Dr Dinah Parums. Principal Pathologist. Liver and Biliary Tract Pathology. Teaching Handout.
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Dr Dinah Parums. Principal Pathologist. Liver and Biliary Tract Pathology. Teaching Handout.

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Dr Dinah Parums. Principal Pathologist. Liver and Biliary Tract Pathology. Teaching Handout.

Dr Dinah Parums. Principal Pathologist. Liver and Biliary Tract Pathology. Teaching Handout.

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Dr Dinah Parums. Principal Pathologist. Liver and Biliary Tract Pathology. Teaching Handout. Dr Dinah Parums. Principal Pathologist. Liver and Biliary Tract Pathology. Teaching Handout. Presentation Transcript

  • The Liver and the Biliary Tract Dr Dinah Parums Principal Histopathologist July 2007
  • Normal Liver     QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.  A ver ag e liver weig h t is 1 ,4 0 0 to 1 ,8 0 0 g m s L ower b or d er can b e felt u n d er th e r ig h t cost al m ar g in on d eep in sp ir ation T h e r ig h t lob e is six tim es th e size of t h e left D u al b lood su p p ly - 4 0 % h ep atic ar t er y - th e r est b y th e h ep atic p or tal vein B ile d r ain s in t o th e r ig h t an d left h ep atic d u ct s, in to th e com m on h ep atic d u ct wh ich join s with th e cyst ic d u ct fr om th e g allb lad d er , t o for m th e com m on b ile d u ct d r ain in g in to t h e d u od en u m via th e A m p u lla of V ater
  • Normal Liver  P  HV QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.   H ist olog y of t h e liver sh ows a solid m ass of p ar en ch ym a co m p osed of h ep at ocyt es an d cells lin in g t h e sin u soid s p ier ced b y p or t al t r act s an d t r ib u t ar ies of t h e h ep at ic vein s T h e liver lob u le h as an ar ch it ect u r e d efin ed b y t h e liver vascu lat u r e H V - t h e h ep at ic vein is at t h e cen t r e of t h e liver lo b u le ( som et im es called t h e C en t r al V ein ) P - t h e p or t al t r act - con t ain s t h e p or t al t r iad       h epat ic ar ter iole, bile d u ct an d por t al vein B lood flow is fr om P t o H V B ile flow is fr om H V t o P T h e d ist an ce b et ween t h e H V an d t h e P is 0.5 m m
  • Normal Liver The Kupffer Cell and Sinusoids  One type of cell lining the hepatic sinusoids, the Kupffer cell, is phagocytic and is a component of the mononuclear phagocyte system.  The Kupffer cell helps clear the blood of foreign substances and old erythrocytes.  The other major type of lining cell is a special endothelial cell containing numerous pores permitting free passage of plasma macromolecules between hepatocytes and blood. It is not phagocytic.  Finally, there are scattered lipocytes that store vitamin A and also are responsible for collagen synthesis in liver fibrosis.
  • Normal Liver Bile Bile, the exocrine product of the hepatocytes, is initially secreted into intercellular bile canaliculi and then passes into branches of the bile (hepatic) duct. The bile canaliculi are tiny passageways between adjacent hepatocytes. They are difficult to visualize with the light microscope unless they are selectively stained. Apart from the connective tissue of the portal triads, the structural framework of hepatic lobules consists of reticular fibers which are arranged in small bundles located in the space between the endothelial cells lining the sinusoids and the hepatocytes. This space is called the space of Disse. The space of Disse is too narrow to be seen with the light microscope
  • Hepatic Injury  Inflammation = hepatitis   Portal tracts, lobules Degeneration Damage from toxic or immunologic insult  Accumulation of substances, e.g., steatosis   Cell death   Fibrosis   Centrilobular, submassive, massive necrosis Usually irreversible Cirrhosis
  • Bile  Two major functions Elimination of bilirubin, excess cholesterol, and xenobiotics that are insufficiently water soluble to be excreted in urine  Emulsification of dietary fat in the gut by bile acids (cholic acid, chenodeoxycholic acid)    Unconjugated → Conjugated Reabsorbed in terminal ileum (enterohepatic circulation)
  • Jaundice  Excessive production of bilirubin    Hemolytic anemias, ineffective erythropoiesis Reduced hepatic uptake Impaired conjugation Physiologic jaundice of the newborn  Crigler-Najjar syndromes types I and II  Gilbert syndrome  Viral or drug-induced hepatitis, cirrhosis   Decreased hepatocellular excretion   Dubin-Johnson syndrome, Rotor syndrome Impaired bile flow
