Carcinoid Syndrome of the Gastrointestinal Tract

Definition and Background

• Sleisenger and Fordtran's Gastrointestinal and Liver Disease
• Sabiston Textbook of Surgery

Tumor Origin and Epidemiology

• Foregut NETs (stomach, duodenum, bronchus) - more likely to cause atypical syndrome via histamine
• Midgut NETs (jejunum, ileum, right colon) - classic carcinoid syndrome
• Hindgut NETs (left colon, rectum) - rarely secrete and rarely cause syndrome

Pathophysiology

Typical Carcinoid Syndrome (Midgut)

1. Taken up and stored by platelets
2. Metabolized to 5-hydroxyindoleacetic acid (5-HIAA) by monoamine oxidase and aldehyde dehydrogenase
3. 5-HIAA is excreted in the urine - the key diagnostic marker

Atypical Carcinoid Syndrome (Foregut/Gastric)

Why Liver Metastases are Required

• Liver metastases are present (tumor secretes directly into hepatic veins)
• Rarely: primary retroperitoneal or ovarian tumors that bypass portal circulation
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, p. 512

Clinical Features

1. Flushing

• Most common symptom; sudden onset deep red erythema of the face, neck, and upper chest
• May be associated with warmth, lacrimation, itching, palpitations, facial edema
• Precipitants: stress, alcohol, certain foods (cheese), exercise, catecholamines, calcium, pentagastrin
• Duration varies: brief (2-5 min) early; prolonged (hours) in later disease
• Typical (midgut) flush: salmon-pink to red, facial and neck, non-pruritic
• Gastric (atypical) flush: red, patchy, pruritic, with wheals and central clearing, provoked by food
• Repeated flushing leads to permanent telangiectasia and cyanotic discoloration

2. Diarrhea

• Usually watery; 2-30 stools/day
• Occurs with flushing in 85% of cases, alone in 15%
• Caused by increased 5-HT-mediated colonic motility and shortened intestinal transit
• Steatorrhea may occur in some patients
• Fecal output <1 L/day in most (60%) patients

3. Bronchospasm

• Wheezing and asthma-like symptoms
• Mediated by serotonin in combination with histamine

4. Carcinoid Heart Disease (Hedinger Syndrome)

• Tricuspid valve: plaques on ventricular side of leaflets → tricuspid regurgitation (47%); tricuspid stenosis (42%)
• Pulmonary valve: predominant lesion is stenosis (90%)
• Left-sided involvement only if patent foramen ovale is present

PET-DOTATATE scan: pancreatic NET with liver metastases (A: axial showing pancreatic primary; B: axial showing liver mets; C: coronal whole-body view) - Sabiston Textbook of Surgery

5. Pellagra

• Rare complication (~2%)
• Results from excessive tryptophan diversion toward serotonin synthesis, leading to niacin deficiency
• Manifests as dermatitis, diarrhea, and dementia (the classic "3 Ds")

Diagnosis

Biochemical Markers

Imaging

1. Somatostatin receptor scintigraphy (OctreoScan) - detects primary tumors and metastases using radiolabeled octreotide; exploits the high density of somatostatin receptors on NETs
2. PET-DOTATATE scan - higher sensitivity than OctreoScan; can detect occult primaries and assess metastatic burden
3. CT/MRI abdomen - assess liver metastases and primary tumor
4. Echocardiography - mandatory in all patients with carcinoid syndrome to assess valvular disease

• Bailey and Love's Short Practice of Surgery, 28th ed., p. 992

Treatment

1. Somatostatin Analogues (SSAs) - Mainstay of Medical Therapy

• Octreotide (short-acting and long-acting LAR formulation) and lanreotide are the standard of care
• Reduce both flushing and diarrhea by inhibiting secretion of vasoactive substances
• Shown to improve progression-free survival and quality of life in unresectable disease
• LAR (long-acting repeatable) formulations allow monthly dosing

2. Surgical Treatment

• Resection of primary tumor and hepatic debulking where feasible
• Even partial debulking (>90% reduction in tumor burden) can meaningfully reduce symptoms
• Octreotide cover is mandatory perioperatively to prevent carcinoid crisis (from liberation of vasoactive substances during tumor handling)

