Digestive Diseases



Digestive Diseases


L. Michael Snyder

Michael J. Mitchell




INTRODUCTION

This chapter focuses on several common gastrointestinal (GI) clinical presentations: abdominal pain (acute and chronic); ascites; diarrhea (acute and chronic); GI bleeding upper and lower; hepatomegaly; jaundice; and associated diseases, including hepatitis. When appropriate, the discussion includes radiologic and endoscopic procedures as part of the diagnostic evaluation.


DISEASE STATES ASSOCIATED WITH ABDOMINAL PAIN (ACUTE AND CHRONIC)




□ Etiology



  • Common gynecologic causes of lower quadrant pain include mittelschmerz, ovarian cyst, endometriosis, fibroids, ovarian torsion, pelvic inflammatory disease, ovarian tumor, ectopic pregnancy, infection of the uterus, threatened abortion, and round ligament pain secondary to pregnancy.


  • Medical conditions that may present as acute abdomen are many. Common examples include lower lobe pneumonias, acute myocardial
    infarction (MI), diabetic ketoacidosis (DKA), acute hepatitis, porphyria, adrenal hemorrhage, and musculoskeletal problems. Appendicitis is a clinical diagnosis. The triad of right lower quadrant pain, anorexia, and leukocytosis is the most sensitive diagnostic tool. Nausea and vomiting usually follow the onset of pain. The patient may have a low-grade fever and mild leukocytosis. Fevers with higher temperatures or increased WBC counts suggest perforation.








    TABLE 7-1. Differential Diagnosis of the Acute Abdomen















































































































    Right Upper Quadrant Pain


    Right Lower Quadrant Pain


    Cholecystitis


    Appendicitis


    Choledocholithiasis


    Ruptured ovarian cyst


    Cholangitis


    Meckel diverticulitis


    Hepatitis


    Cecal diverticulitis


    Liver tumors


    Cholecystitis


    Hepatic abscess


    Perforated colon


    Appendicitis


    Colon cancer


    Peptic ulcer disease (PUD)


    Urinary tract infection


    Perforated ulcer


    Small bowel obstruction


    Pancreatitis


    Inflammatory bowel disease (IBD)


    Gastritis


    Nephrolithiasis


    Pyelonephritis


    Pyelonephritis


    Nephrolithiasis


    Ectopic pregnancy


    Pneumonia


    Bowel incarceration



    Pelvic inflammatory disease (PID)


    Left Upper Quadrant Pain


    Lower Left Quadrant Pain


    PUD


    Diverticulitis


    Perforated ulcer


    Sigmoid volvulus


    Gastritis


    Perforated colon


    Splenic disease (e.g., infarct, abscess, or rupture)


    Colon cancer


    Gastroesophageal reflux disease


    Urinary tract infection


    Dissecting aortic aneurysm


    Small bowel obstruction


    Pyelonephritis


    IBD


    Nephrolithiasis


    Nephrolithiasis


    Hiatal hernia


    Pyelonephritis


    Boerhaave syndrome (i.e., rupture of the esophagus)


    Ectopic pregnancy


    Mallory-Weiss tear


    Incarceration


    Diverticulitis


    PID


    Bowel obstruction



    Midepigastric Pain


    PUD


    Perforated ulcer


    Pancreatitis


    Abdominal aortic aneurysm


    Esophageal varices


    Hiatal hernia


    Boerhaave syndrome (i.e., rupture of the esophagus)


    Mallory-Weiss tear




  • Thirty percent of patients with appendicitis have an elevated WBC count, whereas 95% have a left shift.


  • The intensity of pain is somewhat in proportion to the degree of irritation to the parietal peritoneum. Therefore, a retrocecal appendix (which is the most common location) may cause only a dull ache, given the lack of contact with the parietal peritoneum.


□ Laboratory Findings



  • Laboratory studies are undertaken to support a clinical hypothesis. The evaluation generally includes a complete blood count (CBC), liver chemistries, amylase and lipase, coagulation profile, urinalysis, and urine pregnancy test:



    • ▼ Lactic acid level should be obtained for patients with suspected ischemic bowel. An elevated level is associated with tissue hypoperfusion.


    • ▼ Beta-hCG levels must be obtained for all women of childbearing age to exclude the possibility of ectopic pregnancy.


  • Radiographic studies:



    • ▼ Chest radiograph should be obtained on all patients with acute abdomen to rule out free air. Pneumonia may present as an acute abdomen.


    • ▼ Abdominal radiograph is most effective in detecting either bowel obstruction or pneumoperitoneum. An upright and supine view is necessary.


    • ▼ Appendicolith can be seen in 15% of patients with appendicitis, whereas renal stones may also be visualized up to 85% of the time.


    • ▼ Other radiographic findings of acute appendicitis include right lower quadrant ileus, loss of psoas shadow, deformity of the cecal outline, free air, and soft tissue density.


  • Abdominal ultrasound is the study of choice in patients with possible acute cholecystitis or ovarian cyst. A sonographic Murphy sign is more sensitive than a clinical Murphy sign for acute cholecystitis. An inflamed appendix can be visualized with compression ultrasound (sensitivity ranges from 80% to 90%).


  • CT can also be used to diagnose appendicitis in patients whose clinical symptoms are ambiguous.



    • ▼ Air in the appendix or a normal-appearing contrast-filled appendix virtually rules out the diagnosis of appendicitis.


    • ▼ CT will provide an alternate diagnosis in 15% of patients when assessing for appendicitis.


  • Arteriography is the test of choice for patients with suspected mesenteric ischemia.


DISORDERS OF THE ESOPHAGUS


MALLORY-WEISS SYNDROME




PERFORATION OF THE ESOPHAGUS, SPONTANEOUS

In spontaneous perforation, gastric contents are found in thoracocentesis fluid.


PLUMMER-VINSON SYNDROME



DISORDERS OF THE STOMACH


GASTRITIS, CHRONIC



  • A diagnosis of chronic gastritis depends on biopsy of gastric mucosa.


□ Atrophic (Type A Gastritis, Autoimmune Type)



  • Gastric antrum is spared.


  • Parietal cell antibodies and intrinsic factor antibodies help identify those patients prone to pernicious anemia (PA).


  • Characteristics include the following:



    • ▼ Achlorhydria


    • ▼ Vitamin B12-deficient megaloblastosis


    • ▼ Hypergastrinemia (due to hyperplasia of gastrin-producing cells)


    • ▼ Gastric carcinoids


    • ▼ Low serum pepsinogen I concentrations


  • Laboratory findings may be due to other accompanying autoimmune diseases (e.g., Hashimoto thyroiditis, Addison disease, Graves disease, myasthenia gravis, hypoparathyroidism, type 1 DM).


□ Nonatrophic (Type B Gastritis)



  • Gastric antrum is involved.


  • Anemia is caused by iron deficiency, and malabsorption may occur.


  • Helicobacter pylori infection is detectable in approximately 80% of patients with peptic ulcer and chronic gastritis. Diagnosis is by biopsy, culture, direct Gram staining, urease breath test, and serologic tests.


  • Hypogastrinemia is caused by destruction of gastrin-producing cells in the antrum.


  • Chronic antral gastritis is consistently present in patients with benign gastric ulcer.


  • Gastric acid studies are of limited value. Severe hypochlorhydria or achlorhydria after maximal stimulation usually denotes mucosal atrophy.


□ Other Causes



  • Infections (other bacteria [syphilis], viral [e.g., CMV], parasitic [e.g., anisakiasis], fungal)


  • Chemical (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], bile reflux, other drugs)



  • Lymphocytic gastritis


  • Eosinophilic gastroenteritis


  • Noninfectious granulomatous (e.g., sarcoidosis, Crohn disease)


  • Ménétrier disease


  • Radiation


CARCINOMA OF THE STOMACH


□ Laboratory Findings

Carcinoma of the stomach should always be searched for by periodic prophylactic screening in high-risk patients, especially those with PA, gastric atrophy, or gastric polyps.

Cytology: Exfoliative cytology positive in 80% of patients; false-positive result in <2%.

Tumor markers: Increased serum carcinogenic embryonic antigen (CEA) (>5 ng/dL) in 40-50% of patients with metastases and 10-20% of patients with surgically resectable disease. May be useful for postoperative monitoring for recurrence or to estimate metastatic tumor burden. Increased serum AFP and CA 19-9 in 30% of patients, usually incurable. Markers are not useful for early detection.

Gastric analysis: Normal in 25% of patients. Hypochlorhydria in 25% of patients. Achlorhydria following histamine or betazole in 50% of patients.

Core laboratory: Anemia due to chronic blood loss and occult blood in stool.


DISORDERS OF THE PANCREAS


CARCINOMA OF THE PANCREAS


BODY OR TAIL


□ Laboratory Findings

Imaging studies: Most useful tests are ultrasound or CT scanning followed by endoscopic retrograde cholangiopancreatography (ERCP) (at which time fluid is also obtained for cytologic and pancreatic function studies). This combination will correctly diagnose or rule out cancer of the pancreas in ≥90% of cases. ERCP with brush cytology has S/S = ≤25%/≤100%. Radioisotope scanning of the pancreas may be done (75Se) for lesions >2 cm.