  • Cholestasis       Systemic retention of not only bilirubin but also other solutes eliminated in bile, particularly bile salts and cholesterol Due to hepatocellular dysfunction or biliary obstruction Accumulation of bile pigment within the hepatic parenchyma – Kupffer cells Bile ductular proliferation Bile lakes Portal tract fibrosis
  • Hepatic Failure   80% to 90% of hepatic functional capacity must to destroyed Massive hepatic necrosis Fulminant viral hepatitis  Drugs and chemicals, e.g., acetaminophen, carbon tetrachloride, mushroom poisoning    Chronic liver disease Hepatic dysfunction without overt necrosis Acute fatty liver of pregnancy  Tetracycline toxicity  Reye syndrome 
  • Clinical Features         Jaundice Hypoalbuminaemia Hyperammonaemia Fetor hepaticus Palmar erythaema Spider angiomas Hypogonadism Gynaecomastia
  • Complications    Multiple organ failure Coagulopathy Hepatic encephalopathy Metabolic disorder of the CNS and NMS  Elevated blood ammonia level and deranged neurotransmission  Rigidity, hyperreflexia, seizures  Asterixis   Hepatorenal syndrome  Idiopathic renal failure
  • Cirrhosis     Bridging fibrous septa Parenchymal nodules Disruption of the architecture of the entire liver Aetiologies Alcoholic liver disease 60% to 70%  Viral hepatitis 10%  Biliary diseases 5% to 10%  Hereditary hemochromatosis 5%  Wilson disease rare  Cryptogenic cirrhosis 10% to 15% 
  • Portal Hypertension  Prehepatic   Occlusive thrombosis, narrowing of the portal vein Intrahepatic Cirrhosis  Schistosomiasis, massive fatty change, diffuse granulomatous diseases (sarcoidosis, miliary TB)   Posthepatic  Right-sided heart failure, constrictive pericarditis, hepatic vein outflow obstruction
  • Clinical Sequelae   Ascites Portosystemic venous shunts Oesophageal varices 65% of cases  Hemorrhoids  Caput medusae    Splenomegaly Hepatic encephalopathy
  • Drug Induced Liver Disease     Liver is the major drug metabolizing and detoxifying organ in the body Direct toxicity Hepatic conversion of a xenobiotic to an active toxin Immune mechanisms
  • Alcoholic Liver Disease  Hepatic steatosis    Alcoholic hepatitis      Micro and macrovesicular Initially centrilobular Hepatocyte swelling and necrosis Mallory bodies Neutrophilic reaction Fibrosis Alcoholic cirrhosis   Micronodular Irreversible
  • Pathogenesis        Shunting of normal substrates away from catabolism toward lipid biosynthesis Induction of cytochrome P-450 Free radicals generated by microsomal ethanol oxidizing system Alcohol directly affects microtubular and mitochondrial function Acetaldehyde induces lipid peroxidation Neutrophil infiltration Immunologic attack of hepatocytes
  • Causes of Death      Hepatic failure Massive GI hemorrhage Infection Hepatorenal syndrome Hepatocellular carcinoma
  • Nonalcoholic Fatty Liver     Elevated serum aminotransferase levels Low risk for development of hepatic fibrosis or cirrhosis Associated with obesity, type 2 DM, hyperlipidemia Need to exclude other causes
  • Hemochromatosis  Primary or hereditary   HLA-linked autosomal recessive disease Secondary Transfusion dependent  Chronic liver disease 
  • Pathogenesis    Total body iron pool 2 to 6 gm Primary defect in regulation of intestinal absorption of dietary iron, leading to a net iron accumulation of 0.5 to 1.0 g/yr HFE gene on 6p     Interacts with transferrin receptor of intestinal enterocyte and modulates interaction with transferrin-iron complexes C282Y – disulfide bridge disrupted H63D Lipid peroxidation, collagen formation, DNA interactions
  • Morphology    Deposition of hemosiderin in the liver, pancreas, myocardium, pituitary, adrenal, thyroid and parathyroid glands, joints, and skin Cirrhosis, micronodular Pancreatic interstitial fibrosis and parenchymal atrophy → DM
  • Clinical Features        M:F = 5-7:1 Symptoms usually appear in the fifth to sixth decades of life. Classic triad: cirrhosis with hepatomegaly, skin pigmentation, DM (late in course) Cardiac dysfunction, e.g., arrhythmias, cardiomyopathy Atypical arthritis Hypogonadism Tx: phlebotomy, iron chelators
  • Wilson Disease       Autosomal recessive disorder of copper metabolism ATP7B on chr 13 ATP-dependent metal ion transporter on the Golgi of hepatocytes Failure to excrete copper into bile Copper causes progressive liver injury Affects brain, cornea, kidneys, bones, joints, and parathyroid glands Dx: ↓ serum caeruloplasmin, ↑ hepatic copper content, ↑ urinary copper