3. Peptide Receptor Radionuclide Therapy (PRRT)

• Lutetium-177-DOTATATE (^177Lu-DOTATATE) for refractory or progressive disease on SSAs
• Radiolabeled SSA delivers radiation directly to somatostatin receptor-expressing tumor cells

4. Other Modalities

• Hepatic embolization/chemoembolization for liver-dominant disease (but can precipitate carcinoid crisis - requires octreotide prophylaxis)
• Chemotherapy: generally not very sensitive; interferon-alpha may have some role
• Valve replacement surgery for severe carcinoid heart disease: operative mortality now <10%; without treatment, mean survival with carcinoid heart disease is only 1.6 years

5. Symptomatic Management

• Antidiarrheals (loperamide, codeine)
• Antihistamines (H1 + H2) for gastric (histamine-mediated) atypical flushing
• Avoid trigger foods and sympathomimetic drugs

Carcinoid Crisis

• Tumor manipulation (biopsy, surgical resection)
• Sympathomimetic drugs (amphetamines, albuterol)
• Cytolytic therapies (hepatic embolization)
• Spontaneous

• Sabiston Textbook of Surgery

Prognosis

• Median overall survival with carcinoid syndrome: 4.7 years
• Median overall survival without carcinoid syndrome: 7.1 years

• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, Table 34.11 and section on Carcinoid Syndrome
• Sabiston Textbook of Surgery, pp. 1615-1617
• Goldman-Cecil Medicine, Chapter 47 (Carcinoid Heart Disease)
• Bailey and Love's Short Practice of Surgery, 28th ed., p. 992

Investigations in Malabsorption Syndrome

STEP 1: Routine Screening Investigations

Blood Tests

Key screening panel: Haemoglobin, MCV, serum iron/ferritin, folate, B12, albumin, calcium, PT, and serum carotene. Abnormalities in these point strongly toward malabsorption and direct further testing.

• Tietz Textbook of Laboratory Medicine, 7th Edition and Henry's Clinical Diagnosis and Management by Laboratory Methods

STEP 2: Stool Examination

Qualitative Fecal Fat (Sudan III Stain)

• Stool smear stained with Sudan III or Sudan IV stain
• Presence of fat globules (>6 fat globules per high-power field, diameter >8 µm) = steatorrhoea
• Simple, cheap, rapid screening test
• Sensitivity ~75-95% for significant steatorrhoea

Quantitative Fecal Fat (72-hour fecal fat estimation)

• Gold standard for steatorrhoea
• Patient consumes a high-fat diet (70-100 g fat/day) for 2 days before and throughout the collection period
• Stool collected for 72 hours (3 days)
• Normal: <7 g fat excreted per 24 hours (i.e., >93% dietary fat absorbed)
• >7 g/day = steatorrhoea confirmed
• Borderline (8-14 g/day) may occur in secretory/osmotic diarrhoea not due to fat malabsorption
• Limitations: cumbersome, patient compliance poor, requires accurate dietary fat intake records

Fecal Reducing Substances

• Test for carbohydrate malabsorption (especially in children)
• Positive (>0.5% reducing sugars) = carbohydrate malabsorption

Stool for Ova, Cysts, and Parasites (OCP)

• Giardia lamblia is an important treatable cause of malabsorption
• PCR for Giardia or stool antigen-capture ELISA should also be done

Fecal Osmotic Gap

• Distinguishes osmotic from secretory diarrhoea
• Osmotic gap = 290 - 2 × (stool Na + stool K)
• Gap >125 mOsm/kg = osmotic (carbohydrate malabsorption typical)
• Gap <50 mOsm/kg = secretory diarrhoea
• Goldman-Cecil Medicine, Table 126-6

STEP 3: Tests for Specific Types of Malabsorption

A. Tests for Fat Malabsorption / Pancreatic Function

Fecal Elastase-1

• Elastase-1 is a pancreatic enzyme that survives intestinal transit intact and is 5-6 times concentrated in feces
• A single 100 mg stool sample is sufficient
• Cutoff: <200 µg/g stool = pancreatic insufficiency
• Sensitivity for severe pancreatic insufficiency is high; less sensitive for mild disease
• Unaffected by pancreatic enzyme replacement therapy
• Better than fecal chymotrypsin, bentiromide (NBT-PABA), and pancreo-lauryl tests

