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     Dr. Kaboli
                 • Infectious Esophagitis
                    •    Pathobiology
• Infectious esophagitis occurs principally, but not
  exclusively, in immunocompromised patients, usually
  from cancer chemotherapy, post-transplant antirejection
  medication, and acquired immunodeficiency syndrome
  (AIDS) (especially with CD4 counts <200 mm3) .

• Candida albicans , herpes simplex virus type 1 (HSV-1) ,
  and CMV are the most common causes, and coinfection
  with more than one agent may occur.

• In AIDS, CMV esophagitis may coexist with CMV retinitis
  or colitis.
        Clinical Manifestations
• Odynophagia is characteristic and may be severe.

• Dysphagia, weight loss, and gastrointestinal bleeding are common.

• Complications are infrequent but may include tracheobronchial
  fistula, perforation, and hemorrhage.

• Esophageal candidiasis in AIDS is associated with oral candidiasis
  (thrush) in only about two thirds of cases, and HSV esophagitis is
  associated with oral herpetic lesions in about a third of cases.

• In an immunocompetent host, infectious esophagitis is primarily due
  to HSV or Candida.
• On barium swallow, a ―shaggy‖ mucosa suggests
  Candida; numerous small, volcanic-shaped ulcers
  suggest HSV; and large, deep linear ulcers suggest
  CMV (or HIV).

• Multiple biopsies of ulcerated areas with routine
  histologic evaluation provide a definitive diagnosis.

• Candida esophagitis is characterized on endoscopy by
  numerous small white-yellow mucosal plaques
  containing microorganisms, inflammatory cells, and
  necrotic mucosa .
• Positive brushings and biopsy demonstrate Candida
  pseudohyphae with periodic acid–Schiff reagent or
  special silver stains.

• HSV esophagitis on endoscopy begins as numerous
  vesicles that ulcerate to yield small (<2 cm), shallow,
  volcano-shaped ulcers .

• A positive biopsy specimen from the ulcer edge
  demonstrates the characteristic cytopathic effect of HSV
  within squamous epithelial cells—eosinophilic
  intranuclear inclusions.

• CMV esophagitis is characterized by large (>2 cm),
  deep, often linear ulcers; a positive biopsy specimen
  from the ulcer base demonstrates the characteristic
  cytopathic effect of CMV within fibroblasts and
  endothelial cells—basophilic intranuclear inclusions.
• In non-AIDS patients, Candida esophagitis may
  be treated with oral nystatin, 1 to 3 million units
  four times a day, or clotrimazole, 100-mg tablets
  dissolved in the mouth three to five times a day,
  but patients with AIDS require an azole
  antifungal such as oral or intravenous
  fluconazole, 100 to 200 mg/day for 10 to 14

• Ketoconazole and itraconazole are also effective
  but, unlike fluconazole, require normal gastric
  acidity for absorption.
• In resistant cases, intravenous caspofungin, 50
  mg/day (after a 70-mg loading dose), or low-
  dose intravenous amphotericin, 0.3 to 0.5
  mg/kg/day, for 10 to 14 days is effective.

• HSV esophagitis is treated with a nucleoside
  analogue such as acyclovir, 200 to 400 mg
  orally five times a day or 250 mg/m2
  intravenously every 8 hours for 2 weeks.

• Valacyclovir and famciclovir are alternatives; for
  resistant cases, intravenous foscarnet, 60 mg/kg
  every 8 hours for 2 to 4 weeks, is effective.
• CMV esophagitis is treated with intravenous
  ganciclovir, 5 mg/kg every 12 hours for 2 to 4
  weeks; for resistant cases, foscarnet is
  administered intravenously at 60 mg/kg every 8
  hours for 2 to 4 weeks.

• Idiopathic HIV-associated ulcers are treated with
  prednisone, 40 mg/day, tapering by 10 mg/wk
  for 1 month; thalidomide, 200 mg/day, may also
  be effective.

• Because relapse of all forms of infectious
  esophagitis is common in immunocompromised
  patients, maintenance therapy may be required.
    Alkaline Reflux Esophagitis
• Alkaline reflux esophagitis is an uncommon and
  poorly defined clinical entity that develops in the
  setting of repeated and prolonged contact of the
  esophageal epithelium with nonacidic gastric or
  intestinal contents, usually in subjects with a
  destroyed pylorus after total gastrectomy or a
  Billroth II gastroenterostomy.

