PATHOLOGY 2B PANCREAS ROBERTO D. PADUA JR.,MD,DPSP DEPARTMENT OF PATHOLOGY FATIMA COLLEGE OF MEDICINE
Organ Considerations Greek pankreas means “all flesh” Endocrine and exocrine functions 90 grams in men; 85 grams in women Has 3 parts = head, body, and tail Duct of Wirsung = main pancreatic duct that drains into the duodenum at the papilla of Vater
Duct of Santorini = accessory pancreatic duct that drains into the duodenum through a separate minor papilla
Organ Considerations Embryologically arises from the fusion of dorsal and ventral outpouchings of the foregut Constitutes 80-85% of the pancreas Produce digestive enzymes Composed of islets of Langerhans that constitutes only 1-2% of the pancreas
Secretes insulin, glucagon, and somatostatin
Normal pancreatic anatomy
Congenital Anomalies Total absence of the pancreas Rare; associated with widespread severe malformation
Homozygous mutations in the IPF1 gene on chromosome 13q12.1
Congenital Anomalies Most common congenital anomaly Failure of the fetal duct systems of the dorsal and ventral pancreatic primordia to fuse
Predisposes to development of chronic pancreatitis
Congenital Anomalies Ventral primordium of the pancreas fails to rotate properly Congenital abnormalities of the GIT can be seen Down syndrome is a predisposing condition Encirclement of the duodenum by pancreatic parenchyma constriction of the duodenal lumen Contains large number of PP cells in its many irregularly shaped islets
Presents with duodenal obstruction
Congenital Anomalies Most common in the duodenum (2 nd portion) Seen in the stomach, jejunum, ileum, Meckel’s diverticulum, gastric and intestinal diverticula, GB and bile ducts, large bowel, spleen, omentum, abdominal wall Grossly, resembles normal pancreas firm, yellow, lobulated nodules measuring up to 4 cm, sharply circumscribed from the surrounding tissues Central umbilication is present corresponding to the central duct that opens into the lumen (important diagnostic sign)
Microscopically, acinar and ductal tissues are always present; islet tissue is found only in 1/3 of cases
Acute Pancreatitis Group of reversible lesions characterized by inflammation of the pancreas ranging in severity from edema and fat necrosis to parenchymal necrosis with severe hemorrhage Incidence rate : 10-20 cases/100,000 (Western) Approximately 80% of cases = biliary tract disease or alcoholism Gallstones present in 35-60% of cases of acute pancreatits Severe alcoholoc intake = 65% in the US
Idiopathic = 10-20% of cases
Acute Pancreatitis Cationic Trypsinogen (PRSS1) > point mutation with G to A transitions resulting in an arginine (R) to histidine (H) substitution ( called R122H)
> affects a site on the cationic trypsinogen molecule essential for the cleavage (inactivation) of trypsin by trypsin itself resistant inactivation abnormally active trypsin activates other digestive proenzymes pancreatitis
Acute Pancreatitis Cationic Trypsinogen (PRSS1) > hereditary pancreatitis > autosomal dominant disease with > recurrent attacks of severe
pancreatitis usually beginning in
Acute Pancreatitis 2. Serine Protease Inhibitor, Kazal Type 1 (SPINK1) > the gene codes for a pancreatic trypsin inhibitor
> mutations in the SPINK1 gene pancreatitis
Acute Pancreatitis Gross changes vary from a swollen and edematous well-preserved organ to a hemorrhagic and necrotic mass of tissue Pancreatic substance exhibits areas of red-black hemorrhage interspersed with foci of yellow-white, chalky fat necrosis
Foci of fat necrosis may also be found in the extrapancreatic fat depots, (omentum, mesentery, subcutis)
Acute Pancreatitis Peritoneal cavity contains serous, slightly turbid, brown-tinged fluid in which globules of fat can be identified
Extensive parenchymal necrosis accompanied by diffuse hemorrhage within the substance of the gland
Acute Pancreatitis Ranges from trivial inflammation and edema to severe extensive necrosis and hemorrhage Microvascular leakage causing edema Necrosis of fat by lipolytic enzymes An acute inflammatory reaction Proteolytic destruction of pancreatic parenchyma
Destruction of blood vessels with subsequent interstitial hemorrhage
Acute Pancreatitis Acute interstitial pancreatitis Morphologic changes limited to interstitial edema and focal areas of fat necrosis in the pancreatic substance and peripancreatic fat Acute necrotizing pancreatitis Pancreatic tissue necrosis affects acinar and ductal tissues as well as the islets of Langerhans
Hemorrhage results from damage to the vasculature
Earlier changes are represented by acinar cell homogenization, ductal dilatation with epithelial degeneration, diffuse interstitial edema, leukocytic infiltration, and fibroblastic reaction extensive necrosis and hemorrhage of pancreatic tissue
Acute Pancreatitis Anatomic changes strongly suggest autodigestion of the pancreatic substance by inappropriately activated pancreatic enzymes
Activation of trypsin is an important triggering event in acute pancreatitis
Trypsin Trypsinogen Activate other proenzymes Phospholipase Proelastase Disintegration of fat cells Damage elastic fibers of b.v. Acute Pancreatitis Prekallikrein Kallikrein Kinin system Hageman factor Clotting system Complement system Inflammation Small vessel thromboses
Acute Pancreatitis The manner by which alcohol causes pancreatitis is unknown Transient increases in pancreatic exocrine secretion Contraction of the Sphincter of Oddi Direct toxic effects on acinar cells Many authorities think that most cases of alcoholic pancreatitis are sudden exacerbations of chronic pancreatitis, presenting as apparent de novo acute pancreatitis
Chronic alcohol ingestion causes secretion of protein-rich pancreatic fluid deposition of inspissated protein plugs and obstruction of small pancreatic ducts
Acute Pancreatitis Cardinal manifestation = abdominal pain Pain is constant and intense and is often referred to the upper back Full-blown acute pancreatitis is a medical emergency of the first magnitude Symptoms are due to release of toxic enzymes, cytokines, and other mediators with explosive activation of the systemic inflammatory response leukocytosis, hemolysis, DIC, fluid sequestration, ARDS, and diffuse fat necrosis