Histology: Ultrasound-guided needle biopsy has reported sensitivity of 80-90%; false positives are rare.

Tumor markers: Serum markers for tumor (CA 19-9, CEA, and so on) are often normal. In carcinoma of the pancreas, CA 19-9 has S/S = 70%/87%, PPV = 59%, and NPV = 92%; there is no difference in sensitivity between local disease and metastatic disease. Often normal in early stages, they are not useful for screening. Increased values may help differentiate benign disease from cancer. It declines to normal in 3-6 months if cancer is completely removed, so it may be useful for prognosis and follow-up. It detects tumor recurrence 2-20 weeks before clinical evidence. It is not specific for the pancreas because high levels may also occur in other GI cancers, especially those affecting the colon and bile
duct. CEA level in bile (obtained by percutaneous transhepatic drainage) was reported increased in 76% of a small group of cases.

Testosterone: Dihydrotestosterone ratio <5 (normal approximately 10) in >70% of men with pancreatic cancer (due to increased conversion by tumor); less sensitive but more specific than CA 19-9 and present in higher proportion of stage I tumors.

Serum amylase and lipase: May be slightly increased in early stages (<10% of cases); with later destruction of the pancreas, they are normal or decreased. They may increase following secretin-pancreozymin stimulation before destruction is extensive; therefore, the increase is less marked with a diabetic glucose tolerance curve. Serum amylase response is less reliable. See Serum Glycoprotein 2.

Glucose tolerance: Curve is of the diabetic type, with overt diabetes in 20% of patients with pancreatic cancer. Flat blood sugar curve with IV tolbutamide tolerance test indicates destruction of islet cell tissue. Unstable, insulin-sensitive diabetes that develops in an older man should arouse suspicion of carcinoma of the pancreas.

Serum LAP: Increased (>300 U) in 60% of patients with carcinoma of the pancreas due to liver metastases or biliary tract obstruction. It may also be increased in chronic liver disease.

Other: Triolein-131I test demonstrates pancreatic duct obstruction with absence of lipase in the intestine, causing flat blood curves and increased stool excretion.


HEAD (SEE JAUNDICE)



  • The abnormal pancreatic function tests and increased tumor markers that occur with carcinoma of the body of the pancreas may be evident.


□ Laboratory Findings

Core laboratory: Serum bilirubin is increased (12-25 mg/dL), mostly conjugated (increase persistent and nonfluctuating). Serum ALP is increased. Both urine and stool urobilinogen are absent. Increased serum cholesterol (usually >300 mg/dL) with esters is not decreased. Other liver function tests are usually normal. See Serum Glycoprotein 2.

Hematology: Increased prothrombin time (PT); normal after IV vitamin K administration.

Other: Secretin-cholecystokinin stimulation evidences duct obstruction when duodenal intubation shows decreased volume of duodenal contents (<10 mL/10-minute collection period) with usually normal bicarbonate and enzyme levels in duodenal contents. Acinar destruction (as in pancreatitis) shows normal volume (20-30 mL/10-minute collection period), but bicarbonate and enzyme levels may be decreased. Abnormal volume, bicarbonate, or both are found in 60-80% of patients with pancreatitis or cancer. In carcinoma, the test result depends on the relative extent and combination of acinar destruction and of duct obstruction.

Histology: Cytologic examination of duodenal contents shows malignant cells in 40% of patients. Malignant cells may be found in up to 80% of patients with periampullary cancer.



CYSTIC FIBROSIS OF THE PANCREAS

Core laboratory: Hypochloremic metabolic alkalosis and hypokalemia. Serum protein electrophoresis shows increasing IgG and IgA with progressive pulmonary disease; IgM and IgD are not appreciably increased. Serum albumin is often decreased (because of hemodilution due to cor pulmonale; may be found before cardiac involvement is clinically apparent). Serum chloride, sodium, potassium, calcium, and phosphorus are normal unless complications occur (e.g., chronic pulmonary disease with accumulation of CO2; massive salt loss due to sweating may cause hyponatremia). Urine electrolytes are normal. There is excessive loss of electrolytes in sweat and stool. Impaired glucose intolerance in approximately 40% of patients with glycosuria and hyperglycemia in 8% precede DM. There is protein-calorie malnutrition, hypoproteinemia, and fat malabsorption with vitamin deficiency. Stool and duodenal fluid show lack of trypsin digestion of x-ray film gelatin; useful screening test up to age 4; decreased chymotrypsin production.

Saliva findings: Submaxillary saliva is more turbid, with increased calcium, total protein, amylase, chloride, and sodium but not potassium. These changes are not generally found in parotid saliva.

Other findings: Overt liver disease, including cirrhosis, fatty liver, bile duct strictures, and cholelithiasis, in ≤5% of cases. Meconium ileus occurs during early infancy. Chronic or acute and recurrent pancreatitis. Pancreatic insufficiency frequency by age 1 is >90% and in adults >95%. There is increased incidence of GI tract cancers. GU tract abnormalities with aspermia in 98% due to obstructive changes in the vas deferens and epididymis are confirmed by testicular biopsy.


MACROAMYLASEMIA IN VIVO ARTIFACT



□ Laboratory Findings

Core laboratory: Serum lipase is normal; normal pancreatic-to-salivary amylase ratio. Urine amylase normal or low. Serum amylase persistently increased (often 1-4× normal) without apparent cause. Amylase-creatinine clearance ratio <1% with normal renal function is very useful for this diagnosis; it should make the clinician suspect this diagnosis. Macroamylase is identified in serum by special gel filtration or ultracentrifugation technique.


□ Limitations



  • Macroamylase may be found in approximately 1% of randomly selected patients and 2.5% of persons with increased serum amylase level. Same findings may also occur in patients with normal molecular weight hyperamylasemia in which excess amylase is principally salivary gland isoamylase types 2 and 3.



PANCREATITIS


PANCREATITIS, ACUTE


□ Laboratory Findings

Lipase: Serum lipase increases within 3-6 hours with peak at 24 hours and usually returns to normal over a period of 8-14 days, is superior to amylase, increases to a greater extent, and may remain elevated for up to 14 days after amylase returns to normal. In patients with signs of acute pancreatitis, pancreatitis is highly likely (clinical specificity = 85%) when lipase ≥5× upper reference limit (URL), if values change significantly with time, and if amylase and lipase changes are concordant. (Lipase should always be determined whenever amylase is determined.) Urinary lipase is not clinically useful. It has been suggested that a lipase-amylase ratio >3 (and especially >5) indicates alcoholic rather than nonalcoholic pancreatitis. If lipase ≥5× URL, acute pancreatitis or organ rejection is highly likely but unlikely if <3× URL (Figure 7-1).

Amylase: Increase begins in 3-6 hours, rises rapidly within 8 hours in 75% of patients, reaches maximum in 20-30 hours, and may persist for 48-72 hours; there is >95% sensitivity during the first 12-24 hours. The increase may be ≤40× normal, but the height of the increase and rate of fall do not correlate with the severity of the disease, prognosis, or rate of resolution. In patients with signs of acute pancreatitis, amylase >3× ULN or >600 Somogyi units/dL is very suggestive of acute pancreatitis. An increase >7-10 days suggests an associated cancer of the pancreas or pseudocyst, pancreatic ascites, or nonpancreatic etiology. Similar high values may occur in obstruction of the
pancreatic duct; they tend to fall after several days; ≤19% of patients with acute pancreatitis (especially when seen more than 2 days after onset of symptoms) may have normal values, especially with an alcoholic etiology and longer duration of symptoms, even when dying of acute pancreatitis. It may also be normal in relapsing chronic pancreatitis and patients with hypertriglyceridemia (technical interference with test). It is frequently normal in acute alcoholic pancreatitis. Acute abdomen due to GI infarction or perforation rather than acute pancreatitis is suggested by only moderate increase in serum amylase and lipase (<3× URL) and evidence of bacteremia. Of patients with acute alcoholic intoxication, 10-40% have elevated serum amylase (about half are salivary type); they often present with abdominal pain, but increased serum amylase is usually <3× URL. Levels >25× URL indicate metastatic tumor rather than pancreatitis. Serum pancreatic isoamylase can distinguish elevations due to salivary amylase that may account for 25% of all elevated values. (In healthy persons, 40% of total serum amylase is pancreatic type and 60% is salivary type.) Only slight increase in serum amylase and lipase values suggests a different diagnosis than acute pancreatitis. Many drugs increase both amylase and lipase in serum.






Figure 7-1. Algorithm for increased serum amylase and lipase. ULN, upper limit of normal.

