Table Of ContentClinical Pathology of Pancreatic Disorders
PATHOLOGY AND LABORATORY MEDICINE
Series Editors: Stewart Sell and Alan Wu
2. Clinical Pathology of Pancreatic Disorders
edited by John A. Lott, 1997
1. Molecular Diagnostics: For the Clinical Laboratorian
edited by William B. Coleman and Gregory J. Tsongalis, 1997
PATHOLOGY AND LABORATORY MEDICINE
Clinical Pathology
of Pancreatic Disorders
Edited by
JahnA. Latt
The Ohio State University, Columbus, OH
Humana Press *- Totowa, New Jersey
ISBN-13: 978-1-4612-8443-7 e-ISBN: 978-1-4612-3964-2
DOl: 10.1007/978-1-4612-3964-2
© 1997 Humana Press Inc.
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Preface
The pancreas is about the size and shape of the hand; the tail points to the spleen, and
the head is nestled in a loop of the duodenum. Loss of the exocrine (digestive) func-
tions commonly leads to severe gastrointestinal disturbances, malabsorption, a cata-
bolic state, and weight loss in the face of an adequate diet. Loss of endocrine pancreatic
function leads to a large spectrum of disorders associated with the loss of hormone
secretions; the most common and most severe is diabetes mellitus. Loss of the entire
pancreas owing to trauma, surgery, atherosclerosis, or other medical problems leaves
the patient in a digestive and metabolic crisis.
The correct diagnosis of pancreatic disorders remains a challenge given the multi-
faceted function of the pancreas. The clinical laboratory plays an important role, and
other tools such as CAT scans, ultrasound, radiographs, biopsies, and even surgery are
used to make a diagnosis. The emphasis of Clinical Pathology ofP ancreatic Disorders
is on the clinical laboratory definition of pancreatic pathology.
Disorders of the endocrine pancreas can be highly complex, and sophisticated tests
are needed to determine the nature of the disease, its prognosis, and its optimal treat-
ment. Diabetes is the most common of the endocrine diseases; it presents in many
ways, and has varied etiologies. We now know that the diabetes of childhood is usually
an autoimmune disease, and this has a major effect on the treatment of these individuals.
The pancreas is easily inflamed in patients with chronic alcohol abuse, biliary tract
diseases, a cyst or other inflammation in the abdomen, and a host of other miscella-
neous causes including drug sensitivity. Pancreatitis can be mild and transient; severe
disease also occurs, and hemorrhagic, necrotic pancreatitis has a near 100% mortality
rate. The laboratory is important in the differential diagnosis of patients with an acute
abdomen. Patients with pancreatitis are poor surgical risks, and often the laboratory
studies can confirm the presence of pancreatitis. Chronic pancreatitis leads to loss of
gland function and structure; with new bouts of pancreatitis, the patient may show
trivial or no changes in the common laboratory tests.
Transplantation of the pancreas and simultaneous pancreas and kidney transplants
are becoming more common, particularly in patients with diabetes and end-stage kid-
ney disease. Often, euglycemia and normal kidney function can be restored by trans-
planting both organs. Many more transplants would be performed if suitable organs
were available. Rejection and infections remain as the most serious problems. The
ducting of the pancreatic juice into the urinary bladder creates problems, such as blad-
der inflammation and pain, in some patients. Nevertheless, this surgical technique is
superior to other approaches in nearly all patients.
v
Vl Preface
The exocrine disorders of the pancreas are fairly common; in children, cystic fibro-
sis usually leads to pancreatic insufficiency. In adults, repeated bouts of pancreatitis
generally lead to exocrine pancreatic dysfunction after -85% of the gland has been
replaced by nonfunctioning tissue. An amazing fact about the pancreas is the reserve
capacity for both endocrine and exocrine secretions. Extensive destruction of the pan-
creas must occur before pancreatic exocrine insufficiency is clinically evident.