Peripheral vascular collapse and shock with acute renal tubular necrosis may occur
Acute Pancreatitis Pancreatic necrotic foci can undergo secondary infection infected pancreatic necrosis Currently regarded as the most common, most severe, and most lethal of the infectious complications Occurs in 40-60% of patients with acute necrotizing pancreatitis Usually involves Gram-negative organisms from the alimentary tract
can evolve into a chronic form
Acute Pancreatitis Serum amylase level elevation in the first 24 hours Elevation of serum lipase within 72 to 96 hours Glycosuria occurs in 10% of cases Elevated serum C-reactive protein is a reliable marker for the presence of pancreatic necrosis Hypocalcemia – a poor prognostic sign
results from precipitation of calcium soaps in the fat necrosis
Acute Pancreatitis “ Resting” the pancreas by total restriction of food and fluids and by supportive therapy Medical (4-6 hrs) deteriorate emergency laparotomy Others : emergency endoscopic retrograde cholangiopancreatography with or w/o endoscopic papillotomy
Presence of an upper abdominal mass suspected of being pseudocyst and persistent rising jaundice are indications for surgical intervention
SEQUELAE OF ACUTE PANCREATITIS
Chronic Pancreatitis Characterized by inflammation of the pancreas with destruction of exocrine parenchyma, fibrosis, and, in the late stages, the destruction of endocrine parenchyma
Irreversible impairment of pancreatic function
Chronic Pancreatitis Long-standing obstruction of the pancreatic duct Attributed to malnutrition Mutations in the PRSS1 and SPINK1 genes Idiopathic chronic pancreatitis
Mutations in cystic fibrosis transmembrane conductance regulator ( CFTR ) gene
Chronic Pancreatitis Etiologic factors (Rosai and Ackerman, 9 th ed) Obstruction of the ductal system by carcinoma or stones Chronic alcoholism most common
Secondary extension of sclerosing cholangitis
Chronic Pancreatitis Pathogenesis – Hypotheses Ductal obstruction by concretions Alcohol increase protein concentrations in the pancreatic juice ductal plugs obstruct the pancreatic ducts
Toxins including alcohol and its metabolites can exert toxic effect on acinar cells accumulation of lipids in acinar cells acinar cell loss parenchymal fibrosis
Chronic Pancreatitis Pathogenesis – Hypotheses Alcohol-induced oxidative stress generate free radicals in acinar cells membrane lipid oxidation and activation of transcription factors (AP1 and NF κβ ) expression of chemokines attracts mononuclear cells
Promotes fusion of lysosomes and zymogen granules, acinar cell necrosis, inflammation, and fibrosis
Chronic Pancreatitis Pathogenesis – Hypotheses Acute pancreatitis perilobular fibrosis, duct distortion, and altered pancreatic secretions over time and with multiple episodes loss of pancreatic parenchyma and fibrosis
*** Chemokines have been identified in chronic pancreatitis (IL-8, MCP-1) plus TGF- β , PDGF induce the activation and proliferation of periacinar myofibroblasts (pancreatic stellate cells) deposition of collagen fibrosis
Visible calcified concretions
Chronic Pancreatitis Reduced number and size of acini with relative sparing of the islets of Langerhans Variable dilation of the pancreatic ducts Chronic inflammatory infiltrate around lobules and ducts Interlobular and intralobar ducts are dilated with protein plugs in their lumens Ductal epithelium is atrophied or hyperplastic or may show squamous metaplasia
Ductal concretions may be evident
Chronic Pancreatitis S/Sx varies = recurrent attacks of abdominal pain/back pain May be entirely silent until pancreatic insufficiency or DM develops Attacks are precipitated by alcohol abuse, overeating, or the use of opiates and other drugs that increase the tone of the sphincter of Oddi
Diagnosis requires a high degree of suspicion
Chronic Pancreatitis Attack of abdominal pain mild fever and mild to moderate elevation of serum amylase (absent with destruction of acinar cells) Gallstone-induced obstruction Elevation of alkaline phosphatase CT and UTS – visualize calcification
Weight loss and hypoalbuminemic edema from malabsorption caused by exocrine pancreatic insufficiency
Chronic Pancreatitis Acinar necrosis and acute inflammation are seen more often in patients with persistent pain than in those who are free of pain Pancreatic duct drainage (through pancreacojejunostomy or endoscopic removal of ductal stones) Partial pancreatic resection
Near-total pancreatectomy with or without islet autotransplantation
Chronic Pancreatitis Not an immediately life-threatening condition, long term outlook is poor 20-25 year mortality rate of 50%
Hereditary pancreatitis – 40% lifetime risk of developing pancreatic cancer; unclear for other forms
SEQUELAE OF CHRONIC PANCREATITIS
Pancreatic Transplantation Insulin-resistant diabetes mellitus
At present, pancreatic graft survival rates approach 90% at 1 year
Abscess Most often seen as complications of acute pancreatitis
Characterized by the presence of pus and the microbiologic identification of bacteria in over 90% of cases
Non-Neoplastic Cysts Result from anomalous development of the pancreatic ducts May be associated with polycystic disease and von Hippel-Lindau disease Range from microscopic lesions to 3-5 cm in diameter Lined by a glistening duct type cuboidal epithelium or by a completely attenuated cell layer
enclosed in a thin fibrous capsule filled with clear to turbid mucoid or serous fluid
Non-Neoplastic Cysts Related to pancreatitis, trauma, and rarely, to neoplastic obstruction of large ducts They can become very large, and spread beyond the substance of the pancreas Lack of epithelial lining Wall is thick and irregular
Intraluminal content is cloudy or bloody