Increased urinary amylase tends to reflect serum changes by a time lag of 6-10 hours, but sometimes, increased urine levels are higher and of longer duration than serum levels. The 24-hour level may be normal even when some of the 1-hour specimens show increased values. Amylase levels in hourly samples of urine may be useful. Ratio of amylase clearance to creatinine clearance is increased (>5%) and avoids the problem of timed urine specimens and also increased in any condition that decreases tubular reabsorption of amylase (e.g., severe burns, DKA, chronic renal insufficiency, multiple myeloma, acute duodenal perforation). It is considered not specific and now discouraged by some but still recommended by others.

Calcium: Serum level is decreased in severe cases 1-9 days after onset (due to binding to soaps in fat necrosis). The decrease usually occurs after amylase and lipase levels have become normal. Tetany may occur. (Rule out hyperparathyroidism if serum calcium is high or fails to fall in hyperamylasemia of acute pancreatitis.)

Bilirubin: Serum levels may be increased when pancreatitis is of biliary tract origin but is usually normal in alcoholic pancreatitis. Serum ALP, ALT, and AST may increase and parallel serum bilirubin rather than amylase, lipase, or calcium levels. Marked amylase increase (e.g., >2,000 U/L) also favors biliary tract origin. Fluctuation >50% in 24 hours of serum bilirubin, ALP, ALT, and AST suggests intermittent biliary obstruction.

Trypsin: Serum level is increased. High sensitivity makes a normal value useful for excluding acute pancreatitis. But low specificity (increased in large proportion of patients with hepatobiliary, bowel, and other diseases and renal insufficiency; increased in 13% of patients with chronic pancreatitis, 50% with pancreatic carcinoma) and RIA technology limit utility.

C-reactive protein (CRP): Level peaks 3 days after onset of pain; at 48 hours, sensitivity = 65-100% and PPV = 37-77%. Level of 150 mg/L distinguishes mild from severe disease.


Laboratory criteria for severe disease or predictor of mortality:



  • PaO2 < 60 µmol/L.


  • Creatinine >2 mg/dL after rehydration.


  • Blood glucose >250 mg/dL.


  • Hemoconcentration (Hct > 47% or failure to decrease in 24 hours after admission), but Hct may be decreased in severe hemorrhagic pancreatitis.


  • GI bleed >500 mL/24 hours.


  • Presence, volume, and color of peritoneal fluid.


  • Methemalbumin may be increased in serum and ascitic fluid (AF) in hemorrhagic (severe) but not edematous (mild) pancreatitis; may distinguish these two conditions but not useful in diagnosis of acute pancreatitis.


  • WBC is slightly to moderately increased (10,000-20,000/µL).


  • Glycosuria appears in 25% of patients.


  • Hypokalemia, metabolic alkalosis, or lactic acidosis may occur.

Laboratory findings due to predisposing conditions (may be multiple):



  • Alcohol abuse accounts for approximately 36% of cases.


  • Biliary tract disease accounts for 17% of cases.


  • Idiopathic accounts for >36% of cases.


  • Infections (especially viral such as mumps and coxsackievirus, CMV, and AIDS).


  • Trauma and postoperative factors account for >8% of cases.


  • Drugs (e.g., steroids, thiazides, azathioprine, estrogens, sulfonamides; children taking valproic acid) account for >5% of cases.


  • Hypertriglyceridemia (hyperlipidemia—types V, I, IV) accounts for 7% of cases.


  • Hypercalcemia from any cause.


  • Tumors (pancreas, ampulla).


  • Anatomic abnormalities of the ampullary region causing obstruction (e.g., annular pancreas, Crohn disease, duodenal diverticulum).


  • Hereditary.


  • Renal failure and renal transplantation.


  • Miscellaneous (e.g., collagen vascular disease, pregnancy, ischemia, scorpion bites, parasites obstructing the pancreatic duct [Ascaris, fluke], Reye syndrome, fulminant hepatitis, severe hypotension, cholesterol embolization).

Laboratory findings due to complications:



  • Pseudocysts of the pancreas.


  • Pancreatic infection or abscess diagnosed by increased WBC count, Gram staining, and culture of aspirate.


  • Polyserositis (peritoneal, pleural, pericardial, synovial surfaces). Ascites may develop cloudy or bloody or “prune juice” fluid, 0.5-2.0 L in volume, containing increased amylase with a level higher than that of serum amylase. No bile is evident (unlike in perforated ulcer). Gram stain shows no bacteria (unlike infarct of the intestine). Protein >3 g/dL and marked increase in amylase.


  • Adult respiratory distress syndrome (with pleural effusion, alveolar exudate, or both) may occur in approximately 40% of patients; arterial hypoxemia is present.



  • Disseminated intravascular coagulation (DIC).


  • Hypovolemic shock.


  • Others.


□ Prognostic Laboratory Findings



  • On admission

    WBC > 16,000/µL

    Blood glucose >200 mg/dL

    Serum LD > 350 U/L

    Serum AST > 250 U/L

    Age >55 years


  • Within 48 hours

    >10% decrease in Hct

    Serum calcium <8.0 mg/dL

    Increase in BUN > 5 mg/dL

    Arterial pO2 < 60 mm Hg

    Metabolic acidosis with base deficit >4 mEq/L


  • Mortality

    1%, if 3 signs are positive

    15%, if 3-4 signs are positive

    40%, if 5-6 signs are positive

    100%, if ≥7 signs are positive


  • Degree of amylase elevation has no prognostic significance.


  • CT scan, MRI, and ultrasound are useful for confirming diagnosis or identifying causes or other conditions.


PANCREATITIS, CHRONIC

See also Malabsorption.


□ Laboratory Findings

Laboratory findings are often normal.

Imaging studies: CT, ultrasound, and ERCP are most accurate for diagnosing and staging chronic pancreatitis. Radioactive scanning of the pancreas (selenium) yields variable findings in different clinics.

Cholecystokinin-secretin test: Measures the effect of IV administration of cholecystokinin and secretin on volume, bicarbonate concentration, and amylase output of duodenal contents and increase in serum lipase and amylase. This is the most sensitive and reliable test (gold standard) for chronic pancreatitis especially in the early stages. However, it is technically difficult and is often not performed accurately; gastric contamination must be avoided. Some abnormality occurs in >85% of patients with chronic pancreatitis. Amylase output is the most frequent abnormality. When all three are abnormal, there is a greater frequency of abnormality in the tests listed below.



  • Normal duodenal contents:



    • ▼ Volume: 95-235 mL/hour


    • ▼ Bicarbonate concentration: 74-121 mEq/L


    • ▼ Amylase output: 87,000-276,000 mg



  • Serum amylase and lipase increase after administration of cholecystokinin and secretin in approximately 20% of patients with chronic pancreatitis. They are more often abnormal when duodenal contents are normal. Normally, serum lipase and amylase do not rise above normal limits.


  • Fasting serum amylase and lipase are increased in 10% of patients with chronic pancreatitis.

Serum pancreolauryl test: Fluorescein dilaurate with breakfast is acted on by a pancreas-specific cholesterol ester hydrolase-releasing fluorescein, which is absorbed from the gut and measured in serum, preceded by administration of secretin, and followed by metoclopramide. Reported S/S = 82%/91%.

Glucose tolerance test (GTT): In 65% of patients with chronic pancreatitis and frank diabetes in >10% of patients with chronic relapsing pancreatitis. When GTT is normal in the presence of steatorrhea, the cause should be sought elsewhere than in the pancreas.

Laboratory findings due to malabsorption: Occurs when >90% of exocrine function is lost.



  • Bentiromide test is usually abnormal with moderate to severe pancreatic insufficiency but often normal in early cases.


  • Schilling test may show mild malabsorption of vitamin B12 (no longer performed).


  • Xylose tolerance test and small bowel biopsy are not usually done but are normal.


  • Chemical determination of fecal fat demonstrates steatorrhea. It is more sensitive than tests using triolein-131I.


  • Triolein-131I is abnormal in one third of patients with chronic pancreatitis.


  • Starch tolerance test is abnormal in 25% of patients with chronic pancreatitis.

Laboratory findings due to chronic pancreatitis and pancreatic exocrine insufficiency:



  • Alcohol in 60-70%


  • Idiopathic in 30-40%


  • Obstruction of pancreatic duct (e.g., trauma, pseudocyst, pancreas divisum, cancer, or obstruction of the duct or ampulla)


  • Others occasionally (e.g., CF, primary hyperparathyroidism, heredity, malnutrition, miscellaneous [Z-E syndrome, Shwachman syndrome, α1-antitrypsin deficiency, trypsinogen deficiency, enterokinase deficiency, hemochromatosis, parenteral hyperalimentation])


PSEUDOCYST OF THE PANCREAS


□ Laboratory Findings

Imaging studies: Detected by ultrasound or CT scan.

Core laboratory: Serum conjugated bilirubin is increased (>2 mg/dL) in 10% of patients. Serum ALP is increased in 10% of patients. Fasting blood sugar is increased in <10% of patients.


Secretin-pancreozymin stimulation: Duodenal contents usually show decreased bicarbonate content (<70 mEq/L) but normal volume and normal content of amylase, lipase, and trypsin.

