Intestines/Including Rectum

Celiac Disease suspected: tTG IgA test (with or without EMA) plus total IgA, and deaminated AGA IgA and IgG tests - if positive or strong clinical suspicion even if negative, then do EGD Celiac Disease NEJM 2012 DDx: Gluten Sensitivity, Gluten Allergy Celiac Disease NEJM 2012 Celiac Disease NEJM 2012   Celiac Disease NEJM 2012 Medical Progress: Celiac Disease NEJM 2007 Coeliac disease BMJ 2014   Medical Progress: Celiac Disease NEJM 2007   Medical Progress: Celiac Disease NEJM 2007 Medical Progress: Celiac Disease NEJM 2007 DIVERTICULOSIS  A high-fiber diet does not protect against asymptomatic diverticulosis. Gastroenterology. 2012 A high-fiber diet does not protect against asymptomatic diverticulosis. Gastroenterology. 2012 Constipation & low-fiber diet are not associated with diverticulosis. Clin Gastro Hepatol. 2013  Constipation & low-fiber diet are not associated with diverticulosis. Clin Gastro Hepatol. 2013  Constipation & low-fiber diet are not associated with diverticulosis. Clin Gastro Hepatol. 2013  Sigmoid Diverticulitis A Systematic Review JAMA 2013 Sigmoid Diverticulitis A Systematic Review JAMA 2013 PROBIOTICS   Possible Use in : VSL#3 (Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, L. bulgaricus, Streptococcus thermophilus) Align (B. infantis) Culturelle (L. rhamnosus GG) DanActive (L. casei) Mutaflor (E. coli Nissle 1917) Florastor (S. boulardii) GASTROENTERITIS Infectious Toxic Esinophilic Gastroenteritis Eosinophilic Gastroenteritis Medscape  INFLAMMATORY BOWEL DISEASE Inflammatory Bowel Disease NEJM 2009 CROHN'S DISEASE Pathogenesis: Please review Figure 1 and Figure 2 of  Lancet 2012  highlighted in purple are processes involved in pathogenesis of CD; added information in black is to show the comparison of CD pathogenesis to the rest of the clinical immunology) Innate and Adaptive Immune mechanisms are involved in pathogenesis.  Innate Immune System Intestinal epithelial cells : Because of 2 factors listed below increased access of intestinal antigen to the immune cells in the lamina propria 1. mucin cover becomes insufficient over single layer of epithelial cells in the inflamed terminal ileum 2. tight junctions become leaky Phagocytic defects: NOD2 defect leads to ineffective autophagy Cell Signaling:  4 types:  2 Membrane bound  TLR (7 types) increased expression of TLR2 and TLR4  and exaggerated lipopolysaccharide response leads to lack of tolerogenic regulatory T cells  CLR (5 types) 2 Cytoplasmic  NLR (6 Types) NLR NOD 2 defect (i.e cytoplasmic cell signaling defect) in Paneth cells (P cells) leads to permeability dysfunction  that in turn leads to increased transepithelial intestinal antigen transport to immune cells in the lamina propria RIG - 1 Helicase receptors (2 Types) Complement (Alternate and Lectin Pathways) Adaptive Immune System The adaptive immune system in Crohn’s disease is now thought to mediate and perpetuate, but probably not start, intestinal inflammation. Bascially there is an imbalance of effector T cells versus natural Regulatory T cells. This leads to the rapid recruitment and inappropriate retention of leuco- cytes is a hallmark of Crohn’s disease.   T-Cell T-Cell Development T-Cell Maturation T-Cell Activation and antigen presentation or Functioning: Th1 and Th17 are involved in CD (secrete interferon γ, TNFα, and interleukins 17 and 22 and defend mucosa against bacteria, fungi, and viruses)  Th1: interferon γ, IL 12 Th2 : IL4, TGF Beta Th17:  interleukins 17 and 22 B-Cell Impaired Development Impaired Functioning  T-cell mediated T-cel independent  Regulatory Immune System Innate System Regulation The ability of dendritic cells to induce tolerogenic regulatory T cells (Treg) might be lost in Crohn’s disease. Secrete IL 10, TGF Beta, IL 35 Adaptive System Regulation Key Points when caring for patient with CD Consider DDx Establish complete disease phenotype including Extraintestinal Symptoms Montreal L  Montreal B Extraintestinal Manifestations Screen for predictors and biomarkers of complicated disease course Educate and counsel your patient about disease and therapy associated with risks and complications Scoring the Severity of Disease  Harvey-Bradshaw Index (HBI) — A simple index of Crohn’s disease activity (PDF) Management Medical Management Quit smoking eInitial therapy directed by Phenotype, Disease