General Pathology (MHS)

The Liver
Sometime in December

Normal Liver • Apoptotic cell death (when there is continuous

• Located in the RUQ of the abdomen injury) –shrunken, pyknotic and intensely
• Wt 1500g (2.5% of TBW) eosinophilic cells obtaining fragmented nuclei
• In surgery, divided into 8 lobes – caudate lobe (1st • Lytic cell death (outcome of balooning
lobe), the remaining (2nd to 8th lobe); designated on degeneration)
the basis of blood supply • Centrilobular – drug and toxic reactions
• Midzonal - rare
• Periportal – eclampsia
• Focal/ spotty – scattered cells within hepatic
lobules
• Bridging necrosis - contigous

C. INFLAMMATION
• Hepatitis – injury to the liver associated with
• Histologically, are composed of hexagonal lobules influx of acute and chronic inflammatory cells
o In the center: terminal hepatic vein • Viral hepatitis
o In the periphery: hepatic tract (portal vein, o quiescent lymphocyte may collect into the
hepatic artery & bile duct) portal tracts
o Hepatic plates with thin layer of endothelial cells o Spill over the periportal parenchyma as
o Stellate cells which are precursors of fibrous activated lymphocytes
tissue which proliferates in cirrhosis
D. REGENERATION
• Regeneration occurs in all but most fulminant
hepatic disease
• Hepatocyte proliferation is marked by:
o Mitoses
o Thickening of the hepatocyte cords
o Disorganization of the parenchymal
architecture

E. FIBROSIS
• Fibrous tissue – formed in response to
inflammation or direct toxic insult
• Points to generally irreversible hepatic damage
Patterns of Hepatic Injury
A. DEGENERATION AND INTRACELLULAR Hepatic Failure
ACCUMULATION • End point
• Swelling (reversible), ballooning (clumping o o 80-90 % of hepatic functional capacity is eroded
organelles) degeneration o 70-95 % mortality
• Morphologic alterations that causes hepatic failure
• Feathery degeneration (in cholestasis)
o Massive hepatic necrosis
• Steatosis (there is displacement of nucleus) o Chronic liver disease – most common route
o Microvesicular - acute fatty liver of o Hepatic dysfunction without overt necrosis
pregnancy • Clinical features
o Macrovesicular – diabetic/ obese px o Jaundice
o Both – alcoholic fatty liver o Hypoalbuminemia
o Hyperammonemia
B. NECROSIS AND APOPTOSIS o Fetor hepaticus
• Ischemic coagulative necrosis- poorly stained & o Portosystemic shunting
mummified, lysed nuclei
o Hyperestrogenemia
MR*, Mel, Eisa (kami ba trans n2?) 1 of 6
 General Pathology – Diseases of the Liver by MHS Page 2 of 6

• Life threatening
o Susceptible to multiple organ failure
o Coagulopathy
 Impaired synthesis of CF II, VII, IX, X
o Massive GI bleeding e.g. gastroesophageal
varices
 Further metabolic load on the liver
• Hepatic encephalopathy
o Subtle behavioral changes to confusion à stupor
àcoma
o Neurologic signs
 Rigidity
 Hyperreflexia
 Asterixis
o Increase ammonia levels
• Hepatorenal syndrome
o Functional abn
 Na retention
 Impaired water excretion
 Decrease renal perfusion and GFR
 Drop in urine output assoc with rising BUN
and creatinine

Cirrhosis
• Among top 10 causes of death
• Characteristics
o Bridging fibrous septae
o Parenchymal nodules formed by septae
o Disruption of the architecture
• Clinical features
• Pathogenesis o May be clinically silent
o Collagen Types I & III are normally in o Anorexia
 Portal tract, central vein, space of Disse o Weight loss
o Type I & III collagen à deposited in lobules o Weakness
o New vascular channels o Osteoporosis
o Deposition of collagen in Space of Disse (loss of o Frank debilitation
hepatic plates and endothelial cells) • Mechanism of cirrhotic
o Loss of fenestrations in sinusoidal endothelial deaths
cells o Progressive liver failure
o No exchange of solutes between hepatocytes & o Complications related to
plasma portal hypertension
o Impaired secretion of proteins o Development of
• Perisinusoidal stellate cells hepatocellular
o Source of fibrosis carcinoma
o Vitamin A fat storing cells (normally)located in
space of Disse Portal Hypertension
o Activated in cirrhosis (stimulated into • Increase resistance to blood
myofibroblasts) flow
 Robust mitotic activity • Pre-hepatic, post hepatic,
 Shift from resting lipocyte to myofibroblast intrahepatic
phenotype • In cirrhosis
 Increase capacity for synthesis of
extracellular matrix
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o Inc resistance to portal flow at the level of  Deficiency of canalicular membrane transporters
sinusoids  Dubin-Johnson syndrome,
o Compression of terminal hepatic vein  Rotor syndrome)Impaired bile flow
o Expansile nodules
• Clinical Consequences Alcoholic Liver Disease
o Ascites – at least 500 ml • Forms
o Intestinal fluid leakage, renal retention of Na & o Hepatic steatosis
H20 o Alcoholic hepatitis
o Portosystemic venous shunts - bypass  Hepatocyte swelling & necrosis
o Rectum, cardioesophageal jxn (65%),  Mallory bodies
retroperitoneum  Neutrophilic reaction
o Falciform ligament (periumbilical collaterals)  Fibrosis
o Congestive splenomegaly – 1,000g o Alcoholic cirrhosis
o Hepatic encephalopathy • Pathogenesis

