and Ian A. D. Bouchier2
(1)
Bishop Auckland, UK
(2)
Edinburgh, Midlothian, UK
The investigation of pancreatic disease remains problematical and unsatisfactory despite the introduction of a host of techniques. The use of MRCP, EUS, ultrasonography or CT to define the anatomy of the gland, coupled with one of the tests of exocrine secretion is probably the most satisfactory method of assessment. Estimation of steatorrhoea, glucose tolerance and serum amylase can provide valuable additional information. These tests are required to determine whether pancreatic disease is present and, if so, its nature. The differentiation of chronic pancreatitis from pancreatic cancer is an important though often unresolved question. The laboratory diagnosis of pancreatic disease can be quite simple in the presence of jaundice, glycosuria or steatorrhoea; it is when the only symptom is abdominal pain that the diagnosis frequently proves extremely difficult.
11.1 Ultrasonography
Procedures are operator dependent, but the test is non-invasive and in experienced hands the results are accurate.
Portable real-time apparatus is available for use at the bedside. High resolution real-time ultrasonography is currently the optimal method. Fasting patients are examined in three main positions: prone, lateral decubitus, and supine. This permits full visualization of the whole pancreas. Effervescent preparations are sometimes required to fill the stomach with gas and enhance contrast. A complete record with serial transverse and sagittal sections takes about 1 h to complete. The simultaneous use of ultrasonic scanning permits fine-needle aspiration of pancreatic lesions for cytological examination. The best results may be obtained by US-guided percutaneous biopsy using the automatic firing 18 gauge needle (Biopty gun).
11.1.1 Endosonography (EUS)
This is promoted as the ideal approach to US appraisal of the pancreas. It permits fine needle aspiration biopsy, but the equipment is expensive, the procedure requires much expertise, and it is not widely available at present.
11.1.2 Interpretation
Normal pancreas reflects few echoes, and interference from other structures, gaseous distention and obesity, can be a problem. The gland may be difficult to locate because of its small size and variable position. It can be identified in about 80% of individuals.
11.1.2.1 Acute Pancreatitis
The thickness of the pancreas increases to about twice normal and the parenchymal echoes lessen or disappear. More importantly the development of abscesses and pseudocysts can be readily detected in acute pancreatitis, and their progress followed by serial scans. The pancreatic scan is abnormal in 58% of patients with acute pancreatitis, and in as many as 92% whose symptoms and signs suggest a pseudocyst, when ultrasonography is the best method for diagnosis.
11.1.2.2 Chronic Pancreatitis
The gland often but not always enlarges, and irregular areas of high and low echoes are characteristic. Calcification gives scattered foci of dense echoes, and this can be detected in about one-third of patients. Positive scans are more often found during clinical relapse. Pancreatic duct abnormalities associated with chronic pancreatitis may be detectable: an increase in calibre up to 2 cm can be found. Although a diagnostic accuracy of 65–94% can be achieved in chronic pancreatitis, the method is not entirely foolproof because carcinoma of the pancreas may cause similar changes.
11.1.2.3 Pancreatic Carcinoma
This can be recognized in about 85% of patients as a well-defined tumour with few internal echoes. Growths >12 mm should be detected, but there is often associated enlargement of the gland or chronic pancreatitis which makes interpretation more difficult. It is easier to diagnose tumours in the body and tail than in the head of the pancreas. Hepatic metastases can be detected in most cases where they are present.
11.1.2.4 Obstructive Jaundice
Ultrasonography should detect dilated extrahepatic ducts in 95% of cases, and when the cause lies in the pancreas its nature can be defined in the vast majority of patients.
11.1.3 Indications
- 1.
First investigation when chronic disease of the pancreas is suspected.
- 2.
First investigation for cholestatic jaundice (in association with hepatobiliary scans).
- 3.
Diagnosis of pancreatic pseudocysts and abscesses.
- 4.
Diagnosis and monitoring acute pancreatitis.
- 5.
Guiding percutaneous pancreatic biopsy.
Magnetic resonance and computed tomography are definitely superior to external ultrasound for non-invasive investigation of morphology, and if freely available should always be considered in case of difficulty.
11.2 Endoscopic Retrograde Cholangiopancreatography (ERCP)
The method is described in Chap. 2. Depending upon the circumstances an attempt may be made to outline only the pancreatic duct, or the biliary system as well. It is generally reserved for cases where therapeutic procedures are planned.
