Path 843-866
Viral Hepatitis
 Systemic viral infections can involve liver in
o Infectious mononucleosis (EBV); may cause mild hepatitis during acute phase
o CMV infection, particularly in newborn or immunosuppressed patient
o Yellow fever virus
o Infrequently in children and immunosuppressed, liver affected in course of rubella, adenovirus, herpes
virus, or enterovirus infections
 Hepatitis A – self-limited disease w/incubation period of 3-6 weeks; only rarely causes fulminant hepatitis
o Acute HAV tends to be sporadic febrile illness
o Small, non-enveloped, positive-strand RNA picornavirus that occupies own genus (Hepatovirus)
 Icosahedral capsid; can be cultured in vitro
o Spread by ingestion of contaminated water and foods; shed in stool for 2-3 weeks before and 1 week
after onset of jaundice
 Spread may occur by consumption of raw or steamed shellfish that concentrate virus from
seawater contaminated w/human sewage
o CD8+ T cells play key role in hepatocellular injury during HAV infection
o Specific IgM antibody against HAV appears in blood at onset of symptoms (marker of acute infection)
 IgG antibody appears ina few months, and IgM response declines (lifelong immunity) – no
routinely available tests for IgG anti-HAV (presence inferred from difference between total and
IgM anti-HAV
o HAV vaccine effective in preventing infection
 Hepatitis B can produce acute hepatitis w/recovery and clearance of virus, nonprogressive chronic hepatitis,
progressive chronic disease ending in cirrhosis, fulminant hepatitis w/massive liver necrosis, and asymptomatic
carrier state
o Chronic liver disease precursor for development of hepatocellular carcinoma
o Spread through close bodily contact through breaks in skin or mucous membranes; unprotected sex or
IV drug use can spread
o Incubation period of 4-26 weeks
o HBV remains in blood until and during active episodes of acute and chronic hepatitis
o In U.S., 70% of those infected have mild or no symptoms and don’t develop jaundice; rest have
nonspecific constitutional symptoms (anorexia, fever, jaundice, and upper right quadrant pain)
 Infection self-limited and resolves w/o treatment; chronic and fulminant disease rare
o Member of Hepadnaviridae family of DNA viruses; 8 HBV genotypes
 Mature HBV virion is spherical double-layered Dane particle that has outer surface envelope of
protein, lipid, and carb enclosing electron-dense hexagonal core
 Partially double-stranded circular DNA molecule
 Genome contains 4 open reading frames coding for
 Nucleocapsid core protein (HBcAg (hepatitis B core antigen)) and longer polypeptide
w/precore and core region (HBeAg (hepatitis B “e” antigen))
o Precore region directs HBeAg toward secretion into blood; HBcAg remains in
hepatocytes for assembly of complete virions
 Envelope glycoproteins (HBsAg (hepatitis B surface antigen)), which consist of 3 related
proteins (large HBsAg (containing Pre-S1, Pre-S2, and S), middle HBsAg (containing PreS2 and S), and small HBsAg (containing S only))
o Infected hepatocytes capable of synthesizing and secreting noninfective surface
protein (mostly small HBsAg)
 Polymerase that exhibits both DNA polymerase activity and reverse transcriptase
activity; genomic replication occurs via intermediate RNA template through unique
replication cycle DNA  RNA  DNA
 HBx protein – necessary for virus replication and may act as transcriptional
transactivator of viral genes and wide variety of host genes
o Implicated in pathogenesis of liver cancer
o

Natural course of disease followed by serum markers
 HBsAg appears before onset of symptoms, peaks during overt disease, and declines to
undetectable levels in 3-6 months
 Anti-HBs antibody rises when acute disease over; not detectable for few weeks to several
months after disappearance of HBsAg; may persist for life, conferring protection
 HBeAg, HBV-DNA, and DNA polymerase appear in serum soon after HBsAg; signify active viral
replication, infectivity, and probable progression to chronic hepatitis
 Appearance of anti-HBe antibodies implies acute infection peaked and is on wane
 IgM anti-HBc becomes
detectable in serum
shortly before onset of
symptoms, concurrent
w/onset of elevated
serum aminotransferase
levels (indicative of
hepatocyte destruction)
 Over period of
months, IgM
antiHBc replaced
by IgG anti-HBc
o Occasionally, mutated strains of
HBV emerge that don’t produce
HBeAg but are replication competent and express HBcAg
 Ominous development – appearance of vaccine-induced escape mutants, which replicate in
presence of vaccine-induced immunity
o Very low levels of HBV DNA can be detected by PCR in blood of some individuals who may have anti-HBe
antibodies; persists for many years
o Virus-specific CD4+ and CD8+ IFN-γ-producing cells causes resolution of acute infection
o Many chronic carriers have virions in hepatocytes w/no evidence of cell injury; hepatocyte damage
results from damage to virus-infected cells by CD8+ CTLs
o Can be prevented by vaccination w/purified HBsAg produced in yeast; induces anti-HBs antibody
response in 95% of infants, children, and adolescents
Hepatitis C – most common chronic blood-borne infection; progression to chronic disease occurs in majority of
HCV-infected individuals, and cirrhosis eventually occurs in 20-30% of patients w/chronic HCV infection
