1' What, if any, is the role of laboratory tests in the diagnosis of CP, especially of uncertain cas

1
1. What, if any, is the role of laboratory tests
in the diagnosis of CP, especially of uncertain
cases ?
2
Laboratory Investigations for Chronic
Pancreatitis
Tests for Structural Abnormalities
Tests for Functional Abnormalities
USS, CT, MRCP, EUS
Endocrine Function Only for documentation
therapy
Exocrine Function
Tumor Markers FNAC
Indirect Tests pancreatic enzymes in duodenal
samples after meal products of digestive enzyme
action on ingested substrates the measurement
of pancreatic enzymes in the stool the
measurement of the plasma concentration of
hormones
Direct Stimulation Tests
Genetic studies for aetiology
3
Indirect Tests

• Lundh Test Meal
• Fecal Fat
• Sudan III Staining
• Chymotrypsin or Elastase-1 in Stool
• Bentiromide Test
• Fluorescein Dilaurate (Pancreolauryl) Test

• Serum trypsinogen
• Other Tests
• triglyceride and cholesteryl breath tests
• H2 and CO2 breath tests
• the dual label Schilling test
• plasma measurements of pancreatic polypeptide and
  amino acids.

Malabsorption occurs only when functional
capacity is reduced to 5 to 10 of normal. most
function tests will be positive only in
far-advanced disease and are less accurate in
early chronic pancreatitis. DiMagno EP, N Engl J
Med 1973 288813.
4
Routine Laboratory Tests

• Not generally useful in making a diagnosis of CP.
  
• The leukocyte count usually normal in the
  absence of infection.
• Alkaline phosphatase or bilirubin may be
  abnormal
• compression of the intrapancreatic bile duct by a
  pseudocyst or fibrosis within the head of the
  pancreas.
• Serum amylase or lipase may be elevated
• acute exacerbations elevations are modest.
  Neither routinely present nor diagnostic for
  chronic pancreatitis.
• Pseudocyst,
• Pancreatic ductal stricture, or
• Internal pancreatic fistula.
• Serum albumin and calcium may be decreased.
• chronic alcoholic patients, in whom one may
  malnutrition, anemia with macrocytosis,
  thrombocytopenia, and leukopenia.

5
Do We Have A Gold Standard?

• Sensitivity, specificity, and accuracy of
  diagnostic tests is measured against a gold
  standard.
• In the case of chronic pancreatitis, the gold
  standard is pancreatic histology.
• the histologic changes not uniform throughout the
  gland, so that a small biopsy specimen may not
  give a complete picture of the presence or
  absence of disease.
• obtaining pancreatic tissue on a routine basis is
  risky and seldom performed.

6
Substitute Gold Standard?

• Prolonged follow-up.
• Most series have not followed patients diagnosed
  with early chronic pancreatitis or possible early
  chronic pancreatitis (patients in whom diagnostic
  tests are not unequivocally positive) for long
  enough to establish the presence or absence of
  chronic pancreatitis with certainty.
• Apart from sensitivity and specificity of test,
  the doctor must consider the availability, cost,
  and risk of each of these tests to maximize
  benefit and minimize risk.

7
Direct Tests Virtual Gold Standard

• The principle
• Maximal volume, bicarbonate secretion, and enzyme
  secretion are related to the functional mass of
  the pancreas.
• The secretion stimulated by constant intravenous
  infusion.
• CCK-octapeptide (40 ng/kg/hour) and
• Secretin (0.25 CU/kg/hour).

8
Direct Tests

• Both the stomach and duodenum are intubated.
• The gastric tube removes gastric secretions
• Interfere with the ability to measure volume and
  bicarbonate secretions from the pancreas
• Low pH may also alter pancreatic enzyme activity.
  
• The duodenal tube
• Infusion of a nonabsorbable marker (such as
  cobalamin or polyethylene glycol (PEG) allows the
  quantitation of secretions without the need for
  complete aspiration of secretions).
• Collection of pancreatic secretions.
• Niederau C, Gastroenterology 1985 881973.