Non-Neoplastic Cysts Complications = perforation and hemorrhage (splenic artery) Small pseudocysts located in the body or tail of the pancreas = excision External drainage (preferred for the infected cysts) Contraindicated if the cysts connect with the ductal system Transgastric cystgastrostomy
Cystojenunostomy to a Roux-en-Y loop of jejunum
Cystic Neoplasms Only 5-15% of pancreatic cysts are neoplastic 5% of all pancreatic neoplasms
Can be benign, borderline malignant, or malignant
Cystic Neoplasms Benign cystic neoplasms consists of glycogen-rich low-cuboidal cells surrounding small cysts Contains clear, thin, straw-colored fluid Account for about 25% of all cystic neoplasms of the pancreas Occurs twice in women than in men; 7 th decade of life Non-specific S/Sx like abdominal pain or palpable abdominal mass
Treatment : surgical resection
Cystic Neoplasms Mucinous cystic neoplasms Almost always arise in women Can be benign, borderline malignant, or malignant Arises in the body or tail Present as painless, slow-growing masses Cysts are lined by columnar mucinous epithelium containing thick, tenacious mucin Diagnosis is only done after removal
Treatment is distal pancreatectomy
Cystic Neoplasms Intraductal papillary mucinous neoplasms ( IPMNs ) Produce cysts containing mucin Can be benign, borderline malignant, or malignant Occurs more frequently in men Involve the head of the pancreas more often than the tail Lack the dense “ovarian” stroma
Arise in the main pancreatic ducts
Cystic Neoplasms Solid-pseudopapillary tumor Seen mainly in adolescent girls and young women Large, well-circumscribed masses with solid and cystic areas Cystic areas are filled with hemorrhagic debris and neoplastic cells grow in solid sheets or as papillary projections Can present with abdominal discomfort because of their large size Alteration of the β -catenin/adenomatous polyposis coli genetic pathway
Treatment : surgical resection
Pancreatic Carcinoma 85% of all cases of pancreatic malignancy 4 th most common cause of death from cancer (US) Incidence is increasing, particularly in women Risk factors : B-naphthylamine or benzidine exposure, cigarette smoking, diet rich in fats, chronic pancreatitis, and DM 10% show familial aggregation consistent with genetic susceptibility
Most patients are elderly (60-80 y/o), with slight male preponderance (1.6:1 ratio)
Pancreatic Carcinoma Diagnosis is made when tumor becomes relatively large (about 5 cm) and has extended beyond the pancreas (85% of cases) Carcinomas of the body and tail grow insidiously and often have already metastasized at the time of diagnosis Associated with peripheral venous thrombi in 25% of patients Diagnosis : CT-scan, MRI, celiac angiography, UTZ, ERCP, seleno-methionine scan, duodenal aspirate, serum test
Tumor markers : SPan1 and CA19-9 antigen
Pancreatic Carcinoma Precursors to Pancreatic Cancer Lesions are called “pancreatic intraepithelial neoplasias” (PaINs) Supported by the following observations The distribution parallels that of invasive cancer Often found in pancreatic parenchyma adjacent to infiltrating carcinomas Patients with PaINs later developed an invasive pancreatic cancer The genetic alterations identified in PaINs are similar to those present in invasive cancers
The epithelial cells in PaINs show dramatic telomere shortening predispose these lesions to accumulate progressive chromosomal abnormalities and to develop invasive carcinoma
Pancreatic Carcinoma K-RAS gene is the most commonly altered oncogene
Activated by point mutation impair GTPase activity of K-ras gene active protein Ras activates several intracellular transduction pathways activation of transcription factors fos and jun
Pancreatic Carcinoma p16 gene (chromosome 9p) is the most frequently inactivated tumor suppressor gene in pancreatic cancer Inactivated in 95% of cases p16 plays a critical role in the control of the cell cycle Inactivation of the p53 tumor suppressor gene (chromosome 17p) seen in 50-70% of pancreatic Ca
Gene product is nuclear DNA-binding protein that acts both as a cell cycle checkpoint and as inducer of cell death (apoptosis)
Pancreatic Carcinoma Tumor suppressor gene (chromosome 18q) is inactivated in 55% of pancreatic cancers Also known as DPC4 , codes for protein that plays an important role in signal transduction from the TGF- β family of cell surface receptors
Normal function of this gene is to suppress growth and promote apoptosis
Inactivated tumor suppressor genes
Pancreatic Carcinoma Methylation abnormalities Hypermethylation of the promoter of a number of suppressor genes is associated with transcriptional silencing of the genes Identified a number of genes that are highly overexpressed in pancreatic cancers
Potential targets for therapeutics and may form the basis for future screening tests
Pancreatic Carcinoma Location : head of the pancreas (60%), body (15%) or tail (5%) Multiple tumors are found in 20% of cases Majority are ductal adenocarcinomas Poorly delineated and firm, with a yellow cut-surface May undergo massive cystic degeneration Duodenal wall is invaded by direct extension in tumors involving the head of the pancreas causing obstruction of the distal CBD
Involved pancreatic ducts are dilated and plugged with necrotic tumor
A cross-section through the head of the pancreas and adjacent CBD showing both an ill-defined mass in the pancreatic substance and the green discoloration of the duct resulting from total obstruction to bile flow.
Pancreatic Carcinoma Graded as well-differentiated, moderately differentiated, and poorly differentiated LPO = glands are well formed, have a large lumen, and are lined by one or few layers of cylindrical or cuboidal epithelium Their overall LPO appearanace may be be particularly suggestive of carcinoma except for the irregularities in the shape and distribution of the glands and the peculiar concentric desmoplastic stroma that surrounds them
Perineural invasion – 90% of cases
Poorly formed glands are present in densely fibrotic stroma within the pancreatic substance with presence of some inflammatory cells.
