Diseases of the Liver

Fe A. Bartolome, M.D.

Department of Pathology & Laboratory Diagnosis

Functions of the Liver

1. processing of dietary amino acids, carbohydrates, lipids and vitamins 2. removal of microbes and toxins in splanchnic blood 3. synthesis of plasma proteins 4. detoxification and excretion into bile of endogenous waste products & pollutant xenobiotics

Patterns of Hepatic Injury

Degeneration & Intracellular Accumulation

Degeneration

• mild to moderate  hepatocyte swelling  reversible • severe damage  ballooning degeneration  irregularly clumped organelles and large clear spaces

Accumulations in Viable Hepatocytes

• iron and copper • triglyceride fat deposits  STEATOSIS  microvesicular – multiple, tiny (e.g. acute fatty liver of pregnancy, alcoholic fatty liver  macrovesicular – single large deposit displacing the nucleus (e.g. obesity, diabetes, alcoholism)

Patterns of Hepatic Injury

Necrosis and Apoptosis •

Types:

1. Ischemic coagulative necrosis – “mummified” liver cells with lysed nuclei 2. Apoptotic cell death – shrunken, pyknotic & intensely eosinophilic cells with fragmented nuclei 3. Lytic necrosis – outcome of ballooning degeneration  (+) shards of cellular debris 4. Liquefactive necrosis - abscesses

Patterns of Hepatic Injury

Necrosis and Apoptosis •

Distribution:

1. Centrilobular – most common; immediately around terminal hepatic vein 2. Mid-zonal and periportal – rare •

Degree of involvement:

1. Focal or spotty – limited to scattered cells within hepatic lobules 2. Interface hepatitis – between periportal parenchyma & inflamed portal tracts 3. Bridging necrosis – span adjacent lobules 4. Submassive necrosis – entire lobules 5. Massive – most of the liver

Patterns of Hepatic Injury

Inflammation • Hepatitis • Influx of acute and chronic inflammatory cells Regeneration • Occurs in all but the most fulminant hepatic diseases • Features: 1. Mitosis 2. Thickening of hepatic cords 3. Disorganization of parenchymal structure

Patterns of Hepatic Injury

Fibrosis • Consequence of inflammation or direct toxic insult to liver • Irreversible • May eventually subdivide liver into nodules of proliferating hepatocytes surrounded by scar tissue 

CIRRHOSIS

Hepatic Failure

• Most severe clinical consequence of liver disease • May be: 1. result of sudden and massive hepatic destruction 2. end-point of progressive chronic liver disease • 80% - 90% loss of hepatic functional capacity

Hepatic Failure

•

Morphologic alterations causing liver failure:

1. Massive hepatic necrosis Mechanisms: (i) direct damage to hepatocytes (ii) immune-mediated hepatocyte destruction a. drug or toxin-induced b. infection – viral hepatitis except hep. C 2. Chronic liver disease – most common cause 3. Hepatic dysfunction without over necrosis – e.g. Reye’s syndrome, tetracycline toxicity, acute fatty liver of pregnancy

Hepatic Failure

•

Clinical Features:

1. Jaundice 2. Hypoalbuminemia  peripheral edema 3. Hyperammonemia  cerebral dysfunction 4. Fetor hepaticus  due to mercaptan “musty” or “sweet & sour” body odor formation by action of GI bacteria on methionine (sulfur-containing) 5. Impaired estrogen metabolism  hyperestrogenemia (a) palmar erythema – 2 o to local vasodilatation (b) spider angiomas – central, pulsing, dilated arteriole from which small vessels radiate (c) hypogonadism & gynecomastia in males

Hepatic Failure

•

Clinical Features:

6. Multi-organ system failure  respiratory failure with pneumonia, sepsis + renal failure  cause of death 7. Coagulopathy  impaired synthesis of factors II, VII, IX and X  (+) bleeding tendency

Hepatic Failure

•

Complications:

1. Hepatic encephalopathy  associated with increased blood ammonia levels  reversible if underlying hepatic condition can be corrected  features: (a) change in consciousness (b) fluctuating neurologic signs – rigidity, hyperreflexia, asterixis

Hepatic Failure

•

Complications:

2. Hepatorenal syndrome  renal failure in patients with chronic liver disease  main renal functional abnormalities: (a) sodium retention (b) impaired free water excretion (c) decreased renal perfusion (d) decreased GFR  decreased urine output with rising BUN & creatinine  ability to concentrate urine retained  hyperosmolar urine without proteins; abnormal sediments; dec. Na +

Cirrhosis

• Most common cause is alcoholic liver disease • Key features: 1. The parenchymal injury & consequent fibrosis are diffuse .

