Eosinophilic Esophagitis (EoE)

Definition

• Esophageal dysfunction symptoms (dysphagia, food impaction in adults; feeding intolerance, GERD-like symptoms in children)
• Histological eosinophilic infiltration of the esophageal epithelium
• Yamada's Textbook of Gastroenterology, 7e
• Robbins & Kumar Basic Pathology

Pathophysiology & Role of IL-5

Link to Food Allergy

• Most patients have a personal or family history of atopic disease: allergic rhinitis, asthma, atopic dermatitis, or food allergy
• Food antigen sensitization (particularly cow's milk, wheat, soy, eggs, nuts, seafood) is a major trigger
• Sensitization often occurs via inflamed skin (the "outside-in" hypothesis), with re-exposure through ingestion driving esophageal inflammation
• Removal of trigger foods via elemental or elimination diets results in histological remission in a significant proportion of patients
• Sleisenger & Fordtran's GI and Liver Disease

Diagnostic Criteria

1. Symptoms of esophageal dysfunction
2. Histology: ≥15 eosinophils per high-power field (eos/HPF) on esophageal biopsy (proximal AND distal biopsies)
3. Exclusion of other causes of esophageal eosinophilia (GERD, parasitic infection, Crohn disease, drug-induced esophagitis, eosinophilic gastroenteritis)
4. PPI-refractory course (helps distinguish from GERD-related eosinophilia)

"The eosinophil density required for the diagnosis of eosinophilic esophagitis is generally more than 15 eosinophils per high-power field on both proximal and distal esophageal biopsies." - Cummings Otolaryngology, Head & Neck Surgery

"The presence of at least 15 eosinophils per HPF is required for a diagnosis, and it is also a cut-off for histological remission (<15 eos/HPF)." - Yamada's Textbook of Gastroenterology, 7e

Endoscopic & Histologic Findings

• Stacked concentric rings ("trachealization" or "feline esophagus") - fixed or transient
• Longitudinal furrows
• White exudates / eosinophilic microabscesses (can mimic candidiasis)
• Mucosal friability ("crepe paper esophagus")
• Strictures (proximal/mid esophagus - distinguishes from GERD which affects distal)

• ≥15 eos/HPF (superficial clustering is characteristic)
• Eosinophilic microabscesses
• Basal cell hyperplasia
• Lamina propria fibrosis (subepithelial)

Key Differentiator from GERD

Treatment

• Dietary elimination (6-food elimination diet or elemental formula)
• Swallowed topical corticosteroids (fluticasone, budesonide) - first-line pharmacotherapy
• Proton pump inhibitors - can induce remission in a subset (~30-40%, per recent meta-analysis, PMID 40089255)
• Dupilumab (anti-IL-4Rα, blocks IL-4 and IL-13 signaling) - FDA-approved biologic; real-world effectiveness confirmed in systematic review (PMID 39998943)
• Esophageal dilation for strictures/food impaction

Ménétrier's Disease

Definition

• Massive foveolar (mucous cell) hyperplasia of the body and fundus
• Giant, tortuous gastric rugal folds with a cerebriform (brain-like) gross appearance
• Protein-losing gastropathy with hypoalbuminemia
• Achlorhydria / hypochlorhydria due to loss of parietal cell mass
• Robbins, Cotran & Kumar Pathologic Basis of Disease
• Harrison's Principles of Internal Medicine, 22e

Pathogenesis

TGF-α overexpression
        ↓
Overstimulation of EGFR (Epidermal Growth Factor Receptor) on gastric epithelial cells
        ↓
Massive proliferation of foveolar (surface mucous) cells
        ↓
Hyperplastic, elongated, tortuous, cystic glands → Giant rugal folds
        ↓
Loss of parietal cells → Hypochlorhydria/Achlorhydria
Loss of protein across leaky mucosa → Hypoalbuminemia → Edema

• In children: most cases are triggered by CMV infection (CMV-induced EGFR activation) - typically self-limited
• In adults: etiology often unknown; CMV and H. pylori have also been implicated
• Yamada's Textbook of Gastroenterology, 7e
• Harrison's Principles of Internal Medicine, 22e

