© UEG. 2019 Presentation by
Enteropathies: From Bench to Bedside
State-of-the-art introduction
Roberto De Giorgio
University of Ferrara, Italy
© UEG. 2019 Presentation by Roberto De Giorgio
University of Ferrara, Italy
No conflict of interest
© UEG. 2019
•
Mixing (enzymes and bile secretion) with chyme from stomach•
Mucosal function•
Splanchnic blood flow•
Intestinal motility (ENS)•
Commensal gut microbiotaGut physiology
…
100 µm
Nerves
Macrophages Mast cells Lymphocytes
Key players for gut physiology
Buhner & Schemann. BBA – Molecular Basis of Diseases 2012, 1:85-92;
Schemann & Camilleri. Gastroenterology 2013, 144:698-704
Epithelia
…
• M, 71 yrs; Past medical history of hypertension, hyperlipidemia, CAD
• Chronic, nonbloody - “watery” - diarrhea started 2 yrs ago
• ~ 12 Kg weigth loss
• Abdominal disconfort, loss of appetite, fatigue
A case of ‘chronic diarrhea’…
• Colonoscopy: ‘lymphocytic colitis’
…no major improvement…
Rx: budesonide
• TSH -ve
• Stool cultures (+ ova and parasites), analysis
C. Difficile (toxin A) -ve
• Glucose-BT, abdo-CT, etc. -ve
• Routine lab tests Mild
hypoalbuminemia
A case of chronic diarrhea…
Villous atrophy (3a)
• Celiac panel (tTG IgA, EmA IgA) -ve
EGDS: normal gastric mucosa; duodenum:
…careful review of his medical records … after a detailed history, found that the patient was started on olmesartan 20 mg / d
(previously on lisinopril) in 2015 for hypertension;
The dose was subsequently increased to 40 mg / d subsequently…
Diagnosis: “Olmesartan-induced villous atrophy with malabsorption”
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ARB-induced enteropathy
Kamal A., et al., Gastroenterol Rep 2019; 7(3):162-167
• N= 82 case reports and case series; n= 5 comparative studies. Total n= 248 pts selected and analysed
• ARBs: >> olmesartan (94%).
Symptom onset: 2 wks -13 yrs from ARB initiation
• N= 92.2% villous atrophy; 60.1% IELs;
98.8% showed negative celiac serology
• GFD failed to relieve symptoms of enteropathy in 97.7% pts.
• 97.4% discontinued ARB symptom remission (2.8% had symptom recurrence after restarting olmesartan)
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What does ‘Enteropathy’ mean ?
•
Wide spectrum of diseases characterized by various degrees of enteric (>small intestine) mucosal damage (e.g. from ‘minimal lesions’ to total atrophy);•
Clinical features range from asymptomatic to severe malabsorption;more commonly pts have (chronic) diarrhea / steathorrea and weight loss;
•
A correct diagnosis is crucial to guide appropriate managementJansson-Knodell C.L., et al., Mayo Clin Proc 2018; 93(4):509-517
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A possible classification of enteropathies
Jansson-Knodell C.L., et al., Mayo Clin Proc 2018; 93(4):509-517
Minimal lesion (> Marsh 1)
Autoimmune
Immune-mediated Infectious Oncological Miscellanea
IEL > 25
Flat mucosa
Celiac Disease (classic & complicated)
Crohn’s Disease
Autoimmune Enteropathy
Drugs (e.g., ARB)
Neoplastic diseases
(Lymphomas) Infiltrative
(Amyloidosis, Collagenous)
CVIS GVHD
Whipple
HIV
Infiltrative (Eosinophilic)
Infections (H. pylori,
Giardia) SIBO
Systemic Autoimmune
Disorders (Thyroiditis)
(Food) Allergies Radiation
Enteritis
Ischemia
HIV NCG/WS
BAM
Celiac Disease (classic & complicated)
© UEG. 2019
A possible classification of enteropathies
Jansson-Knodell C.L., et al., Mayo Clin Proc 2018; 93(4):509-517
Minimal lesion (> Marsh 1)
Infiltrative (Eosinophilic)
Infections (H. pylori,
Giardia) SIBO
Systemic Autoimmune
Disorders (Thyroiditis)
(Food) Allergies Radiation
Enteritis
Ischemia
HIV
Autoimmune
Immune-mediated Infectious Oncological Miscellanea
IEL > 25
NCG/WS
BAM
Celiac Disease (classic & complicated)
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Bile acid-evoked diarrhea: pathophysiology
Rao A.S., et al Gastroenterology 2010; 139:1549-58
BA entero-hepatic circulation and homeostasis
Type 1 BAM
• Ileal resection
• Crohn’s disease Type 2 BAM
• idiopathic Type 3 BAM
• Cholecystectomy
• Pancreatic insufficiency
• SIBO
• Diabetes mellitus
• Celiac disease
• 40% of patient microscopic colitis have BAM
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- Rare disease
- Malabsorptive phenotype - Typical of pediatric age
Past
- Frequent (>1:100)
- Systemic disease with polymorphic presentation - Occurs at any age; persisting disease
Present
Celiac disease has changed…
Coeliac Disease (CD) in the 2019…
EmA
Small intestinal villous atrophy
3. reliable tools for diagnosis 1. autoimmune disorder
2. high prevalence in the general population (≥1%) 4. onset at any age (even in the elderly !); F:M = 2-3:1
5. polymorphic clinical presentation
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Beware of Marsh 1 in pts with suspected CD !
