Documentos de Académico
Documentos de Profesional
Documentos de Cultura
Hepatitis B Virus
• The cause of “serum hepatitis” - Cell surface expression of viral HBsAg and HBcAg
• Can produce: in association with the MHC class I molecules leads
1) Acute hepatitis to activation of cytotoxic CD8+ T lymphocytes and
2) Nonprogressive chronic hepatitis hepatocytes destruction
3) Progressive chronic hepatitis ending in cirrhosis 2) Integrative phase
4) Fulminant hepatitis with massive liver necrosis - Viral DNA is incorporated into the host genome,
5) An asymptomatic carrier state, with or without may occur in hepatocytes not destroyed by the
progressive subclinical dse immune response
6) The backdrop for hepatitis D virus - With cessation of viral replication and the
• Also plays an important role in the development of appearance of antiviral antibodies, infectivity ends
Hepatocellular carcinoma and liver damage subsides. However, the risk of
• Unlike HAV, HBV remains in blood during the last stages hepatocellular carcinoma persists
of a prolonged incubation period (4 to 26 weeks) and • Serologic Dx
during active episodes of acute and chronic hepatitis o After exposure to HBV, the long asymptomatic 4 to
• Also present in all physiologic and pathologic body fluids 26 week incubation period (mean 6-8 weeks) is
with the exception of stool followed by acute dse. lasting many wks. to mos.
• A hardy virus and can withstand extremes of o Most pts experience a self-limited illness
temperature and humidity HBsAg appears before the onset of symptoms,
• Whereas blood and body fluids are the primary vehicles peaks during overt dse, and then declines to
of transmission, virus may also be spread by contact undetectable levels in 3 to 6 mos
HBeAg, HBV DNA, and DNA polymerase • Cirrhosis can be present at the time of dx or may
appear in the serum soon after HBsAg, and all develop during a period of 5 to 10 yrs
signifiy active viral replication • Serologic Dx:
IgM anti-HBc becomes detectable in serum o Incubation period: from 2 10 26 weeks (mean
shortly before the onset of symptoms, between 6 and 12 weeks)
concurrent with the onset of elevated serum o HCV RNA is detectable in blood for 1 to 6 and 12
transaminase levels. During the months, the wks
IgM antibody is replaced by IgG anti-HBc o Circulating RNA persists in many pts despite the
Anti-HBe is detectable shortly after the presence of neutralizing antibodies, incldg. more
disappearance of HBeAg, implying that the than 90% of pts with chronic dse
acute infection has peaked and the dse is on o Clinical course is milder than that of HBV but
the wane individual cases may be severe and
IgG anti-HBs does not rise until the acute dse indistinguishable from HAV or HBV hepatitis
is over and is usually not detectable for a few o A characteristic clinical feature of chronic HCV
wks to several mos after the disappearance of infection is episodic elevations in serum
HBsAg. Anti-HBs may persist for live, transaminases, with intervening normal or near-
conferring protection; this is the basis for normal periods
current vaccination strategies using o Alternatively, transaminases may be persistently
noninfectious HBsAg elevated or may remain normal
o Carrier state is defined by the presence of HBsAg in
serum for 6 mos or longer after initial detection. The
presence of HBsAg alone does not necessarily Hepatitis D Virus
indicate replication of complete virions, and pts may
be asymptomatic and without liver damage
• Also called the delta agent and hepatitis delta virus
o In contrast, chronic replication of HBV virions is
• A unique RNA virus that is replication defective causing
characterized by persistence of circulating HBsAg,
HBeAg, and HBV DNA usually with anti-HBc and infection only when it is encapsulated by HBsAg
occasionally with anti-HBs. Progressive liver • Although taxonomically distinct from HBV, HDV is
damage may occur in these pts absolutely dependent on the genetic information
provided by HBV for multiplication and causes hepatitis
Hepatitis C Virus only in the presence of HBV
• Delta hepatitis arises in two settings:
• A major cause of liver dse worldwide o Acute coinfection
• Main routes of transmission are inoculations and blood Occurs after exposure to serum containing both
transfusions HDV or HBV
• Believed to be the most important cause of transfusion- HBV must become established first to provide
associated hepatitis, being responsible for 90% to 95% the HBsAg necessary for development of
of all cases complete HDV virions
• Sexual transmission and vertical transmission are o Superinfection
infrequent a chronic carrier of HBV with a new inoculum of
• 40% of cases are accounted for sporadic hepatitis of HDV (and HBV) results in dse about 30-50
days later
unknown cause
carrier may be previously “healthy” or may
• Seroprevalence in the US pop. is less than 0.2% but is
have had underlying chronic hepatitis
higher in house contacts, homosexuals, hemodialysis
• Simultaneous coinfection with HBV and HDV results in
pts, hemophiliacs, and IV drug abusers
hepatitis ranging from mild to fulminant, with fulminant
• Pts with unexplained cirrhosis and hepatocellular
dse more likely (3-4%) than with HBV alone
carcinoma have anti-HCV prevalence rates exceeding
• Chronicity rarely develops
50%
• In contrast to HBV, HCV has a high rate of progression • 3 possibilities may arise when HDV is superimposed on
to chronic dse or eventual cirrhosis, exceeding 50% chronic HBV infection:
• Thus, HCV may in fact be the leading infectious cause 1) Mild HBV hepatitis may be converted into fulminant
of chronic liver dse in the Western world dse
• HCV and closely related HGV occupy a genius in the 2) Acute, severe hepatitis may erupt in a previously
Flaviviridae healthy HBV carrier
• A small, enveloped, single-stranded RNA virus with a 3) Chronic, progressive dse may develop (in 80% of
