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Peptic ulcer Disease and Related Disorders (PEPTIC ULCER DISEASE…

- - - - Epigastric tenderness: most frequent finding in GU or DU.
      - Pain may be found to R of midline in 20% (predictive value low though)
      - Evidence of ulcer complication
        
        Tachycardia + orthostasis: dehydration secondary to vomiting or active GI blood loss.
        
        A severely tender, board-like abdomen: a perforation.
        
        Presence of a succussion splash: retained fluid in stomach--> gastric outlet obstruction.
    - - Gastric Outlet Obstruction
        
        least common; in 1–2% of pxs
        
        relative obstruction secondary to ulcer-related infl + edema in peripyloric region; often resolves w/ ulcer healing.
        
        fixed, mechanical obstruction secondary to scar formation in peripyloric areas; requires endoscopic (balloon dilation) or surgical intervention; Signs and symptoms may develop insidiously.
        
        New onset of early satiety, nausea, vomiting, incr of postprandial abdominal pain, and weight loss should make gastric outlet obstruction a possible diagnosis
      - Perforation
        
        second most common ulcer-related complication
        
        6–7% of PUD pxs w/ an estimated 30-day mortality of over 20%.
        
        Penetration: a form of perforation in which ulcer bed tunnels into an adj organ.
        
        DUs tend to penetrate posteriorly into pancreas--> pancreatitis
        
        GUs
        
        Gastrocolic fistulas also described
        
        tend to penetrate into L hepatic lobe.
      - GI Bleeding
        
        most common complication in PUD.
        
        occur in 19.4–57 per 100,000 in a general population or in 15% of pxs.; 30-day mortality rate: 5–10%
        
        Bleeding + complications of UD occur more often in >60 yrs (likely due to incr use of NSAIDs)
        
        Up to 20% of pxs w/ hemorrhage bleed w/o any preceding warning signs or symptoms.
        
        up to 80% of mortality in PUD-related bleeding due to nonbleeding causes (ex multiorgan failure (24%), pulmonary complications (24%), and malignancy (34%))
    - - most commonly encountered dx among pxs seen for upper abdominal discomfort: NUD=functional dyspepsia=essential dyspepsia
        
        etiology not established
        
        a group of heterogeneous disorders typified by upper abdominal pain w/o presence of an ulcer.
      - Others: proximal GI tumors, GERD, vascular disease, pancreaticobiliary disease (biliary colic, chronic pancreatitis), and gastroduodenal Crohn’s disease
    - - Diagnostic evaluation: establish presence of an ulcer
        
        a radiographic (barium study)
        
        sensitivity of single/double contrast barium meals for detecting a DU; 80/90%
        
        Sensitivity for detection decr in small ulcers (<0.5 cm), w/ presence of previous scarring, or in postoperative pxs.
        
        A DU appears as a well-demarcated crater, most often seen in the bulb. A GU may represent benign (discrete crater w/ radiating mucosal folds originating from ulcer margin) or malignant disease (Ulcers >3 cm in size or a. w/ a mass)
        
        up to 8% of GUs that appear to be benign by radiography are malignant by endoscopy or surgery--> a GU must be followed by endoscopy and biopsy.
        
        an endoscopic procedure
        
        most sensitive + specific approach for examining upper GI tract
        
        permitting direct visualization of mucosa + facilitates photographic documentation of a mucosal defect + tissue biopsy to rule out malignancy (GU) or H. pylori.
        
        partic helpful in identifying lesions too small to detect by radiographic examination, for evaluation of atypical radiographic abnormalities, or to determine if an ulcer is a source of blood loss.
      - Methods for diagnosing H. pylori
        
        biopsy urease tests (PyloriTek, CLOtest, Hpfast, Pronto Dry): a sensitivity and specificity of >90–95%.
        
        noninvasive methods
        
        serologic testing
        
        13 C- or 14 C-urea breath test
        
        fecal H. pylori (Hp) antigen test.
        
        (A urinary Hp antigen test + a refined monoclonal Ab stool Ag test, appears promising)
        
        TABLE 348-2
        
        Occasionally, specialized testing such as serum gastrin and gastric acid analysis or sham feeding may be needed in individuals w/ complicated or refractory PUD (“Zollinger-Ellison Syndrome”).
        Screening for aspirin or NSAIDs (blood or urine) may also be necessary in refractory H. pylori–negative PUD patients.
    - - Abdominal pain: poor predictive value for DU or GU.
      - Up to 10% of pxs w/ NSAID-induced mucosal disease can present w/ a complication (bleeding, perforation, and obstruction) w/o antecedent symptoms.
      - Epigastric pain can be present in both DU and GU
        
        Description: burning or gnawing discomfort, also as an ill-defined, aching sensation or as hunger pain.
        
        typical pain pattern
        
        in DU
        
        90 mins to 3 hrs after a meal + frequently relieved by antacids or food.
        
        Pain that awakes from sleep (betw midnight and 3 A.M.): most discriminating symptom, in 2/3 of DU pxs. Unfortunately also present in 1/3 of NUD
        
        Elderly pxs less likely to have abdominal pain as a manifestation of PUD and may instead present w/ a complication such as ulcer bleeding or perforation.
        
        in GU
        
        discomfort may be precipitated by food.
        
