Malabsorption Syndromes

Etiology

Nutrient absorption occurs in 3 distinct stages: luminal, mucosal, and postabsorptive. Malabsorption syndromes are classified based on which of the following stages experiences dysfunction:

• The luminal phase involves mechanical mixing and the action of digestive enzymes.
• The mucosal phase requires a properly functioning mucosal membrane for absorption.
• The postabsorptive phase becomes facilitated by an intact blood supply and lymphatic system.

Because malabsorption can result from disruptions at any point in the digestive or absorptive process, this discussion outlines the key components of each stage and presents representative diagnoses, specifying the nutrients most commonly affected.[3] Surgical resection of the small intestine and inflammation or tissue injury caused by radiation or chemotherapy can reduce the absorptive surface area, leading to widespread malabsorption of one or more nutritional components.

Radiation enteritis can be acute or chronic, and longer-term effects of radiation enteritis have become more common due to greater longevity in many cancer patients. Newer treatment approaches for radiation enteritis, including fecal microbiota transplant [4], stem cell therapy, and organoids, are being evaluated for the treatment of radiation injury.[5]

Fat Malabsorption

Fat malabsorption ranks among the most common malabsorption syndromes and results from impairments in fat digestion and absorption. Lipid processing is emulsification, which suspends fat molecules in aqueous humor to expose lipid molecule surface areas to hydrolytic enzymes. Emulsification starts in the mouth via mastication and lingual lipase and continues with gastric mixing. Although lipid digestion begins in the mouth, only approximately 15% of ingested fat is digested before reaching the duodenum, with the remainder arriving in the duodenum intact before moving to the jejunum. The stomach and pancreas release lipolytic enzymes, and most lipid absorption occurs in the proximal two-thirds of the jejunum (ie, proximal small intestine). 

Further fat solubilization depends on raising the intraluminal pH to approximately 6.5 and mixing fat digestion products with bile salts released by the gallbladder, leading to the formation of micelles. These lipolytic products may aggregate into micelles or larger liposomes, both of which represent absorbable forms of fat. Absorption occurs through diffusion, transient incorporation into the lipid bilayer, and facilitation by various transporters and co-transporters. Bile salts remain in the intestinal lumen, undergo reabsorption in the terminal ileum, and recirculate through the enterohepatic circulation.[6]

Etiologies of Fat Malabsorption

Decreased duodenal pH

An optimal duodenal pH of 6.5 is necessary for effective fat digestion. Zollinger-Ellison syndrome lowers duodenal pH due to excessive gastric acid secretion, which inactivates pancreatic enzymes.

Loss of absorptive intestinal surface area

Loss of absorptive intestinal surface area—caused by diffuse mucosal injury, enterocyte dysfunction, or surgical resection—reduces transit time and limits exposure to digestive enzymes, resulting in global malabsorption. Several conditions contribute to diffuse mucosal or enterocyte dysfunction. Crohn disease and Celiac disease (also known as gluten-sensitive enteropathy, celiac sprue, or nontropical sprue) disrupt nutrient absorption in the proximal small intestine. In celiac disease, an inappropriate immune response to gluten in the proximal duodenum and jejunum impairs iron absorption, often causing anemia, even in the absence of gastrointestinal symptoms.[7] Please see StatPearls' companion resource, "Celiac Disease", for further information. Small bowel resection, often performed during bariatric surgery, removes functional mucosa and contributes to fat malabsorption.

Impaired lipid processing

Impaired lipid processing by bile acids results when bile acid synthesis remains insufficient for effective fat absorption, bile acid secretion becomes compromised, or bile acids fail to undergo proper reabsorption and remain within the intestinal lumen. Unabsorbed bile acids cannot participate in further fat digestion and instead promote colonic water and electrolyte secretion. Inborn errors of metabolism often underlie insufficient bile acid synthesis, which may present as cholestasis or, less typically, as fat malabsorption. Disruption in bile acid production negatively impacts the absorption of both fat and fat-soluble vitamins.[8]