genome that codes for a single polyprotein. This peptide pts) often culminating in cirrhosis
is subsequently processed into functional proteins • Infection by delta agent is worldwide, but prevalence
• Inherently unstable, giving rise to multiple types and varies
subtypes seriously hampering efforts to develop an HCV • 20-40% of HBsAg carriers have anti-HDV
vaccine • In the US, HDV infection is uncommon and largely
• Elevated titers of anti-HCV IgG occuriing after an active restricted to drug addicts and hemophiliacs with
infection do not confer effective immunity prevalence rates of 1-10%
• Characteristic feature of HCV infection: repeated bouts • Homosexual men and health care workers are at low
of hepatic damage as a result of reactivation of a risk for HDV infection for unclear reasons
preexisting infection or emergence of an endogenous, • HDV infection is uncommon in the large population of
newly mutated strain
HBsAg carriers in Southeast Asia and China
• Hallmarks of HCV infection despite the generally
• A 35-nm, double-shelled particle that by electron
asymptomatic nature of the acute illness:
microscopy resembles the Dane particle of HBV
o Progressive infection
• The external coat antigen of HBsAg surrounds as
o Chronic hepatitis
internal polypeptide assembly, designated delta antigen
(HDAg)
• Serologic Dx: • HCV is notorious for chronic infection
o HDV RNA is detectable in the blood and liver just • HAV and HEV do not cause chronic hepatitis in rare
before and in the early days of acute symptomatic exceptions
dse • Fulminant hepatitis is unusual, and almost unheard of
o IgM anti-HDV is the most reliable indicator of recent with HCV
HDV exposure, though appearance is late and • Other infectious or noninfectious causes, particularly
frequently short-lived drugs and toxins, can lead to essentially identical clinical
o Acute coinfection by HDV and HBV is best indicated syndromes
by detection of IgM against both HDAg and HBcAg • Thus serologic and molecular studies are essential for
(denoting new infection with hepatitis B) the diagnosis of viral hepatitis and the distinction
o With chronic delta hepatitis arising from HDV between the various types.
superinfection, HBsAg is present in serum and IgM
anti-HDV persists for mos or longer 1. Acute Asymptomatic Infection with Recovery
o Pts in this group are identified only incidentally on
Hepatitis E Virus
the basis of minimally elevated serum
transaminases or, after the fact, by the presence of
• An enterically transmitted water-borne infection antiviral antibodies.
• Occurring primarily in young to middle-aged adults o HAV and HBV infection worldwide are frequently
• Sporadic infection and overt illness in children are rare subclinical events in childhood, verified only in
• Sporadic infection seems to be uncommon and is seen adulthood by the presence of anti-HAV or anti-HBV
mainly in travelers antibodies
• Characteristic feature of this infection: o Though asymptomatic acute infection is most often
o High mortality rate among pregnant women the case for HCV-infected patients for whom the
approaching 20% exposure event is not known, recovery and
• Disease is self-limited in most cases eradication of the virus are not common
• It is not associated with chronic liver dse or persistent
viremia 2. Acute Symptomatic Infection with Recovery
o Any of the hepatotropic viruses can cause
• Average incubation period after exposure is 6 wks
symptomatic acute viral hepatitis, although this is
• An unenveloped single-stranded RNA virus structurally
uncommon for acute HCV infection
similar to Calciviridae
• A specific antigen (HEV Ag) can be identified in the
o Regardless of the agent, the disease is more or less
the same and can be divided into four phases:
cytoplasm of hepatocytes during active infection and
(1) an incubation period,
virions are shed in the stool during the acute illness
(2) a symptomatic preicteric phase
• Serologic Dx
(3) a symptomatic icteric phase
o HEV RNA and HEV virions can be detected in the (4) convalescence
stool and liver before the onset of clinical illness o Incubation period
o The onset of rising serum transaminases, clinical
Differs in the various viruses
illness, and elevated IgM anti-HEV titers are
Peak infectivity occurs during the last
virtually simultaneous
asymptomatic days of incubation period and
o Symptoms resolve in 2-4 wks, during which time
early days of acute symptoms
IgM is replaced with a persistent IgG anti-HEv titer o Preicteric phase
Marked by nonspecific, constitutional
Other Hepatitis Viruses
symptoms
Malaise is followed in a few days by general
• Some cases of hepatitis are caused by infectious agents
fatigability, nausea, and loss of appetite
according to epidemiologic studies
Inconstant symptoms that can also manifest
• A viral agent bearing similiarities to HCV has been
are weight loss, low-grade fever, headaches,
cloned and designated hepatitis G virus (HGV) muscle and joint aches, and pains and diarrhea
• Transfusion related transmission has been documented 10% of patients with acute hepatitis, most often
• However, HGV appears to be nonpathogenic causing those with hepatitis B, develop a serum
neither liver dse nor exacerbation of liver dse sickness-like syndrome (fever, rash, arthralgias
• That’s why designation of HGV as a “hepatitis” virus is due to circulating immune complexes)
may be premature True origin of these symptoms is suggested by
elevated serum aminotransferase levels
CLINOCOPATHOLOGIC SYNDROMES PE reveals a mildly enlarged, tender liver
In some patients, the nonspecific symptoms
• Clinical syndromes may develop after exposure to are more severe, with higher fever, shaking
hepatitis virus: chills, and headache, sometimes accompanied
o Acute asymptomatic infection with recovery: by right upper quadrant pain and tender liver
serologic evidence only enlargement.
