Hepatobiliary Pathology PDF

HEPATOBILIARY PATHOLOGY DR MBAYAH ETABALÉ DEPARTMENT OF PATHOLOGY MASENO UNIVERSITY PART I: LIVER PATHOLOGY 2   Liver anatomy and function  Bilirubin Metabolism, Jaundice, Cholestasis and Cholestatic Diseases  Hepatitides  Infectious...

HEPATOBILIARY PATHOLOGY DR MBAYAH ETABALÉ DEPARTMENT OF PATHOLOGY MASENO UNIVERSITY PART I: LIVER PATHOLOGY 2   Liver anatomy and function  Bilirubin Metabolism, Jaundice, Cholestasis and Cholestatic Diseases  Hepatitides  Infectious  Viral Hepatitides  Bacterial, Fungal, Parasitic  Non-infectious  Autoimmune Hepatitis  Drugs and Toxins Outline  Alcohol Metabolism and Alcoholic Liver Disease  Non-Alcoholic Fatty Liver Disease  Liver Cirrhosis, Portal Hypertension and Portosystemic Shunting  Inherited Metabolic Liver Diseases  Haemochromatosis  Wilson’s Disease  Alpha-1 Antitrypsin Disease  Liver Failure  Malignant Liver Tumours 3   Review the normal anatomy and physiology of the liver  Write short notes on hyperbilirubinaemia  Discuss hepatotrophic viral hepatitides Objectives  Outline mechanisms of fatty liver disease  Discuss liver cirrhosis  Write brief notes on hepatocellular carcinoma 4 Anatomical Relationships 5  Liver Embryology Before we were born: Essentials of Embryology and Birth Defects, 9e 6 Liver Microanatomy Anatomy and Physiology: An Integrative Approach, 2nd Edition 7 Liver Microanatomy Pathology Illustrated, 7e 8  1. Synthetic Function  Bilirubin  All plasma proteins except  Hormones e.g. oestrogen, immunoglobulins insulin  Glycogen (glycogenesis)  Drugs  Glucose (gluconeogenesis)  Toxins  Aminoacids 4. Endocrine  Lipids: triglycerides, phospholipids, cholesterol,  Angiotensinogen Functions of free fatty acids  Thrombopoietin  Insulin-like growth factor  Bile the Liver 2. Storage 5. Immunological  Glycogen  Kupffer cells  Vitamins (A, D, B12, K)  Lymphocytes  Fe 6. Haemopoiesis  Cu 3. Breakdown of Substrates  Ammonia 9  Jaundice: yellow discoloration of tissues Serum bilirubin > 50 μmol/l Bilirubin Metabolism and Jaundice Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7e 10 Robbin’s Basic Pathology, 10e   Obstruction of bile duct channels  C/F  Jaundice  Pruritus  Xanthomas  Hypovitaminosis A, D, K  ↑ γ-GT Cholestasis  ↑ alkaline phosphatase and  Causes  Cholelithiasis Cholestatic  Tumours: cholangiocarcinoma, head of pancreas carcinoma, ampullary carcinoma Diseases  Post-surgical strictures  Biliary atresia (neonatal cholestasis)  Cystic fibrosis  Choledochal cyst  Ascending cholangitis  Primary biliary cholangitis  Primary sclerosing cholangitis 11 Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7e Cholestasis and Cholestatic Diseases Robbin’s Basic Pathology, 10e 12   Major cause of hepatitis  Hepatotrophic viruses: Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E  Non-Hepatotrophic viruses: Yellow fever, Herpes viruses, Coxsackie, Lassa  Faeco-oral and parenteral transmission  C/F  Asymptomatic  Mild symptoms: nausea, fever, anorexia  Severe symptoms: jaundice, liver failure, death Viral  Right upper quadrant abdominal tenderness Hepatitides  Biochemical changes  ↑ conjugated bilirubin  ↑ ALT, ↑ AST  ↑ PT  Progression  Resolution within 4 – 6 weeks (majority)  Massive liver necrosis --> death  Chronic hepatitis  Cirrhosis  Hepatocellular carcinoma 13  Hepatitis A Virus Hepatitis E Virus  Picornavirus  Calcivirus  RNA virus  RNA virus  Faeco-oral transmission  Faeco-oral transmission  2 to 6-week incubation period  4 to 5-week incubation period HAV, HEV  Mild hepatitis  Mild hepatitis but sever in  0.1% develop fulminant hepatitis pregnancy  Diagnosis: Serum IgM  Chronic disease in immunocompromised host  Effective humoral immunity  Diagnosis:  No chronicity  Serum IgG, IgM  No carrier state  Viral PCR  Life-long immunity  No carrier state  HAV vaccine 14   DNA virus  Synthesised alongside nucleocapsid  