• Treatment is with bile salt–binding or mucosal-
  coating agents such as cholestyramine,
  sucralfate, or colloidal bismuth. Surgical
  fundoplication (intact stomach) or creation of a
  Roux-en-Y limb (after gastrectomy) is performed
  in refractory cases.
       Pill-Induced Esophagitis
• Pill-induced esophagitis commonly develops in patients,
  particularly the elderly, who are taking medication
  improperly (i.e., while supine or with too little liquid).

• It also occurs in patients with a preexisting abnormality,
  such as a stricture, diverticulum, or motor disorder.

• Pills adhere to the esophageal mucosa and cause
  necrosis and ulceration by the topical release of caustic

• Among the common offenders are doxycycline,
  tetracycline, vitamin C, potassium chloride, nonsteroidal
  anti-inflammatory drugs, quinidine, alendronate and
  other bisphosphonates , and iron.
• Odynophagia is characteristic and commonly
  accompanied by dysphagia.

• Ulceration may lead to hemorrhage, perforation, and
  stricture. Upper endoscopy is indicated in nonobvious
  cases to exclude infectious esophagitis.

• Discontinuation of the offending medication and
  treatment with sucralfate suspension (1 g orally four
  times a day for 1 to 2 weeks) or a cocktail (equal parts
  viscous lidocaine, antacid, and diphenhydramine )may
  control the symptoms.

• Once-a-day PPI therapy is useful to prevent aggravation
  by reflux.

• Education about the proper method of taking medication
  may prevent recurrence.
        Radiation Esophagitis

• Radiation esophagitis occurs after chest
  radiation therapy at dose levels that exceed 30
  Gy (3000 rad) .

• At levels higher than 60 Gy, severe esophagitis
  and ulceration can develop and lead to
  hemorrhage, perforation, or fistula.

• Concomitant chemotherapy with cytotoxic
  agents (e.g., doxorubicin [Adriamycin]) can
  potentiate radiation injury.
• Substernal pain, odynophagia, and dysphagia
  are typical.

• Barium swallow and endoscopy can
  demonstrate the extent and severity of mucosal
  inflammation, ulceration, and luminal narrowing;
  endoscopy has the added benefit of biopsy for
  exclusion of infectious esophagitis.

• A liquid diet or intravenous fluids plus the
  treatments described for pill-induced esophagitis
  are helpful.

• Strictures may require bougienage for dilation or
  even esophagectomy with colonic or jejunal
      Eosinophilic Esophagitis
• Eosinophilic esophagitis is an uncommon,
  immunologically mediated entity that is being
  recognized with increasing frequency in children
  and adults aged 20 to 40 years.

• It has a 3 : 1 male-to-female predominance, and
  half the patients have asthma, skin reactions,
  and peripheral eosinophilia.

• The disease is due to food allergy and can be
  manifested as chest pain or heartburn, but solid
  food dysphagia and food impaction are
• Endoscopic findings range from grossly normal
  to a corrugated, inflamed, eroded, or fibrotic
  esophagus in which a single- or multiple-ringed
  esophagus or a stiff, narrowed, noncompliant
  organ is often produced.

• Esophageal biopsy is diagnostic with high (>15
  to 20 per high-power field) concentrations of
  mucosal eosinophils .

• The presence of a dense collagen network
  within the lamina propria accounts for the rigidity
  and propensity to fracture (tear) on bougienage.
• Skin testing for allergy should be performed to identify
  and remove the offending agent or agents—the most
  common being seafood, nuts, milk, eggs, and soy.

• Dietary changes or therapy with oral cromolyn (100 to
  200 mg four times daily), an H1-antagonist (e.g.,
  chlorpheniramine, 4 mg four times daily) plus an H2-
  antagonist (e.g., cimetidine, 300 mg four times daily),
  glucocorticoids (topical fluticasone propionate, 220 μg
  per puff, two puffs swallowed twice to four times daily),
  or a leukotriene receptor antagonist (montelukast) may
  control symptoms, but relapse is common after cessation
  of therapy.

• Monoclonal antibodies to interleukin-5 are being
  investigated as therapy because this cytokine mediates
  the esophageal eosinophilia.
           Caustic Esophagitis
• Caustic esophagitis occurs from accidental ingestion in
  children and from suicidal attempts in adults.

• Among the more common materials ingested are drain
  cleaners (sodium hydroxide), bleach (sodium
  hypochlorite), detergents (sodium tripolyphosphates),
  and disc batteries (sodium hydroxide).