o Acute symptomatic hepatitis with recovery: anicteric o Icteric phase
or icteric If this appears, is caused mainly by conjugated
o Chronic hepatitis: without or with progression to hyperbilirubinemia
cirrhosis Usual in adults with acute HAV infection but not
o Fulminant hepatitis: with massive to submassive in children, but is absent in about half the cases
hepatic necrosis of HBV & majority of HCV cases
• Each of the hepatotropic viruses can cause acute As jaundice appears, these pts enter the icteric
asymptomatic or symptomatic infection phase
• A small number of HBV-infected patients develop Other symptoms begin to abate and the pt feels
chronic hepatitis better
The jaundice is caused predominantly by - less common symptoms: malaise, loss of
conjugated hyperbilirubinemia and not a result appetite, and occasional bouts of mild
of biliary obstruction jaundice
Accompanied by a dark-colored urine related to Physical findings:
the presence of conjugated bilirubin - spider angiomas
Stools may become lighter owing to cholestasis - palmar erythema
A distressing pruritus can be experienced due - mild hepatomegaly
to retention of bile acids - hepatic tenderness
Liver may be mildly enlarged and moderately - mild splenomegaly
tender to percussion Lab studies:
Lab findings - prolongation of prothrombin time
- prolonged prothrombin time - some instances: hyperglobulinemia,
- hyperglobulinemia hyperbilirubinemia, and mild elevations in
- mild elevation of serum alkaline alkaline phosphatase levels
phosphatase In HBV and HCV, occasionally immune
Jaundice and most of other systemic symptoms complex disease may develop secondary to the
abates in a few weeks to several mos as presence of circulating antibody-antigen
convalescence begins complexes, in the form of vasculitis
Recovery is heralded by the generation of (subcutaneous or visceral) &
strong T cell responses against viral antigens glomerulonephritis
expressed on infected liver cells Cryoglobulinemia is found in 35% of pts with
o Chronic Hepatitis chronic HCV hepatitis
Defined as symptomatic, biochemical, or
Key Morphologic Features of Viral Hepatitis
serologic evidence of continuing or relapsing
hepatic disease for more than 6 months, with Acute Hepatitis
histologically documented inflammation and Enlarged, reddened liver; greenish if cholestatic
necrosis Parenchymal changes:
Hepatocyte injury: swelling (ballooning degeneration)
Though hepatitis viruses (HBV, HCV, and HBV
Cholestasis: canalicular bile plugs
+ HDV) are responsible for most cases of
HCV: mild focal fatty change of hepatocytes
chronic hepatitis, there are many other causes
Hepatocyte necrosis: isolated cells or clusters
of chronic hepatitis
Cytolysis (rupture) or apoptosis (shrinkage)
Other causes: chronic alcoholism, Wilson If severe: bridging necrosis (portal-portal, central-central,
disease, α1-antitrypsin deficiency, drugs (e.g., portal-central)
isoniazid, α-methyldopa, methotrexate), and Lobular disarray: loss of normal architecture
autoimmunity Regenerative changes: hepatocyte proliferation
In all instances of chronic hepatitis, etiology is Sinusoidal cell reactive changes:
the single most important indicator of likelihood Accumulation of phagocytosed cellular debris in Kupffer
to progress to cirrhosis cells
Chronic viral hepatitis constitutes a "carrier" Influx of mononuclear cells into sinusoids
state wherein these individuals harbor Portal tracts:
replicating virus and can transmit an organism Inflammation: predominantly mononuclear
Inflammatory spillover into adjacent parenchyma, with
With “carriers” of hepatotropic viruses, there
hepatocyte necrosis
are:
Chronic Hepatitis
1) those who harbor one or more of the viruses
Changes shared with acute hepatitis:
but are suffering little or no adverse clinical
Hepatocyte injury, necrosis, and regeneration
or histologic effects
Sinusoidal cell reactive changes
2) those who have chronic disease by
Portal tracts:
laboratory or histologic findings but are
Inflammation:
essentially free of symptoms or disability
Confined to portal tracts, or
3) those who have clinically symptomatic
Spillover into adjacent parenchyma, with necrosis of
chronic disease
hepatocytes ("interface hepatitis"), or
All constitute reservoirs of infection
Bridging inflammation and necrosis
In HBV, early infection particularly via vertical Fibrosis:
transmission during childbirth produces a Portal deposition, or
carrier state of 90-95% of the time Portal and periportal deposition, or
In contrast, only 1-10% of adult HBV infections Formation of bridging fibrous septa