Pancreatic cyst fluid findings: High fluid viscosity and CEA indicate mucinous differentiation and exclude pseudocyst, serous cystadenoma, other nonmucinous cysts, or cystic tumors. Pancreatic enzymes, leukocyte esterase, and NB/70K are increased in pseudocyst fluid. Increased CA 72-4, CA 15-3, and tissue polypeptide antigen are markers of malignancy; if all are low, pseudocyst or serous cystadenoma is most likely. CA-125 is increased in serous cystadenoma.

Other: Laboratory findings due to conditions preceding acute pancreatitis are noted (e.g., alcoholism, trauma, duodenal ulcer, cholelithiasis) and infection, perforation, and hemorrhage by erosion of blood vessel or into a viscus.


DYSPEPSIA AND PEPTIC ULCER DISEASE



□ Recommended Tests



  • Laboratory investigation may not be necessary in young patients (<45 years of age) who have a normal examination and no indicators for organic disease. The etiology of dyspepsia is presented in Table 7-2.


  • In older patients at increased risk, the minimal laboratory workup should include a CBC, electrolytes, calcium, and liver chemistries.


  • Thyroid tests, hCG, amylase, and stool studies should be ordered if specific features of the history or examination are suggestive.








    TABLE 7-2. Differential Diagnosis of Dyspepsia





















    Structural Disease Involving the Stomach or Esophagus


    Peptic ulcer disease (15-25% of cases)


    Reflux esophagitis (5-15% of cases)


    Gastric or esophageal cancer (<2% of cases)


    Infiltrative disease


    Eosinophilic gastritis


    Crohn disease


    Sarcoidosis


    Other Gastrointestinal-Related Diseases


    Gallstones


    Chronic pancreatitis or pancreatic cancer


    Celiac disease


    Lactose intolerance


    Hepatoma


    Medications


    Nonsteroidal anti-inflammatory drugs


    Digitalis


    Theophylline


    Erythromycin


    Alcohol


    Caffeine


    Nicotine


    Other Possible Causes


    Hypothyroidism


    Hypercalcemia


    Intestinal angina


    Pregnancy


    Nonulcerative dyspepsia*


    * Nonulcerative dyspepsia occurs in up to 60% of cases, but the diagnosis requires the exclusion of other diagnostic entities.




  • Additional studies



    • Upper endoscopy (i.e., esophagogastroduodenoscopy [EGD]): In the majority of cases, this is the study of first choice when further evaluation of dyspepsia is required, including the ability to obtain biopsies. As many as two thirds of endoscopies are completely normal in younger patients (i.e., <45 years of age). Therefore, it is best applied to older patients and to younger patients with classic symptoms.


    • Upper GI radiography: This test is less accurate than upper endoscopy and cannot provide tissue diagnosis. It is best reserved for situations where endoscopy expertise is unavailable, for patients who refuse endoscopy or have low pretest probability of disease, and in situations where endoscopy might be considered unsafe.


  • H. pylori testing


  • Gastric emptying studies: Gastric scintigraphy and gastroduodenal manometry studies generally do not influence medical management and are reserved for patients with normal laboratory tests and a normal EGD, yet who continue to have frequent or protracted vomiting suggestive of a motility disorder. Even in these cases, empiric treatment with prokinetic agents should probably be tried first.


ASCITES



□ Etiology



  • Chronic liver disease (infectious hepatitis and alcoholism) causes 80% of cases of ascites (see Hepatomegaly, Jaundice).


  • Multiple causes, including cirrhosis, peritoneal carcinomatosis, or tuberculous peritonitis, account for 3-5% of cases.


  • Carcinomatosis causes <10% of cases of ascites.


  • Heart failure is responsible for <3-5% of cases, and nephritic syndrome is a rare cause of ascites.


  • Cryptogenic cirrhosis may account for up to 10% of cases.


□ Classification



  • Ascites is currently classified as high gradient or low gradient, depending on the serum ascites albumin gradient (SAAG). Calculation of SAAG involves the difference (not the ratio) between serum values and AF values.


  • High-gradient ascites results from portal hypertension, whether on the basis of cirrhosis or noncirrhosis. Nephrotic syndrome is an exception and will usually cause low-gradient ascites due to marked hypoalbuminemia.


  • Low-gradient ascites usually occurs as the result of cardiac failure, malignant carcinomatosis of the peritoneum, infections (such as TB), perforation of the bowel, connective tissues diseases, systemic lupus erythematosus (SLE), and chemical inflammation as in pancreatitis.



□ Laboratory Findings




  • Culture: Bedside inoculation of AF in blood culture bottles has increased the positive bacterial yield to be interpreted in concert with the cell count. A Gram stain should also be done.



    • Imaging studies and CT scans are useful: Ultrasonography is useful for detecting the presence of ascites as well as for determining the etiology. It may reveal evidence of chronic liver disease, malignancy, hepatomegaly, and pancreatic disorder.


    • Ascites fluid findings: AF examination is the principle diagnostic tool. Using abdominal paracentesis to obtain and study the fluid is crucial to making a diagnosis.






      Figure 7-2. Algorithm for the workup of patients with ascites. AILD, alcohol-induced liver disease; CEA, carcinogenic embryonic antigen; NASH, nonalcoholic steatohepatitis; TB, tuberculosis; TNC, total neutrophil count.



  • Transparent to pale fluid: Is seen in cases of portal hypertension. Neutrophilia in excess of 1,000/mL results in opalescence. A concentration of RBCs in excess of 10,000/mL gives a faint pink tinge, and cell counts >20,000/mL color it red. A traumatic tap is evident by a streak of blood rather than homogeneously red fluid and the tendency to clot. Hepatocellular carcinoma (HCC) and, rarely, metastatic disease can cause a bloody tap. TB is only a rare cause of hemorrhagic ascites.


  • Chylous or milky ascites: Has a higher triglyceride concentration than serum and >200 mg/dL. It is rarely seen and is usually an indication of cirrhosis rather than lymphoma or TB as was previously thought. The triglycerides are >1,000 mg/dL in truly milky ascites. Dark-brown ascites may be seen in significant hyperbilirubinemia, biliary perforation (when ascitic bilirubin is higher than serum bilirubin), pancreatitis, and, rarely, malignant melanoma.


  • Bloody ascites fluid: Once a traumatic tap has been ruled out, 50% of cases are due to HCC. TB rarely causes bloody fluid.


  • Staining: Gram staining has low yield. Even with centrifugation, it has 10% sensitivity in spontaneous bacterial peritonitis (SBP). Acid-fast bacilli (AFB) smear for TB has very low sensitivity. In an appropriate clinical setting of low-grade fever, malaise, and weight loss, a high cell count with lymphocytic predominance and low SAAG is suggestive of TB ascites.


  • Protein concentration of AF categorized ascites into exudative (ascitic protein >2.5 g/dL) or transudative (ascitic protein <2.5 g/dL). The significance of this has never been evaluated adequately and objectively.


  • Cell count and differential: In uncomplicated cirrhosis, the total WBC count is <500 cells/µL with <250 neutrophils/µL. After diuresis, the total cell count may go up, but the neutrophil count remains below 250 cells/µL. In SBP, the total WBC count and neutrophil count are usually, but not always raised. In TB and carcinomatosis, the cell count rises but with a predominance of lymphocytes. In traumatic taps, for every 250 RBCs, one neutrophil is subtracted from the total WBC count.


  • Core laboratory: The serum and AF glucose concentrations are nearly the same in uncomplicated portal hypertension (large numbers of WBCs, bacteria, or tumor cells consume glucose and may lead to diminished levels). Amylase values may be about 3-5 times higher than the serum values. LD levels rise because of release of LD from the neutrophils. The rise occurs in cases of secondary peritonitis, TB, and pancreatitis.


  • Cytology: Has limitations in the diagnosis of malignant ascites and has been replaced largely laparoscopic examination of the peritoneum along with biopsy and culture.


□ Limitations



  • Errors may occur if serum albumin is very low or when serum and ascitic samples are not obtained within a short space of time from each other.


  • A high globulin level in serum may also give a false result.



DISORDERS OF THE PERITONEUM ASSOCIATED WITH ASCITES


CHRONIC LIVER DISEASE (SEE P. 783)

This disease differs from ascites caused by malignancy.


□ Laboratory Findings

Albumin: Almost always ≥1.1 g/dL in cirrhosis (most common cause), alcoholic hepatitis, massive liver metastases, fulminant hepatic failure, portal vein thrombosis, Budd-Chiari syndrome, cardiac ascites, fatty liver, acute fatty liver of pregnancy, and mixed myxedema (e.g., cirrhosis with peritoneal TB). May be falsely low if serum albumin <1.1 g/dL or the patient in shock. May be falsely high with chylous ascites (lipid interferes with albumin assay). Albumin levels <1.1 g/dL in >90% of cases of peritoneal carcinomatosis (most common cause), TB, pancreatic or biliary ascites, nephrotic syndrome, bowel infarction or obstruction, and serositis in patients without cirrhosis.

