth cells are present. Inflammatory cells in the lamina propria do not appear significantly increased, and there is no crypt-destructive process. Electron microscopy confirms the presence of microvilli and the absence of microvillus inclusions.⁸² The characteristic absence of enteroendocrine cells in the small bowel and colon can be confirmed by immunohistochemistry for chromogranin A (see Fig. 9.5, B). Patients with autoimmune polyglandular syndrome I may also have absent or markedly reduced enteroendocrine cells, which may be transient.⁸³ In addition, loss of enteroendocrine cells may be observed in patients with autoimmune enteropathy, along with loss of goblet and Paneth cells. Treatment consists of parenteral feeding with limited oral feeding.

Girault and associates⁸⁴ described a group of patients with dysmorphic features consisting of a prominent forehead, broad nose, hypertelorism, and wooly, easily removable abnormal hair (trichorrhexis nodosa), in association with intractable diarrhea and immunodeficiency, which they termed syndromatic intractable diarrhea because of the constellation of extraintestinal manifestations. Most of the patients reported were of Middle Eastern origin, and their histories included parental consanguinity and similarly affected siblings. The immunodeficiency was characterized by impaired T-cell and antibody responses despite normal immunoglobulin levels. Infants with similar clinical features had been previously reported as having “tricho-hepato-enteric syndrome” (THE)^85,86; in these patients, thin, sparse hair (trichomalacia) was seen in association with hypertelorism and chronic diarrhea, and there was a history of premature delivery with intrauterine growth retardation. In addition, the patients described by Verloes and colleagues⁸⁶ presented with neonatal hemochromatosis, characterized by liver failure, cirrhosis, and multivisceral iron deposition. The phenotypic similarity between THE and the cases described by Girault led Fabre and colleagues to suggest that these manifestations represent a spectrum of the same disorder.⁸⁷ This appeared to be confirmed when mutations in TTC37, described in cases of THE,⁸⁸ were also observed in patients with the features of “syndromic diarrhea.”⁸⁹ TTC37 maps to chromosome 5q14.3-5q21.2 and codes for a tetratricopeptide repeat protein, thespin, whose function is uncharacterized.⁸⁸

Pathogenesis

The strongest and most commonly recognized association of AIE is with the IPEX syndrome, which was initially described by Powell and colleagues.¹⁰⁰ Extraintestinal diseases in these patients include insulin-dependent diabetes, thyroiditis, membranous glomerulopathy, and interstitial nephritis.¹⁰¹ This syndrome has been related to mutations in the FOXP3 gene (Xp11.23).¹⁰² Humans bearing this mutation share a phenotype very similar to that of the Scurfy mouse, showing an absence of naturally occurring CD4+ CD25+ regulatory T cells (Tregs). Mutations in the FOXP3 gene or its promoter region impair suppression of the inflammatory response by regulatory T cells, such that inflammation triggered by a relatively trivial viral infection can result in an extensive autoimmune cascade.^103,104 However, approximately 50% of patients, including females, with otherwise typical clinical manifestations of IPEX have no detectable mutations of FOXP3.¹⁰⁵ The term IPEX-like has been suggested for these cases.¹⁰⁶

One of the hallmarks of this entity, noted in the initial reports of AIE, is the presence of anti-enterocyte antibodies, which can be detected by indirect immunofluorescence using the patient’s serum on frozen sections of normal bowel. Positive fluorescence usually results in a linear pattern along the apex and basolateral border of the enterocyte^{100–101,107–111} (Fig. 9.6, D). The antibodies are predominantly IgG and have been described as complement-fixing,¹⁰⁷ although IgM and IgA have also been described.^109,111 Antibodies reacting against mucus or goblet cells have also been described, and intestinal biopsies in these cases have shown a marked depletion of goblet cells.^112,113