Cancer of the endocrine or exocrine pancreas, particularly the latter, is usually a
disaster for the patient. Adenocarcinoma of the pancreas is often silent until far
advanced, and the prognosis is extremely poor. Death within 3--6 months after diagno-
sis is common. Early resection saves some patients, but the 5-year survival ofpancre-
atic adenocarcinoma is still dismally low. The most common endocrine cancer affects
the islet cells, and predominantly the beta cells. The laboratory's role here is pre-emi-
nent in defining the stage and severity of the disease.
John A. Lott
Contents
Preface ............................................................................................................................ v
Contributors ................................................................................................................... ix
1 Transplantation of the Pancreas or Pancreatic Islet Cells:
A Clinical Laboratory Perspective
John A. Lott .............................................................................................................. 1
2 Exocrine Disorders of the Pancreas
Frederick Van Lente ............................................................................................. 27
3 Biochemical Indicators of Acute Pancreatitis
Steven C. Kamierczak ............................................................................................ 75
4 Neoplastic Disorders of the Pancreas
Peter Muscarella II, William Fisher, Jerome A. Johnson,
and W. Scott Melvin ........................................................................................ 125
5 Biochemistry, Pathogenesis, and Laboratory Diagnosis
of Endocrine Disorders of the Pancreas
Manjula K. Gupta ................................................................................................ 163
Index ........................................................................................................................... 213
vii
Contributors
WILLIAM FISHER • Department of Surgery, The Ohio State University Medical Center,
Columbus,OH
MANJULA K. GUPTA • Department of Clinical Pathology, The Cleveland Clinic
Foundation, Cleveland, OH
JEROME A. JOHNSON • Department of Surgery, The Ohio State University Medical
Center, Columbus, OH
STEVEN C. KAMIERCZAK • Department of Pathology, East Carolina University School
ofM edicine, Greenville, NC
JOHN A. LOTT • Department ofP athology, The Ohio State University, Columbus, OH
W. SCOTT MELVIN· Department ofS urgery, The Ohio State University Medical Center,
Columbus, OH
PETER MUSCARELLA II • Department of Surgery, The Ohio State University Medical
Center, Columbus, OH
FREDERICK VAN LENTE • Department of Clinical Pathology, The Cleveland Clinic
Foundation, Cleveland, OH
ix
1
Transplantation of the Pancreas
or Pancreatic Islet Cells
A Clinical Laboratory Perspective
John A. LoU
INTRODUCTION
Loss of the exocrine and endocrine pancreatic functions leaves the patient with
serious digestive and metabolic problems. Causes of exocrine loss include cystic
fibrosis, atrophic pancreatitis, chronic pancreatitis, infarction of the pancreas, surgical
removal of the gland, atherosclerosis of the pancreas, pancreatic cysts, and other mis-
cellaneous causes. More than about 85% of the acinar cells must be lost before abnor-
malities appear, indicating that the normal pancreas has tremendous exocrine reserves.
Abdominal discomfort and abnormalities in digestion, including steatorrhea, weight
loss, constipation or diarrhea, and flatulence, are typical findings.
Loss of the endocrine functions of the pancreatic islets is much more serious and
common than loss of the exocrine function of the pancreas. Loss of the islet cells leads
to profound disturbances of carbohydrate metabolism owing to the loss of insulin,
glucagon, somatostatin, and other pancreatic hormone secretions; causes are varied
and include autoimmune phenomena, infectious disorders, chronic pancreatitis, tumors,
pancreatectomy, and others. The resulting insulin-dependent diabetes mellitus (100M)
is a disease that afflicts an estimated 300,000-500,000 people in the United States.
Although 100M is observed in adults, approx 75% of cases diagnosed each year are
individuals under 20 yr of age (1).