Ascites fluid findings: AF total protein >2.5 mg/dL in cancer is only 56% accurate because of high protein content in 12-19% of these ascites as well as changes caused by albumin infusion and diuretic therapies. AF/serum albumin ratio is <0.5 in cirrhosis (>90% accuracy). AF/serum ratio of LD (>0.6) or protein (>0.5) is not more accurate (approximately 56%) than only total protein for diagnosis of exudate. AF cholesterol <55 mg/dL in cirrhosis (94% accuracy). Albumin gradient (serum albumin minus AF albumin) reflects portal pressure. Total WBC count is usually <300/µL (50% of cases) and PMN < 25% (50% of cases).

Core laboratory: Liver function tests are abnormal.

Other: Cirrhosis findings are similar with or without HCC. Cardiac ascites is associated with a blood-AF albumin gradient >1.1 g/dL, but malignant AF shows blood-AF albumin gradient <1.1 g/dL in 93% of cases.


INFECTED ASCITIC FLUID


□ Laboratory Findings

Culture: AF in blood culture bottles has 85% sensitivity.

Ascites fluid findings:



  • WBC count >250/µL: sensitivity = 85%, specificity = 93%, and neutrophils >50% are presumptive of bacterial peritonitis.


  • pH < 7.35 and arterial-AF pH difference >0.10; both these findings are virtually diagnostic of bacterial peritonitis and the absence of the above findings virtually excludes bacterial peritonitis.


  • Lactate >25 mg/dL and arterial-AF difference >20 mg/dL are often present. LD is markedly increased. Phosphate, potassium, and gamma-glutamyltransferase may also be increased. Glucose is unreliable for diagnosis. Total protein <1.0 g/dL indicates high risk for SBP.


  • Gram stain shows few bacteria in SBP but many when caused by intestinal perforation. Culture sensitivity is 50% for SBP and approximately 80% for secondary peritonitis. TB acid-fast stain sensitivity is 20-30% and TB culture sensitivity is 50-70%.



SECONDARY PERITONITIS



  • This condition shows polymicrobial infection, total protein >1.0 g/dL, AF/LD greater than serum upper limit of normal, and glucose <50 mg/dL compared with SBP.


  • Prevalence of SBP 15%; due to Escherichia coli approximately 50%, Klebsiella, and other gram-negative bacteria; gram-positive bacteria approximately 25% (especially streptococci).


CONTINUOUS AMBULATORY PERITONEAL DIALYSIS

Monitor dialysate for the following:



  • Infection: Peritonitis is defined as WBC count >100/µL, usually with >50% PMNs (normal is <50 WBC/µL, usually mononuclear cells), or positive Gram stain or culture (most prevalent: coagulase-negative staphylococci, Staphylococcus aureus, Streptococcus sp.; multiple organisms, especially mixed aerobes and anaerobes, occur with bowel perforation). Successful therapy causes a fall in WBC count within the first 2 days and a return to <100/µL in 4-5 days; differential returns to predominance of monocytes in 4-7 days with increased eosinophils in 10% of cases. Patients check outflow bags for turbidity. Turbid dialysate can occur occasionally without peritonitis during the first few months of placing catheter (due to catheter hypersensitivity) with WBC count 100-8,000/µL, 10-95% eosinophils, sometimes increased PMNs, and negative cultures. Occasional RBCs may be seen during menstruation or with ovulation at midcycle. Because of low WBC decision level, manual hemocytometer count rather than an automated instrument must be used.


  • Metabolic change: Assay dialysate for creatinine and glucose; calculate ultrafiltrate volume by weighing dialysate fluid after 4-hour dwell time and subtracting it from preinfusion weight using specific gravity of 1.0.


PANCREATIC DISEASE



  • AF amylase level greater than serum amylase level is specific for pancreatic disease, but both levels are normal in 10% of cases.


  • Methemalbumin in serum or AF and total protein >4.5 g/dL indicates poor prognosis.


MALIGNANT ASCITES



  • Increased fluid cholesterol (>45 mg/dL) and fibronectin (>10 mg/dL) have S/S 90%/82%.


  • Positive cytology has S/S 70%/100%.


  • Increased AF CEA (>2.5 mg/dL) has S/S 45%/100%.



ASCITES IN FETUS OR NEONATE


□ Etiology



  • Nonimmune (occurs in 1 in 3,000 pregnancies):



    • ▼ Cardiovascular abnormalities causing congestive heart failure (CHF) (e.g., structural, arrhythmias) (40% of cases).


    • ▼ Chromosomal (e.g., Turner and Down syndromes are most common; trisomies 13, 15, 16, and 18) (10-15% of cases).


    • ▼ Hematologic disorders (any severe anemia) (10% of cases).


    • ▼ Inherited (e.g., α-thalassemia, hemoglobinopathies, G6PD deficiency)


    • ▼ Acquired (e.g., fetal-maternal hemorrhage, twin-to-twin transfusion, congenital infection [parvovirus B19], methemoglobinemia).


    • ▼ Congenital defects of the chest and abdomen.


    • ▼ Structural (e.g., diaphragmatic hernia, jejunal atresia, volvulus, intestinal malrotation).

      Peritonitis caused by GI tract perforation, congenital infection (e.g., syphilis, TORCH [toxoplasmosis, other agents, rubella, CMV, and herpes simplex], hepatitis), and meconium peritonitis.


    • ▼ Lymphatic duct obstruction


    • ▼ Biliary atresia.


    • ▼ Nonstructural (e.g., congenital nephrotic syndrome, cirrhosis, cholestasis, hepatic necrosis, GI tract obstruction).


    • ▼ Lower GU tract obstruction (e.g., posterior urethral valves, urethral atresia, and ureterocele) is the most common cause.


    • ▼ Inherited skeletal dysplasias (enlarged liver causing extramedullary hematopoiesis).


    • ▼ Fetal tumors, most often teratomas and neuroblastomas.


    • ▼ Vascular placental abnormalities.


    • ▼ Genetic metabolic disorders (e.g., Hurler syndrome, Gaucher disease, Niemann-Pick disease, GM1 gangliosidosis type I, I-cell disease, β-glucuronidase deficiency).


  • Immune (maternal antibodies reacting to fetal antigens [e.g., Rh, C, E, Kell])


PERITONITIS, ACUTE

See Figures 7-3 and 7-4.


PRIMARY PERITONITIS

Ascites fluid findings: Gram stain of direct smear and culture of peritoneal fluid usually shows streptococci in children. In adults, it is caused by E. coli (40-60%) or Streptococcus pneumoniae (15%), other gram-negative bacilli, and enterococci; usually one organism. May be caused by Mycobacterium tuberculosis. Marked increase in WBC (≤50,000/µL) and PMN (80-90%).

Peritoneal lavage fluid findings: Shows WBC count >200/µL in 99% of cases.

Other: Laboratory findings due to nephrotic syndrome and post-necrotic cirrhosis and occasionally bacteremia in children and cirrhosis with ascites in adults.







Figure 7-3. Algorithm for differentiating secondary from spontaneous bacterial peritonitis. AF, ascitic fluid; PMN, polymorphonuclear leukocytes; LD, lactate dehydrogenase; ULN, upper limit of normal; WBC, white blood cell; SBP, spontaneous bacterial peritonitis.


SECONDARY PERITONITIS

Occurs and recurs very frequently in continuous ambulatory peritoneal dialysis. Laboratory findings due to perforation of hollow viscus (e.g., appendicitis, perforated ulcer).

Dialysate findings: Turbid (indicates >300 WBC/µL); Gram stain, culture, and leukocytosis may be absent. It is caused by gram-positive bacteria in approximately 70%, enteric gram-negative bacilli and Pseudomonas aeruginosa in 20-30%, others in 10-20%, and sterile in 10-20%. If more than one pathogen is found, rule out perforated viscus. Usually, more than one organism is found.







Figure 7-4. Algorithm for spontaneous bacterial peritonitis. PMN, polymorphonuclear leukocytes.


DIARRHEA



□ Etiology

Diarrhea can result from any of the following mechanisms:



  • Osmosis: Molecules not normally present in the intestinal lumen increase the osmolality of chime, drawing water into the lumen (i.e., lactose).


  • Secretion: Substances can cause intestinal cells to secrete sodium and water (i.e., cholera toxin).


  • Inflammation results in denuding of the intestinal lining, which in turn disrupts normal absorption, thereby allowing compounds from the lining to leak into the lumen resulting in an increased osmosis.


  • Motility: Hypermotility leads to an increased stool volume. Hypomotility can lead to bacterial overgrowth, which causes diarrhea through several different mechanisms.


  • Anal sphincter dysfunction causes fecal incontinence, which can be interpreted by the patient as diarrhea.