• Sodium hydroxide (lye) produces liquefaction necrosis
  on contact with the oropharynx and esophagus and thus
  has the potential to cause acute ulceration, perforation,
  and later stricture formation.
• When perforation is excluded by contrast (Gastrografin
  and, if negative, barium) swallows, endoscopy may be of
  value to assess the esophageal injury, but passage of
  the scope beyond an area of severe injury is not
  recommended to avoid perforation.

• Emergency esophagogastrectomy is indicated for free
  perforation and mediastinitis. In the absence of these
  complications, esophagitis is treated supportively with
  intravenous fluids and prophylactic antibiotics.

• Steroids in tapering dosage are often given but are
  without proven efficacy.

• A feeding tube is passed under direct vision to provide
  nutrition and a means for later dilation of a tight stricture.

• When strictures are complex and respond poorly to
  dilation, intestinal or colonic interposition should be
  considered to restore oral intake.
• Esophageal motor disease is characterized by
  dysphagia for liquids and solids or chest pain (or

• Although the chest pain may mimic cardiac
  disease and be the dominant complaint, careful
  questioning should also detect dysphagia.

• Recurrent chest pain without dysphagia is rarely
  due to esophageal motor disease.
   Oropharyngeal Dysphagia
• Oropharyngeal dysphagia is due to
  neuromuscular disorders of the oropharynx and
  the skeletal muscle portion of the esophagus,
  including stroke, Parkinson's disease,
  amyotrophic lateral sclerosis, multiple sclerosis,
  myasthenia gravis, polymyositis, and myotonic

• It is characterized by difficulty in bolus transfer
  from the mouth to the esophagus and by nasal
  regurgitation or coughing (from aspiration) with
• Oropharyngeal dysphagia commonly occurs
  amid other signs and symptoms of the
  underlying neuromuscular disorder.

• A modified barium swallow with
  videofluoroscopy is the procedure of choice.

• The swallows are performed with barium of
  different consistencies and with the subject
  swallowing in different head and body positions.

• Nutritional support via diet, swallow maneuvers,
  feeding tubes, or percutaneous endoscopic
  gastrostomy is appropriate, whereas primary
  therapy is directed at the neuromuscular
       Esophageal Dysphagia
• Esophageal dysphagia is due to disease
  of the smooth muscle–lined portion of the

• The dysphagia is not accompanied by
  failure of bolus transfer from the mouth to
  the esophagus, by nasal regurgitation, or
  by coughing with swallowing, and it
  characteristically occurs with liquids as
  well as solids, thus indicating a lack of
  discrimination for bolus size.
• Achalasia and diffuse esophageal spasm are
  primary esophageal motor disorders, whereas
  scleroderma is the most common secondary

• A barium swallow is valuable as a first test
  because it provides evidence to support either a
  motor or mechanical cause of dysphagia.

• When motor disease is suggested, esophageal
  manometry is often diagnostic and provides both
  quantitative and qualitative information about
  peristaltic and sphincter function.
• Epidemiology

• Achalasia is the most common primary
  esophageal motor disorder, with a
  prevalence of about 10 per 100,000

• Its etiology is unknown, and it can occur at
  any age but usually between the ages of
  30 and 60 years.
• Achalasia is characterized histopathologically by degeneration of the
  nerves in Auerbach's plexus, although changes also occur in the
  vagus nerve and swallowing center.

• The consequences of neuronal injury are an increase in LES
  pressure, incomplete LES relaxation with swallowing (achalasia
  means ―failure to relax‖), and complete (100%) aperistalsis in the
  esophageal body.

• Failure of the LES to relax produces an obstruction at the
  gastroesophageal junction that leads to esophageal retention.

• Dilation of the esophageal body occurs as a result of the increase in
  intraluminal pressure and the presence of weak, aperistaltic
       Clinical Manifestations
• Dysphagia for liquids and solids is the primary complaint.

• Regurgitation is common, and nocturnal cough suggests
  aspiration on reclining.

• Atypical chest pain and heartburn occur in about a third
  of cases secondary to increased intraesophageal
  pressure and stasis-induced mucosal inflammation,

• Weight loss is highly variable and should raise concern
  about adenocarcinoma of the esophagus or gastric
• The chest radiograph may show a widened
  mediastinum, air-fluid level, and absent gastric air

• Barium swallow characteristically shows a dilated
  esophagus, air-fluid level, delayed esophageal emptying,
  and a smooth, tapered ―bird's beak‖ deformity at the

• Chagas' disease can mimic achalasia by producing
  megaesophagus, but it also produces megaduodenum
  and often megaureter and cardiomegaly.
• Confirmation is by esophageal
  manometry, which shows the
  characteristic incomplete relaxation of the
  LES with swallows and complete
  aperistalsis in the esophageal body.