Liver disease, particularly hepatic cirrhosis, reduces bile acid synthesis. In gastrointestinal amyloidosis, amyloid deposits within liver stellate cells produce pathological changes similar to those observed in fibrotic liver disease.[9] Cholestasis, defined by reduced or obstructed bile secretion and flow, stems from intrahepatic and extrahepatic pathology.[10]

Small intestinal bacterial overgrowth

Small intestinal bacterial overgrowth (SIBO) develops when the normal microbial balance of the small intestine becomes disrupted.[11][12] Certain bacterial species proliferate and deconjugate bile acids, impairing their function in fat absorption. This overgrowth often arises in the setting of atrophic gastritis or reduced gastric acid secretion, commonly due to proton pump inhibitor (PPI) use. Although PPIs may interfere with vitamin B12 absorption, clinically significant deficiency remains rare. Additional contributors to SIBO include prolonged lactose deficiency, blind loops created by inflammatory bowel disease, gastrointestinal stasis, and conditions that accelerate gastric emptying with incompletely acidified contents.

SIBO typically presents with a patchy distribution within the small intestine, in contrast to the diffuse involvement seen in celiac disease. Chronic bacterial overgrowth may lead to brush border damage and elevated antigliadin antibodies, potentially mimicking celiac disease clinically and serologically. Continued mucosal injury can result in the malabsorption of various nutrients.[13]

Exocrine pancreatic insufficiency

Exocrine pancreatic insufficiency (EPI) results from defective production of pancreatic lipase, colipase, and bicarbonate.[14] Chronic pancreatitis, frequently associated with alcohol use disorder or prolonged biliary obstruction, commonly underlies EPI. Pancreatic resection reduces the functional tissue required for enzyme production. In cystic fibrosis, thick mucus obstructs pancreatic ducts, impairing enzyme delivery and often coexisting with a history of recurrent respiratory tract infections.

Pancreatic cancer contributes to EPI by both obstructing ducts and destroying enzyme-producing tissue. Schwachman-Diamond syndrome, a rare autosomal recessive disorder, affects multiple organ systems and presents with EPI, bone marrow failure, and skeletal abnormalities. Please see StatPearls' companion resource, "Shwachman-Diamond Syndrome", for further information. Additional conditions that impair pancreatic or gastrointestinal function and contribute to fat malabsorption include Zollinger-Ellison syndrome, celiac disease, and prior gastric surgery.

Defects in chylomicron and lipoprotein secretion

Abetalipoproteinemia results from defective apoproteins that impair chylomicron packaging and secretion into the lymphatic system. Mutations in the MTP gene underlie this disorder.[15]

Lymphatic disorders

Intestinal lymphangiectasia involves impaired lymphatic flow that disrupts fat processing. This condition represents one of the most common yet frequently overlooked causes of chronic, noninfectious infantile diarrhea. More frequent etiologies include cow's milk protein allergy and cystic fibrosis.[16]

Whipple disease, caused by Tropheryma whipplei, presents as a systemic illness characterized by diarrhea and weight loss due to malabsorption. Common accompanying symptoms include fever, arthralgias, and abdominal pain. Less frequently, the disease may involve lymphadenopathy, endocarditis, pulmonary manifestations, or central nervous system infections. In certain cases, biopsies yield histological findings that resemble those seen in Mycobacterium avium complex (MAC) infection. Acid-fast staining helps differentiate Whipple disease and MAC from other conditions.[2]

Carbohydrate Malabsorption

Carbohydrate digestion and absorption often refer to starch, lactose, and sucrose in the human diet. Appropriate digestion into monosaccharides is necessary for adequate absorption. Carbohydrate digestion begins with salivary and pancreatic amylase. The resulting products are further processed at the microvillus membrane of the small intestine. Brush border enzymes then hydrolyze that carbohydrate mixture into monosaccharides.

