Systemic Pathology PDF

0 #2 Histology of the Liver Lobules Method:  The liver is divided into Hexagonal structures, lobular architecture.  Central vein in the middle (central part of the lobule).  Central vein (tributary of hepatic vein) with blood to hepatic parenchyma flowing from the portal triads to the central vei...

0 #2 Histology of the Liver Lobules Method:  The liver is divided into Hexagonal structures, lobular architecture.  Central vein in the middle (central part of the lobule).  Central vein (tributary of hepatic vein) with blood to hepatic parenchyma flowing from the portal triads to the central veins.  Each lobule has 3 portal tracts (or triad) on the edges.  Portal triad: contain a bile duct, a small hepatic artery and a portal vein branch, surrounded by type I& III collagen. Ainar Method:  If we look at portal tract as the middle part, then it is an Acinar architecture.  Acinar architecture is defined by microcirculatory layout of the liver → It reflects the oxygen saturation.  More oxygenated blood will be around the portal tract (zone 1), also more toxins levels are present → the first affected in diseases  Zone 3 will be the least oxygenated → If there is hypoxia, zone 3 is the first to be affected.  Circulatory zone is explained better in the acinar architecture.  Zone 1 receives the most oxygenated blood, then blood moves into the different zones to drains into the terminal hepatic vein.  In red, you can see the simple cuboidal epithelium → bile duct  In blue, you can see a very rounded lumen (thick wall): hepatic artery  Hepatic vein usually is collapsed, has a thin wall. Diseases of the Liver  Hepatic injury, Jaundice & cholestasis, Hepatic failure, Cirrhosis, Tumors.  Inflammatory disorders: hepatitis, abscesses.  Drug & toxin-related diseases: alcohol liver disease.  Inborn error of metabolism & pediatric liver disease: Hemochromatosis, Wilson’s disease, neonatal hepatitis & Reye’s syndrome.  Intrahepatic biliary tract disease: PBC, PSC + Circulatory disorders. 1 Histologic Patterns of Hepatic Injury  We have limited changes under the microscope:  Inflammation: acute or chronic hepatitis; portal or lobular.  Degeneration: ballooning, foamy, steatosis (lipids).  Necrosis: coagulative or lytic (hydropic, fragments); Councilman bodies; centrilobular, focal, piece-meal (interface), bridging (fibrous bridges between portal tracts), sub-massive (confluent in a whole row of cells), massive.  Fibrosis: portal, central vein, bridging (bridging could lead to cirrhosis).  Cirrhosis: should be diffuse with regenerative nodules surrounded by fibrosis. Steatosis:  The normal color fat is yellow, but under the microscope we see it white, because when we prepare the slide to examine it under the microscope the fat dissolved and appear as the empty vacuole.  Fat (neutral fat, triglycerides) in liver cells indicates a defect in lipid metabolism or lipoprotein synthesis or unusual amounts of adipose or dietary lipids brought to the liver:  The accommodation fat inside the hepatocyte is called steatosis.  Nucleus is in the periphery because the fat vacuole pushes it. Hepatocytes swelling:  Swelling or hydropic change is a result of defects in membrane and/or mitochondrial function → abnormality in potassium sodium pump and that cause water retention to the cells causing swelling.  Not a fatty change, nucleus is in the middle. Necrosis:  Coagulative necrosis: poorly staining mummified hepatocytes→ shadows of cells.  Councilman or acidophilic bodies (very dense acidophilic): dead hepatocytes.  Lytic necrosis: hepatocytes swell & rupture, fragmentation. 2 Jaundice  Jaundice: yellowish discoloration of skin & sclera (icterus) due to systemic retention of bilirubin (> 2 mg/dl).  Equilibrium between bilirubin production & clearance is disturbed:  Excessive production → excessive heme production.  Reduced hepatocellular uptake.  Impaired conjugation.  Decreased hepatocellular excretion.  