• LES pressure may or may not be elevated.

• However, neither radiographic nor
  manometric criteria can effectively exclude
  pseudoachalasia, or achalasia secondary
  to an infiltrating cancer.
• For this reason, endoscopy is performed
  to examine the area before treatment; if
  findings are suspicious but inconclusive,
  biopsy should be performed, followed by
  examination of the area by endoscopic
  ultrasonography or computed tomography
• A muscle relaxant such as nifedipine, 10 mg
  sublingually before meals, may be helpful.

• More effective treatment requires either
  endoscopic injection of botulinum toxin into the
  LES (20 units per quadrant), pneumatic dilation,
  or surgical Heller myotomy.

• The benefits of botulinum toxin are relatively
  short lived (3 to 6 months) when compared with
  pneumatic dilation, so repeated injections are
  necessary for the life of the patient.
• Pneumatic dilation under conscious sedation inflates a
  balloon (3 to 4 cm in diameter) placed across the LES to
  rupture its musculature; repeated treatment may be
  necessary for maximum benefit.

• A surgical Heller myotomy, which involves direct incision
  of the LES, is usually performed laparoscopically.

• Both pneumatic dilation and Heller myotomy provide
  excellent relief of symptoms for 5 to 10 years in about
  85% of subjects.

• The major risk associated with pneumatic dilation is
  esophageal perforation (average of ≈3%), and the major
  side effect of Heller myotomy is reflux esophagitis

• An antireflux procedure can be combined with a Heller
  myotomy to reduce the risk for postoperative GERD.
    Diffuse Esophageal Spasm
• Clinical Manifestations
• This uncommon motor disorder is manifested
  clinically as intermittent chest pain and
  dysphagia—with chest pain often being the
  dominant complaint but rarely occurring without

• Like achalasia, diffuse esophageal spasm is
  associated with degeneration of the nerves in
  Auerbach's plexus and, in rare instances, can
  evolve to achalasia.
• On barium swallow, diffuse esophageal
  spasm has prominent, spontaneous,
  nonpropulsive tertiary contractions that
  can give rise to the appearance of a
  ―corkscrew‖ esophagus .

• This appearance, however, is not
  pathognomonic because it is also
  observed in asymptomatic elderly patients,
  hence the term presbyesophagus.
• On esophageal manometry, more than
  30% (but less than 100%) of esophageal
  contractions are aperistaltic and
  occasionally repetitive, but manometric
  findings are not pathognomonic because
  the diagnosis of diffuse esophageal spasm
  requires exclusion of diseases that
  produce similar motor changes, such as
  diabetes mellitus , amyloidosis ,
  scleroderma , idiopathic pseudo-
  obstruction, and reflux esophagitis.
• Therapy is principally supportive and empirical.

• Recommendations include reassurance of the benign
  nature of the disease, a trial of smooth muscle relaxants
  (e.g., isosorbide, 10 mg, nifedipine, 10 mg, or
  dicyclomine , 20 mg before meals) or a trial of an
  antidepressant (e.g., amitriptyline, 25 to 50 mg at
  bedtime, imipramine, 25 to 50 mg at bedtime, and
  trazodone, 50 mg three times a day).

• In some instances, relaxation exercises, biofeedback,
  and psychological counseling are helpful adjuncts to
  drug therapy.
• The esophagus is the gastrointestinal
  organ most often affected in scleroderma ,
  and it results in a characteristic
  manometric pattern of low LES pressure
  and weak aperistaltic contractions in the
  smooth muscle portion of the esophageal

• UES and skeletal muscle–lined upper
  esophageal contractions are normal.
• Esophageal involvement in scleroderma
  results in dysphagia, regurgitation, and

• When dysphagia for solids is prominent, it
  probably reflects a peptic stricture or
  adenocarcinoma in Barrett's esophagus.

• Patients with scleroderma should be
  treated prophylactically for GERD .
      Nutcracker Esophagus
• Nutcracker esophagus is a term given to a
  relatively common manometric pattern found in
  patients with noncardiac chest pain.

• This pattern consists of normal peristalsis but
  with contractions of very high amplitude
  (average >180 mm Hg).