o Most common cause of chronic liver disease in U.S.; most common indication for liver transplant
o Member of Flaviviridae family; small enveloped, ss RNA virus; genome codes for single polyprotein
w/one open reading frame
 5’ end encodes highly conserved nucleocapsid core protein, followed by envelope proteins E1
and E2
 2 hypervariable regions (HVR 1 and 2) present in E2 sequence
 Protein (p7) functions as ion channel
 Toward 3’ end are 6 less conserved nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and
NS5B
 NS5B is viral RNA-dependent RNA polymerase
 3’ sequences of both positive and negative-strand RNAs contribute cis-acting functions
essential for viral replication
 Secondary structure and protein-binding properties of highly conserved nontranslated
regions promote HCV /RNA synthesis and genome stability through binding of various
host and viral proteins
 Virus inherently unstable because of poor fidelity of NS5B; in any one patient, HCV circulates as
population of divergent but closely related quasispecies
 E2 protein of envelope is target of many anti-HCV antibodies; also most variable region of entire
viral genome, enabling emergent virus strains to escape neutralizing antibodies
o
o

Elevated anti-HCV IgG occurring after active infection don’t consistently confer effective immunity
Characteristic feature of HCV infection is repeated bouts of hepatic damage (result of reactivation of
preexisting infection or emergence of endogenous, newly mutated strain)
o Incubation period ranges from 2-26 weeks; in 85% of individuals, clinical course of acute infection
asymptomatic and easily missed
 RNA detectable in blood for
1-3 weeks, coincident
w/elevations in serum
transaminases
 Anti-HCV antibodies in 5070% of acute HCV infections;
in remainder, anti-HCV
antibodies emerge after 3-6
weeks
 CD4+ and CD8+ T cells
associated w/self-limited
HCV infections
o Persistent infection and chronic hepatitis hallmarks of HCV infection (80-85% of cases)
 Cirrhosis may develop over 5-20 years after acute infection in 20-30% w/persistent infection
o HCV can actively inhibit IFN-mediated cellular antiviral response at multiple steps (TLR signaling in
response to viral RNA recognition and signaling downstream of IFN receptors that confers antiviral state
on cells)
o Circulating HCV RNA persists in many patients despite presence of neutralizing antibodies; RNA testing
must be performed to assess viral replication and confirm diagnosis of HCV
o Characteristic chronic HCV feature is episodic elevations in serum aminotransferases w/intervening
normal or near-normal periods
o Fulminant hepatic failure rarely occurs
Hepatitis D – RNA virus dependent for life cycle on HBV
o Infection occurs with
 Acute coinfection – exposure to serum w/both HDV and HBV; HBV must become established
first to provide HBsAg necessary for development of complete HDV virions
 Usually transient and self-limited; elimination of HBV leads to elimination of HDV
 High incidence of liver failure among addicts
 Superinfection – when chronic carrier of HBV exposed to new inoculum of HDV; results in
disease 30-50 days later (as severe acute hepatitis)
 Chronic HDV infection occurs in 80-90% of patients
 May have acute phase (active HDV replication and suppression of HBV w/high ALT
levels) and chronic phase (HDV replication decreases, HBV replication increases, ALT
levels fluctuate, and disease progresses to cirrhosis or hepatocellular cancer (HCC))
 Helper-independent latent infection – liver transplant; HDV detected in nuclei of grafted liver
w/in few hours after transplantation w/o evidence of productive HDV infection or HBV
reinfection; due to infection of allograft by HDV alone (infection by HBV prevented by Ig
administered to prevent HBV reinfection)
 HD viremia and hepatitis ensues only when HBV escapes neutralization and coinfection
of graft w/high levels of HBV replication, leading to activation of HDV by helper virus
o Double-shelled particle that resembles Dane particle of HBV
 External coat antigen (HBsAg) surrounds internal polypeptide assembly, designated delta
antigen (HDAg); only protein produced by virus
 Associated w/HDAg is smaller circular molecule of ss RNA
 Replication of virus through RNA-directed RNA synthesis by host RNA polymerase (Pol II)
o IgM anti-HDV is most reliable indicator of recent HDV exposure; appearance late and short-lived
 Acute co-infection of HDV and HBV best indicated by detection of IgM against both HDAg and
HBcAg
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


Chronic delta hepatitis from HDV superinfection – HbsAg present in serum, and anti-HDV
antibodies (IgG and IgM) persist for months or longer
o Treatment limited to IFN-α
o Vaccination for HBV can prevent HDV infection as well
Hepatitis E – enterically transmitted, water-borne infection that occurs primarily in young to middle-aged adults
o Zoonotic disease w/animal reservoirs (monkeys, cats, pigs, and dogs)
o Accounts for more than 30-60% of cases of sporadic acute hepatitis in India
o High mortality rate among pregnant women (20%)
o In most cases, self-limiting; not associated w/chronic liver disease or persistent viremia
o Average incubation period 6 weeks
o Unenveloped, positive-stranded RNA virus in Hepevirus genus
o Specific antigen (HEV Ag) identified in cytoplasm of hepatocytes during active infection