Impaired bile flow → obstructive jaundice  Kernicterus: accumulation of bilirubin in the brain. Types of jaundice: Unconjugated Bilirubin Water-insoluble Water Tightly complexed to serum albumin Cannot be excreted in urine Free form is toxic Lab test: Total bilirubin minus direct bilirubin Conjugated Bilirubin Water-soluble Loosely bound to serum albumin Excess amounts are excreted in urine Nontoxic Lab test: measured by direct bilirubin Lab Evaluation of Liver Disease & Liver Function Test:  Tests of hepatocyte integrity:  AST (SGOT).  ALT (SGPT).  LDH.  Tests of biliary excretory function:  Serum Bilirubin.  Alkaline phosphatase → present in biliary epithelium.  Gamma-glutamyl transpeptidase → present in biliary epithelium.  Tests of hepatocyte function:  Albumin.  Prothrombin time.  Ammonia → increased its level will affect the central nervous system and cause hepatic encephalopathy.  Aminopyrine breath test; galactose elimination. 3 Cholestasis  Systemic retention of bilirubin and other solutes eliminated in bile (e.g. bile salts & cholesterol).  Results from hepatocellular dysfunction & (intra- or extrahepatic) biliary obstruction.  Complication: Jaundice, pruritis, skin xanthomas, malabsorption.  Lab: Elevated bilirubin, alkaline phosphatase, lipids.  Biopsy:    Bile pigment accumulation green to brown in color. Foamy degeneration. Bile duct distension & proliferation.  Bile lakes.   Portal tract fibrosis. Cholangitis & cholangiolitis.  Types:  Intrahepatic.  Extrahepatic.  Accumulation of bile pigment within the hepatic parenchyma.  Hepatocyte swelling and foamy degeneration.  Bile duct proliferation secondary to biliary tree obstruction.  Hepatocyte necrosis, bile lakes, & portal tract fibrosis.  Ductular reaction in cholestasis, proliferation of multiple bile duct canals to overcome the obstruction. Liver Cirrhosis  Irreversible end-stage of chronic liver disease, which leads to parenchymal injury and fibrosis.  Histologic features:  Bridging fibrous septa.  Disruption of entire liver architecture.  Parenchymal nodules.  Etiological classification: 4  Viral hepatitis (10%)       Alcoholic liver disease (60% to 70 Biliary diseases (5% to 10%) Genetic hemochromatosis (5%) Wilson’s disease (Rare) alpha 1-antitrypsin deficiency (Rare)     Drugs (a-methyldopa, acetaminophen) Cancer, syphilis Galactosemia, tyrosinosis. Cardiac cirrhosis Cryptogenic cirrhosis (10% to 15%) Pathogenesis of cirrhosis:  Progressive fibrosis with collagen types I & III deposition in all portions of lobule (stellate cells).  Collagen synthesis & deposition is stimulated by:  Chronic inflammation & cytokine production (TNF, IL-1).  Cytokine production by endogenous liver cells.  Disruption of extracellular matrix.  Direct stimulation of Ito (stellate cells) by toxins.  This is accompanied by alterations in sinusoidal endothelial cells.  Resulting in severe disruption of blood flow & impaired diffusion of solutes & proteins.  Micronodular cirrhosis nodules & scars of uniform size (alcoholic inducer cirrhosis). (B+C)  Macronodular cirrhosis nodules & scars of variable size (> 3mm). (A)  The classification according to size nodule give a hunt to under lining etiology. A B Clinical features:  May be asymptomatic.  Nonspecific symptoms: malaise, anorexia, weight loss, weakness.  Jaundice, ascites, peripheral edema.  Increase Serum transaminases, bilirubin, alkaline phosphatase.  Decrease Serum protein (globulins, albumin, coagulation factors), Hemoglobin.  Advanced disease: frank debilitation & Hepatic failure. Prognosis:  Ultimately will die of:  Progressive hepatic failure.  Portal hypertension.  Hepatocellular carcinoma. 5 C Portal Hypertension  Portal hypertension is characterized by increased resistance to portal blood flow. This condition can be caused by several factors, including:  Pre-hepatic:  Portal vein thrombosis.  Massive splenomegaly.  Hepatic:  Cirrhosis.  Post-hepatic:  Severe right-sided heart failure.  Constrictive pericarditis.  Hepatic vein outflow obstruction. Pathogenesis:  Increased resistance to portal blood flow in sinusoids.  Compression of central veins by perivenular fibrosis & expanding parenchymal nodules.  