9
Direct Tests

• Measure
• Volume
• Bicarbonate
• Amylase, trypsin, chymotrypsin, and lipase
• Measurements are corrected for percentage
  recovery.
• 83 sensitive and 89 specific.
• Heiji HA, Scand J Gastroenterol 1986 2135.
• False-positive results may occur in patients with
  celiac sprue and diabetes mellitus.

10
Do We Need Direct Tests?

• These tests are performed at hardly any centre in
  India and are generally not available.
• In most comparisons with pancreatography (ERP),
  direct hormonal stimulation tests appear to be
  slightly more sensitive for the diagnosis of
  chronic pancreatitis.
• The values for sensitivity in studies range from
  74 to 97, with specificity ranging from 80 to
  90.
• In four studies, the percentage of patients with
  an abnormal hormonal stimulation test and a
  normal pancreatogram ranged from 3 to 20.
• Niederau C, Scand J Gastroenterol 1984
  19161.Braganza JM, Gastroenterology 1982
  821341. Girdwood AH, Dig Dis Sci 1984 29721.
  Malfertheiner P, Hepatogastroenterology 1986
  33110.
• Lankisch PG, Pancreas 1996 12149.
• Bozkurt T, Gut 1994 351132.

11
Do We Need Direct tests??

• Follow up of patients whose diagnosis was based
  solely on an abnormal hormonal stimulation test,
  found chronic pancreatitis developing on
  follow-up in 90.
• Lankisch PG, Pancreas 1996 12149.
• Lambiase L, Gastroenterology 1993 104A315.
• In patients with moderate or severe histological
  changes of chronic pancreatitis, the sensitivity
  of hormonal stimulation testing was 79. In this
  same group of patients, the sensitivity of
  pancreatography was 66.
• Hayakawa T, Am J Gastroenterol 1992 871170.

12
Do We Need Direct tests??

• Limitations not standardised,
• The normal ranges for the test need to be
  established at each center performing the test.
• Test is available if at all only at a very few
  referral centers
• Secretin, is not easily available.
• Expensive, and time consuming.
• False-positive test results have been reported in
  patients with diabetes, Billroth II gastrectomy,
  celiac sprue, cirrhosis, and those recovering
  from an attack of acute pancreatitis.
• This test is most useful in patients with
  presumed chronic pancreatitis without easily
  identifiable structural and functional
  abnormalities on more widely available imaging
  tests.

13
Function Testing In Diagnosing CP

• Abnormal function test results alone are not
  diagnostic of CP
• Mayo Clinic Scoring System
• Layer P. Gastroenterology 1994107 14811487.
• Luneburg Clinic criteria
• Lankish PG. Surg Clin North Am 199979815827.
• An abnormal secretin test does meet diagnostic
  criteria for CP in the Japan Pancreas Society
  criteria
• Homma T. Pancreas 199715 1415
• In each of these diagnostic systems, CP is
  diagnosed by a single diagnostic imaging study
  (e.g., histology, typical CT scan, ERCP, or
  ultrasound identifying calcifications).

Babak Etemad. GASTROENTEROLOGY 2001120682707
14
Classification Of CP

• "Big-duct" disease (No role of lab tests in
  diagnosis)
• Dilation of PD visible on ultrasound, CT, or ERP
• Functional abnormalities
• Often due to alcohol abuse
• Therapy focus decompress dilated PD.
• Small-duct" disease (No role of indirect tests)
• Normal or near-normal US, CT, or ERP.
• Exocrine or endocrine insufficiency uncommon.
• More frequently idiopathic,
• Therapy focus medical rather than surgical or
  endoscopic attempts to decompress the pancreatic
  duct.

15
2. Can Lab tests help differentiate CP from
cancer ?
16
Can Lab tests help differentiate CP from cancer ?