2. The nodularity is part of the diagnosis  reflects balance between regeneration and scarring.

3. Vascular architecture is re-organized parenchymal damage and scarring  by the formation of abnormal interconnections 4.

Fibrosis is the key feature of progressive liver damage.

Cirrhosis

•

Pathogenesis:

Progressive fibrosis & re-organization of vascular micro architecture of liver Collagen deposition (types I & III) in the lobule Loss of fenestration of sinusoidal endothelial cells New vascular channels in the septae Create delicate or broad septal tracts Impaired hepatocellular protein secretion (albumin, clotting factors, lipoproteins) Shunting of blood around the parenchyma

Cirrhosis

•

Main characteristics

1. Bridging fibrous septae  link portal tracts with one another & portal tracts with terminal hepatic vein 2. Parenchymal nodules  contain proliferating hepatocytes encircled by fibrosis  micronodules - < 3 mm diameter  macronodules - > 3 mm to several cm 3. Disruption of architecture of entire liver

Alcoholic Liver Disease

Hepatic Steatosis

• Alcoholic fatty liver • Moderate alcohol intake  microvesicular • Chronic alcohol intake  macrovesicular • Enlarged, soft, yellow, greasy liver • Completely reversible

Alcoholic Liver Disease

Alcoholic Hepatitis

• Characteristics: 1. Hepatocyte swelling & necrosis  ballooning due to accumulation of fat, water & proteins 2. Mallory bodies – eosinophilic cytoplasmic inclusions in degenerating hepatocytes 3. Neutrophilic reaction – accumulate around degenerating hepatocytes 4. Fibrosis – (+) activation of sinusoidal stellate cells & portal tract fibroblasts

Alcoholic Liver Disease

Alcoholic cirrhosis

• Final, irreversible; 10 – 15% of alcoholics • Micronodular with scattered larger nodules  “ hobnail ” appearance of liver surface • Broad expanses of tough, pale scar tissue due to ischemic necrosis & fibrous obliteration of nodules  Laennec cirrhosis 

Short-term ingestion of up to 80 gm of alcohol (~8 beers) over one to several days



FATTY LIVER



Daily intake of 160 gms or more for 10-20 years



SEVERE INJURY

Alcoholic Liver Disease

Alcohol Effects

1. Alcohol through action of alcohol DH & acetaldehyde DH  excess NADH + H +  increased lipid biosynthesis 2. Impaired assembly & secretion of lipoproteins + increased peripheral fat catabolism  fatty liver 3. Impaired hepatic methionine catabolism  glutathione (GSH) levels  dec. intrahepatic inc. sensitivity to oxidative injury 4. Induction of cytochrome P 450 (a) CYP2E1  inc. alcohol catabolism in ER & inc. conversion of other drugs to toxic metabolites (b) production of reactive O 2 species  hepatocellular dysfunction  damage membrane

Alcoholic Liver Disease

Alcohol Effects

5. Impaired microtubular and mitochondrial function 6. Alcohol  acetaldehyde  (+) lipid peroxidation disrupt cytoskeletal and membrane function  7. Become a major caloric source  nutrients  displace other (+) malnutrition and vitamin deficiencies 8. Lead to chronic gastritis, intestinal mucosal damage and pancreatitis  impaired digestive function 9. Induce release of bacterial endotoxin into portal circulation from gut  (+) liver inflammation 10.Induce release of endothelins endothelial cells  from sinusoidal (+) vasoconstriction & contraction of stellate cells  dec. hepatic sinusoidal perfusion  regional hypoxia

Alcoholic Liver Disease

•

Cause of death:

1. Hepatic coma 2. Massive gastrointestinal hemorrhage 3. Intercurrent infection 4. Hepatorenal syndrome following alcoholic hepatitis 5. Hepatocellular carcinoma

Portal Hypertension

•

Causes:

A. Pre-hepatic 1. Obstructive thrombosis 2. Narrowing of portal vein prior to ramification within the liver B. Intrahepatic 1. Cirrhosis – most common 2. Schistosomiasis 3. Massive fatty change 4. Diffuse fibrosing granulomatous disease (TB) 5. Diseases affecting portal microcirculation

Portal Hypertension

•

Causes:

C. Post-hepatic 1. Severe right-sided heart failure 2. Constrictive pericarditis 3. Hepatic vein outflow obstruction

Portal Hypertension

•

Clinical consequences: Ascites

• collection of fluid in peritoneal cavity • clinically detectable: at least 500 ml.

• contents: < 3 gm/dL of protein (albumin), glucose, Na + , K + , mesothelial cells, mononuclear wbc • Pathogenesis: 1. Sinusoidal HPN  drive fluid into space of Disse  removed by lymphatics 2. Percolation of hepatic lymph into peritoneal cavity  hepatic lymph flow in cirrhosis = 20 L/day 3. Intestinal fluid leakage 4. Renal retention of Na + hyperaldosteronism  & H 2 O due to 2 O activation of RAAS

Portal Hypertension

•

Clinical consequences: Portosystemic Shunts

Inc. portal system pressure Development of by-passes Systemic & portal circulation share common capillary beds Veins around & within rectum Cardio-esophageal junction Periumbilical & abdominal wall hemorrhoids Esophageal varices Caput medusae

Portal Hypertension

•

Clinical consequences: Splenomegaly

• secondary to long-standing congestion • lead to hypersplenism

Hepatic encephalopathy

Interrelationships Among the Complications of Cirrhosis

Cirrhosis Portal hypertension Hepatocellular dysfunction Renal Na + retention Hypoalbuminemia Spontaneous bacterial peritonitis Ascites Hepatorenal syndrome Portosystemic collaterals Hepatic encephalopathy

Circulatory Disorders

Circulatory Disorders

Impaired blood inflow

1. Hepatic artery compromise • thrombus or compression of intrahepatic branch of hepatic artery by embolism, neoplasia, sepsis  localized infarct 2. Portal vein obstruction Extrahepatic: (a) Banti syndrome – subclinical occlusion 2 0 to neonatal umbilical cord sepsis or umbilical vein catheterization (b) Intra-abdominal sepsis (c) Thrombogenic disorders (d) Trauma (e) Pancreatitis  vein splenic vein thrombosis  propagate into portal

Circulatory Disorders

Impaired blood inflow

2. Portal vein obstruction Intrahepatic: (a) Acute thrombosis of intrahepatic portal vein radicle  red-blue discoloration  infarct of Zahn (b) Invasion by primary or secondary carcinoma

Circulatory Disorders

Impaired intrahepatic blood flow

•

lead to massive necrosis of hepatocyes



fulminant hepatic failure

1. Cirrhosis – most common cause 2. Sinusoidal occlusion (a) Sickle cell disease  panlobular parenchymal necrosis (b) DIC  occlude sinusoids (c) Metastatic tumor cells  fill the sinusoids

Circulatory Disorders

Impaired intrahepatic blood flow

3. Systemic circulatory compromise (a) Passive congestion R-sided failure: congestion of centrolobular sinusoids  atrophy of hepatocytes L-sided failure: hepatic hypoperfusion & hypoxia  ischemic coagulative necrosis ( centrolobular necrosis ) Biventricular failure: hypoperfusion + retrograde congestion  centrolobular hemorrhagic necrosis  nutmeg liver

Circulatory Disorders

Impaired intrahepatic blood flow

3. Systemic circulatory compromise (b) Peliosis hepatis • Primary sinusoidal dilatation • Associated with exposure to anabolic steroids , oral contraceptives and danazol • Disappear after cessation of drug treatment