Anastomoses between arterial & portal systems in fibrous bands. Consequences:  Ascites.  Portosystemic venous shunts.  Congestive splenomegaly.  Hepatic encephalopathy. Ascites  Excess (usually serous) fluid in abdominal cavity.  Fluid: albumin, solutes, few mesothelial cells, mononuclear leukocytes.  Neutrophils=secondary infection.  Hydrothorax.  Pathogenesis:  Sinusoidal hypertension: increased hydrostatic pressure & hypoalbuminemia.  Percolation of hepatic lymph into peritoneal cavity.  Renal retention of sodium & water secondary to hyperaldosteronism. 6 Liver Neoplasms Liver Tumors: Tumors and tumor like lesions of the live Hepatic nodules: Epithelial neoplasms:  Focal nodular hyperplasia.  Benign: Liver cell adenoma.  Nodular regenerative hyperplasia.  Malignant:  Macroregenerative nodules.  Liver cell carcinoma.  Cholangiocarcinoma.  Tumors of mixed cell types.  Hepatoblastoma (rare). Epithelial abnormalities:  Liver cell dysplasia (≤1mm):  Large cell type. Non-epithelial neoplasms:  Small cell type.  Benign: Hemangioma.  Borderline: Hemangioendothelioma.  Dysplastic nodules (> 1mm)  Malignant: Angiosarcoma.  Low-grade.  High-grade.  Note: that the most common hepatic neoplasms are metastatic carcinomas (secondary).  Colon, lung, and breast are the most common sites. Hepatic Nodules Focal Nodular Hyperplasia (FNH):  Regenerative capacity of hepatocytes.  A nodular regeneration in response to local vascular injury.  Usually Incidental finding (asymptomatic).  Most common in young to middle age and women of reproductive age.  Solitary focus of hyperplastic hepatocyte nodules with a central fibrous scar.  DO NOT predispose to cirrhosis or malignancy.  A broad fibrous scar with hepatic arterial and bile duct elements and chronic inflammation. Resected specimen showing lobulated contours and a central stellate scar  Remember: In Cirrhosis we must have:  Fibrosis.  Regenerative nodules.  Diffuse. 7 Absence of any of these criteria there will be other differential Diagnosis like nodular or foca. Nodular Regenerative Hyperplasia (NRH):  Diffuse process of non-neoplastic nodules formation (without fibrous septae).  It occurs in association with conditions affecting intrahepatic blood flow.  NRH can lead to portal hypertension. Benign Tumors Cavernous Hemangioma:  Most common benign tumor.  Derived from endothelial cells; induces hemorrhage.  Subcapsular, small, red-blue soft nodules.  Why is it really significant? Blind percutaneous needle biopsy without guidance may cause severe intra-abdominal bleeding that could be fatal. Hepatic (or liver cell) Adenoma:  Usually occurs in women of childbearing age who have used OCPs (may regress on discontinuance use).  Subcapsular, yellow or bile-stained nodule of variable size.  Why is liver cell adenoma significant?  May be mistaken for HCC (hepatocellular carcinoma).  Risk for rupture (esp. in pregnancy)  massive intra-abdominal hemorrhage.  Adenomas carrying β-catenin mutations carry a risk of developing into cancers.  Cords of normal hepatocytes, prominent vascular supply, with no portal tracts. 8 Hepatocellular Carcinoma (HCC) Epidemiology:  Asian and African countries (> 85% of HCC):  Chronic HBV infection.  Aflatoxin increases the risk (toxins produced by certain fungi/asprgillus that are found where agricultural crops are stored)  In 50% of cases, HCC occur without cirrhosis.  M: F >> 8:1, 20 - 40 years.  Western countries:  Incidence increases rapidly due to HCV & chronic alcoholism (more).  In 90% of cases, tumors develop in persons with cirrhosis.  M: F >> 3:1, rarely before 60 years. Pathogenesis:  Major etiologic associations:  Infection with HBV or HCV (continuous bouts of inflammation in addition to their carcinogenic effect on tumor suppressor genes like P53).  Chronic alcoholism.  Aflatoxin (derived from Aspergillus flavus) cause mutation in p53.  Hemochromatosis (accumulation of iron inside the hepatocytes).  Tyrosinemia.  Cirrhosis & HCC:  An important contributor but not a requisite.  HCC in HCV occurs almost exclusively in the setting of cirrhosis. Gross Appearance:  Unifocal (usually massive).  