11.2.1 Interpretation
Provision of clinical information improves the diagnostic accuracy of pancreatogram reporting, and should always be fully supplied.
11.2.1.1 Normal
The pancreas has a duct which passed obliquely cranially from the ampulla and then is roughly transverse. The diameter decreases smoothly and maximal figures are 6.5 mm in the head to 3 mm in the tail. The side ducts are variably filled. There is a wide variation in ductal anatomy. In addition the examination is complicated by, and may be unsatisfactory in, the annular or malfused pancreas. In elderly patients the duct system may widen up to 10 mm, and ductular ectasia and narrowing can occur without defmite pathological significance.
11.2.1.2 Chronic Pancreatitis
The main duct becomes dilated and tortuous. It may show strictures or contain filling defects. The earliest changes occur in the duct branches, which show variation in calibre and frank dilation, but these are difficult to detect. In advanced and calculous pancreatitis there may be complete obstruction to the proximal flow of contrast. Pancreatic fistulas can sometimes be seen. ERCP in acute pancreatitis will usually demonstrate a pseudocyst when it occurs, but needs to be done cautiously. The main reason for ERCP in this circumstance is identification and treatment of choledocholithiasis.
11.2.1.3 Carcinoma
Abnormalities of the duct system such as obstruction or stenosis occur in 65–80% of patients and the diagnostic rate is highest in the group amenable to surgical removal. The collection of pure pancreatic juice for cytology at the time of ERCP improves the diagnostic rate to 92%.
11.2.2 Indications
- 1.
Evaluation of chronic and acute relapsing pancreatitis, especially detection of pancreatic ductal abnormalities or biliary calculi requiring surgical treatment.
- 2.
Differential diagnosis of chronic pancreatitis and carcinoma.
- 3.
Collection of pure pancreatic juice.
- 4.
Extraction of bile duct stones.
- 5.
Positioning of biliary and pancreatic stents.
11.3 Magnetic Resonance Cholangiopancreatography (MRCP)
This is the best standard method for imaging the pancreas and bile ducts, generally with gadolinium enhancement. It is preferable to ERCP as the initial procedure. Magnetic resonance uses a very strong magnetic field and pulses of radiowaves to obtain 3D pictures without ionising radiation. Atoms, especially hydrogen in water and fat, absorb and emit radiofrequency energy. Variable pulses create interpretable patterns detected by antennae.
This is particularly useful in the biliary and pancreatic systems, with T2 weighting of images.
11.4 Computed Tomography (CT)
This technique allows a clear transverse sectional picture of the body by transmitting a series of X-rays at different angles. The beam is received by scintillation or ionization detectors instead of film, and the result displayed as an undistorted two-dimensional picture. Although no preparation is essential a low residue diet may help to eliminate gas, and administration of propantheline IM or glucagon IV reduce bowel motility artefacts. Dilute oral barium or iodine contrast media and IV iodine contrast media may help to delineate adjacent bowel and blood vessels respectively. Obesity may actually improve results by provision of greater tissue contrast.
CT scanning can diagnose some pancreatic lesions missed by US. The main indication is probably the investigation of patients in whom other tests have failed to provide a diagnosis, unless the procedure is readily available. Serial CT scanning is especially useful in acute pancreatitis.
11.5 Angiography
Super-selective angiography or phlebography can be useful ancillary investigations.
11.5.1 Interpretation
11.5.1.1 Acute Pancreatitis
Arteries are displaced with moderate dilation and irregularity of the major vessels. There is increased vascularity, but with no alteration in capillary or venous circulation. If a pseudocyst develops the vessels become sparse and are stretched.
11.5.1.2 Chronic Pancreatitis
Deformity and stenosis of the surrounding vessels with tortuosity and beading of the intrapancreatic vessels is characteristic.
11.5.1.3 Tumours
Irregular, narrowed and infiltrated vessels are seen. Carcinomas are often poorly vascularised. Angiography can be used to size tumours >1–2 cm in diameter and to assess operability. Endocrine tumours such as insulinomas are often hypervascular with a fine anastomotic pattern. They can be detected if >1 cm in diameter, but unfortunately these tumours are usually rather small.
11.6 Other Radiology
11.6.1 Chest X-Ray
This is helpful in the diagnosis of fibrocystic disease of the pancreas when there is evidence of chronic chest infection In acute pancreatitis basal atelectasis or a pleural effusion (often left-sided) may be present.