Circulatory Disorders

Hepatic venous outflow obstruction

1. Hepatic vein thrombosis (a) Budd-Chiari Syndrome • Obstruction of two or more hepatic veins • Liver enlargement, pain and ascites • Causes: i. Myeloproliferative diseases ii. Coagulation disorders iii.Paroxysmal nocturnal hemoglobinuria iv. Hepatocellular carcinoma

Circulatory Disorders

Hepatic venous outflow obstruction

1. Hepatic vein thrombosis (b) Inferior vena cava thrombosis • Involves hepatic portion of IVC • Obliterative hepatocavopathy 2. Veno-occlusive disease (Sinusoidal obstruction syndrome) • occurs primarily in immediate weeks after BM transplant • tender hepatomegaly, ascites, weight gain & jaundice • obliterative changes in terminal hepatic vein due to sinusoidal damage

Jaundice and Cholestasis

JAUNDICE

• • retention of bilirubin functions of bile: 1. Emulsification of fat 2. Elimination of systemic waste products • Rate of bilirubin production = rate of hepatic uptake, conjugation and biliary excretion

Jaundice

Unconjugated Bilirubin Water-insoluble at physiologic pH Conjugated Bilirubin Water-soluble Tightly complexed to serum albumin Weak association with albumin Not excreted in urine even when blood levels high Can be excreted in urine

Jaundice

Cholestasis

• retention of bilirubin and other solutes eliminated in bile • Causes: 1. Hepatocellular dysfunction 2. Intrahepatic or extrahepatic biliary obstruction • Features: 1. Jaundice 2. Pruritus – deposition of bile acids in skin 3. Skin xanthomas – due to hyperlipidemia & impaired excretion of cholesterol 4. Inc. serum alk. phos. – released due to detergent action of retained bile salts on hepatocyte membrane 5. Deficiency of fat soluble vitamins (A, D or K)

Cholestasis

• Morphology: 1. Accumulation of bile pigment within the hepatic parenchyma  distention of bile ducts and ductules 2. Bile stasis   induce proliferation of duct epithelial cells ductal proliferation 3. Portal tract edema & periductal neutrophilic infiltrates 4. Prolonged cholestasis  hepatocytes  focal detergent dissolution of bile lakes with cellular debris & pigments 5. Portal tract fibrosis

Infectious Disorders

• • • • • • •

Viral hepatitis Miliary tuberculosis Malaria Staphylococcal bacteremia



2 0 to TSS Salmonellosis



Candida typhoid fever Parasitic & helminthic infection

Viral Hepatitis

•

Hepatotropic viruses

1. Hepatitis viruses 2. Epstein-Barr virus 3. Cytomegalovirus 4. Yellow fever 5. Children & immunocompromised  rubella, adenovirus, herpesvirus, enterovirus, CMV

Hepatitis Viruses

• Small, non-enveloped, ssRNA • Picornavirus genus

Hepatovirus

• Serology:

Hepatitis A

Hepatitis B

• Hepadnaviridae • present in all physiologic and pathologic body fluids  blood & body fluids the primary vehicle for transmission • Incubation period: 4 – 26 weeks • MOT: 1. Transfusion 2. Blood products 3. Dialysis 4. Needle stick accidents among health care workers 5. IV drug abuse 6. Sexual contact 7. Vertical transmission – lead to carrier state for life

Hepatitis B

• Protein sequences encoded by HBV genome 1. HBcAg – nucleocapsid “core” protein; remains in hepatocytes for assembly of complete virion 2. HBeAg – secreted into blood 3. HBsAg – envelope glycoprotein 4. DNA polymerase – with reverse transcriptase activity 5. HBx protein – necessary for virus replication  acts as transcriptional activator of viral genes; play a role in development of HCC in HBV-infected patients

Hepatitis B

• Spectrum of illness 1. Acute infection with resolution 2. Chronic hepatitis  evolve cirrhosis  HCC or carrier 3. Fulminant hepatitis with massive liver necrosis 4. Backdrop of hepatitis D infection

Hepatitis B

• Carrier state – (+) HBsAg in serum for 6 months or longer after initial detection • Serology:

Hepatitis C

• Most common chronic blood-borne infection  accounts for 50% of all patients with chronic liver disease in the US • Flaviviridae family genus

