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Diseases of the liver
Liver
Normal liver has smooth
brown surface
Weight: 1200-1600 g
Maintaining body metabolic homeostasis:
Lipid and carbohydrate metabolism: production
and secretion of glucose
Protein synthesis: albumin, coagulation factors
Detoxification and drug metabolism
Excretion of bilirubin
Synthesis and excretion of bile salts
Liver anatomy and
histology
Patterns of hepatic injury
Inflammation
Steatosis: accumulation of fat droplets within
hepatocytes
Cell death: those cells closer to the central vein are more
susceptible to ischemia, toxins and drugs leading to
“centri-lobular” necrosis
Fibrosis: Irreversible, affect blood flow and hepatocyte
function
Cirrhosis: End stage liver disease with diffuse fibrosis
and regenerating nodules
Steatosis
Alcohol, Obesity, Diabetes
Hyperlipidemia
Clinical picture:
Silent, or fatigue,
malaise, right upper
quadrant discomfort
Liver cirrhosis
Definition: bridging fibrous septa and parenchymal
nodules with disruption of architecture.
End stage for many diseases affecting the liver
Mechanism: cell death, regeneration and fibrosis
Clinical consequences of liver disease
Hepatic dysfunction:
Decrease synthesis capacity leading to :
Hypoalbuminemia:
edema, ascitis, muscle
wasting, weight loss
Hypoglycemia:
Coagulation
weakness and syncope
factor deficiency: bleeding
Decrease detoxification capacity leading to:
Hyperammonemia
and increase toxic
metabolites: Encephalopathy (altered behavior
and consciousness that may lead to deep coma
and death)
Injury
to other organs by active toxins
Hepato-renal syndrome:
Renal
failure without intrinsic or functional
causes of renal failure.
Clinical picture liver disease
Jaundice: yellow discoloration of skin and sclera due to
accumulation of bilirubin
Cholestasis: systemic accumulation of bilirubin, bile salts and
cholesterol (usually secondary to obstruction)
Portal hypertension in cirrhosis: increased resistance to portal
blood flow
Esophageal varices
Ascitis
Splenomegaly
Hemorrhoids
Malignancy on top of cirrhosis
Jaundice
Accumulation of bilirubin in tissue leading to yellow
discoloration of skin and sclera
Normal serum level: 0.3-1.2 mg/dl; jaundice appears
with levels above 2.0-2.5 mg/dl
Source of bilirubin: the breakdown of old red blood cells
in the spleen releases heme that changes into bilirubin by
specific enzymes.
Bilirubin
Conjugation is a function of the liver by
adding glucuronic acid to bilirubin
-
-
Unconjugated
Albumin
bound
Insoluble in
water, toxic
-
-
Conjugated
Loosely bound
to albumin
Water soluble,
non-toxic,
excreted in
urine
Laboratory evaluation of liver disease
Hepatocyte function:
Hepatocyte injury (enzymes normally present inside the
hepatocytes and released with injury):
Serum albumin
Prothrombin time: prolonged in liver cirrhosis
Serum ammonia
Serum aspartate aminotransferase (AST)
Serum alanine aminotransferase (ALT)
Serum lactate dehydrogenase
Biliary excretory function:
Serum bilirubin
Serum alkaline phosphatase
Serum gamma-glutamyl transpeptidase
Selected disorders of the liver
Viral hepatitis
Drug-induced hepatitis
Autoimmune hepatitis
Alcoholic hepatitis
Hemochromatosis
Wilson disease
Neoplasms of the liver
Hepatitis A virus
RNA virus
Mode of transmission: contaminated water and food
Incubation period: 2-6 weeks
Virus shedding: 2-3 weeks before and 1 week after
appearance of jaundice
No carrier state
No increase risk for chronic hepatitis, or carcinoma
Because viremia is transient, no need to screen
donated blood
Hepatitis B virus
Ds-DNA virus
Mode of transmission: parenteral (blood products,
contaminated needles and IV drug abuse), and body
fluids (including saliva)
Incubation period: 4-26 weeks
Carrier state: yes
Hepatitis B infection: Possible outcomes
Possible outcomes of infection:
Subclinical or acute hepatitis with recovery and
clearance (85%); 1% of those may develop
fulminant hepatitis and death
Healthy carriers (10%)
Persistent infection (5%): 80% recover and 20%
develop chronic hepatitis
20% of chronic hepatitis patients develop cirrhosis
and 10% of those develop hepatocellular carcinoma
Hepatitis C
Ss-RNA virus
Mode of transmission: parenteral, sexual, 40%
unknown source. It is present in the saliva.
Incubation period: 2-26 weeks
HCV is the leading cause for chronic liver disease
Outcomes of infection:
Hepatitis D
Defective RNA virus that needs Hep B capsule to
replicate
Mode of transmission: Parenteral
Coinfection of B and D: mild disease with recovery in
most cases, <5% chronic hepatitis
Superinfection by D after B: accelerated more severe
hepatitis; 80% chronic hepatitis
Hepatitis E
ssRNA virus
Mode of transmission: water-borne
Incubation period: 2-8 weeks
Endemic in certain populations; 40% in Indian
population
Self-limited infection but with higher mortality in
pregnant females
The points to remember
Hepatitis A
Hepatitis B
Hepatitis C
Transmission
Oral-fecal
Parenteral
Parenteral
Carrier state
None
Present
Present
Chronic
hepatitis
None
5-10%
>70%
Fulminant
hepatitis
0.1%
0.1-1.0%
Rare
Carcinoma
No
Yes
Yes
Drug-indued hepatitis
Predictable or unpredictable (idiosyncrasy)
Mechanisms: direct toxicity, conversion of drug to an
active toxin, immune-mediated
A long list of drugs can cause different forms of injury:
hepatitis, fibrosis, granulomas, necrosis, cholestasis,
vascular disorders and neoplasia
Example: Acetaminophen overdose induces centrilobular
necrosis
Autoimmune hepatitis
More in females (70%)
The absence of serologic markers for viral hepatitis
Elevated serum IgG levels
High titers of autoantibodies (antinuclear, anti-smooth
muscle, and anti-microsomal)
Associated with other forms of autoimmune disorders
such as rheumatoid arthritis and ulcerative colitis
Risk for cirrhosis is 5%
Respond to immunosuppressive drugs
Alcoholic liver disease
100,000 death annually related to alcohol; 20,000 are
related directly to end-stage liver cirrhosis
Effects on liver:
80% fatty liver (steatosis)
10% alcoholic hepatitis
10% cirrhosis
Hereditary hemochromatosis
Autosomal recessive disease characterized by increased
body iron, most of which is deposited in the liver and
pancreas.