activity, Comorbidities, Individual characteristics of drug and patients Fast acting short term agent  Steroids and  TNF blocker (Infliximab - IV, Adalimumab - SC, Certolizumab - SC, Natalizumab - IV) Long term maintenance  Thiopurines  (Azathiopurine or Mercaptopurine) MTX Thiopurines and TNF blocker in combination  is better for mucosal healing and symptoms control increased risk of infection and malignancies L1 Mild to moderate Severe or Refractory L2, L3, L4 Mild to moderate Severe or Refractory PREDNISONE IS OKAY DURING INDUCTION B3p (Perianal Fistula) PREDNISONE NOT  RECOMMENDED Cipro (1000 mg / day) and Metronidazole (750 - 1500 mg / day) during induction Infliximab and Adalimumab for both induction and maintenance Certolizumab for induction Thiopurines but not MTX for maintainance Post-operative Maintainance  Anemia: IDA or ACD Arthopathy and Osteoporosis Peripheral artrhopathy Pauciarticular (usually large joints like Knees) Correlates with the Disease activity  Polyarticular (Small Joints like MCP) Does not correlate to the disease activity Axial arthropathy Spondylitis Isolated Sacroiliitis Treatment NSAIDS PT TNF Blocker for Spondylitis Osteoporosis Prevention (if long term steroids use) Ca and Vitamin D Bisphosphates Episcleritis, Uveitis  Payoderma Gangrenosum and Erythema Nodosum Clinical Dx (biopsy not needed) New Therapeutics IL 12 Pathway (also seen in RA, Psoriasis, MS) Blockade of Leucocyte migration, adhesion, and homing Surveillance programs and follow-up plan Infection  TB HIV Infectious Hepatitis CMV C. Diff Colitis Immunization Status Based on annually updated authority recommendations for patients with Primary and Secondary Immunodeficiencies Pneumococcal,  influenza,  hepatitis,  human papillomavirus, and  herpes zoster vaccines  Note HZV has to be given before therapy, rest can be given either before or during (killed vaccines) Malignancy Colorectal Cancer L3: enrolled in surveillance program 8 yrs after the onset of symptoms Colonoscopy 1-2 to 1-3 yrs afterwards  After 20 yrs defaults to the initial schedule PSC if present increases the risk of right sided CRC Cervical Cancer Women with Crohn’s disease might have a higher risk of an abnormal Pap smear compared with healthy controls and those who use immunomodulators have a higher risk of an abnormal Pap smear associated with HPV infection and need close cervical cancer screening  Lymphoma Thiopurines and TNF blockers associated with B cell lymphoma  Safety Thiopurines and approved biological agents (except natalizumab because of absence of data) are generally regarded as safe with regard to conception, pregnancy, and breastfeeding and should be continued Antibiotics, sulfasalazine, and methotrexate are contraindicated during breastfeeding Crohn’s disease BMJ 2014 Crohn's Diseases Lancet 2012  ULCERATIVE COLITIS  Pathogenesis: Please review Lancet 2013  highlighted in purple are processes involved in pathogenesis of UC; added information in black is to show the comparison of UC pathogenesis to the rest of the clinical immunology) Innate and Adaptive Immune mechanisms are involved in pathogenesis.  Innate Immune System Intestinal epithelial cells : Because of 2 factors listed below increased access of intestinal antigen to the immune cells in the lamina propria 1. mucin subtype 2 (Mucin 2) synthesis is decreased over colonic mucosa. 2. Also, there is possible defects in the tight junctions  3. note: intestinal epithelial cells also secrete anti-microbial peptides, which is more than normal in patients with UC Normal Intestinal Microflora ulcerative colitis seems to result from a breakdown of the homoeostatic balance between the host’s mucosal immunity and the enteric microflora, which results in an aberrant immune response against commensal non-pathogenic bacteria  Phagocytic defects: NOD2 defect leads to ineffective autophagy Cell Signaling: of macrophages and dendritic cells of lamina propria 4 types:  2 Membrane bound  TLR (7 types) Normal intestine express TLR 3 and 5, and TLR 2 and 4 are absent. In UC, TLR 4 is in abundant.  Via TLR-4, NFkB pathway is activated that leads to increased production of TNF-α, interleukins 12, 23, 6, and 1β from activated macrophages and dendritic cells  CLR (5 types) 2 Cytoplasmic  NLR (6 Types)  RIG - 1 Helicase receptors (2 Types) Complement (Alternate and Lectin Pathways) Adaptive Immune System T-Cell T-Cell Development T-Cell Maturation T-Cell Activation and antigen presentation or Functioning: The balance between Th1 and Th2 has been used to differentiate between ulcerative colitis and Crohn’s disease.  