Hepacivirus

• HCV RNA polymerase with poor fidelity unstable   inherently (+) genomic instability & antigenic variability within one individual response   evade IFN-mediated anti-viral repeated bouts of hepatic damage • Persistent infection and chronic hepatitis are the hallmarks of HCV infection • MOT: 1. inoculations 4. sexual transmission 2. blood transfusions 5. perinatal 3. hemodialysis

Hepatitis C

• potential outcomes: Stable cirrhosis Death

Hepatitis C

• serology:

Hepatitis D

• hepatitis delta virus • replication defective  HBsAg cause infection only when encapsulated by • co-infection vs. superinfection

Hepatitis D

• serology:

Hepatitis G

• • Flavivirus similar to HCV MOT: 1. Contaminated blood or blood products 2. Sexual contact • 75% cleared from plasma; 25% chronic • Site of replication: mononuclear cells  increase in serum transaminases not hepatotropic  no • No pathologic effect • Commonly co-infects patients with HIV  disease protects against HIV

Hepatitis

• Clinicopathologic Syndromes: 1. Acute asymptomatic infection with recovery  Minimal serum transaminase elevation  Common in HCV-infected patients 2. Acute symptomatic infection with recovery  4 phases: (a) Incubation period (b) Pre-icteric phase – non-specific S/Sx (c) Icteric phase – conjugated hyperbilirubinemia (d) Convalescence

Hepatitis

• Clinicopathologic Syndromes: 3. Chronic hepatitis • Asymptomatic, biochemical or serologic evidence of continuing or relapsing hepatic disease for more than 6 months, with histologically documented inflammation and necrosis 4. Fulminant hepatic failure • Hepatic insufficiency progresses from onset of symptoms to hepatic encephalopathy within 2 – 3 wks • Extrahepatic complications (a) coagulopathy & bleeding (b) cardiac instability (e) electrolyte & acid imbalance (c) renal failure (d) ARDS (f) sepsis

Hepatitis

• Morphology: • • • • •

Acute Hepatitis

Ballooning degeneration glass hepatocytes  ground Periportal necrosis with inflammatory infiltrates Lobular disarray 2 patterns of hepatocyte death: 1. cytolysis 2 0 to rupture of cell membrane 2. apoptosis due to anti-viral cytotoxic T cells severe acute hepatitis  necrosis (+) bridging

Hepatitis

• Morphology: • • • •

Chronic Hepatitis periportal lymphoid aggregates Periportal necrosis & fibrosis Bridging necrosis & fibrosis Hallmark of irreversible liver damage is deposition of fibrous tissue

Liver Abscess

• common in developing countries • usually pyogenic  multiple, small abscesses • parasitic – usually solitary  amebic & echinococcal • reach liver via: 1. Portal vein 2. Arterial supply 3. Ascending infection in biliary tract cholangitis  ascending 4. Direct invasion from nearby source 5. Penetrating injury • Clinical: RUQ pain, fever, tender hepatomegaly

Autoimmune Hepatitis

• chronic form of hepatitis; indolent or severe • Features: 1. Female preponderance – young or post-menopausal 2. (-) viral serologic markers 3. Inc. serum IgG and  -globulin 4. Inc. serum titers of autoantibodies, including: ANA ( antinuclear Ab ); SMA ( anti-smooth muscle Ab ) & anti LKM1 ( anti-liver/kidney microsomes Ab ); (-) AMA ( anti-mitochondrial Ab ) • Subgroups:   Type 1 – (+) ANA and/or SMA; most common Type 2 – (+) anti-LKM1; younger patients

Drug & Toxin-Induced Hepatic Disease

• Mechanism of injury: 1. Direct toxicity 2. Hepatic conversion of a xenobiotic to an actual toxin 3. Immune mechanisms  hapten drug or metabolite acts as • Types of injury: 1. Hepatocyte necrosis 2. Cholestasis 3. Insidious liver dysfunction • Reye syndrome – children given ASA; extensive accumulation of fat droplets within hepatocytes (microvesicular steatosis)