o Virions shed in stool during acute illness
o Before onset of clinical illness, HEV RNA and HEV virions detected by PCR in stool and serum
o Onset of rising serum aminotransferases, clinical illness, and elevated IgM anti-HEV titers virtually
simultaneous; symptoms resolve in 2-4 weeks; IgM replaced w/persistent IgG anti-HEV titer
Hepatitis G – flavivirus; called HGV or GBV-C; transmitted by contaminated blood or blood products and sexual
contact; not hepatotropic and doesn’t cause elevations in serum aminotransferases
o Replicates in bone marrow and spleen
o Doesn’t cause known human disease
o Commonly co-infects individuals infected w/HIV; dual infection somewhat protective against HIV disease
Clinicopathologic Syndromes of Viral Hepatitis
o Acute asymptomatic infection w/recovery – HAV and HBV infection in childhood; identified incidentally
on basis of minimally elevated serum transaminases
o Acute symptomatic infection w/recovery – peak infectivity during last asymptomatic days of incubation
period and early days of acute symptoms
 Disease phases: (1) incubation, (2) symptomatic preicteric phase, (3) symptomatic icteric phase,
(4) convalescence
o Chronic hepatitis – symptomatic, biochemical, or serologic evidence of continuing or relapsing hepatic
disease for more than 6 months
 Most HCV infections, small number of HBV infections
 In some, only signs are persistent elevation of serum transaminases
 Physical findings include spider angiomas, palmar erythema, mild hepatomegaly, hepatic
tenderness, and mild splenomegaly
 Lab studies show prolongation of PTT; sometimes hyperglogulinemia, hyperbilirubinemia, and
mild elevations of ALK
 In HBV and HCV, immune complex disease may develop secondary to presence of circulating
antibody-antigen complexes (vasculitis and glomerulonephritis)
 Cryoglobulinemia found in 35% of chronic HCV patients
 Age at time of infection = best determinant of chronicity for HBV; the younger they are, the
more chance they will be chronic
 Although uncommon, patients can recover completely
 Goal of Tx: slow disease progression, reduce liver damage, and prevent cirrhosis/cancer
 HCV – any individual w/detectable HCV RNA in serum needs medical attention
 Tx based on combo of pegylated IFN-α and ribavirin
 Response to therapy depends on viral genotype (genotype 2 or 3 infections have best
responses)
o Carrier state – can mean (1) individuals who carry virus but have no liver disease or (2) those who harbor
virus and have nonprogressive liver damage but are essentially free of symptoms or disability
 HBV – healthy carrier is individual w/o HBeAg but w/presence of anti-HBe, normal
aminotransferases, low or undetectable serum HBV DNA, and liver biopsy shoing lack of
significant inflammation and necrosis
 Less than 1% of infections acquired by adults produce this state


 Infection early in life in endemic areas gives rise to this state in 90% of cases
 HCV – yields carrier state in 10-40% of cases
o Coinfection w/HIV – 10% of HIV patinets infected w/HBV and 30% w/HCV
 Chronic HBV and HCV among leading causes of morbidity and mortality for HIV patients
 Anti-HIV agents may cause hepatotoxicity in some patients w/HBV or HCV coinfection
Morphology
o HBV-infected hepatocytes show cytoplasm packed w/spheres and tubules of HBsAg, producing finely
granular cytoplasm (ground-glass appearance)
o HCV-infected liver shows lymphoid aggregates w/in portal tracts and focal lobular regions of hepatocyte
macrovesicular steatosis
o Acute hepatitis – hepatocyte injury = diffuse swelling (ballooning degeneration); cytoplasm looks empty
and contains scattered eosinophilic remnants of organelles
 Cholestasis (bile plugs in canaliculi and brown pigmentation of hepatocytes)
 Canalicular bile plugs from cessation of contractile activity of hepatocyte pericanalicular
actin microfilament web
 Patterns of hepatocyte cell death
 Rupture of PM leading to focal loss of hepatocytes; sinusoidal collagen reticulin
framework collapses where cells disappear; scavenger macrophage aggregates mark
sites of hepatocyte loss
 Apoptosis – caused by anti-viral CTLs; apoptotic hepatocytes shrink, become intensely
eosinophilic, and have fragmented nuclei
o CTLs may still be present in immediate vicinity
o Apoptotic cells rapidly phagocytosed by macrophages
 Confluent necrosis of hepatocytes (bridging necrosis) in severe cases of acute hepatitis;
connects portal-to-portal, central-to-central, or portal-to-central regions of adjacent
lobules; hepatocyte swelling and regeneration compress sinusoids
o Radial array of hepatocyte plates around terminal hepatic vein lost
 Kupffer cells hypertrophy and hyperplasia; laden w/lipofuscin pigment as result of phagocytosis
of hepatocellular debris
 Portal tracts infiltrated w/mixture of inflammatory cells, which may spill into adjacent
parenchyma, causing apoptosis of periportal hepatocytes (interface hepatitis)
 Cells in canals of Hering proliferate, forming ductular structures at parenchymal interface
(ductular reaction)
o Chronic hepatitis
 In mildest forms, inflammation limited to portal tracts and consists of lymphocytes,
macrophages, occasional plasma cells, and rare neutrophils or eosinophils
 Liver architecture usually well preserved; smoldering hepatocyte apoptosis throughout
lobule may occur