Monosaccharides can be absorbed passively or actively. Any remaining carbohydrates that are not absorbed, including nonabsorbable cellulose, are fermented in the colon by bacterial degradation. When fatty acids are released due to bacterial fermentation, colonic epithelial cells absorb them for energy. Signs and symptoms of excessive bacterial fermentation in carbohydrate malabsorption include acidic stool, flatulence, and bloating.[6]

Etiologies of Carbohydrate Malabsorption

Carbohydrate malabsorption can result from impaired enzymatic breakdown, reduced absorptive capacity, or structural abnormalities of the small intestine. A deficiency in pancreatic amylase can hinder the hydrolysis of complex carbohydrates into disaccharides. Inadequate disaccharidase activity further compromises carbohydrate digestion, with lactase deficiency representing the most common type. Adult-onset lactase deficiency affects the majority of the global population. Lactase, an enzyme found on the surface of small intestinal microvilli, breaks down lactose into glucose and galactose. During early childhood, the downregulation of lactase activity often leads to the complete absence of the enzyme in some individuals, resulting from reduced enzyme synthesis rather than a structural defect. Congenital forms of lactase deficiency, along with other disaccharidase deficiencies such as sucrase and trehalase deficiencies, also contribute to carbohydrate malabsorption.[17]

Loss of functional or structural absorptive surface area in the small intestine resulting from diffuse mucosal injury secondary to various conditions, further exacerbating carbohydrate malabsorption. Diffuse mucosal injury, as seen in celiac disease and tropical sprue, impairs nutrient absorption across all three segments of the small intestine. Tropical sprue, which more commonly leads to megaloblastic anemia due to folate and vitamin B12 deficiencies, tends to affect individuals living in or visiting endemic regions, eg, Puerto Rico, the Caribbean, northern South America, West Africa, Southeast Asia, and India. Please see StatPearls' companion resource, "Tropical Sprue", for further information. Overgrowth of aerobic bacteria frequently accompanies this condition.

Autoimmune enteropathy, a pediatric condition, produces villous blunting and crypt hyperplasia resembling celiac disease. Intestinal lymphangiectasia disrupts normal fat and protein absorption, often leading to peripheral edema and lymphocytopenia due to impaired lymphatic flow. Inflammatory bowel diseases (eg, Crohn disease and ulcerative colitis) may obstruct lymphatic drainage or form blind loops, contributing to bacterial overgrowth and functional mucosal loss.

Additionally, functional loss of small intestine mucosa may result from blind loops, which occur secondary to inflammatory bowel disease or other causes of entero-enteric or enterocolic fistulas, which create sites for bacterial proliferation and stagnation. Moreover, mural diseases (eg, systemic sclerosis) lead to fibrosis of the muscularis propria (ie, smooth muscle cells of the muscularis propria are replaced by collagen), weakening peristalsis, promoting stasis, and facilitating the development of diverticula. Ingestion of nonabsorbable carbohydrates, eg, sorbitol and cellulose, further exacerbates malabsorption symptoms. Absolute loss of mucosal surface area, eg, that resulting from small bowel resection, represents the most direct structural cause of carbohydrate malabsorption.

Protein Malabsorption

Protein digestion and absorption begin as proteolysis in the stomach with proenzymes that become activated in an acidic environment. The extent of proteolysis depends on the degree of acidity (pH), gastric motility for mixing, and other dietary constituents present during the process. For example, the duodenal and jejunal release of cholecystokinin (CCK) depends on the release of amino acids in the stomach. Amino acids stimulate the release of CCK, which in turn stimulates the release of pancreatic enzymes.

Additional release of amino acids occurs in the duodenum through the action of other proteases. After various levels of protein digestion by pancreatic enzymes, amino acids, dipeptides, and tripeptides are ready for absorption via brush border sodium-dependent amino acid co-transporters. These co-transporters carry proteolysis products both passively and secondarily through their indirect use of energy from sodium-potassium ATPase pumps. Different classes of amino acid transporters select particular amino acids based on their being neutral, alkaline, or acidic. Further selectivity exists for the specific transport of dipeptides and tripeptides.[6]

Etiologies of Protein Malabsorption

Protein malabsorption may result from impaired secretion or activity of pancreatic substances, particularly bicarbonate and proteases. Conditions, eg, chronic pancreatitis and cystic fibrosis, often disrupt normal enzyme production or delivery, thereby limiting the breakdown of dietary proteins into absorbable amino acids and peptides. These defects compromise intraluminal digestion, a critical early step in protein assimilation.