yields a carrier state HBV: "ground-glass" hepatocytes, "sanded" nuclei
Individuals with impaired immunity are likely to HCV: bile duct epithelial cell proliferation, lymphoid
become HBV carriers because the protective T aggregate formation
cell response does not develop Cirrhosis: The end-stage outcome
This situation is less clear with HDV, although
there is a well-defined low risk of
posttransfusion hepatitis D, indicative of a Morphology of Acute and Chronic Hepatitis
carrier state in conjunction with HBV
HCV can clearly induce a carrier state given its ACUTE HEPATITIS
high rate of chronicity
Clinical features are extremely variable and are
• Hepatocyte injury takes the form of diffuse swelling
not predictive of outcome ("ballooning degeneration"), so cytoplasm looks
- some only manifest with persistent empty and contains only scattered eosinophilic
elevations of serum transaminases remnants of cytoplasmic organelles
- most common symptom: fatigue
• Cholestasis, an inconstant findings, with bile plugs in linking of fibrous septa between lobules (bridging
fibrosis)
canaliculi and brown pigmentation of hepatocytes
• Continued loss of hepatocytes and fibrosis results
• Canalicular bile plugs result from cessation of the
in cirrhosis, with fibrous septae and hepatocyte
contractile activity of the hepatocyte pericanalicular actin
regenerative nodules
microfilament web
• This pattern of cirrhosis characterized by irregularly
• Two patterns of hepatocyte cell death are seen
sized nodules separated by variable but mostly broad
1) Rupture of cell membranes leads to cytolysis and scars
focal loss of hepatocytes
- sinusoidal collagen reticulin framework • Historically, this pattern of cirrhosis has been termed
postnecrotic cirrhosis (but it should be noted that the
collapses where the cells have disappeared,
this term has been applied to all forms of cirrhosis in
and scavenger macrophage aggregates
which the liver shows large, irregular-sized nodules with
mark sites of hepatocyte loss
broad scars, regardless of etiology
2) Apoptosis
- more conspicuous • Autoimmune hepatitis, hepatotoxins (carbon
- caused by anti-viral cytotoxic T cells tetrachloride, mushroom poisoning), pharmaceutical
- Apoptotic hepatocytes shrink, become drugs (acetaminophen, α-methyldopa), and even alcohol
intensely eosinophilic, and have fragmented may give rise to a cirrhotic liver with irregular-sized large
nuclei; effector T cells may still be present in nodules
the immediate vicinity • In some cases that come to autopsy, the inciting cause
- Apoptotic cells also are phagocytosed within of the so-called postnecrotic cirrhosis cannot be
hours by macrophages and hence might be determined at all ("cryptogenic cirrhosis")
difficult to find despite a brisk rate of
hepatocyte injury
• Morphology of the end-stage cirrhotic liver is neither
helpful in determining the basis of the liver injury, nor
can it be easily related to any specific set of clinical
- In severe cases of acute hepatitis, confluent circumstances.
necrosis of hepatocytes may lead to
bridging necrosis connecting portal-to- Clinical course of Viral hepatitis
portal, central-to-central, or portal-to-central
regions of adjacent lobules • Unpredictable course
- Hepatocyte swelling and regeneration
compress sinusoids • Pts experience spontaneous remission or may have
- the more or less radial array of the indolent disease without progression for many years
parenchyma is lost. • However, some have rapidly progressive disease and
• A characteristic and usually prominent feature of acute
develop cirrhosis within a few year
hepatitis: Inflammation
• Major causes of death:
• Kupffer cells undergo hypertrophy and hyperplasia o cirrhosis, with liver failure
and are often laden with lipofuscin pigment due to o hepatic encephalopathy
phagocytosis of hepatocellular debris
• Portal tracts are usually infiltrated with a mixture of
o massive hematemesis from esophageal varices
inflammatory cells o hepatocellular carcinoma in those with long-
standing HBV (particularly neonatal) or HCV
• Inflammatory infiltrate may spill over into the adjacent infection.
parenchyma to cause necrosis of periportal hepatocytes;
this "interface hepatitis" can occur in both acute and Bacterial, Parasitic, and Helminthic Infections
chronic hepatitis
• Finally, bile duct epithelia may become reactive and • Extrahepatic bacterial infections particularly sepsis can
even proliferate to form poorly defined ductular induce mild hepatic inflammation and varying degrees of
structures (ductular reaction), particularly in cases of hepatocellular cholestasis
HCV hepatitis.