Transmission routes:  Released into circulation  Blood transfusion  Indicates active viral replication  Sharing needles, needle-stick  Polymerase injuries and other medical mishaps  Sex  Longer incubation  Vertical transmission  Variable clinical picture and course Hepatitis B  Viral Ags  Asymptomatic (~ 70%)  Jaundice (weeks) Virus  HBsAg  Chronic hepatitis (~ 5 – 10%)  Envelope protein  Diagnostic  If with hepatitis D infection, ~ 80%  HBcAg  Fulminant failure and death  Nucleocaspid protein  Chronic carrier state  Intracellular  Cirrhosis  Important for virion assembly  Patients may also get HDV  HBeAg infections 15   Flavivirus  Transmission  Blood transfusion  Sharing needles, needle-stick injuries, etc.  Sex  Vertical transmission  Long incubation period Hepatitis C  Acute infection typically subclinical  Very high rate of persistence Virus  Persistent infection predisposes to HCC  Slow progression of disease  Decades to reach cirrhosis  Chronic hepatitis and cirrhosis in ~ 20 – 30%  Hepatosteatosis  Dx  HCV RNA Rubin’s Pathology: Clinicopathologic Foundations of 16 Medicine, 7e   AKA delta agent  Defective RNA virus  Parenteral transmission  Dependent on HBV for its life cycle  Coinfection – both viruses infect patient Hepatitis D  Superinfection – HDV infects a patient with HBV Virus  Severe hepatitis  Carrier state  Diagnosis:  HDV PCR  IgM, IgG antibodies  HBV vaccination confers immunity 17   Ascent from the GI/biliary tract (biliary stasis/obstruction)  Enteric bacteria  Liver flukes (F. busca, C. sinensis)  Echinococcosis  Haematogenous seeding  S. aureus Non-Viral   S. typhi T. pallidum Infectious  S. haematobium  E. histolytica Hepatitides  HSV  CMV  Plasmodium  Leishmania  Direct spread e.g. bacterial cholecystitis  Penetrating injury to the liver 18 Echinococcal Cyst Echinococcal Cyst 19 Entamoebic Abscess Pyogenic Infections Pathology Illustrated, 7e 20   Immune-mediated chronic hepatitis  Anti-Liver Kidney Microsome-1 Antibodies  Features of autoimmune disease:  Anti-Liver Cytosol-1 1. Genetic predisposition: 4. Therapeutic response to  HLA DRB1 immunosuppressants 2. Association with other autoimmune diseases:  Predilection for women (3 times  Rheumatoid arthritis more common) Autoimmune  Autoimmune thyroiditis  Chronic hepatitis Hepatitis  Sjögren syndrome 3. Presence of autoantibodies  No viral markers  ANA  May lead to cirrhosis  Anti-Smooth Muscle Actin Antibodies  Anti-Mitochondrial Antibodies  Anti-Soluble Liver Antigen (SLA) / Liver-Pancreas (Anti-LP) Antigen Antibodies 21 Morphology of Hepatitis: Acute Hepatitis Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7e Wheater’s Pathology: A Text, Atlas and Review of Histopathology, 6e 22 Morphology of Hepatitis: Chronic Viral Hepatitis Wheater’s Pathology: A Text, Atlas and Review of Histopathology, 6e 23  Pathology Illustrated, 7e Alcohol Metabolism 24  Pathology Illustrated, 7e Alcoholic Liver Disease 25 Robbin’s Basic Pathology, 10e Alcoholic Liver Disease 26   Alcoholic steatosis  Fatty change – soft yellow liver  Fibrosis  Alcoholic hepatitis  Fatty change Alcoholic Liver  Hepatocyte necrosis  Inflammation Disease  Predominantly mononuclear  PMNs may also be present  Fibrosis  +/-Mallory’s hyaline  Alcoholic cirrhosis 27   Causes fat into the liver  Metabolic syndrome  Increased fatty acid synthesis  Obesity by the liver  DM  Impaired fatty acid oxidation by the liver  Malnutrition  Non-Alcoholic  Kwashiorkor Increased esterification of fatty acids into TGs  AIDS wasting Fatty Liver  TPN  Decreased apolipoprotein synthesis by the liver Disease  Hepatitis C  Impaired secretion of  Pregnancy apolipoprotein by the liver (NAFLD)  Reye’s syndrome  Poisons: P, CCl4  Inborn errors of metabolism  Mechanisms  Increased trafficking of free 28 Non-Alcoholic Fatty Liver Disease (NAFLD) Robbin’s Basic Pathology, 10e 29   