□ Laboratory Findings

Endoscopy: Lower endoscopy may help. One series has a 20% yield in identifying a pathologic diagnosis. In non-HIV-infected patients, the role of sigmoidoscopy versus colonoscopy is unclear. When clinically suspected, even if no gross abnormalities are noted, consider doing blind biopsies looking for lymphocytic and collagenous colitis. The yield of biopsy with no gross abnormalities ranges
from 6% to 42%. Upper endoscopy is useful for making the diagnosis of sprue, Whipple disease, and other small bowel infiltrative processes.

Radiology: An upper GI series with small bowel follow-through is most commonly used when evaluating for Crohn disease. Enteroclysis is superior, with 100% sensitivity and 98% specificity for small bowel involvement with Crohn disease.

Recommended laboratory tests of stool:



  • Fecal leukocytes.


  • Stool for osmolality gap: The osmolality gap is calculated by the following formula: 2 (stool Na + K). The accuracy is fair in distinguishing between osmotic (if gap is 50) and secretory (if gap is >50) diarrhea.


  • Stool for pH: For carbohydrate intolerance (e.g., lactose or sorbitol), one small study found the pH <5.6. For bile acid-induced diarrhea, the pH is usually over 6.8.


  • Stool for fecal fat: This test is used to detect steatorrhea on the basis of malabsorption.


  • Qualitative: Sensitivity is 97-100%, but the specificity varies from 56% to 86%.


  • Quantitative: Based upon a 72-hour collection, the patient should be on a 75- to 100-g fat diet. A nutritional consult is advised to maximize compliance.


  • Test(s) for infectious agents (e.g., stool culture, O&P examination, rotavirus detection) based on clinical presentation.

Other recommended tests:



  • Nutrition indices: CBC, albumin, and potassium (sensitivity of hypokalemia is 100% for pancreatic cholera or [VIPoma]) are routine studies in the evaluation of chronic diarrhea.


  • Hormonal studies: TSH, fasting serum gastrin level, calcitonin level, and 24-hour urine collection for 5-hydroxyindoleacetic acid (5-HIAA) are recommended.


  • D-xylose testing: This tests for small bowel malabsorption syndromes (e.g., sprue, Crohn disease, amyloidosis). Twenty-five grams of D-xylose are administered. A 5-hour urine collection and a 1-hour serum sample are obtained. A decreased amount of D-xylose in the urine and serum indicates small bowel malabsorption. The sensitivity of the test is decreased in the following situations: creatinine clearance of <30 mg/dL, portal hypertension, ascites, delayed gastric emptying, fiber supplements, glucose load, aspirin, and glipizide.


  • Bentiromide test (to test for pancreatic exocrine insufficiency): N-benzoyl-L-tyrosyl para-aminobenzoic acid (NBT PABA) is administered orally. The molecule is cleaved by chymotrypsin; PABA is absorbed and then measured in a 6-hour urine collection. PABA alone is a somewhat inaccurate measure, so additional markers have been used to increase the accuracy.



  • Serum immune markers: Several serum immune markers performed by ELISA have been found to be valuable for the diagnosis, stratification, and management of IBD (see Celiac Disease):



    • ▼ Deoxyribonuclease (DNAse)-sensitive perinuclear antineutrophil cytoplasmic antibody (P-ANCA) is positive in 60-80% of adults with ulcerative colitis (UC) and in 83% of children with UC. P-ANCA is positive in 10% of patients with Crohn disease.


    • ▼ Anti-Saccharomyces cerevisiae antibody (ASCA) is present in 70% of patients with Crohn disease.


    • ▼ Pancreatic antibody may be positive in 30-40% of patients with Crohn disease.


    • ▼ Outer membrane porin from E. coli (OmpC) antibody: An immunoglobulin A (IgA) response to OmpC is seen in 55% of patients with Crohn disease.


    • ▼ Lactoferrin, stool: A sensitive and specific marker for detecting inflammation or from IBS once infectious causes of inflammation and colorectal cancer are ruled out.


    • ▼ Calprotectin for screening of patients with diarrhea to help distinguish between active IBD and IBS.


DIARRHEA, ACUTE


OSMOTIC DIARRHEA



□ Etiology



  • Exogenous



    • ▼ Laxatives (e.g., magnesium sulfate, milk of magnesia, sodium sulfate [Glauber salt], sodium phosphate, polyethylene glycol/saline)


    • ▼ Drugs (e.g., lactulose, colchicine, cholestyramine, neomycin, paraaminosalicylic acid [PAS])


    • ▼ Foods (e.g., mannitol, sorbitol [in diet candy, chewing gum, soda])


  • Endogenous



    • ▼ Congenital malabsorption



      • Specific (e.g., lactase deficiency, fructose malabsorption)


      • General (e.g., abetalipoproteinemia and hypobetalipoproteinemia, congenital lymphangiectasia, cystic fibrosis)


    • ▼ Acquired malabsorption



      • Specific (e.g., pancreatic disease, celiac sprue, parasitic infestation, rotavirus enteritis, metabolic disorders [thyrotoxicosis, adrenal insufficiency], jejunoileal bypass, bacterial overgrowth, short bowel syndrome, inflammatory disease [e.g., mastocytosis, eosinophilic enteritis])



SECRETORY (ABNORMAL ELECTROLYTE TRANSPORT) DIARRHEA



□ Etiology



  • Exogenous



    • ▼ Drugs



      • Laxatives (e.g., aloe, anthraquinones, bisacodyl, castor oil, dioctyl sodium sulfosuccinate, phenolphthalein, senna)


      • Diuretics (e.g., furosemide, thiazides), asthma (theophylline), thyroid drugs


      • Cholinergic drugs (cholinesterase inhibitors, quinidine, clozapine, angiotensin-converting enzyme [ACE] inhibitors)


    • ▼ Toxins (e.g., arsenic, mushrooms, organophosphates, alcohol)


    • ▼ Infectious agents (for a discussion of infectious causes of diarrhea, see the Infectious Gastrointestinal Diseases section in this chapter and Chapter 13)


  • Endogenous



    • ▼ Hormones (serotonin, calcitonin, VIP)


    • ▼ Gastric hypersecretion (Z-E syndrome, systemic mastocytosis, short bowel syndrome)


    • ▼ Bile salts (e.g., disease or resection of the terminal ileum)


    • ▼ Fatty acids (e.g., disease of small intestine mucosa, pancreatic insufficiency)


    • ▼ Congenital (e.g., congenital chloridorrhea, congenital sodium diarrhea)


□ Laboratory Findings

Stool findings: Watery stool, volume >1 L/day, blood and pus absent, stool osmolality close to plasma osmolality with no anion gap


EXUDATIVE DIARRHEA (INFLAMMATORY CAUSES)


□ Etiology



  • Infection, injury, ischemia, vasculitis, abscess, and/or idiopathic


□ Laboratory Findings



  • Stool contains blood and pus.


MOTILITY DISTURBANCES


□ Etiology



  • Decreased small intestinal motility (e.g., hypothyroidism, DM, amyloidosis, scleroderma)


  • Increased small intestinal motility (e.g., hyperthyroidism, carcinoid syndrome)


  • Increased colonic motility (e.g., irritable bowel syndrome)



INFECTIOUS GASTROENTERITIS



□ Who Should Be Suspected?



  • The major syndromes associated with GI infections include acute vomiting, acute watery diarrhea, inflammatory diarrhea/dysentery, or enteric fever. If a diarrheal syndrome persists for >2 weeks, it is considered persistent or chronic.


  • Patients with infectious gastroenteritis may present with a variety of symptoms including nausea, vomiting, abdominal pain, diarrhea, and anorexia. Enteric fever, however, may be associated with minimal GI symptoms, but have prominent systemic or localized symptoms.


  • When evaluating a patient with a diarrheal illness, a number of issues should be pursued:



    • ▼ Does the patient have any medical conditions, like immune compromise or decreased gastric acidity that would predispose to acquisition or severity of GI infection?


    • ▼ What are the prominent signs and symptoms of disease?


    • ▼ Has the patient had recent travel to regions where transmission of GI illness is endemic?


    • ▼ Has the patient eaten any unusual food? Eaten at any function with mass-produced meals? Eaten any raw or incompletely cooked or pasteurized food?


    • ▼ Has the patient or a close contact worked or resided in a closed community, like a day care center, cruise, inpatient or long-term care facility, or other setting in which transmission of an agent may be facilitated?


    • ▼ What is the interval between likely exposure and onset of symptoms?


    • ▼ Do any of the patient’s recent contacts have similar illness?


    • ▼ What is the duration of clinical symptoms in affected patients?


    • ▼ Has there been new contact with animals: domesticated, farm, or wild?

The following lists provide common agents based on disease presentation. In addition to the clinical presentation, epidemiologic risk should be considered when determining diagnostic and therapeutic strategies.



  • Diarrheal illness may be noninflammatory or inflammatory.



    • Noninflammatory diarrhea is usually caused by disease of the small intestine resulting in hypersecretion or decreased absorption. There is usually abrupt onset and resolution after a brief duration of illness.
      Systemic symptoms are usually absent or mild. Dehydration may be a complication, especially in the young or elderly.


