Liver Overview


Injury patterns:

1.        ballooning degeneration

hepatocyte damage intracellular edema (balloon cells)

2.        intracellular accumulations

a.        fatty change

- etiology: alcohol, CCl4 , inorganic phosphorus, pregnancy, nutritional deficiencies, severe obesity

- liver is swollen, yellow, greasy

- distinct clear vacuoles are evident macrovesicular steatosis

- some conditions microvesicular steatosis (tetracycline use, Reyes syndrome)

- uncomplicated fatty change is reversible

mechanisms of fat accumulation

                                                               i.      increased mobilization of fat

                                                              ii.      increased synthesis of fat within liver

                                                            iii.      decreased ability of liver to release fat

b.        glycogen

enlarged pale liver

etiology: glycogen storage diseases, administration of intravenous glucose with DM

c.        pigment

d.        lipofuscin (recovery from serious liver disease)

e.        iron (hemosiderin, reddish-brown rusty liver)

f.         bile (may accumulate in ducts, canaliculi, hepatocytes)

g.        protein

                                                               i.      Mallorys hyaline (cytokeratin, alcoholic liver disease)

                                                             ii.      alpha-1-antitrypsin (most abundant protease inhibitor produced, PAS stain, hereditary)

                                                           iii.      Hepatitis B surface antigen (ground glass cytoplasm)

3.        hepatocyte necrosis ( release of enzymes, transaminases ALT, AST, GGT)

a.        types

                                                               i.      coagulative (ischemia)

                                                             ii.      apoptosis (toxic or immunologic injury, round opaque hypereosinophilic body w/o nucleus)

                                                           iii.      lytic (injured cells swell and rupture)

b.        distribution

                                                               i.      focal (apoptosis or lytic: viral hepatitis and toxic injury)

                                                             ii.      zonal (zone 3 central portion, circulatory failure)

                                                           iii.      diffuse (overwhelming viral, toxic)

4.        inflammation = hepatitis

may be portal, lobular or both

5.        regeneration

increased numbers of binucleated cells

6.        fibrosis


chronic persistent injury (alcoholism, chronic viral hepatitis)


Functional Patterns of Injury

1.        Jaundice

visible increase in bilirubin (breakdown product of hemoglobin, small component of bile)

skin, sclera, urine

etiologies: increased production (hemolysis), defect in uptake or excretion of bilirubin from hepatocyte, obstruction to flow of bile

metabolism of bilirubin

a.        bilirubin is carried to liver by albumin

b.        taken up by liver cells glucuronic acid (water soluble)

c.        actively excreted into biliary canaliculi bile ducts intestine

2.        Cholestasis

manifestations: jaundice, pruritis (bile deposition in skin), skin xanthomas (cholesterol accumulation), intestinal malabsorption

elevation of alkaline phosphatase

3.        Hepatic (Liver) Failure

etiology: cirrhosis or sudden massive liver injury (toxic tetracycline, Reyes, fatty liver of pregnancy, viral infection, acetaminophen)

reflects 80-90% loss

transplantation is only survival option

major manifestations

a.        jaundice

b.        hypoalbuminemia

c.        coagulopathy

d.        hyperammonemia

e.        hyperestrogenemia

f.         fetor hepaticus

g.        hepatic encephalopathy

h.        hepatorenal syndrome


I.                     Normal

Cellular elements and other Features

1.        Hepatocytes

- liver parenchymal cells

- synthesis of protein, lipids, carbohydrates

- detoxification of hormones and other substances

- production of bile

- there is a large hepatic reserve

- function affected by: 1) large loss of parenchyma (fibrosis, necrosis); 2) change in circulation (bypassing of normal contact of blood with hepatocytes)

2.        Kupffer cells

- phagocytic system;

- decreased circulation decreased Kupffer functioning infection

3.        Stellate (Ito) cells

- perisinusoidal distribution (space of Disse)

- normally store Vitamin A

4.        Bile ducts

- carry bile exreted by the liver to the intestine

- become visible during bile stasis (cholestasis)