100M has a worldwide distribution, although its incidence varies greatly from
country to country; Finland and Greece show rates of 35.3 and 4.6/100,000 people/yr,
respectively. Oifferences in diet, hygienic practices, exposure to viruses, and genetics
may explain the different rates of development (2). Constantly normal blood glucose
concentrations, i.e., euglycemia, are impossible to maintain in patients with diabetes,
even with intense glucose monitoring and insulin therapy, and essentially all diabetics
develop secondary microaneurysms, retinopathy, nephropathy, neuropathy, and cardio-
vascular disease. An abnormally increased glycosylated hemoglobin is a common find-
ing in diabetics and is the harbinger of long-term complications. Although mortality
and complications of 100M vary by country (3), a study in Israel showed that overall
mortality rates for diabetics are nearly the same as that of the general population for
From: Clinical Pathology of Pancreatic Disorders Edited by: f. A. Lott Humana Press Inc., Totowa, NJ
1
2 Lott
the fIrst 15 yr, but by 20 yr of disease progression, the mortality rates accelerated by
a factor of four (4). Clearly, many patients with long-standing diabetes are good can-
didates for pancreas transplantation, the goal being the correction of glycemia to as
close to normal as possible. Pancreas transplantation can prevent the inevitable com-
plications of diabetes; however, existing complications cannot be reversed (5). Trans-
plantation of islet cells remains an experimental procedure. A brief review of the
pathogenesis of diabetes follows. Knowledge of the pathogenesis of IDDM leads to a
better understanding of the diagnosis and treatment with transplantation.
PATHOGENESIS OF DIABETES MELLITUS
IDDM has an autoimmune etiology in the great majority of cases (6), but the cur-
rent consensus is that it also includes a genetic and an environmental component.
The major histocompatibility complex (MHC) on chromosome 6 is the primary gene
associated with susceptibility to IDDM. This region encodes for the MHC class II
molecules; human leukocyte antigen (HLA)-DR and HLA-DQ are two of the best
studied of these. For example, the phenotypes HLA-DR3 and HLA-DR4 are strongly
associated with an increased risk of developing IDDM (7), whereas the phenotypes
HLA-DRll or HLA-DR15 correlate with a decreased risk of IDDM (8). The genetic
component is multifactoriaL The presence of predisposing phenotypes is not suffi-
cient to predict the development of IDDM; only 36% of identical twins of diabetic
patients with the same HLA haplotypes develop IDDM (9). Further, only about
10-15% of patients who develop IDDM have first-degree relatives with IDDM (10).
Pancreatic islet cell destruction appears to follow more than one immune pathway,
including destruction by cytolytic T-cells and autoantibody-mediated killing of islet
cells (11). In one proposed scenario, viral infection of the islets results in an inflam-
matory response that induces surface expression of HLA class II molecules on the
~-cells, allowing them to present cell-specific antigens to CD4+ T-lymphocytes.
Alternatively, soluble ~-cell antigens released by islet cells damaged by nonspecific
inflammatory reactions may be presented to CD4+ T-cells by professional antigen-
presenting cells located within the inflammatory milieu. Either pathway occuring in
genetically susceptible individuals who have lost tolerance to the presented self-antigens
results in the activation of CD4+ T-lymphocytes with subsequent cytokine synthesis.
Also, specifIc CD8+ cytolytic T-cells are generated that target ~-cells through their
expression of HLA class I surface molecules containing cell-specifIc peptides.
B-lymphocyte activation with maturation to plasma cells and production of auto-
antibodies to insulin, islet cells, or glutamic acid decarboxylase (GAD) may also
occur in response to CD4+ T-cell activation. Although these autoantibodies may rep-
resent a nonfunctioning epiphenomenon, they bind to ~-cells and mediate their killing
through interactions with Fc-receptors present on neutrophils, macrophages, natural
killer cells, or by complement activation. These antibodies are not found in all dia-
betics. Hence, they are not commonly used as diagnostic tools, but are currently being
examined as possible predictors of diabetes (12).
The presence of islet-cell antibodies in children without IDDM is a harbinger of
the disease. Of the three autoantibodies, GAD is the best predictor for the develop-
ment of IDDM. CD4+ T-cell-mediated immunity to GAD has a positive correlation
with the development of IDDM (13).