    • Inflammatory diarrhea is characterized by mucosal invasion or cytotoxic damage by the pathogen. The large intestine is most commonly affected. The mucosal invasion typically results in bloody stools with many fecal leukocytes. Systemic symptoms are typical, including fever, abdominal pain and tenderness, nausea and vomiting, headache, and malaise.


  • Syndromes: Clinical manifestations of GI pathogens may be variable and nonspecific. Most infections are self-limited and may be managed symptomatically. Specific diagnostic testing is recommended for severe disease or patients at risk for complication of infection, for infections suspected as part of a local outbreak, or for other epidemiologic purposes.


  • Gastroenteritis with acute vomiting as the prominent symptom. Suspect:



    • ▼ Enteric viruses (e.g., rotavirus, norovirus, enteric adenovirus)


    • ▼ Preformed toxin ingestion/food poisoning (S. aureus, Bacillus cereus)


  • Acute onset of watery diarrhea. Patients may have some vomiting and mild systemic symptoms. Stool shows no increased WBCs or RBCs. Suspect:



    • ▼ Enteric viruses (astrovirus, norovirus or other calicivirus, adenovirus, rotavirus) are most common.


    • ▼ Toxins (e.g., Clostridium perfringens or B. cereus).


    • ▼ Parasites (e.g., Cryptosporidium species, Cyclospora cayetanensis, Giardia lamblia).


    • ▼ Bacterial pathogens (any enteric pathogen may cause mild symptoms.)


  • Inflammatory diarrhea is the prominent symptom (grossly bloody stool, pus or increased fecal WBCs, fever, and significant systemic signs and symptoms). Diagnostic testing is recommended. The syndrome is most commonly caused by bacterial pathogens. Suspect Campylobacter species; Clostridioides (formerly Clostridium) difficile; Escherichia coli; enteroinvasive, or enterohemorrhagic, Plesiomonas; Salmonella species; Shigella species; and Yersinia. Entamoeba histolytica can also cause dysentery.



    • ▼ Enteric fever should be considered in patients with significant fever and recent travel to an endemic area or other epidemiologic risk, whether the patient has diarrhea or not. Stool culture for Salmonella and blood cultures are recommended.


  • Persistent diarrhea as the prominent symptom (2 weeks or longer). This syndrome may occur in immunocompromised patients. In addition to bacterial causes, suspect:



    • ▼ Parasites (e.g., Cryptosporidium species, Cyclospora cayetanensis, G. lamblia, Cystoisospora belli, Entamoeba histolytica).


    • ▼ Consider noninfectious causes, such as persistent compromise of the gut’s resorptive capability, IBD, laxative use, etc.

Note: The GI tract may be the portal for infectious agents, toxins, or poisons that do not cause gastroenteritis, like listeriosis, brucellosis, botulism, hepatitis viruses, organophosphates/insecticides, heavy metals, mushroom toxins, etc.



□ Diagnosis and Reporting

Most cases of diarrheal illness are mild and self-limited, and testing to establish a specific cause is rarely necessary. Diagnostic testing is recommended for patients with profuse, watery diarrhea, passage of stools with blood or mucus, and persistent diarrhea (>48 hours), immunocompromised patients, and patients with severe GI or systemic symptoms (like severe abdominal pain, fever, or hypovolemia). Testing to establish a specific diagnosis is also recommended for patients at risk for complications of GI infections, like patients with IBD, patients involved in any investigation of a possible outbreak of diarrheal illness, and patients who may be at increased risk for transmitting infection to others, like food handlers.

Diagnostic testing: When indicated, diarrheal stool (stool that takes the shape of the transport container) should be submitted. The type of testing will depend on the agent suspected, clinical presentation, source of specimen submitted for testing, and other factors. Diagnostic techniques for microbial pathogens are discussed in other sections of this book.



  • Bacteria: Stool culture is most commonly submitted. Bacterial pathogens are present in high concentrations during acute symptomatic infection. Therefore, submission of a single specimen is usually sensitive for detection of bacterial causes of diarrhea.



    • ▼ For routine cultures, consider Salmonella, Salmonella, Campylobacter, and Shiga toxin or Shiga toxin producing E. coli. Consider culture for Yersinia for patients with abdominal pain consistent with mesenteric adenitis. Consider culture for Vibrio for patients with diarrhea consistent with cholera and possible exposure.


    • ▼ Additional cultures or testing for epidemiologic/infection control purposes may be required for some pathogens. Such testing is typically performed at local department of health labs.


    • Clostridioides (formerly Clostridium) difficile testing is recommended for patients who develop symptoms consistent with C. diff infection >3 days after admission to an inpatient facility. A single specimen is sufficient for diagnosis.


    • ▼ Cultures of blood and other specimens are recommended for high-risk patients like those with sepsis, immunocompromised, or children younger than 3 years.


  • Enteric viruses: Most acute GI syndromes with diarrhea and/or vomiting are caused by viruses, usually norovirus. Viral gastroenteritis is most commonly mild and self-limited with few systemic symptoms and may be effectively treated symptomatically without a specific diagnosis. Four viral pathogens are responsible for most cases of viral gastroenteritis in the United States: norovirus, rotavirus, enteric adenoviruses, and astroviruses.



    • Viral culture is of limited utility. Some clinical laboratories may provide viral culture testing to rule out enteric adenoviruses (serotypes 40 and 41). Antigen detection testing is available for several enteric viruses and provides reliable detection of rotavirus and enteric adenovirus in stool specimens. Molecular diagnostic tests now play an important role in the detection of enteric virus infections.



  • Parasites: O&P testing is not cost-effective for routine testing of patients with GI complaints, but should be considered in patients with persistent diarrhea and specific epidemiologic risks, especially travel to regions with a high endemic rate of enteric parasitic infections, diarrhea in men who have sex with men, patients with HIV infection, etc.



    • Sensitive and specific stool antigen testing is available for Cryptosporidium, Giardia, and E. histolytica. Antigen testing may serve as cost-effective initial testing for patients who require testing to rule out parasitic infection. When other parasites are suspected, three specimens for O&P testing should be submitted, separated by at least 24 hours, over 3-6 days.


  • Molecular diagnostic testing: For bacterial pathogens diagnosed using amplified molecular test methods, confirmation using culture methods is recommended. Isolation of the pathogen in culture may be needed for susceptibility testing or for compliance with public health requirements.


  • Reporting: Many of the agents of infectious gastroenteritis are easily spread from person to person. Therefore, in addition to routine reporting to requesting clinicians, positive test results are often reported by labs to local departments of health and to infection prevention clinicians in hospitals, long-term care facilities, or other closed communities.



DIARRHEA, CHRONIC



□ Etiology



  • Infectious agents (for a discussion of infectious causes of diarrhea, see the Infectious Gastrointestinal Diseases section in this chapter and Chapter 11)


  • IBD (e.g., Crohn disease, UC, collagenous colitis)



  • Carbohydrate malabsorption (e.g., lactase or sucrase deficiency)


  • Foods (e.g., ethanol, caffeine, sweeteners such as sorbitol, fructose)


  • Drugs (e.g., antibiotics, antihypertensive, antiarrhythmic, antineoplastic, colchicine, cholestyramine; see the previous section on acute diarrhea)


  • Laxative abuse, factitious


  • Endocrine (e.g., DM, adrenal insufficiency, hyperthyroidism, hypothyroidism)


  • Hormone-producing tumors (e.g., gastrinoma, VIPoma, villous adenoma, medullary thyroid carcinoma, pheochromocytoma, ganglioneuroma, carcinoid tumor, mastocytosis, somatostatinoma, ectopic hormone production by lung or pancreas carcinoma)


  • Injury caused by radiation, ischemia, and so on


  • Infiltrations (e.g., scleroderma, amyloidosis, lymphoma)


  • Colon carcinoma


  • Previous surgery (e.g., gastrectomy, vagotomy, intestinal resection)


  • Immune system disorders (e.g., systemic mastocytosis, eosinophilic gastroenteritis)


  • Intraluminal maldigestion (bile duct obstruction, pancreatic exocrine insufficiency)


  • Celiac sprue


  • Whipple disease


  • Abetalipoproteinemia


  • Dermatitis herpetiformis


  • Intestinal lymphangiectasia


  • Allergy


  • Idiopathic


OTHER GASTROINTESTINAL CONDITIONS ASSOCIATED WITH CHRONIC DIARRHEA


DIVERTICULOSIS, COLON


□ Laboratory Findings

Core laboratory: Hypochromic microcytic anemia, increased WBCs, increased ESR, and positive occult blood


ENTEROCOLITIS, NECROTIZING, IN INFANCY



□ Laboratory Findings

There may be oliguria, neutropenia, and anemia. Persistent metabolic acidosis, severe hyponatremia, and DIC are a common triad in infants. Bloody stools feature no characteristic organisms; significant organisms are often found by frequent repeated cultures of blood, urine, and stool. Testing for HIV should also be considered.