Loss of absorptive surface area within the small intestine also contributes significantly to protein malabsorption. Diffuse mucosal injury caused by conditions, eg, inflammatory bowel disease, intestinal lymphangiectasia, or surgical interventions, eg, ileal resection, diminishes the functional mucosa required for nutrient absorption. This reduction in surface area shortens transit time and limits the exposure of nutrients to digestive and absorptive mechanisms, further impeding protein uptake.

Vitamin, Mineral, and Trace Element Malabsorption

Various intestinal transport mechanisms accomplish the absorption of vitamins, minerals, and trace elements. Dysfunction at any of these levels results in malabsorption of that specific vitamin, mineral, trace element, or any nutrient dependent on them to be successfully absorbed. Deficiencies include but are not limited to vitamin B12, calcium, iron, folate, vitamin D, magnesium, carotenoids, thiamine, copper, and selenium. The effects of malabsorption of these vitamins, minerals, or trace elements depend on which are deficient and the severity of the deficiency.

Etiologies of Vitamin, Mineral, and Trace Element Malabsorption

Pathologies affecting the stomach or proximal small intestine often impair protein absorption and may contribute to deficiencies in iron and vitamin B12. In cases of fat malabsorption, unabsorbed fatty acids can bind to calcium, magnesium, and other divalent cations, further complicating nutrient uptake.[8] EPI frequently underlies this mechanism by impairing the digestion and absorption of fat-soluble vitamins, including A, D, E, and K.

Loss of absorptive intestinal surface area significantly disrupts protein and micronutrient absorption. Bariatric surgery and intestinal resection reduce the length of functional mucosa available for digestion. Additionally, intestinal diseases, including those previously discussed, as well as acrodermatitis enteropathica, impair nutrient absorption through structural and inflammatory damage. This rare autosomal recessive disorder of zinc malabsorption leads to abnormalities in the skin and mucosal surfaces. Histologic features include villous blunting, crypt hyperplasia, increased inflammatory infiltrate in the lamina propria, and loss of brush border enzymes. As the disease progresses, it contributes to broader malabsorptive deficits affecting multiple nutrients.

Immunodeficiency and HIV/AIDS-Related Enteropathy

In some cases, malabsorption cannot readily be categorized into fat, carbohydrate, or micronutrient malabsorption when malabsorption is more global. This situation can occur in immunodeficiency states, which, when accompanied by diarrhea, are often due to opportunistic infections. These infections interfere with the proper absorption and digestion of nutrients. Infectious organisms include Giardia and Cryptosporidium. A more extensive discussion of the relationships between HIV/AIDS and other immunodeficient states is beyond the scope of this activity, but is mentioned for completeness.[2]

Additional Congenital Causes of Chronic Diarrhea

Congenital glucose-galactose malabsorption

Congenital glucose-galactose malabsorption, a rare autosomal recessive disorder, typically presents before 6 months of age and results from defective glucose and galactose transport across the brush border. Management involves switching to fructose-based formulas and eliminating glucose and galactose from the diet, which significantly improves symptoms.

Congenital chloride diarrhea 

Congenital chloride diarrhea also follows an autosomal recessive inheritance pattern and commonly presents in infancy with profuse watery diarrhea. A hallmark feature includes hypokalemic, hypochloremic metabolic alkalosis and elevated fecal chloride levels. Treatment focuses on aggressive and sustained electrolyte replacement, which yields favorable outcomes.