• Several tumor markers such as
• Peanut agglutinin, pancreatic oncofetal antigen,
  DU-PAN-2, carcinoembryonic antigen, alpha
  -fetoprotein, CA-50, SPan-1, and tissue
  polypeptide antigen. (Cigarette smoking, DDT
  exposure)
• Only one has practical utility CA 19-9.
• Unsuitable for screening
• Valuable adjunct in the diagnosis, prognosis, and
  monitoring of pancreatic cancer.
• In the presence of jaundice, and especially with
  cholangitis, very high values can be found in the
  absence of malignancy (false-positive results).
• In addition, patients with a Lewis blood group
  phenotype (-a,-b) do not express the CA 19-9
  antigen.
• In a recent study, using a cutoff of 37 U/mL,
  sensitivity and specificity were 86 and 87,
  respectively.

17
3. What is the list and cost of suggested tests ?
18
SuggestedDiagnostic Strategy
Suspected CP
Plain abdominal radiography (Rs 100/-),
Abdominal ultrasonography (Rs 250/-), Serum
Trypsin (Rs 6400).
No Diagnosis
Diagnosis
CT Scan (Rs 2000/-)
Diagnosis
No Diagnosis
Direct Function Tests (?)
No Diagnosis
Diagnosis
ERCP (Rs 2500/-)
No further tests for diagnosis.
No Diagnosis
Diagnosis
Stool fat by Sudan III staining (Rs 350/-) Blood
Sugar (F PP Rs 120/-) CA 19,9 (Rs 850/-)
Follow Up MRCP, EUS Value unknown (Rs 4000/- each)
If available
19
Conclusions

• Large number of pancreatic function tests are
  available.
• In choosing a diagnostic test for CP, physician
  must consider sensitivity, specificity, accuracy
  as well as cost, risk, and availability.
• the accuracy of the diagnostic tests depends on
  the stage and etiology of the disease.
• A typical clinical presentation and pancreatic
  calcification on plain X-ray / US scan may be
  enough to make diagnosis in many cases of CCPT
  and CAP.
• Inexpensive and risk free tests are sufficient
  for advanced disease (plain abdominal
  radiography, serum trypsin, fecal fat, fecal
  elastase, or serum glucose).
• In early cases, one may need tests that are more
  sensitive but expensive (CT, ERCP, EUS, MRCP),
  risky (ERCP), or not widely available (direct
  pancreatic function tests).

20
Do We Need Direct tests??

• Follow up of patients whose diagnosis was based
  solely on an abnormal hormonal stimulation test,
  found chronic pancreatitis developing on
  follow-up in 90.
• Lankisch PG, Pancreas 1996 12149.
• Lambiase L, Gastroenterology 1993 104A315.
• May identify a small group of patients with CP
  who have functional abnormalities of stimulated
  secretion but who do not (yet) have structural
  abnormalities identifiable on ERCP.
• Conversely, most of these studies also document
  patients with a normal direct test and an
  abnormal pancreatogram.
• This group of patients is generally less common,
  averaging less than 10 in several studies.
• Long-term follow-up in a small group of these
  patients noted chronic pancreatitis developing in
  0 to 26.
• These studies point out that when the two tests
  disagree, hormonal stimulation testing appears to
  be somewhat more sensitive and specific than
  pancreatography.

21
Which Laboratory Test to Use?

• Large number and variety of tests for CP
  Selection depends on
• the clinical question
• the characteristics of the test.
• and availability of the test
• Malabsorption occurs only when functional
  capacity is reduced to 5 to 10 of normal.
• most function tests will be positive only in
  far-advanced disease and are less accurate in
  early chronic pancreatitis.
• DiMagno EP, N Engl J Med 1973 288813.

22
Routine Laboratory Tests

• Hyperglycemia is seen when diabetes develops in
  advanced chronic pancreatitis.
• Rarely used as a diagnostic test
• Diabetes is a common disease, can coexist!

23
Variations

• Collection of secretin-stimulated pancreatic
  secretions at the time of ERP by placement of a
  catheter in the pancreatic duct (the so-called
  intraductal secretin test)
• Not standardized and does not appear to be as
  accurate as standard direct pancreatic function
  testing.
• Gastroenterologic Endoscopy, Sivak MV (ed) 2nd
  ed. Philadelphia, WB Saunders, 2000, p 1116.