  • Morphology  Liver – fatty change, acute hepatitis, chronic hepatitis, cirrhosis      Rhodanine stain for copper Orcein stain for copperassociated protein Brain – Basal ganglia (putamen) shows atrophy and cavitation Eye – Kayser-Fleischer rings Aka hepatolenticular degeneration
  • Clinical Features      Manifestations rare before 6 yrs Acute or chronic liver disease – most common Neuropsychiatric manifestations Copper chelation therapy with D-penicillamine Liver transplantation
  • α1-Antitrypsin Deficiency    Autosomal recessive disorder AAT is a protease inhibitor, particularly neutrophil elastase released at sites of inflammation AAT gene on chr 14   M allele normal, Z allele abnormal → misfolding of the nascent polypeptide in the hepatocyte ER, accumulation, degradation Leads to pulmonary emphysema due to tissue destructive enzymes
  • Morphology  Round to oval cytoplasmic inclusions of retained AAT      Periodic acid-Schiff (PAS) positive Marked cholestasis with hepatocyte necrosis in newborns Childhood cirrhosis Chronic hepatitis or cirrhosis later in life Tx: liver transplantation
  • Neonatal Hepatitis   Not a specific entity Not necessarily inflammatory    Extrahepatic biliary atresia (20%), toxic, metabolic diseases, AAT deficiency (1.5%), idiopathic (50% to 60%) Neonatal cholestasis (prolonged conjugated hyperbilirubinemia) Present with jaundice, dark urine, light or acholic stools, hepatomegaly
  •  Marked bilirubin stasis in hepatocytes, canaliculi, and Kupffer cells in neonate with extrahepatic bile duct atresia.
  • Reye Syndrome    Rare disease characterized by fatty change in the liver and encephalopathy Children < 4 yo 3 to 5 days after a viral illness      Associated with salicylate (aspirin) use Present with vomiting, irritability or lethargy, hepatomegaly 25% progress to coma Death due to progressive neurologic deterioration or liver failure Tx: symptomatic, supportive
  • Morphology  Liver – microvesicular steatosis   Brain – cerebral oedema   EM – mitochondrial enlargement with disruption of cristae Astrocytes swollen, mitochondrial changes Skeletal muscles, kidneys, and heart may have microvesicular steatosis.
  • Obstructive Biliary Tract Disease
  • Secondary Biliary Cirrhosis      Most common cause is extrahepatic cholelithiasis Biliary atresia, malignancies of the biliary tree and head of the pancreas, and strictures Cholestasis Bile duct proliferation with surrounding neutrophils Periportal fibrosis
  • Primary Biliary Cirrhosis    Middle-aged women M:F = 1:10 Possibly autoimmune     Autoantibodies to mitochondrial pyruvate dehydrogenase 90% Insidious onset, usually presenting with pruritus Hyperbilirubinemia, jaundice, cirrhosis late ↑ alkaline phosphatase, cholesterol
  •  Nonsuppurative, granulomatous destruction of medium-sized intrahepatic bile ducts = florid duct lesion
  • Primary Sclerosing Cholangitis        Inflammation, obliterative onion-skin fibrosis, and segmental dilatation of the obstructed intrahepatic and extrahepatic bile ducts String of beads on ERCP 70% associated with inflammatory bowel disease, particularly ulcerative colitis M:F = 2:1, third through fifth decades Progressive fatigue, pruritus, jaundice Chronic course Increased risk for cholangiocarcinoma
  • Circulatory Disorders
  • Hepatic Artery Inflow   Liver has dual blood supply. Thrombosis of hepatic artery in transplanted liver → loss of organ
  • Portal Vein Obstruction  Extrahepatic Peritoneal sepsis leads to phlebitis  Lymphatic metastases to hilar lymph nodes  Pancreatitis leads to splenic vein thrombosis  Postsurgical thromboses  Banti syndrome umbilical vein catheterization   Intrahepatic thrombus does not cause an ischemic infarction but results in an area of redblue discoloration (infarct of Zahn). Invasive carcinoma  Hepatoportal sclerosis 
  • Impaired Blood Flow Through the Liver       Cirrhosis Sickle cell disease DIC – disseminated intravascular coagulation potentially fatal subcapsular haematoma in pts with eclampsia Right-sided heart failure → congestion of centrilobular sinusoids Left-sided heart failure → hypoperfusion and hypoxia → centrilobular necrosis Peliosis hepatis – primary sinusoidal dilation associated with anabolic steroids, danazol, and oral contraceptives
  • Hepatic Vein Thrombosis      Aka Budd-Chiari syndrome Hepatomegaly, weight gain, ascites, abdominal pain Polycythaemia vera or other myeloprolifera-tive disorders, pregnancy, the postpartum state, oral contraceptive use, PNH, intra-abdominal cancers, esp. HCC Massive intrahepatic abscess or parasitic cyst Centrilobular congestion and necrosis