Cow's milk protein allergy

Cow's milk protein allergy involves an immunologic reaction to 1 or more of the approximately 30 proteins found in cow's milk. Clinical presentation varies widely, ranging from mild symptoms to life-threatening reactions. Diagnosis primarily depends on clinical history and symptom resolution following the elimination of cow's milk protein from the diet.[18]

Microvillus inclusion disease

Microvillus inclusion disease, another rare autosomal recessive disorder, causes severe congenital diarrhea, metabolic disturbances, and failure to thrive, often with high morbidity and mortality. Management typically requires lifelong total parenteral nutrition or small intestinal transplantation. This condition results from mutations in the MYO5B gene [19], with over 200 allelic variants catalogued in the National Center for Biotechnology Information database.[16][20]

Bacterial Malabsorption

Whether transient, curable, or permanent sequelae transpire, bacterial malabsorption is most often due to Giardia lamblia (giardiasis), Tropheryma whipplei (Whipple disease), Cryptosporidium parvum (cryptosporidiosis), and the phylum Microspora (microsporidiosis).[2]

Bile Acid Malabsorption (BAM)

Bile acid malabsorption (BAM) may be classified as primary, resulting from excessive hepatic bile acid production, or secondary, when factors impair the small intestine's ability to reabsorb bile acids efficiently. Secondary BAM can develop under the following various predisposing clinical circumstances that exceed the absorptive capacity of the ileum:

• Type 1: Due to ileal disease, eg, Crohn disease, after ileal surgical resection, or after radiation therapy involving the ileum
• Type 2: Idiopathic BAM occurs when the negative feedback process in the enterohepatic circulation fails to signal the liver to reduce bile acid production. Excessive bile acid production overwhelms the ileum's ability to absorb them, resulting in bile acid diarrhea.
• Type 3: Other gastrointestinal or pancreaticobiliary disease or posttreatment state, eg, celiac disease, SIBO, EPI, microscopic colitis (including collagenous and lymphocytic colitis), HIV-associated enteritis, postinfectious diarrhea, post-ileal resection, postcholecystectomy, and after abdominal or pelvic radiation therapy. Half of the patients receiving chemotherapy experience BAM.[21]
• Type 4: Excessive production of bile acids as an adverse effect of taking metformin for type 2 diabetes

Several other medications may impair absorption through diverse mechanisms and contribute to the development or worsening of malabsorption syndromes.

Epidemiology

Malabsorption affects millions of people worldwide. The fact that malabsorption syndromes have multiple etiologies obscures the prevalence and incidence. However, some malabsorption syndromes can be estimated by discussing the epidemiology of subgroups.

Celiac Disease

Celiac disease is present at its highest rates in Europeans and North Americans. Celiac disease can also be found in parts of India and is rarest in those of Asian, Caribbean, and African descent. Tropical sprue is known for affecting residents and visitors to Puerto Rico, the Caribbean, West Africa, northern South America, Southeast Asia, and India.[2]

Exocrine Pancreatic Insufficiency

The precise prevalence of EPI in the general population remains uncertain; however, estimates can be derived from its occurrence in populations with known risk factors. Among individuals with chronic pancreatitis, EPI affects approximately 85% of those with severe disease and about 30% of those with mild disease. In newborns diagnosed with cystic fibrosis, the incidence reaches 85%.

Prevalence also varies significantly across other conditions. In type 1 diabetes, EPI occurs in 26% to 44% of patients, while in those with HIV/AIDS, the rate ranges from 26% to 45%. Among individuals with inoperable pancreatic cancer, prevalence spans from 50% to 100%. Surgical interventions, eg, distal pancreatectomy and pancreatoduodenectomy, exhibit a broad incidence range, from 19% to 98%. In contrast, individuals with type 2 diabetes tend to exhibit a lower prevalence of EPI.[14]

History and Physical

Clinical History

A malabsorption syndrome should be suspected when a patient’s history includes ongoing or chronic diarrhea, unintentional weight loss despite normal nutrient intake, and greasy, voluminous, foul-smelling stools that reportedly float. Additional components of the history may include flatulence, bloating, and borborygmi. Abdominal pain might be reported, but this is less common in most malabsorption syndromes. 