Pancreatic Carcinoma Histochemical and Immunohistochemical features Positive for mucin stains Consistent reactivity for keratins and EMA Glycoprotein MUC1 is expressed in over 60% of conventional invasive ductal carcinoma
Others : CEA, CA19-9, B72.3, DUPAN-2, YPan-1, SPan-1, Tn and sialosyl-Tn antigens, DF3
Pancreatic Carcinoma Tends to metastasize to multiple LN located around the organ Most commonly involved the LN around the common hepatic artery, hepatoduodenal ligament, posterior pancreaticoduodenal, around the superior mesenteric artery, para-aortic, and anterior pancreatico-duodenal
Microscopic metastasis were found in T1 and T2 lesions
Pancreatic Carcinoma Most common sites of distant metastasis are liver, peritoneum, lung, adrenal, bone, distant LN groups, skin, and CNS
Supraclavicular LN metastasis is sometimes the first manifestation of pancreatic carcinoma
Pancreatic Carcinoma Overall 5-year survival rate = 4% or less with over 90% of patients dying within 1 year of diagnosis Mean survival of 3 months for untreated patients
Even if the tumor is confined at the pancreas at the time of diagnosis, the 5-year survival rate does not exceed 15%
Pancreatic Carcinoma Tumor stage – most important prognostic indicator Microscopic grade – well-differentiated tumor have longer survival rate Tumor size - <4.5 cm have better chance of curative operation
Blood vessel invasion and retroperitoneal margin of resection – decreased survival
TGF-B1 expression – associated with well-differentiated tumor
American Joint Committee for Cancer Staging for Carcinoma of the Pancreas TNM classification criteria T1 No direct extension of the primary beyond the pancreas T2 Limited direct extension to the duodenum, bile duct, or stomach T3 Advanced direct extension incompatible with surgical resection TX Direct extension not assessed N0 Regional nodes not involved N1 Regional nodes involved NX Regional LN not assessed
American Joint Committee for Cancer Staging for Carcinoma of the Pancreas TNM classification criteria M0 No distant metastasis M1 Distant metastasis present MX Distant metastasis not assessed TNM Stages Stage I T1-2, N0, M0 Stage II T3, N0, M0 Stage III T1-T3, N1, M0 Stage IV Any T or N, M1
Pancreatoblastoma Most common form of pancreatic neoplasia in childhood, but can also occur in adults Reported in patients with Beckwith-Wiedemann syndrome and familial adenomatous polyposis of the colon Bimodal age distribution = mean of 2.4 and 33 years
Mean tumor size is 10 cm and partial encapsulation is the rule
Pancreatoblastoma Very cellular tumors, made up of uniform epithelial cells arranged in solid sheets and nests, admixed with well-formed acinar structures and occasional ductular formations “ Squamoid corpuscles” are a constant and characteristic finding Positivity for pancreatic enzymes, endocrine markers, and CEA
Alpha-fetoprotein may be produced by the tumor
Treatment : Surgical resection
ENDOCRINE PANCREAS ROBERTO D. PADUA JR.,MD,DPSP DEPARTMENT OF PATHOLOGY FATIMA COLLEGE OF MEDICINE
Endocrine Pancreas Consists of about 1 million microscopic clusters of cells, the islets of Langerhans Aggregate weight of 1-1.5 grams Β eta cells – 68%; insulin Alpha cells – 20%; glucagon Delta cells – 10%; somatostatin
PP cells – 2%; pancreatic polypeptide that exerts its effect on the GIT stimulation of secretion of gastric and intestinal enzymes and inhibition of intestinal motility
Endocrine Pancreas D1 cells – elaborates VIP, a hormone that induces glycogenolysis and hyperglycemia; stimulates gastrointestinal fluid secretion and causes secretory diarrhea
Enterochromaffin cells – synthesize serotonin and are sources of pancreatic tumors that cause the carcinoid syndrome
Diabetes Mellitus A group of metabolic disorder sharing the common underlying feature of hyperglycemia Hyperglycemia results from defects in insulin secretion, insulin action, or both
Causes multi-organ damage affecting the kidneys, eyes, nerves, and blood vesels
Carbohydrate Metabolism Carbohydrates broken down by salivary, gastric & intestinal (pancreatic) enzymes into simple sugars G G G G G
absorbed by the intestines ( α -glucosidase) into the bloodstream
What is glucose? Glucose is an essential nutrient that provides energy for the proper functioning of the body cells. MAN needs glucose to work CAR needs fuel to move FUEL
Blood Glycogenolysis (-) GLUCAGON (+) INSULIN Fed State Pyruvate/Lactate Amino acids Glycerol / FFA Glycogenesis X X *All cells
Blood Glycogenolysis (+) GLUCAGON (-) INSULIN Postabsorptive / Fasting State Pyruvate/Lactate Amino acids Glycerol / FFA Glycogenesis *6-8hrs after a meal First 24-48hrs Preferentially used by brain, & other non-insulin dependent tissues X
Blood Glycogenolysis (+) GLUCAGON EPINEPHRINE CORTISOL GROWTH HORMONE (-) INSULIN Postabsorptive / Fasting State Glycogenesis After 48hrs of fast Lipolysis Proteolysis Ketogenesis Ketones for brain Pyruvate/Lactate Amino acids Glycerol / FFA
Insulin 4 major cell types in the islets of Islets of Langerhans
F (or PP) cell pancreatic polypeptide.