Clinical Presentation

• Epigastric pain, nausea, vomiting, anorexia
• Peripheral edema - from hypoalbuminemia (albumin loss can approach 10 g/day)
• Weight loss, diarrhea
• Occult GI bleeding (from mucosal erosions)

Classic Case Scenario

A 55-year-old man presents with progressive peripheral edema, epigastric discomfort, and weight loss over several months. Labs show hypoalbuminemia with a normal 24-hour urine protein. Upper endoscopy reveals massively enlarged, lobular, cerebriform gastric folds in the fundus and body with antral sparing. Biopsy shows massive foveolar hyperplasia with elongated, corkscrew-shaped, cystic glands and markedly reduced parietal and chief cells. Gastric acid secretion is absent.

Diagnosis: Ménétrier's Disease

Radiology

• Massively thickened, lobular, often bizarre gastric folds
• Prominent in the proximal stomach and greater curvature
• Antrum generally spared (though involved in up to 50% of cases)
• Folds remain pliable (differentiates from carcinoma, where stomach is rigid/aperistaltic)
• Increased fluid in small bowel may impair optimal barium coating

Histology

• Massive foveolar hyperplasia - the hallmark
• Glands are elongated with a corkscrew/tortuous appearance
• Cystic gland dilation is common
• Marked reduction in oxyntic glands (parietal + chief cells)
• Inflammation is minimal (not a gastritis - key distinction)
• Intraepithelial lymphocytosis in some cases

Comparison with Other Hypertrophic Gastropathies

• Robbins, Cotran & Kumar - Table 17.5

Diagnosis

1. Endoscopy with deep mucosal biopsy (snare technique preferred for full-thickness sample)
2. Barium upper GI / CT - characteristic giant folds
3. Labs: Serum albumin (↓), gastric acid pH (achlorhydria), serum gastrin, CMV and H. pylori serology, CBC
4. A nondiagnostic endoscopic biopsy may require surgically obtained full-thickness biopsy to exclude malignancy

• Zollinger-Ellison syndrome
• Gastric lymphoma / infiltrating carcinoma
• CMV / syphilis / tuberculosis / histoplasmosis gastritis
• Sarcoidosis
• Gastric polyposis (FAP, prolonged PPI use)

Treatment

In children: disease is usually self-limited; viral clearance (CMV) leads to normalization of epithelial proliferation and restoration of gastric anatomy without surgery.

• Harrison's Principles of Internal Medicine, 22e
• Robbins, Cotran & Kumar Pathologic Basis of Disease

Cancer Risk

Sézary Syndrome - Cerebriform Nuclei

What Are Sézary Cells?

• Home to the skin (via cutaneous lymphocyte antigen / CLA and CCR4)
• Circulate in the peripheral blood (leukemic phase)
• Infiltrate lymph nodes

Sézary Syndrome - Definition

"Sézary syndrome is characterized by the triad of diffuse erythroderma, generalized lymphadenopathy, and circulating malignant T cells with cerebriform nuclei - so-called Sézary cells."

• Fitzpatrick's Dermatology

The Classic Triad

• Leonine facies (lion-like face from skin thickening)
• Eyelid edema / ectropion
• Diffuse alopecia
• Hyperkeratosis of palms and soles
• Dystrophic nails
• Elevated IgE and eosinophilia (Th2 cytokine phenotype)
• Andrews' Diseases of the Skin

Peripheral Blood Smear - Sézary Cells

Relationship to Mycosis Fungoides (MF)

Mycosis Fungoides (skin-limited CTCL)
     Patch phase → Plaque phase → Tumor phase
                          ↓
              Sézary Syndrome (leukemic phase)
           [erythroderma + blood involvement]

• In MF: cutaneous lesions progress through patch → plaque → tumor; skin lesions do proceed to tumefaction
• In Sézary Syndrome: generalized erythroderma from onset; skin lesions rarely proceed to tumefaction; leukemic cells circulate in blood

Histology of MF/Sézary - Skin Biopsy

"T cells with irregular nuclei show single-cell infiltration of the epidermis and often form clusters known as Pautrier abscesses... The nuclei of at least a portion of neoplastic cells typically have a cerebriform appearance." - Henry's Clinical Diagnosis and Management by Laboratory Methods

Immunophenotype

Diagnostic Criteria (ISCL/EORTC)

1. Erythroderma
2. Positive T-cell clone in peripheral blood (T-cell receptor gene rearrangement)
3. At least one B2 criterion, which includes:
   • Absolute Sézary cell count ≥1000 cells/mm³ in peripheral blood
   • CD4:CD8 ratio >10
   • Loss of CD2, CD3, CD4, or CD5 from circulating T cells
   • Lack of CD7 or CD26

Note: Sézary cells alone on cytomorphology are not sufficient - they can be found in other inflammatory erythrodermas (reactive conditions). Clonality must be proven.