Key questions in the history, along with a focused physical exam, help create a more targeted approach to diagnosing the patient’s condition. A thorough history boosts cost-effectiveness and saves time. For those patients whose malabsorption syndrome is affected by emotions, early treatment can start through interviews alone. The therapeutic benefit stems from the nurturing of the patient-doctor relationship, which empowers the patient and positively impacts their self-esteem in the face of their malabsorption syndrome.[22]

A review of systems should address the following:

• Symptom duration and timing
• Presence or absence of pain
• pain location, intensity, and radiation
• Precipitating factors and associated symptoms (eg, change in bowel habits/frequency)
• Appearance of the stool including color, bulk, consistency, and odor should be noted (eg, floating, pale, greasy); oil droplets may be seen in the toilet bowl
• Whether or not the presenting symptoms have happened previously
• Peripheral neuropathy
• Hearing loss (due to vitamin and mineral deficiencies)

Additional essential historical components include past medical history (eg., peptic ulcer disease), family history (especially for systemic and gastrointestinal conditions), medications, surgeries, radiation exposure/treatments, caustic substance ingestion, allergies, and social history, including past or present smoking, alcohol use, and recreational drug use.[23]

Physical Examination Features

Physical examination findings that are commonly observed in patients with malabsorption syndromes include:

• Hyperactive or hypoactive bowel sounds, abdominal distention, or tenderness with abdominal palpation
• Pallor (suggesting anemia)
• Muscle wasting
• Abnormal deep tendon reflexes
• Skeletal deformities
• Rashes on skin examination
• Cardiac arrhythmia
• Delayed growth (in infants and children)
• Evidence of poor wound healing
• Ecchymosis
• Decreased visual acuity
• Hearing impairment
• Cognitive impairment

Evaluation

Laboratory testing, imaging, endoscopic evaluation, and biopsies may be required based on the history and physical findings.

General Evaluation for Malabsorption Syndromes

When clinical features raise suspicion of malabsorption syndromes without strongly supporting a specific diagnosis, eg, unintentional weight loss, ongoing diarrhea, or poor wound healing, the following diagnostic testing should be considered:

• Serum studies
  • Comprehensive metabolic panel (electrolyte disturbances, hepatic function, renal function)
  • Complete blood cell count (anemia assessment)
  • Albumin and prealbumin
  • Magnesium
  • Zinc
  • Phosphorous
  • Vitamin levels (eg, vitamin B12, folate, and vitamin D)
  • Iron panel, including serum iron, total iron-binding capacity, ferritin
• Fecal tests
  • Qualitative fecal fat: assessed by Sudan III or Sudan IV staining of a single stool specimen; if the test is positive or there remains high clinical suspicion of fat malabsorption syndrome, then quantitative measurement of fecal fat excretion is performed over 72 hours.
  • Quantitative fecal fat excretion: the gold standard for steatorrhea diagnosis; performed on a 72-hour stool collection while the patient ingests 100 g of dietary fat per day beginning 3 to 5 days before the stool collection begins and continuing until the 72-hour testing period is completed
    • Normal fecal fat excretion is 2 to 7 g over 24 hours. Greater than 21 g of fat over 72 hours is indicative of steatorrhea. This is determined by thoroughly mixing (homogenizing) the stool, extracting the fat with a solvent, then saponifying the fat.
    • Acid steatocrit: a simpler and rapid but less accurate means of measuring fat content in a random sample of stool
    • Near-infrared reflectance analysis (NIRA): comparable accuracy to a 72-hour fecal fat excretion analysis but faster; also measures nitrogen and carbohydrate content in the stool
  • Fecal elastase: Level is low in exocrine pancreatic insufficiency
  • Fecal calprotectin: Elevated level in inflammatory bowel disease
  • Fecal ova and parasites: At least 3 specimens should be collected on separate days

More Specific Evaluation of Malabsorption Syndromes

When clinical findings clearly indicate a diagnosis of a malabsorption syndrome, eg, history of recurrent pancreatitis and alcohol use or gastrointestinal symptoms resolved with gluten avoidance, general evaluation is not necessary. Clinicians can select specific modalities for assessment based on the suspected or most likely diagnosis. Specific assessments for malabsorption syndromes include:

• Breath tests
  • Carbohydrate malabsorption syndromes, such as lactose or fructose intolerance
  • SIBO: positive glucose or lactulose breath tests are supportive but not necessarily definitive for diagnosis
• Jejunal aspirate culture: gold standard for SIBO diagnosis
• Computed tomography (CT): assesses chronic pancreatitis
• Magnetic resonance cholangiopancreatography (MRCP): assesses EPI
• Magnetic resonance (MR) elastography
  • A noninvasive method to ascertain the stiffness of an object.
  • MR elastography helps diagnose conditions, eg, hepatic fibrosis and hepatic amyloidosis, which can cause malabsorption.[24]
• Magnetic retrograde cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP): chronic calcific pancreatitis (history was positive for pancreatitis and alcohol use, or a low fecal elastase measurement), MRCP or ERCP may be diagnostic
• Video capsule endoscopy: Characteristic appearances of Crohn disease, celiac disease, and intestinal lymphangiectasia may be seen.
• Esophagogastroduodenoscopy or small bowel enteroscopy with biopsies: indicated for diagnoses that require both direct visualization and tissue, eg, Crohn disease (findings of visualized duodenal, jejunal, or ileal mucosal cobblestoning findings) or Celiac disease (flattening or reduction of duodenal folds, or mucosal scalloping findings)
• Acid-fast stains: differentiate Tropheryma whipplei versus Mycobacterium avium which are virtually indistinguishable histologically

Clinical Example of an Etiology-Specific Evaluation

Celiac disease often presents in children with diarrhea, growth delay, pallor, and abdominal discomfort within the first 24 hours of life. Symptoms typically worsen upon the introduction of cereals into the diet. Without treatment, the clinical picture may progress to include short stature, delayed puberty, and complications from nutrient deficiencies, eg, rickets due to vitamin D deficiency and iron-deficiency anemia. A history of unexplained iron-deficiency anemia should prompt evaluation for celiac disease. Additional findings may include folate deficiency resulting in megaloblastic anemia, vitamin D deficiency with hypocalcemia, and vitamin K deficiency leading to coagulopathy.

Diagnostic workup includes duodenal or jejunal mucosal biopsies, serologic testing, and a trial of a gluten-free diet. Histological examination typically reveals blunted villi, flattened mucosa, and increased intraepithelial lymphocytes (IELs), which may also involve the stomach, leading to lymphocytic gastritis. Recommended serologic tests include deamidated anti-gliadin peptide IgA, anti-tissue transglutaminase IgA (tTG-IgA), and anti-endomysial IgA antibodies (EMA). Anti-TTG is considered the most sensitive test, while anti-EMA offers the highest specificity.[25] Since 2% to 3% of individuals with celiac disease have total IgA deficiency, total IgA levels should be included in the diagnostic panel.[26] Clinical improvement with gluten avoidance further supports the diagnosis. Histologic abnormalities typically resolve within 3 to 6 months following the initiation of a strict gluten-free diet.[2]

Trials of eliminating certain types of foods or ingredients can be both diagnostic and therapeutic. In addition to its utility in celiac disease, an elimination trial is often useful in carbohydrate malabsorption syndromes such as lactose or fructose intolerance.

Treatment / Management

Treatment in the setting of malabsorption syndromes targets correcting deficiencies, treating the underlying cause, avoiding triggers (typically dietary), and treating symptoms. Failure to properly diagnose a malabsorption syndrome could cause harm due to nutritional deficiencies. Therefore, treatment should focus on treating the underlying cause. Treatment may be solely a matter of food avoidance or supplementation, could be treated medically, or could require surgery (resection or organ transplant).