Initially synthesized as preproinsulin
INSULIN BIOSYNTHESIS Enzymatic cleavage produces
“ secreted in equal amounts”
INSULIN BIOSYNTHESIS Less susceptible to hepatic degradation
marker of insulin secretion
INSULIN BIOSYNTHESIS A chain of 21 amino acids B chain of 30 amino acids
chains held together by two disulfide
Classification of Glucose Transport According to Their Tissue Distribution and Functional Regulation Glucose Organ Transporter HK Coupler Classification Brain GLUT 1 HK-I Insulin independent Erythrocyte GLUT 1 HK-I Insulin independent Adipocyte GLUT 4 HK-II Insulin dependent Muscle GLUT 4 HK-II Insulin dependent Liver GLUT 2 HK-IVL Glucose sensor GK -cell GLUT 2 HK-IVB Glucose sensor (Glucokinase) Gut GLUT 3-symporter - Sodium dependent Kidney GLUT 3-symporter - Sodium dependent
INSULIN SECRETION by beta cells GLUT-2 Voltage-gated Ca ++ channel K + ATP Ca ++ III. Increased ATP closes K-channels resulting in membrane depolarization I. blood glucose high, taken up by B cells via GLUT2 II. Metabolism of glucose generates ATP V. Rise in calcium promotes margination, fusion with membrane, and release of insulin & c-peptide cell (-) SUR G Glucose-6-P Kreb’s cycle (glycolysis) ATP production
IV. Membrane depolarization opens Ca-channel with influx of calcium
PHYSIOLOGIC INSULIN SECRETION 7:00am 7:00pm noon midnight 7:00am prandial insulin secretion, (spikes in response to food) Polonsky. N Engl J Med. 1996;334:777-783 Pancreas secretes approximately 40-50 units of insulin per day Breakfast Lunch Breakfast
Continuous basal insulin secretion (unstimulated) 50%
Meal-stimulated Biphasic Insulin Secretion releases preformed insulin - occurs after 10 minutes - continues as long as an hour
release of preformed insulin, newly synthesized insulin
Early Insulin Secretion Helps Control Post-meal Glucose Levels & DM
Immediate Tissue Membrane transport of glucose Muscle, adipose, liver Intermediate Carbohydrate metabolism Glycogen synthesis Muscle, liver Glycogenolysis Muscle, Liver Gluconeogenesis Liver Lipid metabolism Lipogenesis Liver, adipose Lipolysis Adipose Cholesterol synthesis Liver Ketogenesis Liver Protein metabolism Protein synthesis Liver, muscle, adipose INSULIN ACTION
catabolized primarily in the liver and kidney INSULIN CATABOLISM
insulin-specific protease (insulinase)
Cell = Powerplant Keyhole = Insulin Receptor G G G G G G G Key = Insulin Glucose
Keyhole = Insulin Receptor G G G G G Key = Insulin CELL = POWERPLANT
G G G G G CELL = POWERPLANT Energy G G G G G G
DIABETES Greek MELLITUS Latin Sweet as honey To pass water like a siphon
G G G G G Type 1 DM insulin (key) absent G G G G G Type 2 DM defective insulin receptor (keyhole) with insufficient insulin Insufficient production of insulin or the inability of cells to use insulin (insulin resistance). What causes it?
“ Sweet Urine” Diabetes Mellitus group of metabolic disorders characterized by high blood sugar levels Hyperglycemia can lead to spillage of glucose into the urine (> 180 renal threshold)
Diabetes Mellitus Metabolic abnormality involving protein, fat and carbohydrate processing
Leading to multi-organs complications
SYMPTOMS OF DIABETES Polyuria Polydipsia Polyphagia
SYMPTOMS OF DIABETES Poor Wound Healing Weight Loss Weakness and Fatigue Blurring of Vision
SYMPTOMS OF DIABETES Many have no symptoms. They are noted to have high blood sugar on testing.
RISK FACTORS FOR DIABETES Heredity Old Age Obesity Mothers of large babies
Criteria for diagnosis of DM ADA 2004 Note: criteria should be confirmed by repeat testing on a different day.
CRITERIA FOR DIAGNOSIS OF DIABETES MELLITUS “ prediabetics” – risk for developing type 2 DM (40% risk over 5yrs) & CV disease Level of glycemia at which diabetic chronic complications occur American Diabetes Association 8 hr Fasting Blood Sugar 2 hours after 75g glucose (OGTT) NORMAL < 100 mg/dL < 140 mg/dL IMPAIRED FASTING GLYCEMIA (IFG) 100 and < 126 mg/dL --- IMPAIRED GLUCOSE TOLERANCE (IGT) --- 140 and < 200 mg/dL DIABETES MELLITUS 126 mg/dL 200 mg/dL Symptoms of diabetes and Random Blood Sugar of 200 mg/dL
Etiology of DM Insulin action defect (insulin resistance/ receptor defect)
Excess counter-regulatory hormones (glucagon, catecholamines, cortisol, growth hormone)
Etiologic Classification of DM exocrine I. II. III. IV. Based on pathologic process that leads to hyperglycemia
Etiologic Classification of DM Previous terms: juvenile-onset DM, IDDM absolute insulin deficiency due to autoimmune beta cell destruction Triggered by infectious or environmental stimulus Pathology: “insulitis” pancreas infiltrated by lymphocytes Major susceptibility gene: HLA on chrom6 TYPE IA : presence of immunologic markers (islet cell autoAbs, anti-GAD, anti-insulin abs) I. II. III. IV.
TYPE IB : idiopathic, immunologic markers absent
Diabetes Mellitus Type 1 Mechanisms of B-cell dysfunction T lymphocytes react against B-cell antigens and cause cell damage Locally produced cytokines damage β cells
Autoantibodies against islet cells and insulin are also detected in the blood of 70-80% of patients
Etiologic Classification of DM I. II. III. IV. Genetic predisposition Immunologic trigger No DM with DM Beta cell mass (%) 100 50 20 0 Time (years) Overt DM
Etiologic Classification of DM I. II. III. IV. Previous names: NIDDM, adult-onset DM
Visceral Obesity common (contributes to insulin resistance)
Three Pathophysiologic Mechanisms of Type 2 Diabetes Glucose (G) Insulin (I) I I I I I I I G G G G G G G G I G G G I G Fasting hyperglycemia Postprandial hyperglycemia Carbohydrate Impaired insulin secretion Excessive fatty acid release Reduced peripheral glucose Uptake and usage Excess liver glucose output (gluconeogenesis) Resistance to the action of insulin
Natural history of type 2 diabetes: a progressive disease Post-prandial glucose Abnormal glucose tolerance Insulin resistance Increased insulin resistance Fasting glucose Hyperglycemia Insulin secretion Hyperinsulinemia, then -cell failure Adapted from International Diabetes Center (IDC), Minneapolis, Minnesota. Normal IGT Type 2 diabetes
Diabetes Mellitus Type 2 Inability to adapt to the long-term demands of peripheral insulin resistance and increased insulin secretion Loss of normal pulsatile, oscillating pattern of insulin secretion and attenuation of the first phase of insulin secretion triggered by elevation in plasma glucose
Reflected by a decrease in β -cell mass, islet degeneration, and deposition of islet amyloid (amylin)
Etiologic Classification of DM MODY (Maturity-onset diabetes of the young) primary defect in β -cell function that occurs without β -cell loss, affecting either β -cell mass and/or insulin production single gene mutation (monogenic) islet cell transcription factor (HNF)
Lack of islet cell autoantibodies and insulin resistance syndrome
Etiologic Classification of DM Mutation in insulin receptor leading to severe insulin resistance Type A insulin resistance Rabson-Mendenhall syndrome
Defects in proinsulin conversion
Etiologic Classification of DM exocrine >80% of pancreas destroyed
Etiologic Classification of DM Acromegaly (growth hormone) Cushing’s syndrome (cortisol)
Etiologic Classification of DM
Etiologic Classification of DM
Autoimmune beta cell destruction
Etiologic Classification of DM Genetic syndromes associated with diabetes
Etiologic Classification of DM usually reverts to normal 30-60% risk of developing 50g OGCT (glucose challenge test) - measure plasma glucose 1hr after Threshold: ≥ 130-140mg/dL IV.