Prognosis

Treatment Options

• Fitzpatrick's Dermatology; Andrews' Diseases of the Skin

Abetalipoproteinemia (Bassen-Kornzweig Syndrome)

Definition

• Complete inability to assemble and secrete triglyceride-rich lipoproteins (chylomicrons, VLDL, LDL)
• Intracellular lipid accumulation in enterocytes and hepatocytes
• Severe fat malabsorption with downstream multi-system consequences
• Robbins & Kumar Basic Pathology; Yamada's Textbook of Gastroenterology, 7e

Pathogenesis - The MTP Defect

Normal pathway:
Dietary fat → Enterocyte → MTP transfers lipids to ApoB48 → Chylomicron → Lymphatics → Blood

ABL:
MTP mutation → Cannot transfer lipids to ApoB48
             → Chylomicrons CANNOT be formed
             → Lipids TRAPPED inside enterocytes (vacuoles)
             → Fat-laden enterocytes on biopsy
             → Steatorrhoea
             → Fat-soluble vitamin deficiency (A, D, E, K)

The Three Key Diagnostic Clues Explained

1. Steatorrhoea

2. Duodenal Biopsy - Fat-Laden Enterocytes

• Enterocytes packed with lipid-filled cytoplasmic vacuoles (fat droplets trapped inside)
• Highlighted by Oil Red O stain (especially prominent after a fatty meal)
• Villous architecture is preserved (distinguishes from coeliac disease)

"In the intestine, endoscopic examination reveals a white frosting appearance coating the duodenum and jejunum due to the lipid content in the mucosa. On histological examination, the enterocytes are filled with numerous lipid-filled cytoplasmic vacuoles." - Yamada's Textbook of Gastroenterology, 7e

3. Acanthocytes (Spur Cells)

"Failure to absorb essential fatty acids leads to deficiencies of fat-soluble vitamins as well as lipid membrane defects that can be recognized by the presence of acanthocytes (red cells with spiky membrane protrusions) in peripheral blood smears." - Robbins, Cotran & Kumar Pathologic Basis of Disease

Full Clinical Picture

Multi-System Complications (from Fat-Soluble Vitamin Deficiency)

Neurological Syndrome (Bassen-Kornzweig)

1. Peripheral neuropathy - earliest sign; areflexia, loss of proprioception/vibration (large-fibre), gait ataxia
2. Spinocerebellar degeneration - cerebellar ataxia of gait, trunk, extremities; dysarthria; titubation
3. Retinitis pigmentosa - progressive visual field constriction, ring scotomata
4. Ophthalmoplegia (late)
5. Skeletal deformity - pes cavus, kyphoscoliosis (secondary to early neuropathy)
6. Cardiomyopathy - cardiac enlargement, congestive failure (serious late complication)

"Most untreated patients develop retinitis pigmentosa, peripheral neuropathy, and spinocerebellar degeneration during the first two decades of life." - Bradley and Daroff's Neurology in Clinical Practice

Laboratory Findings

Diagnosis Summary

Treatment

Key point: Early treatment with high-dose vitamin E can prevent neurological deterioration entirely. Late treatment can halt or partially reverse progression. - Yamada's Textbook of Gastroenterology, 7e

Carney Triad vs. Carney Complex - A Critical Distinction

1. Carney Triad

Definition

All three need not be present simultaneously - the triad may be incomplete and evolve over time.