        Nausea and weight loss occur more commonly in GU
        
        Endoscopy detects ulcers in <30% of pxs who have dyspepsia
        
        Variation in intensity or distribution, as well as onset of associated symptoms (ex nausea and/or vomiting) may be indicative of an ulcer complication.
        
        Dyspepsia that becomes constant, is no longer relieved by food or antacids, or radiates to back-->maybe a penetrating ulcer (pancreas).
        
        Sudden onset of severe, generalized abdominal pain-->maybe perforation.
        
        Tarry stools or coffee-ground emesis--> bleeding
        
        Pain worsening w/ meals, nausea, and vomiting of undigested food--> maybe gastric outlet obstruction.
  - - - Gastric Ulcers
      - Duodenal Ulcers
    - - Gastric Ulcers
      - Duodenal Ulcers
    - - H. pylori and Acid Peptic Disorders: majority of PUD; also plays a role in development of gastric MALT lymphoma + gastric adenocarcinoma
        
        epidemiology
        
        Prevalence: depends largely on overall standard of living (developing parts: 80% may be infected by 20, in industrialized: 20-50%, in US: organism rare in childhood)
        
        improved sanitation dramatically decr transmission
        
        factors predisposing to higher colonization rates: poor socioeconomic status + less education (not race)
        
        Other RFs: (1) birth or residence in a developing country, (2) domestic crowding, (3) unsanitary living conditions, (4) unclean food or water, and (5) exposure to gastric contents of an infected individual.
        
        Transmission: person to person: oral-oral or fecal-oral route.
        
        pathophysiology
        
        infection always a. w/ a chronic active gastritis, but only 10–15% of infected develop frank peptic ulceration; >90% of all DUs a. w/ H. pylori, but H. pylori present in only 30–60% of pxs w/ GUs and 50–70% of pxs w/ Dus:////
        
        end result of H. pylori infection (gastritis, PUD, gastric MALT lymphoma, gastric cancer) determined by interplay betw bacterial and host factors
        
        Bacterial factors
        
        able to facilitate gastric residence, induce mucosal injury, and avoid host defense.
        
        Virulence factors: pathogenicity island (cag-PAI) (encodes Cag A and pic B) + Vac A
        
        virulence factors + other bacterial constituents--> target host immune cells (Vac A targets CD4 Ts, inhibiting prolif + can disrupt normal function of B, CD8 T, MQs, and mast cells)--> partial cause of mucosal injury
        
        strains that are cag-PAI +: higher risk of PUD, premalignant gastric lesions, and gastric cancer.
        
        may directly inhibit parietal cell H+,K+ -ATPase activity through a Cag A–dependent mechanism--> low acid production observed after acute infection
        
        Urease generates NH3--> damage epithelial cells.
        
        produce surface factors chemotactic for neutrophils and monocytes--> epithelial cell injury
        
        makes proteases and phospholipases--> break down GP lipid complex of mucous gel--> reducing efficacy of this first line of mucosal defense.
        
        expresses adhesins (OMPs like BabA)
        
        H. pylori LPS: low immunologic activity compared to others
        
        may promote a smoldering chronic inflammation
        
        Host factors
        
        genetic predisposition
        
        inflammatory response: recruitment of all;/
        
        cag-PAI--> introduce Cag A into host--> further cell injury + activation of cytokine production + repression of tumor-suppressor genes
        
        Elevated cytokines found in gastric epithelium of infected: IL-1α/β, IL-2, IL-6, IL-8, TNF-α, and IFN-γ.
        
        mechanisms for epithelial cell injury
        
        activated neutrophil-mediated production of ROS/NOS + enhanced epithelial cell turnover
        
        apoptosis related to interaction w/ T cells (Th1 cells) and IFN-γ. (pathogen binds MHC II on epithelial cells--> apoptosis)
        
        Infection--> mucosal + systemic humoral response--> no eradication, further injury.
        
        human stomach can be colonized by a host of commensal organisms that may affect likelihood of H. pylori–mediated mucosal injury.
        
        duodenal ulceration reason unclear; maybe
        
        H. pylori a. w/ DU more virulent
        
        certain specific bacterial factors (ex DU-promoting gene A (dupA))
        
        gastric metaplasia in duodenum of DU pxs, which may be due to high acid exposure, permits H. pylori to bind to it and etc
        
        H. pylori antral infection--> incr acid production, incr duodenal acid, and mucosal injury.
        Basal and stimulated (meal, gastrin-releasing peptide [GRP]) gastrin release incr in infected, and somatostatin-secreting D cells may be decr. H. pylori infection might induce incr acid secretion through both direct and indirect actions of H. pylori and proinflammatory cytokines (IL-8, TNF, and IL-1) on G, D, and parietal cells. GUs, in contrast, a. w/ H. pylori–induced pangastritis and normal or low gastric acid secretion.
        