• The latter is due to effects of proinflammatory cytokines
released by kupffer cells and endothelial cells in
CHRONIC HEPATITIS
response to circulating endotoxin
• Histo features range from exceedingly mild to severe
• Bacteria that can affect the liver directly:
• Mildest forms: significant inflammation is limited to portal
o Staphylococcus aureus – in toxic shock syndrome
tracts and consists of lymphocytes, macrophages,
o Salmonella typhi – typhoid fever
occasional plasma cells, and rare neutrophils or
eosinophils o 20 or 30 syphilis
• Liver architecture usually well preserved, but smoldering • Bacteria may also proliferate in the biliary tree
hepatocyte necrosis throughout the lobule may occur in compromised by partial or complete obstruction
all forms of chronic hepatitis • Bacterial composition reflects the gut flora, and the
• Even in mild chronic hepatitis due to HCV infection, severe acute inflammatory response within the
common findings are lymphoid aggregates and bile intrahepatic biliary tree is called ascending cholangitis
duct damage in the portal tracts and focally mild to • Major causes of morbidity worldwide wherein the liver is
moderate macrovesicular steatosis frequently involved are parasitic and helminthic
• In all forms of chronic hepatitis: continued interface infections
• Diseases include malaria, schistosomiasis,
hepatitis and bridging necrosis are harbingers of
progressive liver damage strongyloidiasis, cryptosporidiosis, leishmaniasis, and
infections by liver flukes Fasciola hepatica, Clonorchis
• The hallmark of irreversible liver damage is the
sinensis and Opisthorchis viverrini
deposition of fibrous
• Liver abscesses are common in developing countries
• At first, only portal tracts exhibit increased fibrosis, but and mostly represent parasitic infections (e.g. amebic,
with time, periportal septal fibrosis occurs, followed by
echinococcal and (less commonly) other protozoal and • Clinical autoimmune hepatitis exhibiting destruction of
helminthic organisms bile ducts (“autoimmune cholangitis”) may make
• Most abscesses are pyogenic, representing a distinction from primary biliary cirrhosis or primary
complication of a bacterial infection elsewhere sclerosing cholangitis
• Organisms reach the liver by:
1) the portal vein DRUG- AND TOXIN-INDUCED LIVER DISEASE
2) arterial supply
3) ascending infection in the biliary tract (ascending • The liver is subject to potential damage from an array of
cholangitis) pharmaceutical and environmental chemicals because it
4) direct invasion of the liver from a nearby source is the major drug metabolizing and detoxifying organ in
5) a penetrating injury the body
• Majority of hepatic abscesses used to result from portal • Injury may result:
spread of intra-abdominal infections (e.g., appendicitis, 1) from direct toxicity
diverticulitis, colitis) 2) by hepatic conversion of a xenobiotic to an active
• Morphology toxin
o Pyogenic hepatic abscesses may occur as solitary 3) through immune mechanisms (usually by a drug or
or multiple lesions, ranging in size metabolite acting as hapten to convert a cellular
o Bacterimic spread thru the arterial or portal system protein to an immunogen)
tends to produce multiple small abscesses, • Drug reactions may be classified as:
whereas direct extension and trauma usually cause o predictable (intrinsic) reactions
solitary large abscesses may occur in anyone who accumulates a
o Biliary abscesses, usually multiple, may contain sufficient dose
purulent material from adjacent bile ducts o unpredictable (idiosyncratic) reactions
o Gross and microscopic features are those to be depend on idiosyncrasies of the host,
seen in any abscess particularly the host’s propensity to mount an
o Causative organism occasionally can be identified immune response to antigenic stimulus and the
in fungal or parasitic abscesses rate of which the host metabolizes the agent
o Rarely, abscesses located in the subdiaphragmatic major examples:
region, particulary amebic, may burrow into the 1. chlorpromazine
thoracic cavity producing empyema or a lung - agent that causes cholestasis in those pts
abscess who are slow to metabolize it to an
o Rupture of subcapsular liver abscess can lead to innoculous by product
peritonitis or localized peritoneal abscesses 2. halothane
• Liver abscesses are associated with fever and in most - can cause a fatal immune-mediated
instances, right upper quadrant pain and tender hepatitis in some pts exposed to this
hepatomegaly anesthetic on multiple occasions
• Jaundice may result from extrahepatic biliary obstruction • It should be noted that:
• Surgical drainage is often necessary for larger lesions o Injury may be immediate or take weeks to mos. to
while antibiotic therapy may control smaller lesions develop which may present only after severe liver
