Liver pathology lecture 1

babylon university stage fourth
college of medicine lecture 1
dr. athraa falah


the hepatic pathology

general features of hepatic disease
the major primary diseases of the liver are viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (nafld), and hepatocellular carcinoma (hcc).
in the table below there are the most important laboratory tests that evaluate the liver function.
table laboratory evaluation of liver disease

hepatocyte integrity serum aspartate aminotransferase (ast)
serum alanine aminotransferase (alt)
biliary function serum bilirubin (total and direct)
serum alkaline phosphatase
hepatocyte function serum albumin
prothrombin time


patterns of hepatic injury

• hepatocyte degeneration and intracellular accumulations
• hepatocyte necrosis and apoptosis
• inflammation
• regeneration
• fibrosis

clinical syndromes related to liver disease
1. jaundice and cholestasis.
2. hepatic failure
3. cirrhosis
4. portal hypertension
jaundice and cholestasis
alterations of bile formation become clinically evident as yellow discoloration of the skin and sclera (jaundice and icterus, respectively) due to retention of bilirubin, and as cholestasis, characterized by systemic retention of not only bilirubin but also other solutes eliminated in bile.
bilirubin metabolism and elimination.
(1) normal bilirubin production from heme (0.2–0.3 gm/day) is derived primarily from the breakdown of senescent circulating erythrocytes.
(2) extrahepatic bilirubin is bound to serum albumin and delivered to the liver.
(3) hepatocellular uptake and (4) glucuronidation in the endoplasmic reticulum generate bilirubin monoglucuronides and diglucuronides, which are water soluble and readily excreted into bile.
(5) gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. the urobilinogens and the residue of intact pigments are excreted in the feces, with some reabsorption and excretion into urine.

pathophysiology of jaundice
there are two important pathophysiologic differences between the two forms of bilirubin. unconjugated bilirubin is virtually insoluble in water at physiologic ph and exists in tight complexes with serum albumin. this form cannot be excreted in the urine even when blood levels are high.
normally, a very small amount of unconjugated bilirubin is present as an albumin-free anion in plasma. this fraction of unbound bilirubin may diffuse into tissues, particularly the brain in infants, and produce toxic injury which may cause severe neurologic damage, referred to as kernicterus.
in contrast, conjugated bilirubin is water-soluble, nontoxic, and only loosely bound to albumin, and can be excreted in urine.
serum bilirubin levels in the normal adult vary between 0.3 and 1.2 mg/dl, jaundice becomes evident when the serum bilirubin levels rise above 2.0 to 2.5 mg/dl
jaundice occurs when the equilibrium between bilirubin production and clearance is disturbed by one or more of the following mechanisms ( table below ):
(1) excessive extrahepatic production of bilirubin
(2) reduced hepatocyte uptake
(3) impaired conjugation
(4) decreased hepatocellular excretion and
(5) impaired bile flow.
the first three mechanisms produce unconjugated hyperbilirubinemia, and the latter two produce predominantly conjugated hyperbilirubinemia.
table causes of jaundice
predominantly unconjugated hyperbilirubinemia
excess production of bilirubin
hemolytic anemias
resorption of blood from internal hemorrhage (e.g., alimentary tract bleeding, hematomas)
ineffective erythropoiesis (e.g., pernicious anemia, thalassemia)

reduced hepatic uptake
drug interference with membrane carrier systems
some cases of gilbert syndrome

impaired bilirubin conjugation
physiologic jaundice of the newborn {decreased ugt1a1(uridine diphosphate–glucuronyltransferase1a1) activity, decreased excretion}
breast milk jaundice (?-glucuronidases in milk)
genetic deficiency of ugt1a1 activity (crigler-najjar syndrome types i and ii)
gilbert syndrome
diffuse hepatocellular disease (e.g., viral or drug-induced hepatitis, cirrhosis)


predominantly conjugated hyperbilirubinemia
deficiency of canalicular membrane transporters (dubin-johnson syndrome, rotor syndrome)
impaired bile flow