The target of the anti-enterocyte antibodies is still a matter of investigation, although a 75-kilodalton (kDa) antigen reactive with autoantibody in the sera of patients with the IPEX syndrome has been reported.¹¹⁴ This protein is expressed in the epithelial cells of the small bowel, colon, and kidney and may play a role in protein–protein interactions in enterocytes. More than one antigen is likely to be involved. More recently, a 95-kDa antigen identified as villin has been reported in IPEX patients.¹¹⁵

The role of these antibodies in the diagnosis of AIE is debatable. They have been reported to occur after the onset of disease and disappear before restoration of mucosal integrity¹¹⁰; therefore, they may represent an epiphenomenon without playing a causative role in mucosal damage. Similar anti-enterocyte antibodies have been described in adult AIDS patients without digestive symptoms.¹¹⁶ The specificity of anti–goblet cell antibodies has also been questioned. Anti–goblet cell antibodies have been detected in patients with chronic inflammatory bowel disease (Crohn’s and ulcerative colitis) and their first degree relatives¹¹⁷ and in a series of treated and untreated patients with celiac disease and controls.¹¹⁸ Finally, the usefulness of these antibodies for the diagnosis of AIE in young infants is also limited, given that there is little IgG production during the first 3 months of life and that IgG detected in infants is mostly maternal in origin.¹¹⁹

Pathology

The entire GI tract is often involved in AIE. The histopathologic findings in duodenal and small bowel biopsies are typically characterized by severe villus atrophy, crypt hyperplasia, and a mixed inflammatory infiltrate of the lamina propria. Marked inflammatory destruction of intestinal crypts, with extensive apoptosis, is often observed and is similar to that seen in intestinal graft-versus-host disease, suggesting an abnormal immune-mediated attack against intestinal epithelium¹⁰¹ (see Fig. 9.6). However, there appears to be marked variation in the histologic features, with some cases showing milder degrees of intestinal damage. In contrast to gluten-sensitive enteropathy, a condition that also reveals flat villi, intraepithelial lymphocytes in AIE tend to be relatively few in number. A concomitant crypt-destructive colitis and gastritis are present in the majority of cases as well.

The differential diagnosis of AIE includes, in addition to celiac disease and graft-versus-host disease, Crohn’s disease and enterocolitis associated with various immunodeficiency states. A high index of suspicion for AIE should be present when there is a severe inflammatory crypt-destructive process with villous atrophy and increased apoptosis in the bases of the crypts, loss of goblet and Paneth cells, or an intestinal inflammatory process in a patient with other autoimmune phenomena (Fig. 9.7). Testing for circulating anti-enterocyte antibodies is useful in older children and adults but may be of more limited use in young infants. Immunostaining for the FOXP3 gene product applied to formalin-fixed paraffin-embedded GI biopsies may be useful to screen for the IPEX syndrome in young patients with severe diarrhea.¹²⁰

Treatment

Mortality in cases of AIE has been reported to be high, as much as one third of reported cases, but was more frequent in older reports. Diet changes and steroids alone have been largely ineffective, and immunosuppressants appear to be necessary in most cases. Bone marrow transplantation may be curative. Immunosuppression is required in older children and adults.⁹² A good response to sirolimus has been reported in IPEX-like cases.¹⁰⁶ Bone marrow transplantation appears to offer the only cure for IPEX.¹²¹

Major differentiating features for various etiologies of severe diarrhea in early infancy are presented in Table 9.3.

Autoimmune Polyendocrine Syndrome (APS 1)

Autoimmune polyendocrine syndrome (APS 1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is an autosomal recessive disorder with heterogeneous clinical manifestations. It is caused by mutations in the AIRE gene, which codes for a transcription factor primarily expressed in medullary thymic epithelial cells, where negative selection is thought to occur.¹²² The type I form is characterized by various endocrinopathies of an autoimmune nature, often beginning in childhood or early teenage years; by chronic mucocutaneous candidiasis due to a T-cell defect starting soon after birth; and by dystrophy of ectodermal tissues.¹²³ Malabsorption occurs in as much as 25% of patients and appears to result from destruction of intestinal endocrine cells.¹²⁴ A specific deficiency of cholecystokinin-producing enteroendocrine cells has been reported in one patient, with seeming reappearance of the cells when the diarrhea abated.⁸³ Small bowel biopsy specimens show mild changes or can even be normal, in contrast to the crypt-destructive inflammation usually seen in AIE.