Predictable (intrinsic) or unpredictable (idiosyncratic)  Mechanisms:  Direct hepatocyte toxicity  Conversion to a toxic agent Dugs and   Generation of free radicals Immune-mediated damage as a hapten Toxins  Biliary paralysis  Diagnosis:  Association of liver injury with drug / toxin exposure  Recovery upon removal of exposure  Exclusion of other possible causes 30   AR  LOF mutation of HFE gene  HFE protein stimulates hepatic synthesis of hepcidin which blocks intestinal absorption of Fe  Excessive accumulation of Fe, usually deposited in liver  Other sites: pancreas, heart, pituitary, thyroid, parathyroid, adrenal, joints, skin (bronze colour) Hereditary  Symptoms begin after deposition of ≥ 20 g of Fe (Normal Fe pool is 2 - 6 g)  Hepatomegaly Haemochroma   Abdominal pain Abnormal skin pigmentation tosis   Deranged glucose levels / diabetes mellitus Cardiac dysfunction (cardiomyopathy, arrhythmia)  Arthritis  Hypogonadism (amenorrhoea, reduced libido)  Excessive Fe is hepatotoxic due to lipid peroxidation, stimulation of collagen deposition, DNA damage by ROS  Micronodular cirrhosis  Predisposition to HCC 31 Haemochroma Dark brown liver; also shown are lymph nodes and a pancreas tosis Bronze coloration of the Caucasian skin (extreme right) in haemochromatosis compared to the normal skin coloration 32   AR  LOF mutation in the ATP7B gene which encodes a transmembrane Cu- transporting ATPase  Functions of ATPase transporter  Transports intestinally absorbed Cu into hepatocytes where it complexes with Wilson’s apocaeruloplasmin to form caeruloplasmin  Transports Cu from hepatocytes into biliary canaliculi Disease  Defect leads to Cu accumulation in tissues  Liver (steatosis, hepatitis, cirrhosis, failure)  Putamen – Parkinsonian symptoms  Cornea – Kayser Fleischer rings  Kidney  Bones and joints  PTH glands  Rx  Long-term Cu chelation therapy with D-penicillamine, Trientine  Liver transplantation Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7e 33   SERPINA1 mutation resulting in reduced levels of α1-Antitrypsin  AR but the expression of the clinical entity follows a codominant fashion in homozygotes  Allelic types include:  PiZZ  PiMZ  Pi Null α1-Antitrypsin  M – medium (normal); S – Slow; Z – Very Slow  Affected individuals can have normal or reduced expression of A1AT (A1AT)  Synthesis of A1AT occurs in hepatocytes Deficiency  The Z mutation results in misfolded AAT which cannot be secreted by the hepatocyte  AAT accumulates in the liver and is degraded by the lysosomes  Microscopy  Round to oval cytoplasmic globular inclusions of retained A1AT  Strongly positive PAS staining  Cholestasis  Cirrhosis 34 α1-Antitrypsin (AAT) Deficiency Robbin’s Basic Pathology, 10e 35   End stage of many liver diseases  Destruction of normal liver architecture by fibrous bands around regenerative nodules of hepatocytes  Results from persistent liver cell necrosis  Causes  Drugs and toxins, e.g., alcohol, methotrexate, methyldopa Liver Cirrhosis  Infections, e.g., Hepatitis B, C and D  Autoimmune diseases – autoimmune hepatitis, primary biliary cholangitis  Metabolic conditions, e.g., haemochromatosis, α1-antitrypsin deficiency, Wilson’s disease (excess accumulation of copper)  Biliary obstruction, e.g., gallstones, strictures, sclerosing cholangitis, cystic fibrosis  Venous blood flow obstruction  Cryptogenic i.e., cause unknown 36   Stellate cells (of Ito) found in the Space of Disse are activated and transformed into myofibroblast-like cells under the influence of cytokines such as TGFα, PDGF and TGF-β  The activated cells synthesise collagen leading to fibrosis  The fibrotic bands encircle clusters of regenerating hepatocytes  Disruption of vascular and biliary flow  Complications:  Liver failure  Portal hypertension  Hepatocellular carcinoma Liver Cirrhosis 37 Pathology Illustrated, 7e Liver Cirrhosis 38 Portal