¹³C Mixed-Chain Triglyceride Breath Test

• Patient given ¹³C-labeled medium- and long-chain fatty acids orally with a standard meal (toast and butter)
• Breath samples collected over 5 hours; exhaled ¹³CO₂ expressed as % of administered dose
• Normal: 25-40% excretion
• Sensitivity 89%, specificity 81% for pancreatic insufficiency

¹⁴C-Triolein Breath Test

• Oral ¹⁴C-labeled triglyceride → measures ¹⁴CO₂ in expired air
• Decreased expiration = decreased triglyceride absorption (steatorrhoea from any cause)
• Two-stage test: if ¹⁴CO₂ increases with oral pancreatic enzyme supplementation in the second stage → pancreatic insufficiency confirmed; no change → mucosal/other cause
• Limitation: requires scintillation counter and isotope facilities

Secretin-Cholecystokinin (CCK) Test / Direct Pancreatic Function Tests

• Gold standard for exocrine pancreatic function
• IV secretin or CCK given; duodenal aspirate collected and analyzed for bicarbonate and enzyme output
• Reduced bicarbonate concentration or enzyme output = exocrine pancreatic insufficiency
• Invasive but most sensitive for mild-moderate pancreatic insufficiency

Serum Lipase and Amylase

• Markedly elevated in acute pancreatitis; may be low or normal in chronic pancreatic insufficiency

B. Tests for Mucosal (Enterogenous) Malabsorption

D-Xylose Absorption Test

• Most valuable differential diagnostic test for distinguishing mucosal malabsorption from pancreatic maldigestion
• D-xylose (a pentose sugar not normally found in the body or diet) is passively absorbed in the small intestine without requiring pancreatic enzymes
• Procedure: 25 g D-xylose in water is given orally after overnight fast
• Urine collected for 5 hours; normal excretion >4-5 g in 5 hours
• <3 g excreted = enterogenous (mucosal) malabsorption (proximal small bowel disease)
• Normal D-xylose with steatorrhoea = pancreatic insufficiency (pancreatic enzymes not needed for xylose, so xylose absorbed normally)
• Caveat: In renal disease, urine values unreliable - measure blood D-xylose at 2 hours instead (normal: >20 mg/dL)
• False-positive (low urine xylose) also in: ascites, delayed gastric emptying, vomiting, SIBO (bacteria catabolize xylose in the gut)

Lactose Tolerance Test / Lactose Hydrogen Breath Test

• Used to diagnose lactase deficiency (most common disaccharidase deficiency)
• Lactose tolerance test: 50 g oral lactose load; blood glucose rise <20 mg/dL above fasting + symptoms = positive
• Lactose hydrogen breath test (preferred):
  • 50 g lactose orally; breath H₂ measured at 0, 30, 60, 90, 120, 180 min
  • Rise in H₂ ≥20 ppm above baseline = lactase deficiency (unabsorbed lactose fermented by colonic bacteria → H₂)
  • Cannot differentiate primary from secondary lactase deficiency
• These two tests agree in ~95% of cases

Hydrogen Breath Test for Bacterial Overgrowth (SIBO)

• Lactulose hydrogen breath test or glucose hydrogen breath test
• Lactulose or glucose given orally; breath H₂ measured serially
• Two-peak pattern (early small bowel peak + late colonic peak) = SIBO
• Glucose breath test: early H₂ rise >12-20 ppm above baseline = SIBO
• Also: jejunal aspirate culture (>10⁵ CFU/mL = gold standard for SIBO)

Bile Acid Malabsorption Tests (ileal function)

• SeHCAT (selenium-homocholic acid taurine) scan: radiolabeled synthetic bile acid given orally; whole-body retention measured at 7 days; <15% retention = bile acid malabsorption
• Useful in terminal ileal disease (Crohn disease), post-ileal resection diarrhoea

C. Test for Terminal Ileal Function

Schilling Test (Vitamin B12 Absorption)

• Oral radioactive ¹⁴C- or ⁵⁷Co-labeled vitamin B12 → large intramuscular "flushing" dose of non-radioactive B12 given simultaneously
• Urine collected for 24 hours; radioactivity measured
• Stage 1 (B12 alone): Low urinary radioactivity = B12 malabsorption
• Stage 2 (B12 + Intrinsic Factor): If corrected by IF → pernicious anaemia / gastric cause
  • If NOT corrected → ileal disease, SIBO, or pancreatic insufficiency
• Stage 3 (B12 + IF + antibiotics): If corrected → SIBO
• Largely replaced by serum B12 + IF antibody testing + Methylmalonic acid (MMA) levels in modern practice