5.        Portal tracts

6.        Circulation

                                                               i.      Portal vein

- carries blood from the alimentary canal, pancreas, spleen liver

- blood from the portal vein is carried to the sinusoids between the hepatocyte cords

                                                              ii.      Hepatic artery

- supplies oxygenated blood to liver

- blood mixes with portal vein blood (this gives some protection, but lower oxygen tension can damage cells farthest from hepatic artery branches)

                                                            iii.      Central veins

- hepatic venules

- empty into IVC

- RHF dilation of central veins and sinusoids atrophy, necrosis

                                                             iv.      Lymphatics

- lymph vessels are present (ascites formation)

II.                   Hepatitis

1.        Viral Hepatitis

necrosis (apoptosis, lysis) of hepatocytes with an associated inflammatory response

inflammatory response may be minimal

Yellow fever primarily affects liver

description of clinicopathologic syndromes

a.        Carrier State (best characterized: HBV)

b.        Asymptomatic infection

c.        Acute hepatitis

- resolution in weeks-months

- preicteric phase: malaise, fatigue, nausea, anorexia, fever

- icteric phase: jaundice, cholestasis

- hepatocyte necrosis and mononuclear inflammation

- ballooning degeneration

- bridging necrosis

- steatosis (HCV)

d.        Fulminant hepatitis

- hepatic failure within 2-3 weeks of symptoms onset

- necrosis of entire lobules or parts of lobules

e.        Chronic hepatitis

- hepatitis of at least 6 months duration based on biochemical or clinical findings

- portal inflammation (lobule at limiting plate = interface hepatitis) with periportal hepatocyte necrosis

- initially: portal fibrosis (may develop portal-portal and/or portal-central bridging fibrosis)

chronic hepatitis C

- portal: lymphoid aggregates +/- bile duct injury

- lobular: acidophilic bodies, sinusoidal lymphocytosis +/- steatosis

                                                               i.      Hepatitis A



2-6 week incubation

injury: immunologic response (not cytopathic effect)

usually complete recover

never produces chronic hepatitis

diagnosis: antibody titers

                                                             ii.      Hepatitis B

DNA (hepadenovirus)

core, e and surface antigens

parenteral transmission, close contact

4-26 week incubation

injury: immunologic response (primarily cytotoxic T cells)

extrahepatic manifestations: arthiritis, membranous nephropathy

clinical outcomes

a.        subclinical disease recovery

b.        acute hepatitis recovery or (fulminant hepatitis death)

c.        healthy carrier

d.        persistent infection recovery or (chronic hepatitis cirrhosis hepatocellular carcinoma, death)

                                                           iii.      Hepatitis C

RNA (flavivirus)

parenteral transmission, rarely sexual

2-26 week incubation

direct cytopathic and immune-mediated hepatocyte injury

no effective vaccine

45% of alcoholics with liver disease have Hepatitis C

chronic hepatitis > 70%

diagnosis: PCR

clinical outcomes

a.        resolution

b.        chronic hepatitis stable disease or (cirrhosis hepatocellular carcinoma, stable cirrhosis, death)

c.        fulminant hepatitis

                                                            iv.      Hepatitis D


superinfection of cells only already infected with hepatitis B

direct cytopathic effect

incubation: 3-7 weeks

if coinfected with Hep B acute hepatitis recovery

if superinfected after Hep B chronic hepatitis (80%)

                                                              v.      Hepatitis E


India, Mexico, sub-Saharan Africa (rare in U.S.)

transmitted enterically; water-borne

incubation: 6 weeks

high mortality in pregnant women (20%)

diagnosis: serology

2.        Autoimmune Hepatitis

- female predominance

- histology indistinguishable from chronic viral hepatitis (plasma cells may be more prominent)

- diagnosis: serological testing (circulating autoantibodies), ANA, anti-smooth muscle (ASMA), anti-liver/kidney microsomal (ALKM)