Pathogenesis

The pathogenesis of NEC is incompletely understood but is believed to be multifactorial, resulting from a combination of genetic predisposition, intestinal immaturity with inadequate motility, a heightened and inappropriate inflammatory response, abnormal microbial colonization, and an imbalance in microvascular tone.¹²⁵ Ischemic damage in NEC has been postulated to be due, in part, to circulatory alterations that divert blood away from abdominal organs to the heart and brain during episodes of hypoxia (the “diving reflex”). Intramural vessels are hypothesized to be the primary target of a combination of ischemia and inflammation, mediated by the release of vasoconstrictor agents such as peptide endothelin-1 and free radicals such as nitric oxide.¹²⁶ Because NEC usually occurs after the beginning of enteral feeding, enteral alimentation has also been proposed as a contributing factor. Human milk appears to reduce the risk for NEC.¹²⁷ A number of different bacterial pathogens have also been associated with NEC, as well as various cytokines. Endotoxin, platelet-activating factor, and tumor necrosis factor-α have also induced ischemic damage in experimental models of NEC.¹²⁸

Pathology

The ileocecal region, a vascular “watershed,” is most frequently involved, although 25% of pediatric patients may have involvement of only the ileum or colon. Disease extending from the ligament of Treitz to the rectum (pan-NEC) may be seen in fatal cases. Continuous and discontinuous involvement occurs in an equal proportion of children. The affected bowel is typically distended, with a grayish or purple color (if hemorrhage is present). The wall is thin and fragile, with grossly discernable gas bubbles in cases of pneumatosis (Fig. 9.8). Ischemic hemorrhagic necrosis is the predominant histologic manifestation; it may be limited to the mucosa, or it may involve the entire thickness of the bowel wall. Increasing degrees of inflammatory cell infiltrates occur with progression of disease and appear to be a response to both necrosis and bacterial proliferation. In contrast to infectious colitis, crypt microabscesses are uncommon in patients with NEC.¹²⁹ Although mesenteric thromboembolism, most frequently resulting from umbilical artery catheterization in neonates, can also cause necrosis of the bowel, occlusion of large vessels is uncommon in patients with NEC; however, it may be noted in autopsy cases, where it is believed to be a secondary phenomenon. Intestinal pneumatosis develops as a result of fermentation of intraluminal contents due to bacterial overgrowth. Healing changes include reepithelialization, granulation tissue formation, and fibrosis, which can be associated with stenosis and strictures in infants who survive (Fig. 9.9).

Treatment

Medical therapy includes stopping enteral feeds, administration of antibiotics, intravenous fluids, and parenteral nutrition along with circulatory support. Surgery is indicated for patients with intestinal perforation, for those with progressive clinical deterioration despite optimal medical management, and for resection of strictures and stenoses in convalescing patients. The goal of surgery is to resect only grossly necrotic tissue and, thus, to preserve as much bowel as possible. Obtaining intraoperative frozen sections for assessment of viability of surgical margins is neither indicated nor useful.

Pathology

The endoscopic appearance is usually characteristic, with swollen opaque villi, white nodules, or submucosal elevations.^144,145 Histologic features include blunted villi with dilated lacteals (Fig. 9.10). The finding of occasional dilated lymphatics in a biopsy specimen from a patient without significant symptoms is not infrequent and is of no diagnostic importance. Conversely, mucosal biopsies may be nondiagnostic when the lesions are focal, and they almost always fail to detect lymphangiectasia located within deeper layers of the bowel wall. Dietary therapy is the cornerstone of treatment and is designed to maintain protein levels.¹⁴⁵ Localized forms of intestinal lymphangiectasia may be amenable to surgical resection.¹⁴⁶