11.6.2 Straight Abdominal Radiograph
The plain radiograph of the abdomen is helpful in acute pancreatitis. An isolated distended loop of jejunum in the upper abdomen, the ‘sentinel loop’, may be demonstrated, or there may be absence of gas in the transverse colon, the ‘colon cut-off’ sign. The pancreas may be seen to be calcified and stones may be present in the duct. There may be diffuse abdominal calcification following the fat necrosis that occurs in acute pancreatic inflammation.
11.6.3 Barium Meal
Helpful signs of pancreatic disease are pressure deformities and displacement of the stomach and duodenum. Expanding pancreatic lesions enlarge the retrogastric space and deform the posterior wall of the stomach. The indentation is smooth in the case of pseudo- cysts of the pancreas. In cancer the enlargement is usually slight and any infiltration of the stomach results in a rigid appearance. Changes in the gastric antrum are also seen. The duodenum may be enlarged and there may be depression of the ligament of Treitz. Pressure on the medial wall of the duodenum will give the inverted-3 sign of Frostberg which is an indication of a pancreatic mass, but does not differentiate cancer from inflammation. Pressure on the lateral aspect of the duodenum with rigidity and compression may occur in pancreatic cancer.
Barium studies are seldom used to diagnose suspected pancreatic disease.
11.7 Laparoscopy (Peritoneoscopy)
With the advent of laparoscopic surgery, there is a wealth of experience in flexible laparoscopy among gastrointestinal surgeons, whose help should normally be enlisted for this investigation.
The procedure procedure for rigid laparoscopy is described in Chap. 16. An infragastric method has been devised for diagnosis and staging pancreatic cancer. Direct visualization permits biopsy or aspiration for cytology and avoids the hazards of laparotomy.
11.8 Histology and Cytology
Guided biopsy with an automatically fired needle is a technique which yields tissue samples, and histology is definitely better than cytology where it is possible. Material for cytology may be obtained by several other methods:
- 1.
aspiration of the pancreas by direct puncture at laparotomy or laparoscopy using a standard 21-gauge needle;
- 2.
a guided percutaneous puncture with a Chiba needle;
- 3.
collection of pancreatic juice during ERCP or duodenal intubation for the testing of pancreatic function.
- 4.
fine needle aspiration during EUS
At least four smears are made onto slides, which are fixed at once in 95% alcohol and stained by the Papanicolou method. Positive results are obtained in at least 75% of pancreatic cancer patients while false-positive results are rare.
11.9 Hormonal Tests of Pancreatic Exorine Function
The pancreatic exocrine sections after pancreatic stimulation can be assessed directly by duodenal drainage. Secretin stimulates the output of fluid and bicarbonate by the gland and cholecystokinin-pancreozymin (CCK-PZ) stimulates the output of enzymes. A variety of function tests has evolved using one or both hormones in different doses. The normal values of a particular laboratory depend upon the procedure used and the methods for determining the enzymes in the duodenal juice. Anyone of a number of variations on the basic test is satisfactory provided the laboratory consistently uses the same method, and establishes the range of normality. Completeness of collection of duodenal juice is important. This may cause problems after gastric surgery, where only a normal result is absolutely conclusive.
The many different methods which are used to stimulate pancreatic exocrine function make the comparison of pancreatic function tests difficult. It is debatable whether pancreozymin increases the diagnostic accuracy of secretin tests, and its use is associated with a significant number of reactions.
On the other hand enzyme analysis is definitely meaningful after pancreozymin and many investigators find alterations in the enzyme output of the gland to be a sensitive test of pancreatic inflammatory disease. Multiple enzyme determinations are necessary for routine clinical use. Trypsin is usually measured nowadays, but either amylase or lipase assays are also satisfactory.
Although time-consuming and relatively unpleasant for the patient, a test of pancreatic exocrine secretion is probably the most sensitive index currently available for pancreatic function.
11.9.1 Secretin Test
11.9.1.1 Method
The patient fasts overnight. A double-lumen gastroduodenal tube is passed and positioned fluoroscopically so that the tip lies in the third part of the duodenum. Alternatively, two separate nasogastric tubes can be passed, one being positioned with the tip at the third part of the duodenum and the other sited in the gastric antrum. The patient lies tilted to the left side with the head and shoulders supported by a pillow. Continuous suction is applied to both tubes at a subatmospheric pressure of 5–10 mmHg, and this is interrupted by frequent manual aspirations to ensure patency of the tubes. The patient is not required to expectorate. The gastric aspirate is discarded. The aim is to collect duodenal samples uncontaminated by gastric secretions.