neonatal jaundice.
because the hepatic machinery for conjugating and excreting bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient and mild unconjugated hyperbilirubinemia, termed neonatal jaundice or physiologic jaundice of the newborn. this may be exacerbated by breastfeeding, as a result of the presence of bilirubin-deconjugating enzymes in breast milk
hereditary hyperbilirubinemias.
multiple genetic mutations can cause hereditary hyperbilirubinemia(tablebelow).
in crigler-najjar syndrome type i hepatic ugt1a1 is completely absent. the liver is morphologically normal by light and electron microscopy. however, serum unconjugated bilirubin reaches very high levels, producing severe jaundice and icterus. without liver transplantation, this condition is invariably fatal.
table 18-3 hereditary hyperbilirubinemias
disorder inheritance defects in bilirubin metabolism liver pathology clinical course
unconjugated hyperbilirubinemia
crigler-najjar syndrome type i autosomal recessive absent ugt1a1 activity none fatal in neonatal period
crigler-najjar syndrome type ii autosomal dominant with variable penetrance decreased ugt1a1 activity none generally mild, occasional kernicterus
gilbert syndrome autosomal recessive decreased ugt1a1 activity none innocuous
conjugated hyperbilirubinemia
dubin-johnson syndrome autosomal recessive impaired biliary excretion of bilirubin glucuronides due to mutation in canalicular multidrug resistance protein 2 (mrp2) pigmented cytopasmic globules ?epinephrine metabolites innocuous
rotor syndrome autosomal recessive decreased hepatic uptake and storage?
decreased biliary excretion?
none innocuous

crigler-najjar syndrome type ii is a less severe, nonfatal disorder in which ugt1a1 enzyme activity is greatly reduced. the only major consequence is extraordinarily yellow skin. phenobarbital treatment can improve bilirubin glucuronidation .
gilbert syndrome is a relatively common, benign, inherited condition presenting with mild, fluctuating hyperbilirubinemia, in the absence of hemolysis or liver disease. it affects 3% to 10% of the u.s. population. the mild hyperbilirubinemia may go undiscovered for years. when detected in adolescence or adult life it is typically in association with stress, such as an intercurrent illness, strenuous exercise, or fasting. individuals who have gilbert syndrome may be more susceptible to adverse effects of drugs that are metabolized by ugt1a1.
dubin-johnson syndrome is an autosomal recessive disorder characterized by chronic conjugated hyperbilirubinemia. it is caused by a defect in hepatocellular excretion of bilirubin glucuronides across the canalicular membrane. the liver is darkly pigmented because of coarse pigmented granules within the cytoplasm of hepatocytes . the liver is otherwise normal. apart from chronic or recurrent jaundice of fluctuating intensity, most patients are asymptomatic and have a normal life expectancy.
cholestasis
it is a pathologic condition of impaired bile formation and bile flow, leading to accumulation of bile pigment in the hepatic parenchyma. it can be caused by:
-extrahepatic or intrahepatic obstruction of bile channels, or by
-defects in hepatocyte bile secretion.
patients may have jaundice, pruritus, skin xanthomas (focal accumulation of cholesterol), or symptoms related to intestinal malabsorption, including nutritional deficiencies of the fat-soluble vitamins a, d, or k.
-a characteristic laboratory finding is elevated serum alkaline phosphatase and ?-glutamyl transpeptidase (ggt) enzymes.
morphology.
- accumulation of bile pigment within the hepatic parenchyma.
-elongated green-brown plugs of bile are visible in dilated bile canaliculi.
-rupture of canaliculi leads to extravasation of bile, which is quickly phagocytosed by kupffer cells.
-dropinglets of bile pigment also accumulate within hepatocytes, which can take on a fine, foamy appearance (feathery degeneration).
extrahepatic biliary obstruction is frequently amenable to surgical alleviation. in contrast, intrahepatic cholestasis is not benefited by surgery (short of transplantation), and the patient s condition may be worsened by an operative procedure.
infectious disorders of liver

viral hepatitis
unless otherwise specified, the term viral hepatitis is applied for hepatic infections caused by a group of viruses known as hepatotropic virus (hepatitis viruses a, b, c, d, and e) that have a particular affinity for the liver.
table the hepatitis viruses
virus hepatitis a hepatitis b hepatitis c hepatitis d hepatitis e
type of virus ssrna partially dsdna ssrna circular defective ssrna ssrna
viral family hepatovirus related to picornavirus hepadnavirus flaviridae subviral particle in deltaviridae family calicivirus
route of transmission fecal-oral (contaminated food or water) parenteral, sexual contract, perinatal parenteral intranasal cocaine use is a risk factor parenteral fecal-oral
mean incubation period 2–4 weeks 1–4 months 7–8 weeks same as hbv 4–5 weeks
frequency of chronic liver disease never 10% ?80% 5% (coinfection) ?70% for superinfection never
diagnosis detection of serum igm antibodies detection of hbsag or antibody to hbcag pcr for hcv rna 3rd-generation elisa for antibody detection detection of igm and igg antibodies hdv rna serum hdag in liver pcr for hev rna detection of serum igm and igg antibodies