- HLA-B8 and DRw3

3.        Toxic and Drug-induced Hepatitis

- symptoms parallel viral hepatitis

- necrosis: carbon tetrachloride, mushrooms, aflatoxins, halothane

- steatosis: alcohol, tetracycline, salicylates (Reye syndrome), amiodarone, methotrexate

- cholestasis: anabolic steroids, contraceptive steroids, cholorpromazine

- hepatic venous occlusion: Vitamin A (toxic doses)

Two categories

a.        predictable toxins

- direct liver injury in proportion to the dose of the agent in most or all subjects

- physiochemical effect: carbon tetrachloride

- metabolic pathway effect: chemotherapy, alcohol, tetracycline

b.        idiosyncratic agents

- hypersensitivity

- halothane (anesthetic), isoniazid (Tb treatment)

III.                 Cirrhosis

definition: hepatic fibrosis with regeneration of hepatocytes that create nodules of liver parenchyma

alteration of circulation

1. shunting of blood away from liver

2. shunting of blood within liver away from sinusoids

clinical manifestations (most problems attributable to circulatory changes)

1. loss of liver parenchyma

2. active parenchymal disease

Pathologic Classification (have little correlation with clinical findings)

1. Micronodular cirrhosis

2. Macronodular cirrhosis


1. Alcoholic liver disease (60-70%)

2. Viral hepatitis

3. Biliary disease

4. Primary Hemochromatosis

5. Wilsons disease

6. alpha-1-antitrypsin deficiency

7. cryptogenic cirrhosis (cirrhosis of unknown etiology)

1.        Clinical Manifestations and Pathophysiology of Cirrhosis

                                                               i.      Portal hypertension

- etiology: anastomoses between portal venous and hepatic arterial, fibrosis, compression of hepatic veins by nodules, thrombosis/obstruction of hepatic or portal veins, severe RHF, constrictive pericarditis

1.        Ascites

- fluid accumulation within peritoneal cavity

- increase in hydrostatic pressure within portal circulation

- hypoalbuminemia

- sodium retention

- flow of lymph through liver capsule into peritoneal cavity

2.        Varices

- anastomoses

- locations: hemorrhoidal plexus, gastroesophageal junction, umbilical vein ( varicosities on abdominal wall = caput medusa)

- complications: massive bleeding from esophageal varices, shunting of blood from liver

clinical outcome of anastomoses

- circulating endogenous estrogens ( gynecomastia and testicular atrophy in men, palmar erythema, spider angiomas)

- increased levels of ammonia (hepatic encephalopathy rigidity, hyperreflexia, asterixis)

- fetor hepaticus: musty body odor from increased mercaptans

- decreased drug clearance

- decreased enteric bacteria clearance (normally cleared by Kupffer cells)

3.        Hypersplenism

etiology: chronic congestion of spleen

increased enlargement increased destruction of erythrocytes, leukocytes, platelets

symptoms: anemia, leukopenia, thrombocytopenia

                                                             ii.      Decreased synthesis of proteins

albumin ( edema, ascites), clotting factors ( coagulopathy)

                                                           iii.      Susceptibility to further (ischemic) liver damage

                                                            iv.      Hepatorenal syndrome

                                                              v.      Hemorrhage

etiology: decreased clotting factors, thrombocytopenia, varices

2.        Pathogenesis of Cirrhosis by Etiology

                                                               i.      Alcoholic liver disease

1.        steatosis

occurs in anyone who consumes alcohol (reversible)

macrovesicular fatty change

2.        alcoholic hepatitis

seen with chronic abuse (not dose related)

reversible but often cirrhosis

compounding factors: viral hepatitis, poor nutrition

hallmarks: steatosis, mallorys hyaline, banquet pattern, inflammation (neutrophils), hepatocytes necrosis, centrilobular fibrosis

3.        cirrhosis


10-15% of alcoholics

women have a higher risk

< 80g/day: reversible

>160g/day: severe injury/cirrhosis

                                                             ii.      Viral hepatitis cirrhosis

vast majority are HCV

usually after chronic hepatitis (sometimes after severe fulminant, post-necrotic hepatitis)