Multifocal (variable sized nodules).  Diffusely infiltrative.  Tumors are yellow-white, punctuated by bile staining and areas of hemorrhage or necrosis.  All patterns of HCC have a strong propensity for invasion of vascular channels:  Extensive intrahepatic metastases.  Occasionally snake-like masses of tumor invade the portal vein or IVC extending into the right side of the heart. 9  A unifocal, massive neoplasm replacing most of the right hepatic lobe in a no cirrhotic liver; a satellite tumor nodule is directly adjacent.  Pale yellow in appearance. Microscopic Appearance:  Well-differentiated (Hepatocytes arranged in thick cords, trabeculae or glandular patterns).  Moderately differentiated.  Poorly differentiated (anaplastic or multinucleate tumor giant cells).  Other features:  Loss of reticulin stains (important sign).  Bile pigment.  Acidophilic hyaline inclusions resembling MB. Tumor cells are arranged in nests, sometimes with a central lumen  Normal (left) and HCC (right).  Note how the collagen in left picture appears black stained with reticulin stain.  while in the HCC there’s loss of reticulin stain. 10 Bile production by tumor cells Normal liver cell plates 1-2 cell thickness Fibrolamellar variant of HCC:  Seen in young adults, M=F.  NO association with cirrhosis or other risk factors.  Better prognosis than conventional HCC.  Gross appearance:  Single, large, hard "scirrhous" mass.  Microscopic appearance:  Groups of well-differentiated oncocytic cells separated by lamellae of dense collagen. Cholangiocarcinoma:  Well differentiated adenocarcinomas (glands and tubules lined by highly atypical cells).  Abundant desmoplastic stroma.  Firm gritty consistency.  NO bile pigment or hyaline inclusions seen.  Higher and Earlier Extrahepatic spread in comparison to HCC. Clinical picture of HCC:  Silent hepatomegaly.  Often encountered in individuals with cirrhosis:  Rapid increase in liver size, worsening of ascites, or the appearance of bloody ascites, fever, & pain call attention to HCC  90% of patients have very high levels of serum α-fetoprotein (non-specific) (>1000 ng/mL). Prognosis of HCC:  The overall prognosis of HCC is grim (depends mainly on stage).  The median survival is 7 months.  Prognosis is better for individuals who have:  A single tumor., < 2 cm in diameter., Good LFT (liver function test).  Causes of death:  Profound cachexia (muscle wasting syndrome).  GI or esophageal variceal bleeding.  Liver failure.  Rarely, rupture of the tumor with fatal bleeding. 11 Treatment of HCC:  The most effective therapies are:  Surgical resection of smaller tumors.  Liver transplantation for patients with small tumors and good liver function.  Tumor recurrence rate is > 60% at 5 years.  The best hope for preventing HCC in regions endemic for HBV infection is a comprehensive anti-HBV immunization program. Anatomy and Histology of the Pancreas  The pancreas is approximately 20 cm in length and weighs between 60-140 grams. It is composed of a head, body, and tail, with the pancreatic duct emptying into the duodenum or the common bile duct.  Histologically, the pancreas consists of two components:  Exocrine portion: Constitutes 80-85% of the pancreas and consists of numerous glands (acini) lined by columnar basophilic cells containing zymogen granules, which form lobules. The ductal system produces enzymes such as trypsin, chymotrypsin, aminopeptidase, and amylase).  Endocrine portion: Comprises the islets of Langerhans, which are densely supplied by capillaries.  The islets consist of four main cell types: beta cells (insulin), alpha cells (glucagon), delta cells (somatostatin), and PP cells (pancreatic polypeptide).  Additionally, there are two minor cell types: D1 cells (producing vasoactive intestinal polypeptide, VIP) and enterochromaffin cells (producing serotonin). Diseases of the pencreas  Congenital anomalies.  Exocrine pancreas:  Cystic fibrosis.  Acute pancreatitis.  Chronic pancreatitis.  Carcinoma of the pancreas.  Endocrine pancreas:  Diabetes mellitus.  Islet cell tumors. 12