Hepatic Disease Associated with Pregnancy

Pre-eclampsia

• Subclinical hepatic disease a primary manifestation part of HELLP syndrome   hemolysis, elevated liver enzymes, low platelet • Morphology:    fibrin deposition in periportal sinusoids hemorrhage into space of Disse periportal hepatocellular coagulative necrosis

Hepatic Disease Associated with Pregnancy

Acute fatty liver of pregnancy (AFLP)

• sub-clinical hepatic dysfunction to hepatic failure, coma and death • 3 rd trimester; with multiple metabolic defects • diagnosis depends on: a) high index of suspicion b) characteristic microvesicular steatosis demonstrated on frozen tissue sections OR with stain (oil red-O or Sudan black) • Treatment: termination of pregnancy

Hepatic Disease Associated with Pregnancy

Intrahepatic cholestasis of pregnancy

• Characteristics: a) onset of pruritus in 3 rd trimester b) darkening of urine with occ. light stools c) jaundice – conjugated hyperbilirubinemia • Mechanism: altered hormonal state + biliary secretion defects  cholestasis • Increased incidence of fetal distress, stillbirth and prematurity

Nodules & Tumors

Nodular Hyperplasia • • non-cirrhotic liver nodules types: 1. Focal nodular hyperplasia  spontaneous mass lesion; female preponderance  Morphology: a) central stellate scar with large arterial vessels exhibiting fibromuscular hyperplasia  (+) narrowed lumen b) Intense lymphocytic infiltration c) bile duct proliferation

Nodules & Tumors

Nodular Hyperplasia 2. Nodular regenerative hyperplasia • (+) development of portal HPN • Associated with conditions affecting intrahepatic blood flow  renal transplant, BM transplant, vasculitic conditions • Morphology: plump hepatocytes surrounded by atrophic cells; no fibrosis

Nodules & Tumors

Benign Neoplasms Cavernous hemangioma • Most common; blood vessel tumor • Soft nodules < 2 cm diameter immediately beneath the capsule • Clinical significance: mistaken for metastatic tumors  blind percutaneous biopsies not done

Nodules & Tumors

Benign Neoplasms Liver cell adenomas • Cell of origin: hepatocytes • Young women on oral contraceptives  discontinuance of use regress on • Clinical significance: 1. Present as intrahepatic mass  mistaken for HCC 2. If subcapsular  (+) rupture  intraperitoneal hemorrhage 3. May harbor HCC – rare • Morphology: cords of hepatocytes with clear cytoplasm (w/ glycogen), absent portal tracts & prominent arterial vessels and draining veins

Nodules & Tumors

Malignant Tumors • Primary tumors uncommon  often involved in metastatic spread Hepatoblastoma • rare; most common liver tumor of young children • fatal if not resected • (+) activation of

Wnt/ β-catenin

mutations of β-catenin signaling pathway  stabilize Angiosarcoma • rare; malignant endothelial neoplasm • associated with exposure to vinyl chloride, arsenic or Thorotrast • highly aggressive, metastatic, fatal

Nodules & Tumors

Cholangiocarcinoma • malignancy of biliary tract • risk factors: 1. Primary sclerosing cholangitis 2. Congenital fibropolycystic diseases of biliary system 3. Previous exposure to Thorotrast 4. Chronic liver fluke infection (O. sinensis) • Morphology: resemble sclerosing adenocarcinoma  well defined glandular & tubular structures separated by dense collagenous stroma

Nodules & Tumors

Hepatocellular Carcinoma • male preponderance; 20 – 40 y/o • Risk factors: 1. Viral infection – chronic HBV & HCV infection  cirrhosis no 2. Chronic alcoholism – (+) cirrhosis 3. Food contaminants – aflatoxin from

Aspergillus flavus

bind covalently with cellular DNA  (+) p53 mutation  • >85% occur in countries with high rates of chronic HBV and HCV infections

Hepatocellular Carcinoma Infection with HBV/HCV and HCC • Viral DNA integrated into host cell genome  instability  insertional mutagenesis (+) genomic • Chronic liver cell injury & accompanying regenerative hyperplasia  (+) spontaneous mutations • HBx protein encoded by HBV  activate host cell proto oncogenes and disrupt cell cycle control • HCV core protein with oncogenic potential