        H. pylori infection also a. w/ decr duodenal mucosal HCO3 production
        
        type + distribution of gastritis--> ultimate gastric and duodenal pathology observed.
        
        presence of antral-predominant gastritis: a. w/ DU formation
        
        gastritis involving primarily corpus: --> development of GUs, gastric atrophy, and ultimately gastric carcinoma
        
        FIGURE 348-8
        
        the bacterium
        
        a gram-negative microaerophilic rod found most in deeper portions of mucous gel or betw mucous layer + gastric epith
        
        may attach to gastric epith but normally doesn't invade cells.
        
        It is strategically designed to live within the aggressive environment of the stomach: multiple sheathed flagella.
        
        Initially resides in antrum but, over time, migrates toward more proximal segments of stomach.
        
        capable of transforming into coccoid form (a dormant state)
        
        genome:
        essential determinants of pathogenesis + colonization: outer membrane pr (Hop prs), urease, and vacuolating cytotoxin (Vac A); majority contain cag pathogenicity island (cag-PAI): encode components of a type IV secretion island that translocates Cag A into host cells--> Cag A activates a series of cellular events important in cell growth + cytokine production.
        extensive genetic diversity
        
        first step in infection: dependent on bacteria’s motility + ability to produce urease (produces ammonia from urea--> alkalinizing surrounding pH)
        
        Additional bacterial factors: catalase, lipase, adhesins, PAF, and pic B (induces cytokines)
      - NSAID-Induced Disease
        
        epidemiology
        
        spectrum of induced morbidity: nausea and dyspepsia (prevalence 50–60%) to a serious GI complication (ex peptic ulceration (15–30% of taking regularly)) complicated by bleeding or perforation in as many as 1.5% of users per year.
        
        4–5% of pxs develop symptomatic ulcers within 1 year.
        
        Unfortunately, dyspeptic symptoms do not correlate w/ NSAID-induced pathology; >80% of pxs w/ serious complications did not have preceding dyspepsia; lack of warning signs--> important to identify pxs at incr risk for morbidity and mortality of NSAID usage (no dose of NSAID is completely safe)
        
        H. pylori infection incr risk of PUD-associated GI bleeding in chronic users of low-dose aspirin.
        
        RFs
        
        Established: advanced age, history of ulcer, concomitant use of glucocorticoids, high-dose NSAIDs, multiple NSAIDs, concomitant use of anticoagulants, clopidogrel, and serious or multisystem disease.
        
        Possible: concomitant infection w/ H. pylori, cigarette smoking, and alcohol consumption
        
        pathophysiology
        
        neutrophil adherence to gastric microcirculation: essential role in initiation of NSAID-induced mucosal injury.
        
        pathogenetic pathways by which systemically administered NSAIDs may lead to mucosal injury: FIGURE 348-9
        
        Injury to mucosa also occurs as a result of topical encounter.
        
        Aspirin and many NSAIDs: weak acids that remain in a nonionized lipophilic form within stomach--> NSAIDs migrate across lipid membranes of epithelial cells--> cell injury once trapped IC in an ionized form.
        
        Topical NSAIDs: alter surface mucous layer--> back diffusion of H+ and pepsin--> leading to further epithelial cell damage.
        
        enteric-coated or buffered preparations also a. w/ risk of peptic ulceration.
        
        interplay betw H. pylori and NSAIDs: each of these aggressive factors is independent and synergistic RFs for PUD and its complications such as GI bleeding
      - Gastric Ulcers
      - Pathogenetic Factors Unrelated to H. pylori and NSAIDs in Acid Peptic Disease
        
        Cigarette smoking
        
        have ulcers more frequently, decr healing rates, impair response to therapy, and incr ulcer-related complications (ex perforation)
        
        mechanism unknown: Theories: altered gastric emptying, decr proximal duodenal HCO3 production, incr risk for H. pylori infection, and cigarette-induced generation of noxious mucosal free radicals.
        
        Genetic predisposition
        
        First-degree relatives of DU pxs 3x as likely
        
        Incr frequencies of blood group O and of nonsecretor status, however, H. pylori preferentially binds to group O ags
        
        Additional factors postulated to predispose individuals to developing PUD and/or upper GI bleeding: genes encoding NSAID-metabolizing Es (CYP2C9 and CYP2C8)
        
        Psychological stress but conflicting results.
        
        Diet but no convincing studies
        
        Specific chronic disorders have strong a. w/ PUD: (1) advanced age, (2) chronic pulmonary disease, (3) chronic renal failure, (4) cirrhosis, (5) nephrolithiasis, (6) α1-antitrypsin deficiency, and (7) systemic mastocytosis.
        
        Disorders w/ a possible association: (1) hyperparathyroidism, (2) CAD, (3) polycythemia vera, (4) chronic pancreatitis, (5) former alcohol use, (6) obesity, (7) African-American race, and (8) three or more doctor visits in a year.
        
        TABLE 348-1
        
        Independent of inciting or injurious agent, PUs develop as a result of an imbalance betw mucosal protection/repair and aggressive factors. Gastric acid plays an important role in mucosal injury
      - Duodenal Ulcers