INFLAMMATORY BOWEL DISEASE



REGIONAL ENTERITIS (CROHN DISEASE)



□ Laboratory Findings

Histology: Endoscopic biopsy may show granulomas in >60% of cases of Crohn disease but in only 6% of cases of UC.

Serology: Atypical perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) are found in <15% of cases of Crohn disease but in ≤70% of ulcerative colitis patients. Anti-S. cerevisiae (baker’s or brewers’ yeast) antibodies (ASCA) are found in approximately 60% of Crohn disease cases but in only approximately 10% of cases in ulcerative colitis.

Lactoferrin and calprotectin can help distinguish between IBD and noninflammatory IBS.

Hematology: Increased WBC, ESR, CRP, and other acute-phase reactants correlate with disease activity. A mild increase of WBC indicates activity, but a marked increase suggests suppuration (e.g., abscess). ESR tends to be higher in disease of the colon than of the ileum. Anemia is due to iron deficiency or vitamin B12 or folate deficiency or chronic disease.

Core laboratory: Decreased serum albumin; increased γ-globulins; hyperchloremic metabolic acidosis; dehydration; and decreased sodium, potassium, and magnesium. There are mild liver function test changes due to pericholangitis (especially increased serum ALP). There are laboratory changes due to complications or sequelae (e.g., malabsorption, perforation and fistula formation, abscess formation, arthritis, sclerosing cholangitis, iritis, uveitis).


ULCERATIVE COLITIS, CHRONIC NONSPECIFIC



□ Laboratory Findings

Serology: P-ANCA are found in 70% of ulcerative colitis patients but only occasionally in cases of Crohn disease. Stools are negative for usual enteric pathogens and parasites.


Hematology: With diarrhea and fever, hemoglobin <7.5 g/dL, increased neutrophil count, and ESR > 30 mm/hour indicate severe disease.

Core laboratory: Serum ALP often increased slightly. Other liver function tests are usually normal. Stools are positive for blood.


□ Other Considerations



  • Laboratory changes due to complications or sequelae (e.g., hemorrhage, carcinoma, electrolyte disorders, toxic megacolon with perforation).


  • The lower sensitivity of combined serologic tests only modestly influences pretest and posttest probability in IBD but is very useful in distinguishing Crohn disease from UC. Serial measurements are not useful and do not correlate with disease activity; titers are stable over time.


MALABSORPTION



□ Etiology



  • Inadequate mixing of food with bile salts and lipase (e.g., pyloroplasty, subtotal or total gastrectomy, gastrojejunostomy)


  • Inadequate lipolysis due to lack of lipase (e.g., CF of the pancreas, chronic pancreatitis, cancer of the pancreas or ampulla of Vater, pancreatic fistula, vagotomy)


  • Inadequate emulsification of fat due to lack of bile salts (e.g., obstructive jaundice, severe liver disease, bacterial overgrowth of the small intestine, disorders of the terminal ileum)


  • Primary absorptive defect in the small bowel


  • Inadequate absorptive surface due to extensive mucosal disease (e.g., regional enteritis, tumors, amyloid disease, scleroderma, irradiation)


  • Biochemical dysfunction of mucosal cells (e.g., celiac sprue syndrome, severe starvation, or administration of drugs such as neomycin sulfate, colchicine, or PAS)


  • Obstruction of mesenteric lymphatics (e.g., by lymphoma, carcinoma, intestinal TB)


  • Inadequate length of normal absorptive surface (e.g., surgical resection, fistula, shunt)


  • Miscellaneous (e.g., “blind loops” of the intestine and diverticula, Z-E syndrome, agammaglobulinemia, endocrine and metabolic disorders)


  • Infection (e.g., acute enteritis, tropical sprue, Whipple disease [Tropheryma whippelii]; in common variable hypogammaglobulinemia, 50-55% of patients have chronic diarrhea and malabsorption caused by a specific pathogen such as G. lamblia or overgrowth of bacteria in the small bowel)


□ Laboratory Findings

Core laboratory: Serum cholesterol may be decreased. Decreased serum carotene, albumin, and iron; increased stool weight (>300 g/24 hours) and stool fat (>7 g/24 hours).


Hematology: PT may be prolonged because of malabsorption of vitamin K and increased ESR.

Anemia is caused by deficiency of iron, folic acid, vitamin B12, or various combinations, depending on their decreased absorption.

Other: Normal D-xylose test, low serum trypsinogen, and pancreatic calcification on radiograph of the abdomen establish diagnosis of chronic pancreatitis. If calcification is absent (as occurs in 70-80% of cases), abnormal contents of pancreatic secretion after secretin-cholecystokinin stimulation or abnormal bentiromide tests establish diagnosis of chronic pancreatitis.


□ Recommended Tests

Fat absorption indices (steatorrhea): Direct qualitative stool examination. Two or more random stool samples are collected on diet of >80 g of fat daily.

Serum trypsinogen: <10 ng/mL in 75-85% of patients with severe chronic pancreatitis (those with steatorrhea) and 15-20% of those with mild to moderate disease; occasionally low in cancer of the pancreas; normal (10-75 ng/mL) in nonpancreatic causes of malabsorption.

Carotene tolerance test: Measure serum carotene following daily oral loading of carotene for 3-7 days. Low values for serum carotene levels are usually associated with steatorrhea. Increase of serum carotene by >35 µg/dL indicates previously low dietary intake of carotene and/or fat. Patients with sprue in remission with normal fecal fat excretion may still show low carotene absorption.

Vitamin A tolerance test (for screening steatorrhea): Measure plasma vitamin A level 5 hours after ingestion. Normal rise is 9× fasting level. A flat curve occurs in liver disease. It is not useful after gastrectomy. With vitamin A as ester of long-chain fatty acid, flat curve occurs in both pancreatic disease and intestinal mucosal abnormalities; when water-soluble forms of vitamin A are used, the curve becomes normal in patients with pancreatic disease but remains flat in intestinal mucosal abnormalities. An abnormal result indicates a defect in small bowel mucosal absorption function (e.g., sprue, Whipple disease, regional enteritis, TB enteritis, collagen diseases involving the small bowel, extensive resection). Abnormal pancreatic function does not affect the test.


CARBOHYDRATE ABSORPTION INDICES



  • Disaccharide malabsorption


□ Etiology



  • Primary malabsorption (congenital or acquired) because of absence of specific disaccharidase in brush border of small intestine mucosa


  • Isolated lactase deficiency (also called milk allergy, milk intolerance, congenital familial lactose intolerance, lactase deficiency) (is most common of these defects; occurs in approximately 10% of whites and 60% of blacks; infantile type shows diarrhea, vomiting, failure to thrive, malabsorption, and so on; often appears first in adults; become asymptomatic when lactase is removed from diet)



  • Sucrose-isomaltose malabsorption (inherited recessive defect)



    • ▼ Oral sucrose tolerance curve is flat, but glucose plus fructose tolerance test is normal. Occasionally, there is an associated malabsorption with increased stool fat and abnormal D-xylose tolerance test, although intestinal biopsy is normal.


    • ▼ Hydrogen breath test after sucrose challenge.


    • ▼ Intestinal biopsy with measurement of disaccharidase activities.


    • ▼ Sucrose-free diet causes cessation of diarrhea.


  • Glucose-galactose malabsorption (inherited autosomal recessive defect that affects the kidney and intestine)



    • ▼ Oral glucose or galactose tolerance curve is flat, but IV tolerance curves are normal.


    • ▼ Glucosuria is common. Fructose tolerance test is normal.


  • Secondary malabsorption



    • ▼ Resection of >50% of the colon disaccharidase activity. Lactose is most marked, but there may also be sucrose. Oral disaccharide tolerance (especially lactose) is abnormal, but intestinal histology and enzyme activity are normal.


  • Diffuse intestinal disease—especially celiac disease in which activity of all disaccharidases may be decreased, with later increase as the intestine becomes normal on gluten-free diet; cystic fibrosis of the pancreas, severe malnutrition, UC, severe Giardia infestation, blind loop syndrome, β-lipoprotein deficiency, and effect of drugs (e.g., colchicine, neomycin, birth control pills). Oral tolerance tests (especially lactose) are frequently abnormal, with later return to normal with gluten-free diet. Tolerance tests with monosaccharides may also be abnormal because of defect in absorption as well as digestion.


  • Small intestinal bacterial overgrowth (see Figure 7-4)



    • ▼ Quantitative aerobic and anaerobic culture of aspirate of small bowel content showing >105 cfu/mL of anaerobic organisms is considered diagnostic. The utility of culture is limited, however, because it requires invasive collection; there may be sampling error due to limited regions of involvement within the small bowel, and culture techniques and interpretation are not standardized.


    • 14C-D-xylose breath test has good specificity.


    • ▼ Hydrogen breath tests (glucose-H2, lactulose-H2)—not recommended because of limited sensitivity and specificity.


CELIAC DISEASE (GLUTEN-SENSITIVE ENTEROPATHY, NONTROPICAL SPRUE, IDIOPATHIC STEATORRHEA)

Mar 20, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Digestive Diseases
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