• Pts may survive with early recognition and Mx damage has developed
o Injury may take the form of hepatocytes necrosis,
AUTOIMMUNE HEPATITIS cholestasis, or insidious onset of liver dysfunction
o Drug-induced chronic hepatitis is clinically and
• A syndrome of chronic hepatitis in pts with a histologically indistinguishable from chronic viral
hepatitis
heterogenous set of immunologic abnormalities
o Histologic markers of viral infection are critical for
• Histo features are indistinguishable from chronic viral
making the distinction
hepatitis
• Predictable rxns are ascribed to:
• Dse may run an indolent or severe course and typically
o Acetaminophen
responds dramatically to immunosuppressive therapy
o Tetracycline
• Salient features include:
o Antineoplastic agents
o Female predominance (70%), particularly young to
o Amanita phalloides toxin
perimenopausal women
o Absence of viral serologic markers o Carbon tetrachloride
o Elevated serum IgG levels (>2.5 gm/dl) o Alcohol (certain extent)
o High serum titers of autoantibodies in 80% of cases, • Idiosyncratic reactions are caused by:
incldg antinuclear, anti-smooth muscle, and o Sulfonamides
antimitochondrial antibodies o Methyldopa
o An increased frequency of HLA-B8 or HLA-DRw3 o Allopurinol
• Other forms of autoimmune dses present in pts are • Reye syndrome
Rheumatoid arthritis, thyroiditis, Sjogren syndrome, & o a potentially fatal syndrome of mitochondrial dysfxn
ulcerative colitis in liver, brain and elsewhere, occurs predominantly
• A subgroup of pts exhibits antibodies either to in children given acetylsalicylic acid (aspirin) for the
liver/kidney microsomes or “soluble liver antigen” relief of virus-induced fever
(cytokeratins 8 and 18), suggesting 3 types of o features extensive accumulation of fat droplets
autoimmune hepatitis exist within hepatocytes (microvesicular steatosis), is
• Clinical presentation is similar to other forms of chronic rare
hepatitis • Drug-induced liver dse is followed usually by recovery
• Autoimmune hepatitis may present in an atypical fashion on removal of drug
with associated dse involving other organ systems, • Exposureto a toxin or therapeutic agent should always
hampering diagnostic efforts be included in the diff. Dx of liver dse
Alcoholic Liver Disease - liver is mottled red with bile-stained
areas
• The leading cause of liver dse in most western countries - liver may be of normal or increased size
is excessive alcohol consumption - often contains visible nodules and
• Adverse effects of chronic alcohol consumption lead to fibrosis indicative of evolution to
development of overlapping forms of liver dse: cirrhosis
1) Hepatic steatosis
2) Alcoholic hepatitis o Alcoholic Cirrhosis
3) Cirrhosis (collectively referred to as alcoholic liver Final and irreversible form of alcoholic liver dse
dse) usually evolves slowly and insidiously
• Morphology At first, the cirrhotic liver is yellow-tan, fatty, and
o Hepatic Steatosis (Fatty liver) enlarged, usually weighing more than 2 kg
Small (microvesicular) lipid droplets During the span of years, it is transformed into
accumulate in hepatocytes after even moderate a brown, shrunken, less than 1 kg in weight
intake of alcohol Arguably, cirrhosis may develop more rapidly in
With chronic intake of alcohol, lipid the setting of alcoholic hepatitis within 1-2
accumulates to the point of creating large clear years
macrovesicular globules, compressing and Initially, developing fibrous septa are delicate
displacing the nucleus to the periphery of the and extend through sinusoids from central vein
hepatocytes to portal regions as well as from portal tract to
Transformation is initially centrilobular, but may portal tract
involve the entire lobule in severe cases Regenerative activity of entrapped
Macroscopic appearance of fatty liver of parenchymal hepatocytes regenerates fairly
chronic alcoholism: uniformly sized “micronodules”
- large (up to 4-6 kg) The nodularity becomes more prominent
- soft organ that is yellow Scattered larger nodules create a “hobnail”
- greasy appearance on liver surface
- readily fractured As fibrous septa dissect and surround nodules,
- though there is little or no fibrosis at the liver becomes more fibrotic loses fat, and
outset, fibrous tissue develops around the shrinks progressively in size
central veins & extends into the adjacent Parenchymal islands are engulfed by ever
sinusoids with continued alcohol intake wider bands of fibrous tissue and liver is
Up to the time that fibrosis appears, fatty converted to a mixed micronodular and
change is completely reversible if there is macronodular pattern
abstention from further intake of alcohol Ischemic necrosis and fibrous obliteration of
nodules eventually create broad expanses of
o Alcoholic Hepatitis tough, pale scar tissue (Laennec cirrhosis)
Characterized by: Bile statis often develops