Assessing and improving nutritional status should be included in any treatment plan, regardless of diagnosis.[14][27] Treatment for lactose intolerance, regardless of cause, includes avoidance of limiting dairy intake, using lactose-free dairy products, and possibly taking lactase supplements. Treating rheumatoid arthritis and other autoimmune diseases with disease-modifying antirheumatic drugs (DMARDs), anti-necrosis factor-alpha, or glucocorticoids could cause Tropheryma whipplei infection in Whipple disease to progress, which could prove fatal.[27]

Pancreatic enzyme replacement is indicated for the treatment of exocrine pancreatic insufficiency. Bile acid malabsorption is typically managed with a low-fat and low-fiber diet, and bile salt binders such as cholestyramine, colestipol, and colesevelam are commonly employed. Malabsorption caused by bacterial infection is typically managed with antibiotics unless it results in a self-limited illness. ERCP may be effective in alleviating malabsorption by removing obstructing stones in cases of chronic pancreatitis or choledocholithiasis. 

Differential Diagnosis

Due to overlapping symptoms, malabsorption syndromes may be challenging to distinguish from other gastrointestinal conditions. Malabsorption typically leads to osmotic diarrhea, which must be differentiated from secretory diarrhea. This distinction relies on calculating the stool osmotic gap, defined as the difference between 290 mOsm/L—normal stool osmolality—and twice the sum of stool sodium and potassium concentrations. A low osmotic gap (<50 mOsm/L) indicates secretory diarrhea, while a high osmotic gap (>100 mOsm/L) suggests osmotic diarrhea.

Some differentials are specific to a malabsorption syndrome or presenting symptom include:

• Primary intestinal lymphangiectasia (Waldmann disease): differential diagnosis includes constrictive pericarditis, Crohn disease, Whipple disease, systemic sclerosis, intestinal tuberculosis, and sarcoidosis
• Ongoing diarrhea early in life: cystic fibrosis, congenital chloride malabsorption, congenital glucose-galactose malabsorption, pancreatic insufficiency, cow’s milk protein allergy [28]

Prognosis

Malabsorption syndromes typically are not life-threatening. However, the severity and duration of some malabsorption syndromes can be life-threatening or even fatal. Examples include severe malnutrition from prolonged EPI, life-threatening electrolyte disturbances from prolonged, intractable diarrhea, and bowel perforation.[14] Meanwhile, other malabsorption syndromes, eg, lactose intolerance, are unlikely to significantly adversely affect a patient’s health. That is partly due to disease progression and partly due to the efficacy of disease management (eg, avoidance, supplementation, supportive care).

Food intolerances, eg, lactose intolerance and malabsorption, rarely cause serious nutrient deficiencies but can substantially diminish quality of life. These intolerances frequently contribute to symptoms of irritable bowel syndrome and other functional gastrointestinal disorders. Identifying and managing food intolerances and malabsorption syndromes can enhance cost-effectiveness through conservative measures, including dietary modifications. In complex cases, eg, short bowel syndrome in infancy, caregivers often manage frequent nighttime pump alarms, toileting, stoma or gastrostomy care, and enteral tube feeding throughout the day. Proper evaluation and treatment of malabsorption syndromes not only support patient health but also reduce the demands placed on caregivers, whose well-being plays a vital role in overall patient outcomes.[29][30]

Complications

The complications that can arise from malabsorption and maldigestion are numerous and may affect multiple body systems. When malabsorption is severe enough, poorly controlled, or of long enough duration, complications include but are not limited to the following:

• Gastrointestinal symptoms (eg, chronic diarrhea, bloating, flatulence)
• Malnutrition
• Weight loss/failure to thrive
• Vitamin, mineral, trace element deficiencies (eg, vitamin D, B12, iron, folate)
  • Osteomalacia, rickets, coagulopathy, visual and hearing impairment, skin changes
• Hematologic disorders: anemia, coagulopathy
• Musculoskeletal dysfunction:
  • Growth delay (in children)
  • Skeletal deformities (eg, rickets)
  • Bone mineral density abnormalities (eg, osteoporosis)
  • Cachexia
• Electrolyte disturbances
• Cardiovascular arrhythmias
• Neurologic dysfunction: peripheral neuropathy and ataxia [14]
• Endocrine dysfunction: parathyroid dysfunction and chronic fatigue