  • Veno-Occlusive Disease     Shortly after bone marrow transplantation 25% incidence Subendothelial swelling and reticulated collagen Due to toxic endothelial injury secondary to chemotherapy and radiation therapy
  • Hepatic Neoplasms  Metastatic carcinomas – most common Colon  Lung  Breast    Benign tumors Primary liver carcinoma Hepatocellular carcinoma  Cholangiocarcinomas  Hepatoblastoma – children  Angiosarcoma – associated with vinyl chloride, arsenic, or Thorotrast exposure 
  • Benign Tumors  Cavernous hemangioma – most common   Well-circumscribed, subcapsular, < 2 cm Focal nodular hyperplasia Young to middle aged adults  Poorly encapsulated  Central fibrous scar  Response to local vascular injury 
  • Focal Nodular Hyperplasia
  • Liver Cell Adenoma       Women of childbearing age who have used oral contraceptives Often subcapsular Sheets and cords of hepatocytes Portal tracts are absent Prominent vessels throughout Risk for rupture, esp during pregnancy
  • Hepatocellular Carcinoma  Annual incidence Americas, Northern Europe, Australia 3-7 cases/100,000  Southern Europe 20 cases/100,000  Southeast China, Taiwan 150 cases/100,000      HBV carrier since infancy = 200 fold risk Cirrhosis in 85% to 90% vs 50% M:F = 3:1 vs 8:1 Sixth to seventh decades vs third to fifth
  • Pathogenesis  Infection with HBV Genomic instability with integrated HBV DNA  Integration pattern is clonal  HBV X-protein disrupts cell cycle control  Certain HBV proteins inactivate p53   Chronic liver disease, esp HCV and Etoh    Cirrhosis plays an important role. Hepatocarcinogens in food (aflatoxins from the fungus Aspergillus flavus) Repeated cycles of cell death and regeneration, i.e., chronic hepatitis, with possible mutations
  • Morphology   Unifocal, multifocal, or infiltrative Strong propensity for vascular invasion      Portal vein or IVC involvement Well-differentiated – intracellular bile Scant stroma → soft Metastasizes to LN, lung, bone, adrenal Fibrolamellar carcinoma 20-40 yo, M=F  No assoc. with cirrhosis or other risk factors  Tumor cells separated by dense collagen  Better prognosis 
  • HCC
  • Clinical Features        Rapid increase in liver size Sudden worsening of ascites Appearance of bloody ascites, fever, pain ↑ serum AFP, esp if > 1000 ng/ml Median survival 7 months Death due to GI or esophageal variceal bleeding or liver failure with hepatic coma Surgical resection for smaller tumors   Recurrence rate 60% at 5 yrs Liver transplantation
  • Disorders of the Gallbladder
  • Cholelithiasis   Very common Cholesterol stones Bile is supersaturated with cholesterol  Gallbladder stasis  F>M  Obesity  Advancing age   Pigment stones – calcium bilirubinate salts Asian more than Western  Chronic hemolytic syndromes 
  • Clinical Features     Asymptomatic Biliary colic Cholecystitis Gallstone ileus
  • Cholecystitis  Acute calculous Obstruction of GB neck or cystic duct  RUQ pain radiating to right shoulder  Fever, nausea, leukocytosis  Potential surgical emergency    Acute acalculous – seriously ill pts Chronic Recurrent attacks of pain  Nausea and vomiting  Associated with fatty meals 
  • Choledocholithiasis     Stones within the biliary tree West – from gallbladder Asia – primary ductal and intrahepatic stone formation Symptoms due to: Biliary obstruction  Pancreatitis  Cholangitis  Hepatic abscess 
  • Cholangitis    Acute inflammation of bile ducts Due to biliary obstruction, usually choledocholithiasis Bacterial infection from gut, i.e., gram negative aerobes     Fever, chills, abdominal pain, jaundice Latin America and Near East: Fasciola hepatica, schistosomiasis Far East: Clonorchis sinensis, Opisthorchis viverrini AIDS: cryptosporidiosis
  • Biliary Atresia         1/3 of cases of neonatal cholestasis 1 in 10,000 live births Complete obstruction of bile flow caused by destruction or absence of all or part of the extrahepatic bile ducts Acquired inflammatory disorder Normal stools to acholic stools Bile ductular proliferation on liver bx Cirrhosis by 3 to 6 months of age. Require liver transplantation
  • Gallbladder Carcinoma        Seventh decade F>M Discovered at late stage, usually incidental Exophytic and infiltrating types Adenocarcinoma Local extension into liver, cystic duct, portahepatic LNs Mean 5 yr survival 1%
  • Cholangiocarcinoma         Older pts M>F Painless jaundice, N/V, weight loss Opisthorchis sinensis (liver fluke), PSC, inflammatory bowel disease Tumors usually small at dx yet not resectable Klatskin tumor – arises at bifurcation Adenocarcinoma Mean survival 6 to 18 months
  • Questions?