Jaundice & Cholestasis

• Bilirubin- end product of
heme degradation
• UGT1A1 – a product of UGT
1 gene located on
chromosome 2q37
• Causes of Jaundice
o Predominantly
Unconjugated
Hyperbilirubinemia Metabolic Liver Diseases
 Excess production A. Non-alcoholic fatty liver disease & steatosis
of bilirubin • Strong assoc with obesity, dyslipidemia,
 Hemolytic anemias hyperinsulinemia and insulin resistance
 Resorption of blood • Small and large vesicles of fat acumulate in
from internal hepatocytes
hemorrhage • Also an intermediate form of renal damage
 Ineffective • Cirrhosis may occur, presumably the result of
erythropoiesis years of subclinical pregression
syndromes (e.g.,
pernicious anemia, B. Hemochromatosis
thalassemia)
• Excessive accumulation of body iron
 Reduced hepatic
• Total body iron 2-6 g normally, 0.5 g is stored in
uptake
the liver
 Drug interference
• May exceed 50 g, 1/3 accumulate in the liver
with membrane
• Fully developed cases exhibit
carrier systems
o Micronodular cirrhosis
 Some cases of Gilbert syndrome
o Diabetes mellitus (75-80 % of cases)
 Impaired bilirubin conjugation
o Skin pigmentation (75-80 % of cases)
 Physiologic jaundice of the newborn (decreased
• Hemochromatosis gene – 6p21.3
UGT1A1 activity, decreased excretion)
o HFE gene regulates intestinal absorption of
 Breast milk jaundice (β-glucuronidases in milk)
dietary iron
 Genetic deficiency of UGT1A1 activity (Crigler-
• Excessive iron
Najjar syndrome types I and II)Gilbert syndrome
o Lipid peroxidation via iron catalyzed free
(mixed etiologies)Diffuse hepatocellular disease
radical reactions
(e.g., viral or drug-induced hepatitis, cirrhosis)
o Stimulation of collagen formation
o Predominantly Conjugated Hyperbilirubinemia
 General Pathology – Diseases of the Liver by MHS Page 4 of 6

o Interaction of reactive oxygen species and • Treatment

iron itselfwith DNA à lethal injury à o Penicillamine
predisposition to hepatocellular carcinoma • Diagnosis
• Morphology o Decrease serum ceruloplasmin
o Hereditary hemochromatosis o Increase hepatic copper
 Deposition of hemosiderin o Increase urinary excretion of copper
 Cirrhosis
 Pancreatic fibrosis D. α1 antitrypsin deficiency
o Liver • Autosomal recessive disorder
 Golden yellow hemosiderin granules in • Most commonly diagnosed genetic liver disease
the cytoplasm in periportal hepatocytes in children
 Stain blue with Prussian blue • α1 antitrypsin:
 Progressive involvement of the lobule o Inhibition of protease, part.. elastase,
 Direct hepatotoxin cathepsin G, and proteinase 3 (from
• Hereditary hemochromatosis neutrophils)
o Often in males, evident before 40 o Small 384 amino acid plasma glycoprotein
o Hepatomegaly synthesized by hepatocytes
o Abdominal pain o Gene at chromosome 14
o Skin pigmentation • Pulmonary emphysema & liver disease
o Derranged glucose homeostasis • Morphology
o Cardiac dysfunction o Round to oval cytoplasmic inclusions
o Strongly PAS positive and diastase resistant
C. Wilson disease o Neonatal hepatitis, fibrosis, cirrhosis
• Autosomal recessive • Clinical features
• Accumulation of toxic levels of copper in many o Neonatal hepatitis
tissues and organs (liver, brain & eye) o May remain silent until cirrhosis occurs later
• Cerulloplasmin- in life
o Copper +α2 globulin (ER)  10-20 % of newborns
o 90-95 % of plasma copper • Treatment liver transplantation
o Desialylated, endocytosed by liver, excreted
in the bile E. Neonatal cholestasis
• Gene ATP7B, chromosome 13 – encodes 7.5 kB • 1 in 2500 live birth
transcript for transmembrane copper transport • Major conditions:
ATPase o Biliary atresia
• 1:200 – frequency of mutated alleles o Neonatal hepatitis
• Defective biliary excretion leads to copper • Morphologic features
o Lobular disarray
accumulation in the liver à reactive oxygen
species à toxic liver injury
o Giant cell transformation of hepatocytes
(unique feature)
• Liver Changes
o Hepatocellular and canalicular cholestasis
o Fatty change with vacuolated nuclei
o Mononuclear infiltration of portal areas
o Acute hepatitis like
o Reactive changes in Kupffer cells
o Chronic hepatitis
o Extramedullary hematopoiesis
o Massive liver necrosis
• Brain changes
Hepatic Disease Assoc with Pregnancy
o Basal ganglia, paticularly the putamen is
A. Preeclampsia
affected
• 7-10 % of pregnancies
• Eye lesion
o Kayser Fleischer rings – deposits of copper in
• Maternal HPN, proteinuria, peripheral edema,
coagulation abnormalities, varying degrees of
Decemet’s membranes in the cornea
DIC
• Clinical features
• Eclampsia –if with convulsions and hyperreflexia
o Onset is variable, rare before 6 years old
o Acute or chronic liver disease • HELLP syndrome – hemolysis, elevated liver
o Neuropsychiatric manifestation enzymes, low platelets
 General Pathology – Diseases of the Liver by MHS Page 5 of 6