 Chronic HCV – lymphoid aggregates and bile duct reactive changes in portal tracts; focal
mild to moderate macrovesicular steatosis (more prevalent in genotype 3)
 Continued interface hepatitis and bridging necrosis between portal tracts and portal tracts-totermianl hepatic veins harbingers of progressive liver damage
 Hallmark of chronic liver damage = deposition of fibrous tissue (portal tracts  periportal septal
fibrosis  linking of fibrous septa (bridging fibrosis) esp. between portal tracts)
 Continued loss of hepatocytes and fibrosis results in cirrhosis; irregularly sized nodules
separated by mostly broad scars (post-necrotic cirrhosis)
Fulminant hepatic failure – hepatic insufficiency that progresses from onset of symptoms to hepatic
encephalopathy within 2-3 weeks in those w/o chronic liver disease
o In HBV-induced fulminant hepatitis, massive apoptosis
o Morphology: distribution of liver destruction can be entire or random area; with massive loss of mass,
liver may shrink, become limp, red organ covered by wrinkled, too-large capsule
 Necrotic areas have muddy red, mushy appearance w/hemorrhage

Complete destruction of hepatocytes in contiguous lobules leaves collapsed reticulin framework
and preserved portal tracts
o Ductular reaction – proliferation and differentiation of stem/progenitor cell population in canals of
Hering (oval cells); maturation of oval cells creates hepatocytes and bile duct cells
 If parenchymal framework preserved, regeneration resulting from hepatocyte replication can
completely restore liver architecture
 More massive destruction of confluent lobules  regeneration disorderly (nodular masses of
liver cells that produce more irregular liver on healing)
o Fibrous scarring may occur in patients w/protracted course of submassive or patchy necrosis  cirrhosis
o Liver transplant is only option for those whose disease doesn’t resolve before secondary infection and
other organ failure develop
Bacterial, Parasitic, and Helminthic Infections
 Extrahepatic bacterial infections (particularly sepsis) can induce mild hepatic inflammation and varying degrees
of hepatocellular cholestasis (effects of pro0inflammatory cytokines released by Kupffer cells and endothelial
cells in response to circulating endotoxin)
 Bacteria that infect liver directly – Staph aureus (toxic shock syndrome), Salmonella typi (typhoid fever), and T.
pallidum (secondary or tertiary syphilis)
 Bacteria (gut flora) proliferate in biliary tree when outflow obstructed (ascending cholangitis)
 Malaria schistosomiasis, strongyloidiasis, cryptosporidiosis, leishmaniasis, echinococcosis, and infections by liver
flukes Fasciola hepatica and Clonorchis sinensis
 Liver abscesses – usually caused by echinococcal and amebic infections (can be other protozoa or helminths)
o Most pyogenic
o Organisms reach liver by portal vein, arterial supply, ascending infection in biliary tract (ascending
cholangitis), direct invasion of liver from nearby source, or penetrating injury
o Morphology – bacteremic spread through arterial or portal system produces multiple small abscesses;
direct extension and trauma usually cause large solitary abscesses
 Biliary abscesses usually multiple; may contain purulent material from bile ducts
 Rupture of subcapsular liver abscesses can lead to peritonitis or localized peritoneal abscesses
 Echinococcal infection has characteristic cystic structure – wall laminated; hooklets and intact
organisms can be identified; calcification in cystic wall common
o Associated w/fevere, RUQ pain, and tender hepatomegaly; jaundice may result from extrahepatic biliary
obstruction
Autoimmune Hepatitis
 Chronic progressive hepatitis; pathogenesis attributed to T cell-mediated autoimmunity (hepatocyte injury
caused by IFN-γ produced by CD4+ and CD8+ T cells and CD8+ T-cell-mediated cytotoxicity)
o Injurious immune reaction triggered by viral infections, certain drugs (minocycline, atorvastatin,
simvastatin, methyldopa, interferons, nitrofurantoin, and pemoline), and herbal products (black cohosh)
 Occurs w/other autoimmune disorders (SLE, celiac disease, RA, thyroiditis, Sjögren syndrome, ulcerative colitis)
 Absence of serologic markers of viral infection, elevated serum IgG and γ-globulin levels, and high serum titers
of autoantibodies
 Type 1 – presence of antinuclear (ANA), anti-smooth muscle (SMA), anti-actin (AAA), and anti-soluble liver
antigen/liver-pancreas antigen (anti-SLA/LP) antibodies
o Much more common than type 2 in U.S.; associated w/HLA-DR3 serotype
 Type 2 – anti-liver kidney microsome-1 (ALKM-1; directed against CYP2D6) and anti-liver cytosol-1 (ACL-1)
 Prominent inflammatory infiltrates of lymphocytes and plasma cells; clusters of plasma cells in interface of
portal tracts and hepatic lobules
 Atypical presentation – symptoms primarily from involvement of other organ systems OR asymptomatic and
progress to cirrhosis w/o clinical diagnosis
 Acute appearance of clinical illness common; fulminant presentation w/onset of hepatic encephalopathy w/in 8
weeks of disease osnet possible
 Autoimmune cholangitis – histologic destruction of bile ducts
 Prednisone alone or in combo w/azathioprine mainstay therapy
 Liver transplantation indicated for patients w/end-stage liver disease
Drug and Toxin-Induced Liver Disease
 Most common cause of fulminant hepatitis in U.S.