Key Features

"The Carney triad is a syndrome of unknown cause defined by the co-occurrence of GIST, paraganglioma, and pulmonary chondroma, usually occurring in females." - Robbins, Cotran & Kumar Pathologic Basis of Disease

Carney Triad vs. Carney-Stratakis Dyad (Carney-Stratakis Syndrome)

"Evaluation has identified that tumors part of the Dyad carry mutations in the SDH family of genes, whereas those associated with the triad do not have such mutations." - Sleisenger & Fordtran's GI and Liver Disease

2. Carney Complex

Definition

• NAME syndrome: Nevi, Atrial myxoma, Myxoid neurofibromas, Ephelides
• LAMB syndrome: Lentigines, Atrial myxoma, Mucocutaneous myxomas, Blue nevi

The Components

"Carney complex is an autosomal dominant disorder characterized by spotty skin pigmentation, myxomas (heart, skin, breast), psammomatous melanotic schwannomas, and endocrine tumors involving the adrenals, Sertoli cells, somatotropes, thyroid, and ovary." - Harrison's Principles of Internal Medicine, 22e

Genetics

• PRKAR1A is a tumour suppressor - mutations cause loss of inhibition of PKA (protein kinase A) signalling, leading to uncontrolled cell proliferation

Key Clinical Points for Carney Complex

1. Cardiac myxomas are life-threatening - can embolize, causing stroke or peripheral ischaemia. Recognition of the syndrome and surgical removal is lifesaving
2. Cushing syndrome in Carney complex is atypical - patients are often thin (not obese) with normal or only mildly elevated urinary free cortisol; may show periodic/cyclical Cushing's (fluctuating cortisol production)
3. Pigmentation distribution is characteristic - vermilion border of lips, lacrimal caruncle, conjunctival semilunar fold, sclera (not perioral like Peutz-Jeghers)
4. Cardiac myxomas are recurrent (20%) and multichambered (unlike sporadic myxomas which are usually solitary left atrial)
5. Screen first-degree relatives - autosomal dominant inheritance

• Andrews' Diseases of the Skin; Fitzpatrick's Dermatology

Side-by-Side Comparison Table

Hepatitis C - Councilman Bodies / Acidophil Bodies

The Terminology - Councilman Body vs. Acidophil Body

"Apoptotic hepatocytes were first clearly described in yellow fever by William Thomas Councilman and therefore have been referred to as Councilman bodies; while apoptosis occurs in many forms of liver disease, by convention this eponym is restricted to that disease. In other settings in which apoptotic hepatocytes are seen (e.g., acute and chronic hepatitis), the term acidophil bodies is used, due to their deeply eosinophilic staining characteristics."

• Robbins, Cotran & Kumar Pathologic Basis of Disease

What Is an Acidophil / Councilman Body?

Hepatocyte under immune attack (CD8+ T cells, cytokines)
        ↓
Caspase activation → Programmed cell death
        ↓
Hepatocyte SHRINKS (opposite of necrosis which swells)
        ↓
Nuclear chromatin condensation (pyknosis)
        ↓
Nuclear fragmentation (karyorrhexis)
        ↓
Cell fragments into small, densely eosinophilic globules
        ↓
ACIDOPHIL BODY (deeply pink/eosinophilic, anucleate or with pyknotic nucleus)

Hepatitis C Liver Biopsy - Histological Features

Complete Histological Picture of Chronic HCV

• No "ground glass" hepatocytes - Ground glass cells (HBsAg-laden smooth ER) are specific to HBV, not HCV

Mechanism of Hepatocyte Death in HCV

HCV RNA replication in hepatocytes
        ↓
Viral antigens presented on MHC Class I
        ↓
CD8+ cytotoxic T lymphocytes recognize and attack infected hepatocytes
        ↓
Perforin/granzyme pathway → Caspase activation → APOPTOSIS
Fas/FasL pathway → Caspase activation → APOPTOSIS
        ↓
Acidophil bodies form
        ↓
Hepatic stellate cell activation by cytokines (TGF-β, TNF-α)
        ↓
Perisinusoidal myofibroblasts → Collagen deposition → FIBROSIS → CIRRHOSIS

"Adaptive immune cells play a critical role in viral hepatitis, with CD4+ and CD8+ T cells being particularly important in the eradication of virus-infected hepatocytes and in causing liver injury in chronic disease." - Robbins & Kumar Basic Pathology

Summary - Key Points for Exams