A basal collection of duodenal material is made for 10–30 min during which time the pH must be >7.5. This is followed by the IV injection over 2 min of 1.0 unit secretin/kg body weight in 10–20 ml of normal saline. Following the secretin stimulus the duodenum is aspirated continually for 60 min. The colour and pH of the gastric and duodenal aspirates are checked frequently to ensure an uncontaminated collection. The duodenal aspirate is collected into iced containers. The volume of the duodenal aspirate is recorded. An aliquot of the pooled collected provides a satisfactory measure of pancreatic function for clinical purposes. A variation of the method is to collect and assay timed samples of the duodenal aspirates. The sample for estimation is well mixed with an equal volume of glycerol to increase enzyme stability and analysed for bicarbonate and enzyme concentration. Amylase is often measured, but a variety of other pancreatic enzymes have been studied and in general give comparable results to amylase. However, amylase is an unreliable measure of pancreatic function in infants, where trypsin provides a better index. Biliary pigment output may be recorded as + to ++++ but is of little clinical value. A search can be made for malignant cells using the cytological methods described.
11.9.1.2 Interpretation
Normal
In adults the average volume is 3.2 ml/kg body weight with a lower limit of 2.0 ml/kg. The average bicarbonate concentration is 108 mEq/1 with a lower limit of 90 mEq/l. The average amylase concentration is 14.2 units/kg body weight with a lower limit of 6.0 units/kg body weight, but results vary depending upon the method used for amylase estimation. Amylase values for infants are slightly lower than the adult range. In adults neither age nor sex influences the output of bicarbonate.
Acute pancreatitis
The secretin test is potentially hazardous and thus of little practical value.
Chronic pancreatitis
There is a reduction in the output of bicarbonate, and values as low as 30 mEq/l are recorded. The volume is usually normal but may also be reduced.
Cancer of the pancreas
In cancer involving the head and body of the gland there is a reduction in the volume of pancreatic secretion with normal bicarbonate concentration. In diffuse involvement of the gland by malignant growth there is often a reduction in total bicarbonate output. In cancer of the tail, function is usually normal.
Haemochromatosis
It is claimed that in haemochromatosis there is a high volume flow (10–20 ml/kg body weight) with a low bicarbonate.
Diabetes mellitus
Although there is some controversy the evidence suggests that in idiopathic diabetes mellitus exocrine pancreatic function may be reduced. Some studies on patients with idiopathic diabetes have revealed a number with associated chronic pancreatitis and pancreatic cancer.
Other diseases
Disturbed pancreatic function has been recorded in patients with coeliac disease, ulcerative colitis and amyotrophic lateral sclerosis. A high volume of pancreatic flow has been recorded in 50–70% of cirrhotic patients and about 40% have reduced concentrations of bicarbonate and enzymes. Alcoholic liver disease may, of course, be associated with alcoholic pancreatitis. Heavy cigarette smoking (20+ per day) will reduce pancreatic secretion. Neither the use of CCK/PZ together with secretin, nor the further estimation of enzyme output have clearly been shown to improve the diagnostic accuracy of the secretin test.
11.9.2 Augmented Secretin Test
11.9.2.1 Method
An IV infusion of 2 units secretin/kg body weight is given at a rate of 1 unit/kg/min. The duodenum is aspirated for 1 h and the volume and bicarbonate output are measured.
11.9.2.2 Interpretation
Normal subjects have a mean volume of 2.7 ml/kg body weight with a lower limit of 1.8 ml/kg body weight. The normal mean bicarbonate concentration is 78 mEq/1 with a lower limit of 54 mEq/1. In chronic pancreatitis the mean volume is 1.7 ml/kg body weight and the mean bicarbonate concentration is 25 mEq/l. In cancer of the pancreas the mean volume output is 1.1 ml/kg body weight and the mean bicarbonate output is 36 mEq/1. This test is claimed to be the most reliable not only in distinguishing normals from patients with pancreatic disease but also in the differentiation of chronic pancreatitis from cancer. The accuracy of the test is increased by relating the volume output to the body weight.
11.9.2.3 Continuous High-Dose Infusion of Secretin
The maximum response of the pancreas to the intravenous infusion of secretin is reached at rates of 4–6 units/min. The continuous infusion of secretin in this dose for 2 h has been suggested as a test of pancreatic exocrine function.