                                                           iii.      Metabolic causes (all autosomal recessive)

1.        Primary hemochromatosis

autosomal recessive (chromosome 6, HFE gene)


excessive absorption of iron deposition of hemosidirin in various organs (liver, pancreas, spleen, heart)

symptoms: bronzing, cirrhosis, DM, cardiomyopathy, arrhythmias, 200X risk of hepatocellular carcinoma

menstruation: protective

pathology: liver is enlarged and brown, micronodular cirrhosis, Prussian blue stain

pathogenesis: 20g iron accumulation directly toxic (free radicals, collagen production, interacts with DNA)

diagnosis: high serum iron

(other causes of iron overload: Sickle cell, blood transfusions, etc.)

2.        Wilsons disease

autosomal recessive disorder of copper metabolism (defective excretion in bile)

chromosome 13 (ATP7B gene)

copper accumulates in liver (adolescent cirrhosis), brain (atrophy of basal ganglia lentiform nucleus Parkinsons like movement disorder and psychiatric disturbances), eye (Kayser Fleischner rings: cornea deposits)

diagnosis: low levels of ceruloplasmin (protein carrier of copper), increased copper in urine

3.        alpha-1-antitrypsin deficiency

autosomal recessive (A1AT is synthesized by liver but not released)

90%: liver AND lung disease (10%: both)

ineffective transport from ER Golgi

clinical manifestations: neonatal cholestasis, hepatitis, cirrhosis, symptomatic emphysema (10%), increased risk of HCC

diagnosis: low A1AT in serum, PAS positive cytoplasmic inclusions in hepatocytes

                                                            iv.      Biliary cirrhosis

clinical features: edema of portal tracts, bile ductular proliferation, bile accumulation (initially in zone 3)

1.        Extrahepatic biliary obstruction

gallstones, neoplasms of biliary tract, inflammatory and traumatic strictures of major ducts, fibrotic pancreas


correction of obstruction arrest progress of liver disease

2.        Primary biliary cirrhosis (PBC)

destruction of intrahepatic bile ducts chronic progressive cholestatic liver disease

epidemiology: middle aged women

unknown etiology (autoimmune?)

granulomas complete cirrhotic nodules

diagnosis: elevation of anti-mitochondrial antibodies (M2 antigen of pyruvate dehydrogenation complex), elevated serum lipids, elevated ALT, AST, alkaline phosphatase

hypergammaglobulinemia, abnormal cell immunity

symptoms: jaundice, pruritis, fatigue

3.        Primary sclerosing cholangitis (PSC)

diffuse inflammatory disorder of extrahepatic and large intrahepatic bile ducts

epidemiology: young men, 3-5th decades

unknown etiology (autoimmune?)

diagnosis: p-ANCA (80%)

4% of patients with ulcerative colitis

70% of PSC have inflammatory bowel disease

cholangiogram: strictures, beading, dilation

symptoms: fatigue, cholestasis, jaundice, pruritis cirrhosis, biliary stones

bile ducts have periductal  onion-skin  pattern

increased risk for cholangiocarcinoma






middle aged women

young men, UC 70%





granulomatous destruction of small intrahepatic bile ducts

strictures and onion-skin fibrosis of large and extrahepatic ducts



ANA, p-ANCA ; gold-standard : cholangiogram

Natural History

liver transplantation 10-15 years after

major complication: cholangiocarcinoma


IV.                 Neoplasms of the Liver

1.        Focal nodular hyperplasia

epidemiology: any age

nodular overgrowth of hepatocytes around an AV malformation

characteristic central stellate scar

contains bile ducts

2.        Hepatic adenoma

young women, oral contraceptives

risk for rupture and bleeding

no bile ducts as part of portal triad in lesion (otherwise, look normal)

presentation: hemorrhage within or around adenoma massive bleeding

3.        Hepatocellular Carcinoma

risk factors: cirrhosis from any cause, Hepatitis B, C (with cirrhosis), Aflatoxin, hemochromatosis