• However, a reduction in contraction amplitude
  by calcium-channel blockers has no consistent
  effect on chest pain, and chest pain can be
  relieved by medications (e.g., trazodone) that
  have no effect on amplitude.
• Patients with chest pain and nutcracker
  esophagus commonly exhibit symptoms and
  signs of depression or anxiety.

• Treatment of these disorders with

• (1) amitriptyline (25 to 75 mg at bedtime),
  imipramine (25 to 50 mg at bedtime), and
  trazodone (50 mg three times a day) or

• (2) alprazolam (0.25 to 0.5 mg three times a
  day) and clonazepam (0.5 to 1 mg twice a day)
  may relieve the chest pain.

• Tumors of the esophagus may be benign or

• Benign tumors are uncommon and include
  fibrovascular polyps, leiomyomas, papillomas,
  lipomas, neurofibromas, and granular cell

• When large, benign tumors can cause
  dysphagia or chest pain from obstruction or
• Malignant tumors of the esophagus currently
  occur at a rate of about 14,000 cases per year in
  the United States and are divided about equally
  between squamous cell carcinoma and

• Rare primary malignancies include
  leiomyosarcoma, melanoma, lymphoma, and

• Tumors metastatic to the esophagus usually
  originate from the breast, lung, or skin
     Squamous Cell Carcinoma
• The incidence of squamous cell carcinoma in
  the United States is about 2.6 per 100,000, with
  men having a three- to fourfold higher risk than
  women and blacks a four- to fivefold higher risk
  than whites.

• Regions of high risk also exist in the Transkei of
  South Africa, China's Linxian and Yangcheng
  provinces, and Kashmir and Bombay in India.

• The risk for squamous cell cancer is higher with
  heavy alcohol and tobacco use, papillomavirus
  infection, lye ingestion, achalasia, Plummer-
  Vinson syndrome, tylosis, celiac disease, and
  radiation exposure.
• The clinical manifestation is typically rapidly
  progressive dysphagia for solids, anorexia, and
  weight loss.

• Less commonly, squamous cell carcinoma is
  accompanied by hypercalcemia
  (pseudohyperparathyroidism), hoarseness
  (recurrent laryngeal nerve paralysis), or
  tracheoesophageal fistula.

• Barium swallow generally reveals a bulky,
  eroded, partially obstructing esophageal mass
  that is proved to be squamous cell carcinoma by
  endoscopic biopsy.

• Adjacent lymph node invasion is common
  because the esophagus lacks a serosal layer.
• Hematogenous metastases usually spread
  to the liver, lungs, kidney, heart, and bone.

• Endoscopic ultrasonography or CT, or
  both, are used for staging.

• Squamous cell carcinoma is
  radiosensitive, and chemoradiation
  therapy, with or without subsequent
  surgery, can improve the outcome.
• Nonetheless, late-stage diagnosis is the
  rule, so the overall 5-year survival rate is
  only 20 to 30%.

• Palliation for dysphagia caused by
  inoperable, obstructing cancers is better
  with brachytherapy than with endoscopic

• Other options include bougienage or tumor
  ablation by laser, heater probe, or alcohol
• Adenocarcinomas are equally as common as
  squamous cell cancers but, unlike squamous
  cancers, arise principally in the distal end of the
  esophagus , because the predominant risk for
  adenocarcinoma is Barrett's esophagus.

• However, only about 40% of patients with
  esophageal adenocarcinoma have a history of
  heartburn, and heartburn occurs in an even
  smaller percentage of those with Barrett's
• The diagnosis of adenocarcinoma is typically
  made at endoscopy in a patient with dysphagia,
  anorexia, and weight loss secondary to a lumen-
  encroaching lesion.

• Lymphatic spread is common.

• Adenocarcinomas are radioinsensitive; although
  chemoradiation therapy and surgery may
  improve survival, 5-year survival rates are less
  than 20%.

• Palliation is the same as for inoperable
  squamous cell carcinoma.
• Oral bisphosphonates have been linked to esophageal
  adenocarcinoma and squamous cell carcinoma
  according to a post-marketing Food and Drug
  Administration (FDA) lette.

• The reasons why they should increase the risk are not
  understood, although crystalline material similar to
  alendronate has been identified in biopsies of patients
  with erosive esophagitis suggesting a potential for

• At present, the FDA recommends that oral
  bisphosphonates not be used in patients with Barrett's

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