 Genetic variability influences susceptibility to drug-induced injury, which may result from
o Direct toxicity to hepatocytes or biliary epithelial cells, causing necrosis, apoptosis, or disruption of
cellular function
o Hepatic conversion of xenobiotic to active toxin
o Immune mechanisms, usually by drug or metabolite acting as hapten to convert cellular protein into
immunogen
 Drug reactions may be predicatble (intrinsic) or unpredictable (idiosyncratic)
o Idiosyncratic drug reaction considered in any patient receiving therapeutic drug who develops evidence
of liver damage
 Chlorpromazine – causes cholestasis in patients slow to metabolize to innocuous byproduct
 Halothane – can cause fatal immune-mediated hepatitis in some patients exposed to it on multiple occasions
 May take form of hepatocyte necrosis, cholestasis, or insidious onset of liver dysfunction
 Hepatic injury predictable w/overdoses of acetaminophen, Amanita phalloides toxin, CCl4, and (sort of) EtOH
 Acetaminophen is leading cause of drug-induced acute liver failure
 Idiosyncratic reactions evolve w/subacute course; usually high bilirubin levels
 Reye syndrome – syndrome of mitochondrial dysfunction in liver, brain, and elsewhere; characterized by
microvesicular steatosis; development associated w/administration of aspirin for relief of fever
 Long-term methotrexate administration for psoriasis can cause liver injury (steatosis and fibrosis)
 Alcoholic Liver Disease – leading cause of liver disease in most Western countries
o 3 forms of liver disease
 Hepatic steatosis – microvesicular lipid droplets accumulate in hepatocytes; w/chronic intake,
lipid accumulates creating large clear macrovesicular globules that compress and displace
hepatocyte nucleus to periphery of cell
 Fibrous tissue develops around terminal hepatic veins and extends into sinusoids
 Fatty change completely reversible if abstention from further EtOH intake
 Alcoholic hepatitis – characterized by
 Hepatocyte swelling and necrosis: cells undergo swelling (ballooning) and necrosis
o Swelling results from accumulation of fat and water; also proteins normally
exported; in some cases, cholestasis in surviving hepatocytes and mild
deposition of hemosiderin in hepatocytes and Kupffer cells
 Mallory bodies: visible as eosinophilic cytoplasmic clumps in hepatocytes
o Hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments
 Neutrophilic reaction: neutrophils permeate hepatic lobule and accumulate around
degenerating hepatocytes, particularly those w/Mallory bodies
 Fibrosis: activation of sinusoidal stellate cells and portal tract fibroblasts (fibrosis)
o Most sinusoidal and perivenular, separating parenchymal cells
o Periportal fibrosis may predominate w/repeated bouts of heavy EtOH intake
 Cirrhosis – irreversible; usually evolves slowly and insidiously
 Liver is yellow-tan, fatty, and enlarged at first; transforms into brown, shrunken, nonfatty organ
 Initially developing fibrous septa delicate; extend through sinusoids from central-toportal and portal-to-portal regions
 Regenerative activity of entrapped parenchymal hepatocytes generates uniform
micronodules; nodularity becomes more prominent
 Scattered large nodules create hobnail appearance on surface of liver
 As fibrous septa dissect and surround nodules, liver becomes more fibrotic, loses fat,
and shrinks
 Ischemic necrosis and fibrous obliteration of nodules eventually create broad expanses
of tough, pale scar tissue (Laennec cirrhosis)
 Bile stasis develops
o Short-term ingestion of 80 g EtOH [6 beers (8 oz ea) or 8 oz of 80-proof] over several days generally
produces mild, reversible hepatic steatosis
 Daily intake of 80 g or more generates significant risk for severe hepatic injury
 Daily ingestion of 160 g or more for 10-20 years associated w/severe injury
o Only 10-15% of alcoholics develop cirrhosis
 Women more susceptible to hepatic injury than men – due to estrogen increasing gut
permeability to endotoxins, which increase expression of LPS receptor CD14 in Kupffer cells,
predisposing to increased production of pro-inflammatory cytokines and chemokines
 Cirrhosis rates higher in African Americans (with comparable intake to other races)
 Genetic factors – polymorphisms in detoxifying enzymes and some cytokine promoters
 ALDH*2 (genetic variant of ALDH) found in 50% of Asians has very low activity; unable to
oxidize acetaldehyde and don’t tolerate alcohol
 Co-morbid conditions – iron overload and infections w/HCV and HBV increase severity
o Exposure to EtOH causes steatosis, dysfunction of mitochondrial and cellular membranes, hypoxia, and
oxidative stress
o Steatosis results from
 Shunting of normal substrates away from catabolism and toward lipid biosynthesis as result of
generation of excess NADH by alcohol dehydrogenase and acetaldehyde dehydrogenase
 Impaired assembly and secretion of lipoproteins
 Increased peripheral catabolism of fat
o Acetaldehyde (major intermediate metabolite of EtOH) induces lipid peroxidation and acetaldehydeprotein adduct formation, disrupting cytoskeletal and membrane function
o Cytochrome P450 metabolism produces ROS