11.10 Test Meals: The LUNDH Test
Attempts have been made to measure the secretion of pancreatic enzymes in response to various test meals. The test described by Lundh is the most widely used.
11.10.1 Method
After an overnight fast the patient swallows a tube which is screened into position so that the tip lies between the ampulla of Vater and the duodenojejunal flexure. Duodenal juice is drained by siphonage into a container which is kept on ice. The drainage is maintained by intermittent gentle suction. Once the tube is in the required position a resting sample of duodenal juice is obtained. This is followed by the administration of the test meal comprising 18 g corn or soya bean oil, 15 g Casilan (protein),40 g glucose and a flavouring agent, made up to 300 ml with warm water. After ingestion of the meal the duodenum is drained over 2 h, the samples being pooled into four collections, each of 30 min. They should be collected in containers immersed in ice and may be kept for delayed analysis by addition of an equal volume of glycerol and stored in a freezer. The pH, volume and trypsin content of the samples are measured. The four samples can be analysed separately but are more conveniently pooled and the tryptic activity expressed as the mean tryptic activity of the aspirate.
Tryptic activity is measured by a variety of methods. There is a simple method in which a measurement is made of the rate at which H+ ions are liberated by the hydrolysis of a specific substrate N-benzoyl-L-arginine ethylester hydrochloride. This is achieved by measuring the time taken to neutralize a known amount of alkali. The results are expressed in international units (mEq H+ min/ml). A sample kit is available which is based on this method (BoehringerMannheim). Radioimmunoassay kits have also been employed for analyses of both duodenal and serum trypsin.
11.10.2 Interpretation
The normal mean 2-h tryptic activity is 15.4 iu with a range of 11–20 iu.
In pancreatic inflammatory disease associated with steatorrhoea the mean tryptic activity is usually <2 iu. In those patients in whom pancreatic inflammatory disease presents mainly as abdominal pain the values of tryptic activity are usually below the normal range. Low values are found in pancreatic cancer but equally low values may occur in biliary obstruction from other causes. The values are reduced for non-pancreatic causes of steatorrhoea, but they are not as low as in pancreatogenous steatorrhoea. Normal values are found in liver disease. Using a more complex method for estimating tryptic activity, Lundh found the normal range to be 161–612 μg trypsin/ml with a mean of 310 μg trypsin/ml. Markedly depressed values were found in chronic pancreatitis and cancer of the pancreas.
11.10.3 Indications
This test is recommended because it is simple to perform and entails little discomfort for the patient. It gives reproducible results and has proved to be a reliable method in the diagnosis of chronic pancreatitis, particularly when steatorrhoea is present. It is also helpful in the diagnosis of ampullary cancer with or without jaundice. It is of little value in the retrospective diagnosis of acute pancreatitis. However, it may be less reliable than the augmented secretin test in discriminating between the normal and abnormal pancreas.
11.10.4 Modifications
- 1.
Zieve et al. introduced a meal containing 14 g corn oil, 15 g dextrose, 12 g skimmed milk powder, 218 ml skimmed milk and 8 g chocolate syrup. The volume of the meal is about 250 ml. It is introduced down the polyvinyl tube into the duodenum and aspiration of the duodenal contents is undertaken for 2 h.
- 2.
Pure pancreatic juice may also be collected by cannulation of the pancreatic duct and IV injection of 1 unit/kg secretin. Unfortunately results of the analysis of the fluid collected via ERCP are no more accurate or informative than analysis of the duodenal aspirate.
The lactoferrin levels in patients with chronic pancreatitis are much higher than normal controls or patients with pancreatic cancer. In addition, trypsin concentrations are uniformly low in pancreatic cancer (up to 12 μg/ml) though variable in chronic pancreatitis. The combination of tests is a very reliable method of separating cancer from chronic pancreatitis.
- 3.
A modification of this method is the ratio of lactoferrin: total protein in pancreatic juice. In chronic pancreatitis this ratio is >0.5%, whereas in controls including normals individuals, acute pancreatitis and carcinoma of the pancreas the ratio is <0.03%.
11.11 Tubeless Oral Pancreatic Function Tests (Fig. 11.1)
The goal of satisfactory tests of pancreatic secretion without the requirement for the need for intubation or handling stools has been reached. Methods are based on the pancreatic enzyme activity on bentiromide, fluorescein dilaurate and triolein. None of these tests diagnose or exclude pancreatic carcinoma.
Fig. 11.1
Fluorescein dilaurate test of pancreatic function
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