most common liver cancer in trans-Saharan Africa and Southeastern Asia (parallels hepatitis B epidemiology)

epidemiology: older, male, alcohol, nutrition

histology: tend to form cords, with thick cell plates

lesion usually surrounded by abnormal (cirrhotic) tissue

other factors: age, gender, chemicals, alcohol, nutrition, iron accumulation

symptoms: non-specific upper abdominal pain, weight loss, fatigue, elevated AFP

invasion of large veins, hepatic veins, portal veins

metastasizes to lungs, regional lymph nodes, bones

median survival: 7 months

treatment: resistant to radiation, difficult to resect

only hepatic tumor that makes bile

elevated AFP (alpha fetoprotein)

                                                               i.      Fibrolamellar Hepatocellular Carcinoma

less than 5% of HCC

teenagers and young adults

more indolent growth

younger, otherwise healthy patients

central stellate scar (but larger than focal nodular hyperplasia)

histology: well-diffentiated

4.        Cholangiocarcinoma

resembles bile duct epithelium

primary adenocarcinoma of bile duct epithelium

second most common primary malignant liver tumor

etiology: bile stasis/bile inflammatory disorders (PSC=primary sclerosing cholangitis, parasitic infections clonorchis sinensis), thorotrast, anabolic steroids

route of spread: perineural

very poor prognosis

Klatskin tumor

5.        Metastases

most common cancer of the liver in the United States (colon, breast)

6.        Vascular neoplasms

                                                               i.      Hemangioma

most common benign liver tumor; usually incidental

                                                             ii.      Angiosarcoma

etiology: vinyl choloride, thorotrast, aresenic

7.        Hepatoblastoma

hepatic analog of Wilms tumor

resembles fetal liver tissue

aggressive, rapidly growing

V.                   Biliary Calculi (Cholelithiasis)

10-20% of adults in developed countries

two major types: 1) cholesterol [80%]; 2) bilirubin [20%]; 3) calcium

epidemiology: native Americans, age, female sex, pregnancy, obesity, disorders of bile acid metabolism, hyperlipidemia

biliary lipid supersaturation with cholesterol multilamellar vesicles gallbladder hypermotility and cholesterol nucleation gallstones

composition of bile: bile salts, lecithin, cholesterol, bilirubin, electrolytes, protein

more likely to occur in gallbladder than ducts (stasis, concentration)

symptoms: biliary colic, RUQ pain radiates to right scapula, colicky

pathologic findings

1. Rokitansky-Aschoff sinuses: microscopic diverticula of mucosa

2. mild infiltration by lymphocytes and plasma cells

3. muscular thickening of gallbladder wall

composition of calculi

1. cholesterol (85%) [etiology: decrease in bile salts]

2. bilirubin [etiology: increase in bilirubin (chronic hemolytic disease, infection by specific organisms)]

3. calcium calculi

complications of calculi

1. acute cholecystitis (see below)

2. extrahepatic bile duct obstruction (biliary colic, nidus, ascending cholangitis secondary biliary cirrhosis)

3. gallstone ileus (rare; obstruction of intestine)

4. adenocarcinoma (gallstones, porcelain gallbladder is associated)

VI.                 Acute Cholecystitis

etiology: obstruction of cystic duct, chemical irritation from bile, enteric bacteria

15% do not have gallstones (= acalculus acute cholecystitis; etiology: bacterial infection, regurgitation of pancreatic juice, ischemia)

lack of treatment necrosis, bile peritonitis

VII.               Cholesterolosis

macrophages ingest cholesterol, yellow streaks within the mucosa

VIII.             Biliary Stricture

[not emphasized not on test]

progressive destruction/fibrosis of biliary tree jaundice

may be auto-immune (associated with Hashimotos) or post-operative

IX.                 Neoplasms of the Biliary Tract

risk factors: occurs in very elderly patients, associated with gallstones (most cases), calcification

locations: common bile duct, ampulla of vater, hepatic ducts (mimics inflammatory strictures = Klatskin tumor)