Th1: interferon γ, IL 12 (note: activated in CD) Th2 : Modified atypical Th 2 response is seen in UC. Cytokines produced by activated macrophages and dendritic cells by TLR pathway leads to differentiation of T cells to Th2 causing production of IL4; there is also increased recruitment of gut-specific T cells into lamina propria that perpetuates the cycle of inflammation;  Like wise, NK T-cells that are in increased number in lamina propria activate Th 2 response and cytokine production. At first IL4 is produced, but rapidly it is changed to IL13 that is produced in abundance. Interleukin-5–producing Th2-polarized T cells are also present in ulcer- ative colitis.  Th17:  interleukins 17 and 22 (note: activated in CD) B-Cell B cell activation leads to pANCA, anti-tropomyosin, antibacterial antibodies. Usually, it is IgG1. The epithelial antigen that leads to such antibody production is also shared in Eyes, Joints, Biliary  Epithelium, Skin etc. This explains the extra intestinal manifestation of UC Impaired Development Impaired Functioning  T-cell mediated T-cel independent  Regulatory Immune System Innate System Regulation There is also some imbalance of toleregenic T cells in in UC. IL -10 receptor dysfunction leads to loss of IL 10 function Lancet 2013 .  But such Regulatory T cell dysfunction have not been reported in UC NEJM 2011 Adaptive System Regulation Clinical Feature:  Diarrhea, Blood in stool  Present early on in the disease  Disease Severity (based on Number of BM / day, inflammatory markers etc):  Mild  Moderate Severe  Treatment:  Key is to be aggressive upfront before bowel remodeling (irrespective of mild, moderate or severe disease process) Mesalamine Monitor for renal side effects (typically yearly) Sulfasalazine (melamine but has sulfa component which causes more side effects)  Immunomodulator Azathioprine  Risk of Lymphoma goes high on Azathioprine  Note: MTX (mostly for CD) is not for UC Biologics: Anti-TNF (5 of them are there)  Newer therapy that effects Neutrophil chemotaxis is used as well.  http://dx.doi.org/10.1016/S0140-6736(16)32126-2 http://dx.doi.org/10.1016/S0140-6736(16)32126-2 References:  UC BMJ 2013 Ulcerative Colitis Lancet 2013  Ulcerative Colitis NEJM 2011 Microscopic Colitis Lymphocytic Colitis Collagenous Colitis: also, has lymphocyte, but has collagen band  Pathogenesis:  Role of colon is to absorb water. These pathological changes prevents water absorption, and hence diarrhea (watery diarrhea) Etiology:  Largely unknown but Medications (PPI, NSAIDs)  Diagnosis:  Colonoscopy, and Biopsy Small percentage of patient have localized to right colon, hence, full colonoscopy is essential Treatment:  Budesonide (works very dramatically)  Expensive  Alternative:  Imodium (scheduled use is necessary)  Oral Manifestation of Crohn’s Disease NEJM 2015 Proctitis DDx: Non-Infectious Etiology Radiation Ischemic (Infrequent due to extensive collateral blood supply) Inflammatory (CD, UC) Infectious Etiology MSM (4 Most prevalent DDx are) Gonorrhea HSV Chlymadia Trachomatis Serovar D through K:  Most common cause of nongonoccal urethritis, and mucopurulent cervicitis Can cause procitis, usually mild and responds to one dose of Azithro Serovar L1, L2, L3: lymphogranuloma venereum (LGV) Usually cause more severe disease 3 Stages of LGV produce 3 distinct clinical syndromes Primary (painless ulcer that usually resolves spontaneously) Secondary (10-30 days, hallmark is lymphadenitis) Inguinal or Femoral Lymphadenitis (or both; may suppurate and form abscess, sinus or fistula) if Penis or Vagina is a site of inoculation  Proctitis( If rectum is a site of inoculation) Tertiary (fibrosis and strictures leading to chronic genital ulceration, genital elephantiasis, anal fistulae and strictures, frozen pelvis, and infertility) Syphilis Ongoing infectious colitis also causing proctitis Bacteria: shigella, Escherichia coli, Clostridium difficile  Protozoa: amoebiasis  Virus: CMV Case 2-2006: A 31-Year-Old, HIV-Positive Man with Rectal Pain (DDx of Proctitis) Haemorrhoids types  Internal  Grade I Grade II Grade III Grade IV External  Hemorrhoids NEJM 2014