o EtOH-induced impaired hepatic metabolism of methionine leads to decreased intrahepatic glutathione
levels, sensitizing liver to oxidative injury
 Induction of CYP2E1 and other P450 enzymes by EtOH increases EtOH catabolism in ER and
enhances convertsion of other drugs (e.g., acetaminophen) to toxic metabolites
o Major source of calories that displaces other nutrients, leading to malnutrition and deficiencies of
vitamins (such as thiamine); compounded by impaired digestive function, primarily related to chronic
gastric and intestinal mucosal damage, and pancreatitis
o EtOH causes release of bacterial endotoxin from gut into portal circulation, inducing inflammatory
responses in liver (activation of NF-κB, and release of TNF, IL-6, TGF-α)
o EtOH stimulates release of endothelins from sinusoidal endothelial cells, causing vasoconstriction and
contraction of activated stellate cells (myofibroblasts), leading to decrease in sinusoidal perfusion
o Cells respond in increasingly pathologic manner to stimulus that originally was only marginally harmful
o Steatosis may become evident as hepatomegaly w/mild elevation of serum bilirubin and ALK
o Alcoholic hepatitis appears acutely after bout of heavy drinking; often have high bilirubin, ALK, and often
neutrophilic leukocytosis
 May clear slowly w/proper nutrition and total cessation of EtOH consumption
o Lab findings of alcoholic cirrhosis – elevated serum aminotransferase, bilirubin, ALK, low protein
(globulins, albumin, and clotting factors), and anemia; AST/ALT 2.0-2.5
o End-stage alcoholic liver disease causes of death: hepatic coma, massive GI hemorrhage, intercurrent
infection, hepatorenal syndrome, hepatocellular carcinoma
Metabolic Liver Disease
 Nonalcoholic Fatty Liver Disease (NAFLD) – group of conditions that have hepatic steatosis in individuals who
consume 20 g of EtOH per week or less; most common cause of chronic liver disease in U.S.
o Includes hepatic steatosis, steatosis accompanied by minor non-specific inflammation, and non-alcoholic
steatohepatitis (NASH)
o NASH – condition w/hepatocyte injury that may progress to cirrhosis in 10-20% of cases
 Main components = hepatocyte ballooning, lobular inflammation, and steatosis
o Fibrosis occurs w/progressive disease
o Condition strongly associated w/obesity, dyslipidemia, hyperinsulinemia, and insulin resistance
o
o
o

More than 70% of obese people have some form of NAFLD
Contributes to progression of other liver diseases (HCV, HCC)
Pathogenesis occurs by hepatic fat accumulation and hepatic oxidative stress
 Oxidative stress acts on accumulated hepatic lipids, resulting in lipid peroxidation and release of
lipid peroxides, which can produce reactive oxygen species
o Liver biopsy is most reliable diagnostic tool for NASH
o Serum AST and ALT elevated in 90% of patients; AST/ALT ratio <1
o Droplets of fat predominantly triglycerides
o Steatohepatitis (NASH) characterized by steatosis, parenchymal inflammation (mainly neutrophils),
Mallory bodies, hepatocyte death (ballooning degeneration and apoptosis), and sinusoidal fibrosis
o Cirrhosis may result from years of subclinical progression of necroinflammatory and fibrotic processes
 When cirrhosis established, steatosis tends to be reduced
Hemochromatosis – excessive accumulation of body iron, usually due to abnormal regulation of intestinal
absorption of dietary iron; most deposited in liver and pancreas
o Iron can accumulate in heart, joints, or endocrine organs
o Recessive inherited disorder caused by excessive iron absorption
o Hemosiderosis – secondary hemochromatosis; caused by parenteral administration of iron or other
o 98% of iron pool stored in hepatocytes
o Characteristic features of disease
 Micronodular cirrhosis (all), diabetes mellitus (75-80%), and skin pigmentation (75-80%)
 Iron accumulation lifelong; injury slow and progressive
 Males predominate w/slightly earlier clinical presentation
o Excessive iron directly toxic to host tissues
 Lipid peroxidation via iron-catalyzed free radical reactions
 Stimulation of collagen formation by activation of hepatic stellate cells
 Interaction of ROS and iron itself w/DNA, leading to lethal cell injury or predisposition to HCC
o Actions of iron reversible in cells that aren’t fatally injured; removal of excess iron w/therapy
o Main regulator of iron absorption is protein hepcidin (LEAP1) encoded by HAMP gene
 Also has antibacterial activity; produced in hepatocytes
 Transcription increased by inflammatory cytokines and iron; decreased by iron deficiency,
hypoxia, and ineffective erythropoiesis
 Binds to iron efflux channel (ferriportin; FPN), causing internalization and proteolysis of FPN
 Prevents release of iron from intestinal cells and macrophages
 Hepcidin ultimately lowers plasma iron levels
o Other proteins involved in iron metabolism
 Hemojuvelin (HJV) – expressed in liver, heart, and skeletal muscle
 Transferrin receptor 2 (TfR2) – expressed in hepatocytes, where it mediates uptake of
transferrin-bound iron
 HFE – product of hemochromatosis gene (encodes HLA class I-like molecule that regulates