1. Hepatocyte swelling and necrosis Mallory bodies are rarely evident at this stage
- single or scattered foci of cells undergo Thus, end-stage alcoholic cirrhosis comes to
swelling (ballooning) and necrosis resemble, both micro and macroscopically, the
- swelling results from accumulation of fat cirrhosis developing from viral hepatitis and
and water and proteins that normally are other causes
exported • Pathogenesis
2. Mallory bodies o Short-term ingestion of up to 80 gm of ethanol (8
- scattered hepatocytes accumulate tangled beers or 7 oz of 80-proof liquor) generally produces
skeins of cytokeratin intermediate mild, reversible hepatic changes, such as fatty liver
filaments and other proteins, visible as o Daily intake of 80 gm or more of ethanol generates
eosinophilic cytomplasmic inclusions in significant risk of severe hepatic injury
degenerating hepatocytes o Daily ingestion of 160 gm or more for 10-20 years is
- inclusions are characteristic of but not associated more consistently with severe injury
specific feature because they are also o Only 10-15% if alcoholics, however, develop
seen in primary biliary cirrhosis, Wilson
cirrhosis
dse, chronic cholestatic syndromes,
o Reasons are:
hepatocellular tumors
3. Neutrophilic reaction Decreased gastric metabolism of ethanol
- neutrophils permeate the lobule and Differences in body composition
accumulate around degenerating Women are more susceptible to hepatic injury
hepatocytes, part. those having Mallory than are men
bodies Genetic susceptibility may exist but no reliable
- lymphocytes & macrophages also enter genetic markers of susceptibility have been
portal tracts and spill into the parenchyma identified
4. Fibrosis o Relationship between hepatic steatosis and
- almost always accompanied by a brisk alcoholic hepatitis as precursors to cirrhosis both
sinusoidal and periventricular fibrosis causally and temporally is not yet clear
- periportal fibrosis may occasionally o Cirrhosis may develop without antecedent evidence
predominate, particulary with repeated of steatosis or alcoholic hepatitis
bouts of heavy alcohol intake o In the absence of a clear understanding of the
- cholestasis and mild deposition of pathogenic factors influencing liver damage, no
hemosiderin (iron) in hepatocytes and “safe” upper limit for alcohol consumption can be
Kupffer cells may develop in some cases proposed (despite the current popularity of red
Macroscopic appearance: wines for amelioration of CVD)
o Detrimental effects of alcohol and its byproducts on There may be no clinical or biochemical
hepatocellular function: evidence of liver dse alternatively
Hepatocellular steatosis results from Alcohol withdrawal and provision of an
1) shunting of normal substrates away from adequate diet are sufficient Tx
catabolism and toward lipid biosynthesis
owing to generation of excess NADH by 2 o Alcoholic hepatitis
major enzymes of alcohol metabolism, Tends to appear relatively acutely, usually after
alcohol dehydrogenase a bout of heavy drinking
2) impaired assembly and secretion of Symptoms & lab manifestations may be
lipoproteins minimal or those of fulminant hepatic failure
3) increases peripheral catabolism of fat Between these 2 extremes are nonspecific
induction of CP450 leads to augmented symptoms of malaise, anorexia, weight loss,
transformation of other drugs to toxic upper abdominal discomfort, tender
metabolites hepatomegaly
free radicals, generated during microsomal Lab findings
ethanol-oxidizing system oxidation of alcohol, - hyperbilirubinemia
react with cellular membranes and proteins - elevated alkaline phosphatase levels
alcohol directly affects microtubular & - neutrophilic leukocytosis
mitochondrial function and membrane fluidity acute cholestatic syndrome may appear,
acetaldehyde (major intermediate metabolite of resembling large bile duct obstxn
alcohol en route to acetate prod’n) induces lipid may be superimposed on established cirrhosis
peroxidation and acetaldehyde-protein adduct with proper nutrition and total cessation of
formation, further disrupting cytoskeletal and alcohol consumption, it may clear slowly
membrane fxn in some pts, hepatitis persists despite
alcohol induces immunologic attack on hepatic abstinence and progresses to cirrhosis
neoantigens, possibly the result of alcohol-
induced or acetaldehyde-induced alteration in o Alcohol cirrhosis
hepatic proteins
Manifestations are similar to other forms of
o alcohol is food and can become a major calorie cirrhosis
source in the diet of an alcoholic, displacing other Include those of portal Htn (with life-threatening
nutrients and leading to malnutrition and vitamin variceal hemorrhage), jaundice, ascites, other
deficiency (Vit.B12) stigmata (e.g., grossly distended abdomen,
o compounded by impaired digestive fxn related to wasted extremities, caput medusae)