hepatitis a virus
hepatitis a virus (hav) is a benign, self-limited disease with an incubation period of 3 to 6 weeks. hav does not cause chronic hepatitis or a carrier state and only rarely causes fulminant hepatitis, so the fatality rate associated with hav is about 0.1%.
hav occurs throughout the world and is endemic in countries with substandard hygiene and sanitation, where populations may have detectable antibodies to hav by the age of 10 years. clinical disease tends to be mild or asymptomatic, and is rare after childhood.
affected individuals have nonspecific symptoms such as fatigue and loss of appetite, and often develop jaundice. overall, hav accounts for about 25% of clinically evident acute hepatitis worldwide .
specific igm antibody against hav appears in blood at the onset of symptoms, constituting a reliable marker of acute infection ( fig. below ). fecal shedding of the virus ends as the igm titer rises. the igm response usually begins to decline in a few months and is followed by the appearance of igg anti-hav. the latter persists for years, perhaps conferring lifelong immunity against reinfection by all strains of hav. however, there are no routinely available tests for igg anti-hav. the presence of this antibody is inferred from the difference between total and igm anti-hav.

the sequence of serologic markers in acute hepatitis a infection
hepatitis b virus (hbv)
hbv can produce:
(1) acute hepatitis with recovery and clearance of the virus,
(2) nonprogressive chronic hepatitis,
(3) progressive chronic disease ending in cirrhosis,
(4) fulminant hepatitis with massive liver necrosis, and
(5) an asymptomatic carrier state.
hbv-induced chronic liver disease is an important precursor for the development of hepatocellular carcinoma. the clinical outcomes of hbv infection are show in figure below .

? the potential outcomes with hepatitis b infection in adults
liver disease due to hbv is an enormous global health problem. one third of the world population (2 billion people) have been infected with hbv, and 400 million people have chronic infection. the carrier rate is largely dictated by the age at infection, being the highest when infection occurs in children perinatally and the lowest when adults are infected.
the mode of transmission of hbv occurs in different ways:
-perinatal transmission during childbirth .
-horizontal transmission (through minor cuts and breaks in the skin or mucous membranes among children with close bodily contact),
-unprotected heterosexual or homosexual intercourse and intravenous drug abuse (sharing of needles and syringes) .
the incidence of transfusion-related spread has decreased greatly in recent years due to screening of donated blood.
approximately 70% have mild or no symptoms and do not develop jaundice. the remaining 30% have nonspecific constitutional symptoms such as anorexia, fever, jaundice, and upper right quadrant pain. in almost all cases the infection is self-limited and resolves without treatment. chronic disease rarely occurs in adults in non-endemic areas. fulminant hepatitis is also rare, occurring in approximately 0.1 to 0.5% of cases.
the natural course of the disease can be followed by serum markers ( figure below).


sequence of serologic markers for hepatitis b viral hepatitis demonstrating (a) acute infection with resolution and (b) progression to chronic infection.

• hbsag appears before the onset of symptoms, peaks during overt disease, and then declines to undetectable levels in 3 to 6 months.
• anti-hbs antibody does not rise until the acute disease is over and is usually not detectable for a few weeks to several months after the disappearance of hbsag.
• hbeag, hbv-dna, and dna polymerase appear in serum soon after hbsag, and all signify active viral replication. persistence of hbeag is an important indicator of continued viral replication, infectivity, and probable progression to chronic hepatitis. the appearance of anti-hbe antibodies implies that an acute infection has peaked and is on the wane.
• igm anti-hbc becomes detectable in serum shortly before the onset of symptoms, concurrent with the onset of elevated serum aminotransferase levels (indicative of hepatocyte destruction). over a period of months the igm anti-hbc antibody is replaced by igg anti-hbc.
hepatitis b can prevented by vaccination and by the screening of donor blood, organs, and tissues.