Dx criteria: ≥95mg/dl fasting
1 . > 45 yrs, if normal, repeat at 3-year intervals 2. Check at a younger age: - have a first-degree relative with diabetes - high-risk ethnic population (e.g., African- American, Hispanic American, Native American, Asian-American, Pacific Islander) - have delivered a baby > 9 lb - have been diagnosed with GDM - hypertensive ( > 140/90) - have HDL < 35 mg/dl and/or triglyceride > 150 mg/dl Recommendations for DM Testing (ADA 2004)
- cardiovascular, cerebrovascular diseases
Glycemic goals 1 American Diabetes Association. Diabetes Care 2004; 27:S15–S35. 2 American Diabetes Association. Diabetes Care 2002; 25:S35–S49. 3 American Association of Clinical Endocrinologists. Endocrine Pract 2002; 8 (Suppl. 1):40–82. 4 European Diabetes Policy Group. Diabet Med 1999; 16:716–730. Fasting/pre-prandial plasma glucose < 140 < 180 Postprandial plasma glucose < 110 90–130 Biochemical index AACE 3 ADA 1,2 mg/dl mmol/l mg/dl mmol/l 5.0–7.2 < 10.0 < 6.5 < 7 HbA 1c (%) < 6.0 < 7.8
HBA1c Excess blood sugar non-enzymatically binds to portion of Hgb (irreversible) A1C levels provide a 2- to 3-month index of glycemic control Assess overall blood glucose control 1. Pickup JC. In: Pickup JC, Williams G, eds. Textbook of Diabetes . 3rd ed. Boston, Mass: Blackwell Science; 2003. 2. Clark N. In: Leahy JL, Cefalu WT, eds. Insulin Therapy . New York, NY: Marcel Dekker, Inc.; 2002. 3. Cefalu WT. In: Leahy JL, Cefalu WT, eds. Insulin Therapy . New York, NY: Marcel Dekker, Inc.; 2002.
Albumin Fructosamine (1-2 weeks)
It cannot be cured. But it can be controlled by keeping blood sugar level within normal range. Diabetes Mellitus
Why do I need to control Diabetes?
COMPLICATIONS OF UNCONTROLLED DIABETES
Morphology of Diabetes Reduction in the number and size of islets Leukocytic infiltration of the islets (insulitis) β -cell degranulation by EM Subtle reduction in islet cell mass – DM 2 Amyloid replacement of islets – DM 2
Islet cell hyperplasia in newborns of diabetic mothers
MACROVASCULAR COMPLICATIONS Diabetics are prone to have high bad cholesterol. When cholesterol is too high, the walls of large blood vessels become narrowed, even clogged. This problem is called accelerated atherosclerosis.
Hallmark of diabetic macrovascular disease
Narrowed and clogged blood vessels decrease blood flow to all parts of your body especially the heart and brain. This can lead to heart attack and stroke. MACROVASCULAR COMPLICATIONS
MI is the most common cause of death in diabetics
Gangrene of the lower extremities result of advanced vascular disease 100X more common in diabetics MACROVASCULAR COMPLICATIONS
vascular lesion associated with hypertension
Longstanding high blood sugar also damages the small blood vessels supplying the eyes (retinopathy), kidneys (nephropathy), and nerves (neuropathy) MICROVASCULAR COMPLICATIONS
Erectile difficulty and impotence may happen due to damage to nerves going to the sexual organ.
Normal retina Diabetic retinopathy Preproliferative Proliferative Vitreous Hemorrhage BLINDNESS
Diabetic Neuropathy Peripheral Neuropathy Autonomic Neuropathy Erectile difficulty Constipation
Diabetic Nephropathy Renal failure is 2 nd only to MI as a cause of death Three lesions encountered renal vascular lesions – arteriosclerosis
pyelonephritis and necrotizing papillitis
Diabetic Nephropathy Capillary basement membrane thickening Occur throughout their entire length Detected by EM within a few years of onset Diffuse mesangial sclerosis Diffuse increase in mesangial matrix and is always associated with basement membrane thickening Seen in most patients with disease of >10years Manifest with nephrotic syndrome proteinuria, hypoalbuminemia, edema
Diabetic Nephropathy Nodular glomerulosclerosis Kimmeltiel-Wilson lesion -- ball-like deposits of a laminated matrix situated in the periphery of the glomerulus PAS positive containing trapped mesangial cells Seen in 15-30% of long-term diabetics
Major cause of morbidity and mortality
Diabetic Nephropathy Renal atherosclerosis and arteriosclerosis
Hyaline arteriosclerosis affects both the afferent and efferent arterioles
POORLY-CONTROLLED DIABETICS are … 2-4 times more prone to HEART DISEASE 25 times more prone to BLINDNESS 90 times more prone to NEUROPATHY 5 times more prone to GANGRENE
17 times more prone to KIDNEY DISEASE
HOW DO I PREVENT COMPLICATIONS?
