Malabsorption Syndromes — Celiac Disease, Whipple Disease and Tropical Sprue

Malabsorption is impaired nutrient absorption at any point where nutrients are absorbed. Maldigestion is impaired digestion within the intestinal lumen or at the brush border. The two are interdependent, so exams often use 'malabsorption' for both. A defect can arise from inherent or acquired mucosal disease (celiac disease, tropical sprue, Whipple disease), congenital transport defects, impaired motility, disrupted bacterial flora, infection or pancreatic and biliary problems.

The clinical picture follows what is not absorbed: chronic diarrhoea with steatorrhoea, weight loss, bloating, and deficiency states — iron-deficiency anaemia, macrocytic anaemia (B12 and folate), osteoporosis or osteomalacia, glossitis, cheilitis and oedema from protein loss. In children, growth failure is a frequent presentation of celiac disease.

• Qualitative fecal fat: Sudan III or IV staining of a single stool sample — a screening test.
• Quantitative fecal fat: the gold standard for steatorrhoea. A 72-hour stool collection while the patient eats about 100 g of fat per day (starting 3–5 days earlier). Normal excretion is 2–7 g per 24 hours; more than 21 g over 72 hours indicates steatorrhoea.
• Fecal elastase: low in exocrine pancreatic insufficiency (separates maldigestion from mucosal malabsorption).
• Breath tests: lactose/fructose malabsorption and small intestinal bacterial overgrowth (glucose or lactulose).
• Blood tests: haemoglobin, MCV, iron studies, B12, folate, vitamin D, albumin, calcium and coagulation (vitamin K).

The D-xylose test was used to assess absorptive function of the small-bowel mucosa. A 25 g oral dose is given; the test is abnormal if the 1-hour serum level is below 20 mg/dL or the 5-hour urinary excretion is below 4 g (StatPearls, in tropical sprue). The 2025 European consensus on malabsorption states that D-xylose testing 'has been used in the past … but its clinical usefulness is limited' — it is mostly an exam favourite today.

Celiac disease is an immune-mediated enteropathy in genetically predisposed people, triggered by dietary gluten — a protein in wheat, barley and rye. It affects about 1% of the global population. Nearly all patients carry HLA-DQ2 or HLA-DQ8, though many carriers never develop disease. Gluten is broken down to peptides such as gliadin, which are deamidated by tissue transglutaminase (transglutaminase 2); deamidation raises their binding to HLA-DQ2/DQ8 and triggers T-cell activation and mucosal inflammation.

The mucosal lesion is villous atrophy with crypt hyperplasia and infiltration of the lamina propria by immune cells, leading to malabsorption of iron, B12, folate and fat-soluble vitamins. Symptoms include diarrhoea, bloating, weight loss and fatigue, but extra-intestinal features are common: anaemia, osteoporosis, growth failure and skin disease. Dermatitis herpetiformis, an intensely pruritic vesicular rash, is pathognomonic and may be the only presentation.

1. First test: tTG-IgA (tissue transglutaminase IgA) in patients who are not IgA deficient; measure total IgA at the same time. In IgA deficiency, use IgG-based tests.
2. The patient must be eating gluten — for at least 6–8 weeks — before testing.
3. Endomysial antibody (EMA) is a confirmatory serology when tTG-IgA is borderline; it relies on indirect immunofluorescence and is not a routine first test.
4. Duodenal biopsy confirms the diagnosis in most patients and shows the extent of mucosal damage.
5. In children, a non-biopsy approach is acceptable if tTG-IgA is more than 10 times the upper limit of normal with a positive EMA and the family agrees.

The only effective treatment is strict lifelong exclusion of gluten — a gluten-free diet — which relieves symptoms and prevents complications. Complications include malnutrition, osteoporosis, anaemia, associated autoimmune disease and enteropathy-associated T-cell lymphoma. About 1% of patients have refractory celiac disease — persistent symptoms and villous atrophy despite 6–12 months of a strict gluten-free diet; type 1 usually has a better prognosis than type 2.

Whipple disease is a systemic infection by Tropheryma whipplei, a gram-positive bacillus that is PAS-positive and acid-fast negative. It was first described by George Hoyt Whipple as 'intestinal lipodystrophy' in a man with malabsorption, mesenteric lymphadenopathy, arthralgia and skin pigmentation; the bacterium was identified only in 1992. It is rare and associated with HLA-B27. Host factors matter: patients show altered macrophage function and an impaired type 1 T-cell response.

Diagnosis rests on small-bowel biopsy showing PAS-positive foamy macrophages in the lamina propria. If this is negative, the diagnosis can be made from two of three: PAS-positive foamy macrophages in a biopsy of involved tissue, PCR detection of T. whipplei (or its 16S rRNA), and immunohistochemistry. PAS-positive macrophages are not pathognomonic and PCR turns negative quickly once antibiotics start.

One recommended regimen is an initial phase of ceftriaxone 2 g daily or penicillin G 2 million units every 4 hours for 2 weeks, followed by trimethoprim-sulfamethoxazole (160/800 mg) twice daily for 12 months. Meropenem is an option in penicillin allergy. Agents that cross the blood-brain barrier are preferred, relapse can occur years later, and CNS symptoms are often the first sign of relapse.

Tropical sprue is an acquired malabsorption syndrome in people living in or visiting the tropics, with multiple deficiencies — most notably vitamin B12 and folic acid. Its cause is unknown and probably multifactorial: the prevailing hypothesis is an acute intestinal infection that injures enterocytes, impairs motility and predisposes to small intestinal bacterial overgrowth. It is seen mainly between latitudes 30° N and 30° S; in South Asia it is most often diagnosed in India, where it ranks second to celiac disease as a cause of malabsorption. It usually affects residents or travellers who stay more than 1 month in an endemic area.

Biopsy changes are non-specific: early normal mucosa, then reduced villous height progressing to villous atrophy, increased crypt depth, intraepithelial lymphocytes, lamina propria inflammation and lipid beneath the basement membrane. Diagnosis is by exclusion of other causes of chronic diarrhoea (infections, celiac disease, bacterial overgrowth), supported by megaloblastic anaemia with low B12 and folate, high methylmalonic acid and homocysteine.

Treatment is tetracycline 250 mg four times daily (or TMP-SMX or a quinolone) plus folic acid 5 mg daily and iron, with B12 supplementation as needed, for 3 to 6 months — extended to a year in relapsing disease or endemic regions.