intestinal absorption of dietary iron); mutation here most common adult form; most common
HFE mutation is C282Y (other common one is H63D)
o Mutations in HAMP or HJV cause severe form of hereditary hemochromatosis (juvenile
hemochromatosis)
o Mutations in HFE and TfR2 cause classic form of hereditary adult hemochromatosis
o Mutations of FPN cause distinctive iron storage disease different from hemochromatosis
o TMPRSS6 – serum protease that is iron sensor that suppresses HAMP expression
o Morphologic changes characterized principally by deposition of hemosiderin (liver, pancreas,
myocardium, pituitary gland, adrenal gland, thyroid, parathyroid, skin; detected by Prussian blue stain),
cirrhosis, and pancreatic fibrosis
 With increasing iron load, progressive involvement of rest of lobule, along w/bile duct
epithelium and Kupffer cell pigmentation
 Iron is direct hepatotoxin; inflammation absent
 Liver slightly larger, dense, and chocolate brown
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Fibrous septa develop slowly, leading to micronodular pattern of cirrhosis in intensely
pigmented liver
o Biochemical determination of hepatic tissue Fe standard for quantitating hepatic Fe content
o Pancreas become intensely pigmented, has diffuse interstitial fibrosis, and may exhibit some
parenchymal atrophy
 Hemosiderin found in acinar and islet cells; sometimes in interstitial fibrous stroma
o Heart often enlarged w/hemosiderin granules in myocardial fibers (brown coloration)
o Skin pigmentation – hemosiderin deposition in dermal macrophages and fibroblasts; most results from
increased epidermal melanin production; gives skin slate-gray color
o Joint synovial linings – acute synovitis may develop due to hemosiderin deposition; excessive deposition
of calcium pyrophosphate damages articular cartilage, producing pseudo-gout
o Testes may be small and atrophic; not usually significantly pigmented
 Atrophy secondary to derangement in hypothalamic-pituitary axis resulting in reduced
gonadotropin and testosterone levels
o Principal manifestations include hepatomegaly, abdominal pain, skin pigmentation (particularly sunexposed areas), deranged glucose homeostasis or frank DM due to destruction of pancreatic islets,
cardiac dysfunction (arrhythmias, cardiomyopathy), and atypical arthritis
 In some, hypogonadism (amenorrhea in female; impotence and loss of libido in male)
o Classic triad of pigment cirrhosis = hepatomegaly, skin pigmentation, and diabetes mellitus develops
later in course of disease
o Significant cause of death = HCC; treatment for iron overload doesn’t reduce risk
o Screening involves demonstration of high serum iron and ferritin, exclusion of secondary causes of iron
overload, and liver biopsy if indicated
o Heterozygotes accumulate excessive iron, but not to level of significant tissue damage
o High iron levels treated by regular phlebotomy; normal life expectancy
o Neonatal hemochromatosis (congenital hemochromatosis) – severe liver disease and extrahepatic
hemosiderin deposition; not inherited
 Liver injury, leading to hemosiderin accumulation, occurs in utero
 Extrahepatic hemosiderin deposition detected by buccal biopsy; needs to be documented for
correct diagnosis
 No specific treatment except supportive care and liver transplant if necessary
Most common causes of hemosiderosis – disorders associated w/ineffective erythropoiesis (severe forms of
thalassemia and myelodysplastic syndromes)
o Excess iron results from increased absorption as well as transfusions
o Alcoholic cirrhosis often associated w/modest increase in stainable iron in liver cells; represents EtOHinduced redistribution of iron (total body iron not significantly increased)
o Can result from ingesting large quantities of alcoholic beverages fermented in iron utensils (Bantu
siderosis)
o Chronic HBV and HCV infection may increase iron storage in hepatocytes
Wilson disease – autosomal recessive disorder caused by mutation of ATP7B gene, resulting in impaired copper
excretion into bile and failure to incorporate copper into ceruloplasmin
o Marked by accumulation of toxic levels of copper, principally liver, brain, and eye
o Normally 40-60% of ingested copper absorbed in duodenum and proximal small intestine; transported
to portal circulation complexed w/albumin and histidine; free copper dissociates and is taken up by
hepatocytes
o Copper incorporated into enzymes and binds to α2-globulin (apoceruloplasmin) to form ceruloplasmin,
which is secreted into blood; excess copper transported into bile; ceruloplasmin eventually desialylated,
endocytosed by liver, and degraded in lysosomes; released copper excreted in bile
o ATP7B gene encodes transmembrane copper-transporting ATPase expressed on hepatocyte canalicular
membrane; most of patients are compound heterozygotes containing different mutations on each allele
 Deficiency in ATP7B protein causes decrease in copper transport into bile, impairs its
incorporation into ceruloplasmin, and inhibits ceruloplasmin secretion into blood
 Causes copper accumulation in liver and decrease in circulating ceruloplasmin