Checking Your Blood Sugar
Why do I need to check my blood sugar? Checking your blood sugar with a meter helps see how food, physical activity and medicines affect blood sugar level. The readings can help you manage diabetes day by day.
Keep a record of the test results to review with your doctor.
What is a good self-testing blood glucose goal? Your doctor will set the appropriate goal for you. The self-testing blood glucose goals for most people with diabetes are as follows: Premeals 80-120mg/dL At bedtime 100-140mg/dL
Guarding Your Heart
Guarding the Heart Keep blood pressure under 130 / 80 Keep blood sugar controlled Keep cholesterol controlled LDL (bad cholesterol) < 100mg/dL HDL (good cholesterol) > 40 (men) > 50 (women) Exercise. Lose weight if needed.
Take an aspirin once a day.
Guarding Your Kidneys
Guarding the Kidneys Keep blood pressure under 130 / 80 Keep blood sugar well-controlled Avoid dehydration. If there's vomiting or diarrhea, consult your doctor. Do not self-medicate especially with If you have proteinuria, see a dietitian
for individualized meal planning.
Guarding the Kidneys See a doctor for bladder or kidney infections. You may have an infection if you have: pain or burning when you urinate frequent urge to go to the bathroom urine looks cloudy or reddish
back pain or on the side below the ribs
Caring for Your Eyes
PROPER EYE CARE Good blood sugar control.
Visit your eye doctor at least once a year.
Caring for Your SKIN
Use talcum powder in areas where skin touches skin, such as armpits and groin.
Skin care Use an oil-in-water skin cream or lotion. Moisturizing soaps may help.
Don't take bubble baths if your skin is dry.
Skin care Moisturize your skin to prevent chapping, especially in cold or windy weather. See a dermatologist about skin problems you are not able to solve yourself.
Do not scratch dry or itchy skin.
Skin care Wash minor cuts with soap and water. Use an antibiotic cream or ointment if your doctor says it's okay. Cover minor cuts with sterile gauze. See a doctor right away if you get a major cut, burn, or infection.
Do not use Mercurochrome antiseptic, alcohol, or iodine to clean skin because they are too harsh .
Caring for Your FEET
Footcare Wash your feet in lukewarm, NOT HOT , Dry your feet well especially between the toes. Wash your feet everyday
Talcum powder may be used in between the toes.
Check your feet everyday Check for cuts, sores, red spots, swelling, and If you have trouble bending over, a mirror Footcare
may be used or ask a family member to
Keep your skin soft and smooth Footcare Rub a thin coat of lotion or cream over the top and bottom of your feet.
Do not put lotion between your toes.
Trim toenails each weekend and when needed Footcare Trim the toenails straight across and smooth them with an emery board or nail file. Do not cut into the corners or rip off hangnails.
Do not scrape calluses with blades.
Wear shoes and socks at all times Wear shoes that fit well and protect your feet. Footcare Check the insides of the shoes before putting them on. Do not wear tight socks, rubber bands, or garters around your legs.
Do not wear restrictive or ill-fitting shoes.
Protect your feet from hot and cold Wear shoes at the beach or on hot pavement. Footcare If your feet are cold, wear seamless socks at night.
Do not put hot water bottle or heating pad on your feet.
Do not wade in floodwaters without boots Footcare
Put feet up when you are sitting. Wiggle toes for 5 min, 2-3 x a day. Footcare Keep blood flowing to your feet Move ankles up, down and sideways to improve blood flow. DO NOT cross your legs for long periods of time.
DO NOT smoke. Smoking reduces blood flow to your feet.
Caring for Your TEETH
Caring for Your TEETH A film of bacteria, saliva and food particles (dental plaque) constantly forms on the teeth. Bacteria feed on sugars and starches in foods and produce acids that damage teeth enamel.
Caring for Your TEETH High blood sugar gives bacteria more food supply producing more acid, damaging the enamel leading to tooth decay.
Caring for Your TEETH If plaques are not removed with brushing and flossing, it hardens under the gumline into “tartar”. Tartar irritates the gums causing gum inflammation (gingivitis).
Brush your teeth at least twice a day especially after each meal and snack. Use soft-bristled brush. Floss daily . Caring for Your TEETH
See your dentist at least 2x a year. Consult your diabetes doctor prior to any dental extraction. Caring for Your TEETH
LIVING WITH DIABETES EDUCATION DIET EXERCISE MEDICINES
BALANCED DIET Benefits
BALANCED DIET wellnessbread.com Eat more of the foods at the bottom. Eat less of the foods at the top.
BALANCED DIET Eat your meals and snacks at about the same times each day. Do not skip meals or snacks. Take your medicines at about the same times each day. How can I keep my blood glucose at a healthy level? National Diabetes Information Clearinghouse (NIDDK, NIH)
Exercise at about the same times each day.
Eat more of whole grain breads and cereals, vegetables and fruits. Use table salt and sugar in moderation. Eat fewer fried and high-fat foods such as potato chips, french fries or biscuits. Trim off extra fat from pork and beef. Eat chicken without the skin. Healthy Eating National Diabetes Information Clearinghouse (NIDDK, NIH)
Limit alcoholic drinks to one or two a day.
EXERCISE Lowers blood glucose levels Benefits
Promotes healthier heart & circulation
AEROBIC EXERCISES exercise the cardiovascular system
(heart, lungs, circulation)
EXERCISE 20 to 30 minutes workout 4 to 5 times a week Start slowly and increase gradually Warm up and cool down for at least 5 to 10 minutes before and after workout. How Often?
Include stretching exercises.
Talk with your doctor about exercise especially if you have eye, nerve, or vascular complications. Some exercises may not be appropriate for you. Exercise every day at about the same time. Exercise soon after eating, when blood glucose levels are highest. Carry simple sugars with you. Wear well-fitting shoes and socks. Exercise Dos
Exercise with a friend if possible.