Mostly due to increased iron absorption and
accumulation over the years.
Due to mutations in the hemochromatosis gene (HFE); a
gene that regulates iron absorption.
Excess iron damages DNA, lipids and stimulates
collagen formation (fibrosis)
Clinical picture:
Males are more affected; 50-60 years old
Liver cirrhosis, skin pigmentation, diabetes
(pancreatic fibrosis), risk for hepatocellular
carcinoma.
Diagnosis: elevated serum and tissue iron.
Early detection and therapy by phlebotomy and iron
chelators lead to normal life expectancy
Wilson disease
Autosomal recessive disorder characterized by accumulation of
copper in liver, brain and eyes, among other organs
Less common than hemochromatosis
The mutated gene is located on chromosome 13; the mutation leads
to failure to excrete copper into bile, and its accumulation in tissue
Clinical picture: neuropsychiatric manifestations, acute and
chronic liver disease
Diagnosis: Clinical picture, increased hepatic and urinary copper,
and decreased serum copper binding protein.
Biliary disease
Secondary biliary cirrhosis: secondary to extrahepatic
bile obstruction by stones, atresia or tumors
Primary biliary cirrhosis: immune-mediated destruction
of intrahepatic bile ducts, more in females
Primary sclerosing cholangitis: chronic fibrosis of intraand extra-hepatic bile ducts; more in men, association
with ulcerative colitis
Tumor of the liver
Liver cell adenoma
Occurs in women of childbearing age in relation to
oral contraceptives; it regresses on discontinuation
of hormones
Well circumscribed mass
Sheets of hepatocytes with no
portal tracts
Liver cell adenoma
Significance of this benign tumor:
It may be mistaken for carcinoma
Subcapsular adenomas are at risk for rupture,
especially during pregnancy leading to lifethreatening intraabdominal hemorrhage
Hepatocellular carcinoma (HCC)
Risk factors:
Strongly associated with hepatitis B and C infection.
The carrier state for hepatitis B carries 200-fold
increased risk for HCC
Chronic liver disease (e.g. alcohol)
Hepatotoxins
Clinical picture:
Often patient already
has liver cirrhosis,
with rapid increase in
liver size, worsening
ascites, fever and pain;
elevated serum alpha
fetoprotein levels
Median survival is 7 months (death from bleeding, liver failure, or
profound cachexia)
Metastatic carcinoma
The most common malignant tumors in the liver
Usually multiple lesions
The most common primary sites are colon, lung,
breast, pancreas and stomach
The Pancreas
The Pancreas
85% exocrine: enzymes
15% endocrine: insulin,
for digestion
glucagon and others
Acute and chronic
Diabetes
pancreatitis
Tumors
Cystic fibrosis
Tumors
Pancreatic exocrine enzymes
Acute pancreatitis
Acute pancreatitis
Clinical presentation: abdominal pain radiating to the
back, elevated serum amylase and lipase, hypocalcemia
Rise in serum lipase is more specific for pancreatitis.
Complications: infections, abscess, pseudocyst
Mortality is high: 20-40%, from shock, sepsis or acute
respiratory failure, acute renal failure, disseminated
intravascular coagulation
Chronic pancreatitis
Progressive destruction of pancreatic parenchyma and
its replacement by fibrosis
Predisposing factors: alcohol, hypercalcemia or
idiopathic
30% of idiopathic cases have been found to have
mutation in CFTR gene
Complications: Pseudocyst, malabsorption, 2ry diabetes
Diagnosis: abdominal pain, malabsorption, calcifications
on X-ray
Pancreatic adenocarcinoma
The 5th most frequent cause of death from cancer
Risk factors: smoking
CP: symptoms are late; pain and jaundice
Prognosis is poor: 5% survive for 5 years
Islet cell tumors
Rare compared to adenocarcinoma
Insulinomas: secrete insulin hypoglycemia
behavioral changes, confusion and coma. Over
90% are benign
Gastrinomas: secrete gastrin increase acid
production duodenal and gastric ulcers
Gallbladder
Gallstones
Afflict 10% of adult population in
Western countries
Costs of management: $6 billion a
year
20 million patients are estimated
to have gallstones totalling several
tons
Made of cholesterol, bilirubin and
calcium salts with different
concentrations
Two types: cholesterol and
pigmented stones
Gallstones
Cholesterol
Western > others
Advancing age
Female sex
Obesity
Hyperlipidemia and
bile stasis
Pigmented
Asian > Western
Hemolytic anemia
Biliary infection
Complications: empyema, perforation, fistula,
inflammation, obstruction, pancreatitis
Acute cholecystitis
Calculous: acute inflammation of a gallbladder that has
stones. It may represent a medical emergency; no
associated infection initially
Acalculous: no stones, in severely ill patients, severe
trauma, burns and sepsis
Chronic cholecystitis
Almost always associated with gallstones