24
Fecal Fat

• A 72-hour collection of stool while the patient
  is consuming a 100 g/day fat diet provides the
  best evidence of fat maldigestion. 7 or less of
  ingested fat appears in the stool.
• The semi-qualitative analysis of fecal fat can
  also be performed with a Sudan III stain of a
  random specimen of stool.
• More than six globules per high-power field is
  considered to be positive but, again, the patient
  must be ingesting adequate fat to allow
  measurable steatorrhea.
• Sudan III staining of stool is positive only in
  patients with substantial steatorrhea.
• Measurement of fecal fat is not useful in the
  diagnosis of mild or moderate disease. And the
  test is not specific for pancreatic disease.

25
Chymotrypsin or Elastase-1 in Stool

• Fecal chymotrypsin is abnormal in most patients
  with chronic pancreatitis and steatorrhea.
• False-positive tests have been reported in other
  malabsorptive conditions (sprue, Crohn's
  disease), in diarrheal diseases when the stool is
  diluted, and in severe malnutrition.
• The test is normal in the absence of steatorrhea,
  so the test is positive only in advanced chronic
  pancreatitis.
• Fecal elastase has advantages over fecal
  chymotrypsin in that it is very stable in passage
  through stool and easy to measure.
• the test accurate in the presence of steatorrhea
  but inaccurate in less advanced chronic
  pancreatitis.
• the test may be falsely abnormal in other
  diseases causing steatorrhea, such as short bowel
  syndrome or small bowel bacterial overgrowth.

26
Bentiromide Test

• The synthetic peptide NBT-PABA is specifically
  cleaved by the pancreatic endopeptidase,
  chymotrypsin, to NBT and PABA.
• PABA is absorbed in the intestine, conjugated in
  the liver, and excreted in the urine. It can be
  measured in either the serum or the urine.
• Limitations
• In patients with severe pancreatic insufficiency
  and malabsorption, the sensitivity is 80 to 90
  In mild to moderate impairment, sensitivity is
  low 40.
• Administering free PABA on a separate day or
  giving14C-PABA or paraminosalicylic acid
  simultaneously with NBT-PABA may identify
  patients with abnormal NBT-PABA test result
  caused by mucosal disease of the small bowel.
• Erroneous reults in
• Prior gastric surgery, small bowel disease, liver
  disease, renal insufficiency, the use of certain
  drugs (acetaminophen, benzocaine,
  chloramphenicol, lidocaine, phenacetin, procaine,
  sulfonamide, sulfonylurea, and thiazides), and
  after certain foods (prunes and cranberries)

27
Fluorescein Dilaurate (Pancreolauryl) Test

• Fluorescein dilaurate is given in the middle of a
  breakfast meal. It is an ester, poorly soluble in
  water, that is hydrolyzed by carboxylesterase
  into lauric acid and free water-soluble
  fluorescein.
• The fluorescein is readily absorbed into the
  intestine, partly conjugated in the liver, and
  excreted in the urine.
• Urine is collected for 10 hours after breakfast,
  and the fluorescein excreted in the urine is
  measured.
• Pancreolauryl test is highly sensitive and
  specific for advanced pancreatic disease and less
  so for mild and moderate disease.

28
Serum trypsinogen (trypsin)

• Very low levels of serum trypsinogen (lt20 ng/mL)
  are reasonably specific for chronic pancreatitis,
  but levels this low are seen only in advanced
  chronic pancreatitis with steatorrhea.
• is inexpensive, widely available, and risk-free,
  although it is accurate only in long-standing and
  far-advanced chronic pancreatitis.
• not decreased in patients with other forms of
  steatorrhea, but low levels of serum trypsinogen
  may be seen in patients with pancreatic ductal
  obstruction, including malignant obstruction.

29
Other Tests

• Include
• triglyceride and cholesteryl breath tests
• H2 and CO2 breath tests
• the dual label Schilling test
• plasma measurements of pancreatic polypeptide and
  amino acids.
• None of these tests have been shown to have
  increased sensitivity over the indirect tubeless
  tests described previously.
• Many of these tests require radioactive isotopes
  or expensive equipment making their utility less
  desirable.