Diabetes Pills Insulin Medicines
DIABETES PILLS Diabetes pills are not insulin.
Instead, they help lower blood sugar in other ways.
DIABETES PILLS Diabetes pills work in one of three ways: stimulate the pancreas to release more insulin sulfonylureas meglitinides increase the body's sensitivity to insulin metformin thiazolidinediones slow breakdown of starches into glucose
DIABETES PILLS - stimulate the pancreas to release more insulin - generally taken one to two times daily before meals Glibenclamide / Glyburide (Euglucon, Glynorm)
Gliclazide (Diamicron, Glubitor)
DIABETES PILLS - stimulate the pancreas to release more insulin
- taken before each of three meals
DIABETES PILLS - increase the body's sensitivity to insulin decrease glucose made by the liver
Metformin (Glumet, I-max, Humamet)
DIABETES PILLS It can make you sick if you drink more than about 2 to 4 alcoholic drinks a week. nausea, diarrhea, and other stomach symptoms. These usually go away.
metallic taste in the mouth
DIABETES PILLS - increase the body's sensitivity to insulin
- taken once or twice daily with food
Nausea, vomiting and other stomach symptoms.
DIABETES PILLS Alpha-glucosidase inhibitors - slow breakdown of starches into glucose - should be taken with first bite of each meal
Acarbose (Glucobay, Gluconase)
DIABETES PILLS Alpha-glucosidase Inhibitors
stomach problems (gas, bloating, and diarrhea) that most often go away after taking the medicine for awhile
INSULIN If your pancreas no longer makes enough insulin, you need to take insulin. You inject the insulin just under the skin with a small, short needle.
TYPES OF INSULIN
Hyperglycemia and Hypoglycemia “ When controlling diabetes, blood sugar may become too high or too low. This should be taken seriously.”
Hyperglycemia Hyper (Latin) – more Glycemia (Latin) – sugar in blood +
Hyperglycemia: Causes If not treated, can lead to Coma & Death.
Hyperglycemia: Signs and Symptoms
Hyperglycemia: What to do?
Hypoglycemia Hypo (Latin) – low Glycemia (Latin) – sugar in blood +
Hypoglycemia: Causes delaying or skipping a meal eating too little food at a meal getting more exercise than usual taking too much diabetes medicine
Drinking excessive amount of alcohol
B LOOD G L U C O S E mg/dL Hypoglycemia: Symptoms & Signs LETHARGY COMA CONVULSIONS Sweating Tremor Palpitations Irritablity PERMANENT DAMAGE DEATH HEADACHE 90 - 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 -
Hypoglycemia: What to do? Have one of these quick-acting sugars: 1 or 2 teaspoons of sugar or honey 1/2 cup (4 oz.) of any fruit juice 1/2 cup (4 oz.) of regular soda
5 or 6 pieces of hard candy
Hypoglycemia: What to do? Take the right amount of medicine at the right time. Try to keep a regular meal schedule. Carry an ID card with your name and emergency response Carry fast-acting sugar at all times. Do not drive or operate equipment if you feel your blood sugar is low. Make sure family and friends know how to treat low blood sugar. If they find you not making sense or unconscious, they should take
you to the nearest hospital immediately.
Sick-day Guide Tell your doctor that you are sick. If you have a glucose meter, test your blood sugar every 4 hours. Write down the results of the test. Drink plenty of fluids if your blood sugar is too high. Try eating crackers or soup if you can't eat your usual food.
Drink clear liquids if you can't eat at all. You can eat or drink something with sugar in it if you have trouble keeping food down.
Sick-day Guide Call your doctor RIGHT AWAY if: your blood sugar is over 300 for two tests in a row you can't keep fluid down you feel more sleepy than usual
you have trouble breathing
Patient education is the key to success in diabetes management
Pancreatic Endocrine Neoplasms Account for 2% of all pancreatic neoplasms Occur anywhere along the length of the pancreas Propensity to elaborate pancreatic hormones
3 most distinctive clinical syndrome
Hyperinsulinism (Insulinoma) Most common of the pancreatic endocrine neoplasms Attacks of hypoglycemia occur with blood glucose levels below 50mg/dl The attacks consist principally of such CNS manifestations of confusion, stupor, and loss of consciousness
The attacks are precipitated by fasting or exercise and are promptly relieved by feeding or parenteral administration of glucose
Hyperinsulinism (Insulinoma) Generally benign (90%), solitary, arises within the pancreas Small (<2cm), encapsulated, pale to red-brown nodules Microscopically, giant islets with preservation of the regular cords of monotonous cells and their orientation to the vasculature
Immunohistochemistry, insulin positive tumor cells
Zollinger-Ellison Syndrome (Gastrinomas) Marked hypersecretion of gastrin by a gastrin-producing tumor Association of pancreatic islet cell lesion with hypersecretion of gastric acid and severe peptic ulceration (90-95% of patients) May arise in the pancreas, peripancreatic region, or the wall of the duodenum More than half are locally invasive or have already metastasized at the time of diagnosis
May be associated with MEN syndrome
Other Pancreatic Endocrine Neoplasm Alpha-cell tumors (Glucagonoma) Associated with increased serum levels of glucagon Presents with mild DM, characteristic skin rash (necrolytic migratory erythema), and anemia
Occur most frequently in pre- and postmenopausal women
Other Pancreatic Endocrine Neoplasm Delta-cells tumors (Somatostatinomas) Associated with DM, cholelithiasis, steatorrhea, and hypochlorydria Difficult to localized pre-operatively
Requires high plasma level of somatostatin for diagnosis
Other Pancreatic Endocrine Neoplasm Watery diarrhea, hypokalemia, achlorydria, or WDHA syndrome
Associated with increased release of vasoactive intestinal polypeptide (VIP) from a tumor
Other Pancreatic Endocrine Neoplasm Pancreatic carcinoid tumors
Endocrinologically asymptomatic despite the presence of high levels in plasma