STEP 4: Serological Tests for Specific Diseases

STEP 5: Endoscopy and Biopsy

Upper GI Endoscopy + Duodenal Biopsy

• Standard of care for suspected mucosal disease
• At least 4-6 biopsies from D2/D3 recommended for celiac disease
• Histological findings guide diagnosis:
  • Celiac disease: villous atrophy, crypt hyperplasia, increased intraepithelial lymphocytes (Marsh classification)
  • Whipple disease: PAS-positive foamy macrophages in lamina propria
  • Giardiasis: trophozoites attached to epithelium, mild villous blunting
  • Lymphoma / lymphangiectasia / amyloidosis: characteristic appearances
  • SIBO: variable, often normal or mild changes

Push Enteroscopy / Video Capsule Endoscopy

• For visualization of mid/distal small bowel beyond reach of standard endoscope
• Useful for Crohn's disease, NSAID enteropathy, small bowel tumours

Colonoscopy with Terminal Ileum Biopsy

• Assess terminal ileum (Crohn's disease, TB)

STEP 6: Imaging Studies

Plain X-ray Abdomen

• Pancreatic calcification → chronic pancreatitis (exocrine insufficiency)
• Dilated loops of bowel → obstruction / SIBO predisposition

Barium Follow-Through / Small Bowel Enteroclysis

• Demonstrates structural small bowel abnormalities
• Findings: flocculation/segmentation of barium (celiac), mucosal thickening (Crohn, lymphoma), strictures, fistulae, blind loops (SIBO), jejunal diverticulosis

CT Enterography / MR Enterography

• Now largely replaced barium enteroclysis as preferred cross-sectional small bowel imaging
• Detects: mucosal changes, mesenteric lymphadenopathy, bowel wall thickening, strictures, fistulae
• CT can also show: pancreatic calcification, pancreatic atrophy, biliary dilatation
• MRI avoids radiation; preferred in younger patients and follow-up imaging

Ultrasound Abdomen

• Non-invasive, no radiation
• Biliary obstruction, pancreatic disease (calcifications, duct dilatation, stones)
• Small bowel wall thickening (Crohn's, Whipple's - hyperechoic appearance)
• Mesenteric lymph nodes

MRCP / ERCP

• MRCP: non-invasive assessment of biliary and pancreatic duct anatomy
• ERCP: gold standard for biliary/pancreatic ductal disease; also therapeutic (stenting, stone removal)
• Distinguishes chronic pancreatitis from pancreatic tumours

¹¹¹In-Octreotide Scintigraphy / PET-DOTATATE

• For neuroendocrine tumours (gastrinoma, somatostatinoma) causing malabsorption

STEP 7: Special Tests in Selected Cases

Summary Algorithm

Suspected Malabsorption
        ↓
Routine bloods (CBC, iron, folate, B12, albumin, Ca, PT, carotene)
+ Stool for OCP, fat (Sudan stain), reducing substances
        ↓
Steatorrhoea confirmed?
   YES                              NO
    ↓                               ↓
Fecal elastase              Carbohydrate malabsorption tests
D-Xylose test               (lactose/H₂ breath test)
Serum amylase/lipase        Protein-losing enteropathy
                            (fecal alpha-1 antitrypsin)
    ↓
D-Xylose ABNORMAL           D-Xylose NORMAL
(Mucosal disease)           (Pancreatic/Biliary)
    ↓                               ↓
Celiac serology             Imaging pancreas (CT/MRCP)
Upper endoscopy + biopsy    Fecal elastase
Capsule endoscopy           Secretin stimulation test
        ↓
Specific diagnosis → targeted management

• Henry's Clinical Diagnosis and Management by Laboratory Methods - Tests for Steatorrhoea and Malabsorption (pp. 394-396)
• Tietz Textbook of Laboratory Medicine, 7th Edition - Investigation of Maldigestion and Malabsorption (Box 52.8)
• Goldman-Cecil Medicine - Table 126-6: Tests for the Evaluation of Malabsorption
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease - Noninvasive Evaluation of GI Digestive and Absorptive Function (Ch. 104)