Hepatocellular Carcinoma • Morphology:  Gross 1. Unifocal large mass 2. Multifocal 3. Diffusely infiltrative

Hepatocellular Carcinoma • Morphology:  Microscopic:  Well differentiated  trabecular pattern or acinar, pseudoglandular pattern  Poorly differentiated  pleiomorphic with anaplastic giant cells

bile

Hepatocellular Carcinoma • Clinical features:  upper abdominal pain or fullness  malaise, fatigue, weight loss  hepatomegaly with irregularity or nodularity • Laboratory:  increased tumor markers – serum AFP and serum CEA  not conclusive  false (+) in non-neoplastic conditions (e.g. cirrhosis, chronic hepatitis, massive liver necrosis, fetal neural defects such as anencephaly)

GALLSTONES (CHOLELITHIASIS) 1. Cholesterol stones a. Composition: mostly cholesterol monohydrate b. Risk factors: • Female gender • Obesity • Pregnancy • Oral contraceptive & HRT • Incidence increases with age

GALLSTONES (CHOLELITHIASIS) 2. Pigmented bilirubinate stones a. Composition: calcium salts & B1 b. Risk factors • Chronic hemolytic anemias • Cirrhosis • Bacteria (ascending cholangitis) • Parasites  Ascaris or Clonorchis sinensis

GALLSTONES (CHOLELITHIASIS) Clinical features of gallstones 1. Presentation • Frequently asymptomatic • Biliary colic: RUQ pain due to impacted stones 2. Diagnosis: ultrasound 3. Complications: a. cholecystitis b. choledocholithiasis – calculi within biliary tract c. biliary tract obstruction d. pancreatitis e. cholangitis

INFLAMMATORY CONDITIONS OF GALL BLADDER Acute cholecystitis • Acute inflammation of the GB, usually caused by cystic duct obstruction by gallstones • Presentation: 1. biliary colic 2. RUQ tenderness on palpation 3. nausea and vomiting 4. low-grade fever and leukocytosis • Complications: 1. gangrene of GB 3. fistula formation 2. perforation and peritonitis 4. gallstone ileus

INFLAMMATORY CONDITIONS OF GALL BLADDER Chronic cholecystitis • Ongoing chronic inflammation of the GB usually caused by gallstones • Micro: chronic inflammation & Rokitansky-Aschoff sinuses • Late complication: calcification of the gallbladder (“porcelain gallbladder”  high association with carcinoma

INFLAMMATORY CONDITIONS OF GALL BLADDER Ascending cholangitis • Bacterial infection of the bile ducts ascending up to the liver, usually associated with obstruction of bile flow • Presentation: biliary colic, jaundice, high fever and chills • Organisms: gram negative enteric bacteria

MISCELLANEOUS CONDITIONS OF GALL BLADDER Cholesterolosis • Gross: yellow speckling of the red-tan mucosa  “strawberry GB” • Micro: collections of lipid-laden macrophages within the lamina propria • No clinical significance

MISCELLANEOUS CONDITIONS OF GALL BLADDER Hydrops of the gallbladder (mucocele) • Chronic obstruction of the cystic duct  normal GB contents  resorption of enlargement of GB by the production of large amounts of clear fluid (hydrops) or mucous secretions (mucocele)

BILIARY TRACT CANCER Cancer of the gallbladder 1. Clinical presentation • Frequently asymptomatic • Cholecystitis • Enlarged palpable GB (Courvoisier law) • Biliary tract obstruction (uncommon) 2. X-ray: may have calcified GB (porcelain GB) 3. Micro: adenocarcinoma 4. Prognosis: poor  5-yr survival ~ 1%

BILIARY TRACT CANCER Bile duct cancer • Bile duct CA – carcinoma of the extrahepatic bile ducts • Cholangiocarcinoma – CA of intrahepatic bile ducts • Klatskin tumor – CA of the bifurcation of the R & L hepatic bile ducts • Risk factors: a. Asia – Clonorchis (Opistorchis) sinensis b. Primary sclerosing cholangitis • Presentation: biliary tract obstruction • Prognosis: poor