 Copper causes toxic liver injury through production of ROS by Fenton reaction
Once hepatic capacity for incorporating copper into ceruloplasmic exceeded, there may be sudden
onset of critical systemic illness
 Non-ceruloplasmin-bound copper spills over from liver into circulation, causing hemolysis and
pathologic changes in brain, corneas, kidneys, bones, joints, and parathyroids
 Urinary excretion of copper markedly increases
o Liver bears brunt of injury, but disease may present as neurologic disorder
 Steatosis mild to moderate w/vacuolated nuclei (glycogen or water) and occasionally focal
hepatocyte necrosis
 Acute or chronic hepatitis; moderate to severe inflammation and hepatocyte necrosis
w/features of macrovesicular steatosis, vacuolated hepatocellular nuclei, and Mallory bodies
 Cirrhosis develops
 Massive liver necrosis – rare manifestation indistinguishable from that caused by virus or drugs
 Demonstration of hepatic copper content of more than 250 µg/g dry weight most helpful for Dx
 In brain, toxic injury primarily affects basal ganglia (putamen), which shows atrophy and
cavitation
 Nearly all patients w/neurologic involvement develop eye lesions (Kayser-Fleischer rings) green
to brown deposits in Desçemet’s membrane in limbus of cornea
o Most common presentation acute or chronic liver disease
o Neuropsychiatric manifestations – mild behavioral changes, frank psychosis, or Parkinson disease-like
syndrome (such as tremor)
o Biochemical diagnosis based on decrease in serum ceruloplasmin, increase in hepatic copper content
(most sensitive and accurate), and increased urinary excretion of copper (most specific)
o Long-term copper chelation therapy (D-penicillamine (Trientine)) or zinc-based therapy alters progress
o Those w/hepatitis or unmanageable cirrhosis require liver transplant for survival
α1-antitrypsin deficiency – autosomal recessive disorder marked by very low levels of α1-antitrypsin; major
function of α1-antitrypsin is inhibition of proteases (neutrophil elastase, cathepsin G, and proteinase 3) normally
released from neutrophils at sites of inflammation
o Deficiency leads to development of pulmonary emphysema because activity of destructive proteases
not inhibited; causes liver disease as consequence of accumulation of protein in hepatocytes
o Cutaneous panniculitis, arterial aneurysm, bronchiectasis, and Wegener’s granulomatosis can occur
o α1-antitrypsin synthesized predominantly by hepatocytes; member of serine protease inhibitor (serpin)
family; most common genotype is PiMM
 Some deficiency variants (PiS) result in moderate reduction of serum α1-antitrypsin w/o Sx
 Rare varients (Pi-null) have no detectable serum α1-antitrypsin
 Most common clinically significant mutation is PiZ
 Expression of alleles autosomal codominant (PiMZ heterozygotes have intermediate levels)
o Deficiency variants show defect in migration of secretory protein from ER to Golgi apparatus (PiZ);
mutant polypeptide (α1AT-Z) abnormally folded and polymerizes, creating ER stress, leading to apoptosis
 Accumulated α1AT-Z in ER triggers autophagocytic response, mitochondrial dysfunction, and
activation of NF-κB, causing hepatocyte damage
o Characterized by presence of round-to-oval cytoplasmic globular inclusions in hepatocytes; acidophilic
and indistinctly demarcated from surrounding cytoplasm; PAS-positive and diastase-resistant (only
distinctive feature; otherwise fibrosis and hepatitis vary too much)
 Blobules diminished in size and number in PiMZ and PiSZ genotypes
 Most of globules in hepatocytes surrounding portal tracts
o Neonatal hepatitis w/cholestatic jaundice appears in 10-20% of newborns w/deficiency
o In adolescence, presenting Sx related to hepatitis or cirrhosis
 Attacks of hepatitis may subside w/apparent complete recovery or may become chronic and
lead progressively to cirrhosis
o Disease may remain silent until cirrhosis appears in middle to later life
o HCC develops in 2-3% of PiZZ adults, usually but not always in setting of cirrhosis
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In patients w/pulmonary disease, single most important Tx is quit smoking (markedly accelerates
emphysema and destructive lung disease associated w/ α1-antitrypsin deficiency
Neonatal cholestasis – prolonged conjugated hyperbilirubinemia; caused by cholangiopathies (primarily biliary
atresia) and disorders causing conjugated hyperbilirubinemia in neonate (neonatal hepatitis)
o Finding neonatal cholestasis should prompt search for recognizable toxic, metabolic, and infectious liver
diseases; once identifiable causes have been excluded, idiopathic neonatal hepatitis becomes Dx
o Affected infants have jaundice, dark urine, light or acholic stools, and hepatomegaly
o Morphologic features include lobular disarray w/focal liver cell apoptosis and necrosis, panlobular giantcell transformation of hepatocytes, prominent hepatocellular and canalicular cholestasis, mild
mononuclear infiltration of portal areas, reactive changes in Kupffer cells, and extramedullary
hematopoiesis; can blend into ductal pattern of injury, w/bile ductular proliferation and fibrosis of portal
tracts