Hypertension Pathology Illustrated, 7e 39 Portal Hypertension 40   Liver failure may follow acute injury or chronic injury, or it may occur as an acute insult superimposed on otherwise well- compensated chronic liver disease  Causes of acute liver failure:  A: acetaminophen, hepatitis A, autoimmune hepatitis  B: hepatitis B  C: cryptogenic, hepatitis C Liver Failure  D: drugs/toxins, hepatitis D  E: hepatitis E, esoteric causes (Wilson disease, Budd-Chiari syndrome)  F: fatty change of the microvesicular type (fatty liver of pregnancy, valproate, tetracycline, Reye syndrome)  Potentially fatal sequelae of liver failure include coagulopathy, encephalopathy, portal hypertension and ascites, hepatorenal syndrome, and portopulmonary hypertension 41  Feature Mechanism Manifestation Jaundice / icterus Retention of bilirubin in serum Yellow sclerae, skin Encepahlopathy Failure to detoxify NH+4 and Rigidity, hyperreflexia, asterixis, lack excitatory a.a. which result of coordination, altered from protein breakdown consciousness, coma Coagulopathy Failure of hepatic synthesis of Easy bruising and prolonged clotting clotting factors time of blood DIC Failure of the damaged liver to What Happens remove activated coagulation When The Liver factors Portal Diminished blood flow Ascitis, caput medusa, upper GI Fails? hypertension through hepatic portal venous bleeding, haematochezia, circulation encephalopathy Hepatorenal Vasodilatation of systemic Oliguria, azotaemia Syndrome vessels > renal hypoperfusion > RAAS activation Oedema Failure of albumin synthesis > Swelling of dependent areas, ascitis ↓ plasma oncotic pressure Hyperoestrogen Failure to detoxify Gynaecomastia, hypogonadism, 42 aemia endogenous oestrogens palmar erythema, spider angiomas   Due to massive abrupt hepatocyte necrosis Acute Liver Failure  Soft shrunken liver with a wrinkled capsule 43   Metastatic (secondary) tumours  Carcinoma (colorectal, stomach, pancreas, breast, etc.)  Melanoma  Primary tumours  Non-Neoplastic  Hyperplastic/regenerative nodules Liver Tumours  Benign  Liver cell adenoma  Haemangioma  Malignant  HCC  Cholangiocarcinoma  Angiosarcoma (rare)  Hepatoblastoma (rare) 44   Morphology  Hepatomegaly  Multiple liver nodules  Punched-in appearance on the surface  Tend to umbilicate (central necrosis) Metastatic Carcinomas to the Liver 45   Majority develop in a cirrhotic liver  Aetiology  Hepatitis B virus  Hepatitis C virus Hepatocellular  Haemochromatosis Carcinoma  Aflatoxin poisoning  Alcoholic liver disease  Smoking  Aetiological differences account for the difference in geographic distribution 46   S/S  Diffusely infiltrating  Epigastric fullness mass  Abdominal discomfort  Microscopy  Abdominal pain  Spectrum ranging from  Weight loss well-differentiated to poorly-differentiated  Hepatomegaly HCC –  Metastasis occur late  Lab findings  Deranged LFTs  Poor prognosis Features  ↑α-FP  Death due to:  Cachexia  Macroscopy  Bleeding oesophageal  Yellow-white, soft, varices haemorrhagic, necrotic  Encephalopathy  Unifocal  Fatal haemorrhage from  Multifocal tumour rupture 47 48   Comes from bile duct epithelium  Adenocarcinoma  Intrahepatic (⅓) versus extrahepatic (⅔)  Male predilection  Elderly, usually > 50 years old  Usually unresectable at diagnosis Cholangiocarcinoma  Risk factors:  Thorotrast contrast medium exposure  Liver fluke infestation  Chronic biliary inflammation: primary biliary cholangitis, primary sclerosing cholangitis  Chronic hepatitis B infection  Chronic hepatitis C infection  NAFLD 49 50 PART II: EXTRAHEPATIC BILIARY TRACT PATHOLOGY 51   Normal Anatomy and Function Outline  Cholelithiasis  Gall Bladder Cancer 52   Review the normal anatomy and physiology of the gall bladder Objectives  Discuss cholecystitis  Write brief notes on gall bladder cancer 53 Normal Anatomy and Function Junqueira’s Basic Histology: A Text and an Atlas, 14e 54  Cholesterol Stones Pigment Stones  Exclusively found in the gall bladder  May be found anywhere in the biliary tree  Consist of 50 – 100% cholesterol  Consist of calcium salts: bilirubin,  Formed when the concentration carbonates and phosphates of excreted cholesterol exceeds  Black stones vs brown stones the solubilising capacity of bile salts  Primarily calcium salts of unconjugated bilirubin Cholelithiasis  Supersaturation leads to  Associated with haemolytic nucleation of cholesterol into anaemias cholesterol monohydrate crystals  Brown stones found within the  With further crystallisation, stone biliary tree size increases in size  Colour due to microbial contamination  Yellow, ovoid, firm  Microbes produce  ± multifaceted phospholipases which break down biliary lecithins to calcium  Largely radiolucent but a soaps minority (~20%) may be radio-  Soapy consistency opaque  Radiolucency 55  Robbin’s Basic Pathology, 10e Cholelithiasis 56   Risk factors:  From inflammation of the gallbladder  Aged > young  Nausea & vomiting  Gender: F > M  Jaundice  Ethnicity: whites > non-whites  Pruritus  Others  Fatigue  OCPs  Intolerance of fatty foods  Obesity  Weight loss  Pregnancy Cholelithiasis  Rapid weight loss  Complications  Spinal cord injury  Empyema  Perforation  Clinical Features  Fistulae  Asymptomatic (≈ 70% to 80%)  Cholangitis  Symptomatic  Cholestasis  Excruciating pain  Constant or "colicky" (spasmodic)  Pancreatitis  From an obstructed gallbladder  Cholangiocarcinoma 57  Acute Calculous Cholecystitis Acute Acalculous Cholecystitis  ≈ 90% of acute cholecystitis  Physical stress  Precipitated by obstruction of the gallbladder neck or cystic duct  Major surgery  Results from chemical irritation of  Severe trauma the gallbladder wall  Severe burns  Mucosal phospholipases hydrolyse biliary lecithin to lysolecithin, which  Sepsis is toxic to the mucosa Acute  Disruption of glycoprotein mucous  Dehydration  Gallbladder stasis and sludging Cholecystitis layer exposing the mucosal epithelium to bile salt injury  Oedema of the gallbladder valve  PG release by the gallbladder wall  Vascular compromise adds to the inflammation  Shock  Distention and increased intraluminal pressure may also  Bacterial contamination: compromise blood flow to the  Enteric flora mucosa  E. coli  Bacterial contamination may later  Clostridia follow  Enterococci  Salmonella 58   C/F  Pain, RUQ  Fever  Nausea, vomiting, intolerance to fatty food  Leucocytosis  Obstructive jaundice  Morphology  Enlarged, distended gall bladder  Congested vessels Acute  Mucosal ulcers Cholecystitis  Thickened wall with oedema and haemorrhage  Serosal and mucosal exudate  ± Pus (empyema)  Complications  Bacterial cholecystitis and ascending cholangitis  Abscess formation  Rupture with peritonitis  Gallstone-induced ileus  Cholangiocarcinoma 59   Causes  Repeated bouts of mild cholecystitis  Sequel to severe acute cholecystitis  Chronic irritation by gallstones  Macroscopy Chronic  Thickened gall bladder wall  Microscopy Cholecystitis  Hypertrophy and hyperplasia of SM bundles  Rokitansky-Aschoff sinuses  Mucosal epithelium trapped in the hyperplastic muscle layer  Lymphocytes  ± Dystrophic calcification  Porcelain gall bladder 60   Relatively uncommon  Age 60+ years (mean 72 years)  ≈ 75% women  Usually irresectable at time of diagnosis  Spread to adjacent structures and distant LNs  Risk factors Gall Bladder  Chronic inflammation  Gallstones (present in 60 – 90% of cases) Cancer  Infections and infestations  Parasites: Fasciola  Pyogenic cholecystitis  Usually preceded by gallstones  Most are adenocarcinomas (≈90%)  ≈ 5% squamous or adenosquamous  ≈ 5% undifferentiated 61   Pathology Illustrated, 7e  Robbin’s Basic Pathology, 10e References  Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7e 62 The End 63