• Morphology
o Normal in size, firm, pale B. Angiosarcoma
o Ischemic infarction can be seen • Tumor of adults
o Fibrin deposits in sinusoid • Associated with vinyl chloride exposure, arsenic
o Hemorrhage in space of Disse or thorotrast
o Hepatic hematoma à rupture • Poor prognosis
• Treatment • Vascularized tissue
o Termination of pregnancy
C. Hepatocellular carcinoma
B. Acute Fatty Liver of Pregnancy • Malignant tumor of
• Spectrum from modest to subclinical hepatic • 85 % of cases of HCC occur in countries with
dysfunction to hepatic failure, coma & death high rates of chronic hepatitis B virus infection
• 20-40 % coexistent preeclampsia • Cirrhosis is present in 85-90 % of patients
• Diagnosis: • Etiologic associations:
o Biopsy – microvesicular steatosis o Viral infection
o Depends on high level of suspicion & o Chronic alcoholism
confirmation by special stains oil red-O o Food contaminants (aflatoxin)
• Morphology
Liver Nodules o Pale tan to yellow liver with nodules
A. Focal Nodular Hyperplasia • Factors implicating HBV & HCV in HCC
• Sponteneous mass lesion o Repeated cycles of cell death and
• Lighter than surrounding liver regeneration
• Well demarcated but poorly encapsulated o Hepatocyte dysplasia result from point
mutation in selected cellular genes
B. Focal Nodular Hyperplasia o Damage DNA repair mechanism
• Sponteneous mass lesion o Genomic instability is more likely in the
• Lighter than surrounding liver presence of integrated HBV DNA, (giving rise
• Well demarcated but poorly encapsulated deletions, translocations, and duplications).
o X-protein, that is a transcriptional activator
Benign Neoplasm of many genes and is present in most tumors
A. Cavernous hemangioma with integrated HBV DNA.
• underneath capsule
• benign tumor of blood vessels, composed of
tortuous vessels
• complication: hemorrhages

B. Liver cell adenoma

• young women in oral contraceptives
• Morphology:
o Pale, yellow tan, and frequently bile stained
nodules
o Well demarcated
o Sheets and cords of cells resembling normal
hepatocytes

Malignant Tumors
A. Hepatoblastoma
D. Cholangiocarcinoma
• Arise from embryonic cells of the liver
• Cells are similar to biliary tract epithelium
• Most common liver cell tumor of young children
• Malignancy of the biliary tree
• Fatal within few years if not resected
• Risk factors:
• Morphology
o Exposure to thorotrast
o Epithelial type
o Primary sclerosing cholangitis
o Mixed epithelial and mesenchymal type
 General Pathology – Diseases of the Liver by MHS Page 6 of 6

o Congenital fibropolycystic disease of the

biliary system
o Opisthorchis sinensis – in the orient

E. Metastatic Tumors
• Breast CA
• Lung CA
• Colon CA
• Leukemia and lymphomas

Quiz
1 – 3 Patterns of Hepatic Injury
4 Cells that are the cause of fibrosis – stellate cells
5 Excess iron – hemochromatosis
6 Accumulation of Cu – Wilson Dse
7 Benign tumor in women on OCPs – liver cell adenoma
8 – 9 S/Sx of portal hypertension – ascites, portocaval
shunts etc

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