•
Marsh 1, i.e. IEL >25%, does not indicate CD•
A wide array of conditions may show Marsh 1:- HP infection / Giardiasis, etc.
- Autoimmune diseases (thyroiditis) - Drugs (NSAIDs)
- Lactose intolerance - NCG / WS
- etc…
…but…
Increased trend of potential CD over the years
77 PCD vs. 658 ACD F/M = 3.2:1 vs. 3.5:1 Mean age: 25 vs. 36 yrs
735 consecutive CD pts
Volta U, Caio G , De Giorgio R. Clin Gastroenterol Hepatol 2016;
ACD: Active Celiac Disease; PCD: Potential Coeliac Disease
© UEG. 2019 Volta U & De Giorgio R, Nat Rev Gastroenterol Hepatol 2012; 9:295-9 5th Consensus Conference on Gluten Related Disorders, Merano 2018
Adverse reaction to gluten or other wheat
proteins (e.g., ATIs)
Negative serology / no flat mucosa at histopathology
Specific IgE + prick to wheat / gluten test
negative
What is NCG / WS ?
Wheat / gluten ingestion evokes IBS-like symptoms…
…and extraintestinal symptoms / signs
Improvement with GFD / challenge re-evokes
symptoms
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CD3+ T lymphocytes:
linear distribution in the deeper part of the mucosa and clusters in the villi
‘palisade’ pattern
‘clusterized IEL’
Possible histological pattern of NCGS ?
Marsh 1 prevalence in NCG / WS
Volta U., et al., BMC Med 2014; 12:85
© UEG. 2019
A possible classification of enteropathies
Jansson-Knodell C.L., et al., Mayo Clin Proc 2018; 93(4):509-517
Autoimmune
Immune-mediated Infectious Oncological Miscellanea
Celiac Disease (classic & complicated)
Flat mucosa
Autoimmune Enteropathy Crohn’s Disease
Drugs (e.g., ARB)
Neoplastic diseases
(Lymphomas) Infiltrative
(Amyloidosis, Collagenous)
CVIS GVHD
Whipple
HIV
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Refractory and non-responsive CD
•
Refractory CD (RCD) (1% of all CD) is characterized by the lack of clinical response and persistence of villous atrophy after at least 1 year of strict GFD•
RCD diagnosis is of paramount importance because it evolves to EATL and ulcerative jejuno-ileitis•
A distinct condition is the GFD-non-responsive CD (7-30% of CD) characterized by symptom persistence but with a normal intestinal mucosa (i.e., villous re-growth)Causes of non-responsive celiac disease
NRCD %
Continued gluten ingestion 36-45%
Incorrect CD diagnosis 12%
IBS 10- 22%
SIBO 6- 9%
RCD and other
complications 9-10%
Lactose intolerance 7-8%
Colitis 7%
Microscopic colitis 6-11%
Eating disorders 2-4%
CVID 1-2%
• The most common cause of NRCD is unintentional gluten intake, but etiologies can be many
Leffler DA, Clin Gastroenterol Hepatol 2007; Dewar DH, World J Gastroenterol 2012
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Refractory CD and other complications
Type 1 Type 2
Severe villous atrophy yes yes
Autoimmune disorders yes no
HLA-DQ2 homozygosity rare common
Clonal TCR-/ gene rearrangement
+ ++
Aberrant T-cell phenotype ≤10%IEL ≥50% IEL Chromosomal abnorfmalities no yes Ulcerative jejunoileitis rare common Resp. to immunosuppress. yes no
Risk of EATL low 60% in 5 yrs
Mortality rate Slightly
increased 5-yr survi- val <50%
Other complications:
•
Ulcerative jejunoileitis•
Small bowel adenocarcinoma•
EATL•
HyposplenismA delayed diagnosis and a poor compliance to GFD increase the
risk for complicated CD
van Gils T, Nijeboer P, et al., Nat Rev Gastroenterol Hepatol 2015; 12: 572-579
Severe malabsorption syndrome with diarrhea and weight loss
Villous atrophy with marked inflammation and apoptotic bodies; IgG and IgA anti-enterocyte Abs
Frequent association with other autoimmune disorders
Good response to steroids and immunosuppressive treatment
Whipple Disease
Rare, chronic infection by Tropheryma Whippeli;
Middle-aged pts
Male >> Females
Small intestinal (including diarrhea, abdominal pain, weight loss) and extraintestinal manifestations (fever, joint pain, cognitive impairment, ataxia, endocarditis and eye involvement)
Diagnosis: PAS+ve intracellular bodies;PCR on biopsies / blood / cerebrospinal fluid
Rx: AntibioticsA
B
PAS+ve
Flat mucosa
Murray JA Rubio-Tapia A, Best PractRes Clin Gastroenterol 2012
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Enteropathy - conclusion
•
Enteropathies encompass a wide spectrum of illness responsible for (usually) chronic / watery diarrhea, nutritional deficits & weight loss.•
A detailed and careful approach can often reveal the underlying cause•
Differential diagnosis is a fundamental strategy in order to identify the disease, address appropriate treatment and establish prognosis© UEG. 2019
Small bowel amyloidosis
Bansal R., et al., Curr Gastroenterol Rep 2018; 20: 11
• AL-λ is the most common type of amyloid and occurs in 53% of pts
• The least common amyloid type is AA and occurs in 10% of pts
• Both AL-λ and AA are most commonly found in the stomach and duodenum