chronic gastric and intestinal mucosal damage and Lab findings reflect developing hepatic
pancreatitis compromise:
o collagen deposition by perisinusoidal hepatic - Elevated serum transaminase levels
stellate cells is a response to many converging - Hyperbilirubinemia
events - Variable elevation of serum alkaline
Kupffer cell activation, with release of phosphatase
proinflammatory cytokines (TNF-α, IL-1 and 6, - Hypoproteinemia (globulins, albumin, and
TGF-β) clotting factors)
- anemia
Amplication of cytokine stimuli by PAF, a
in some instances, liver biopsy may be
lecithin-related lipid released by endothelial
indicated
cells and kupffer cells
cirrhosis may be clinically silent discovered
Influx of neutrophils into parenchyma in
only at autopsy or when stress such as
response to proinflammatory cytokines, with
infection or trauma tips the balance toward
release of their noxious substances
hepatic insufficiency
o These events are exerted by local toxic effects of
alcohol and by alcohol-induced release of bacterial o Long-term outlook for alcoholics with liver dse is
endotoxin into portal circulation form a
variable
compromised gut
o 5-year survival approaches to 90% in abstainers
o Alcohol also induces a vasoconstricting endothelins
free of jaundice, ascites, or hematemesis; drops to
from sinusoidal endothelial cells
50% - 60% to those who continue to imbibe
o Endothelins induce the myofibrolast-like hepatic
o Causes of death in end-stage alcoholic:
stellate cells to contract, decreasing sinusoidal
1) hepatic coma
perfusion and causing regional hypoxia
2) massive GI hemorrhage
o Net effect: chronic d/o featuring:
3) intercurrent infection
Steatosis 4) hepatorenal syndrome after a bout of
Hepatitis alcoholic hepatitis
Progressive fibrosis 5) hepatocellular carcinoma
Marked derangement of vascular perfusion o Nonalcoholic steatohepatitis
o In essence, alcoholic liver dse can be regarded as a An uncommon condition resembling alcoholic
maladaptive state in w/c cells in liver respond in hepatitis occurring in pts who do not drink
increasingly pathologic manner to a stimulus alcohol
(alcohol) that originally was marginally harmful Features liver biopsy findings of steatosis,
• Clinical course mixed inflammatory infiltrate of parenchyma,
o Hepatic steatosis Mallory hyaline, sinusoidal fibrosis
may become evident as hepatomegaly with Pts are largely asymptomatic with
mild elevation of serum bilirubin and alkaline abnormalities in biochemical lab test results
phosphatase levels Nonspecific constitutional symptoms may be
present
Obesity is the most important risk factor (called C282Y), which inactivates this 343-
Type II DM and hypertriglyceridemia are less amino-acid-protein.
common antecedent conditions o Males predominate with slightly earlier clinical
Chief risk is the dev’t of cirrhosis occurring in a presentation
minority of pts Because physiologic iron loss delays iron
accumulation in women
METABOLIC LIVER DISEASE Pathogenesis
• In HH, regulation of intestinal absorption of dietary iron
Nonalcoholic Fatty Liver Disease and Steatohepatitis is lost, leading to net iron accumulation of 0.5 to 1.0
gm/year.
• Nonalcoholic fatty liver disease (NAFL) – resembles • Disease manifests after 20 gm of storage iron have
alcohol-induced liver disease; occurs in patients who are accumulated
not heavy drinkers • Critical site for HFE expression is on the basolateral
• Men and women equally affected surface of the small intestinal crypt epithelial cell
• Strong associations with obesity, dyslipidemia, • (see Figure 18-27 pg 909 sa Robbins 7th edition para
hyperinsulinemia and insulin resistane, and overt type 2 mas maintindihan, although ako di ko pa din
diabetes naintindihan haha)
• Elevated serum aminotransferases and/or gamma o HFE complexes with the transferring receptor,
glutamyl transpeptidase values TfR, enabling the binding of plasma transferring
• Patients are largely asymptomatic; abnormalities only in and its bound iron
biochemical lab tests o The TfR-Tf-iron complex is endocytosed into the
• Most common cause of “cryptogenic” cirrhosis crypt enterocyte
o Acidification of the endosome releases iron into
Morphology the regulatory iron pool of the crypt cell
• Liver biopsy findings: steatosis, multifocal parenchymal This is a sensing mechanism for the
inflammation, Mallory hyaline, hepatocyte death, systemic iron balance
sinusoidal fibrosis o Crypt cells with mutant HFE lack the facilitating
• Large and small vesicles of fat (triglycerides) effect on TfR-dependent iron uptake, thus
accumulation within hepatocytes decreasing the regulatory iron pool in the crypt
• Clinically benign end: no appreciable hepatic cell.
inflammation, hepatocyte death, or scarring Small intestinal crypt cells are
• STEATOHEPATITIS (aka non-alcoholic steatohepatitis) preprogrammed to absorb dietary iron
regardless of the systemic iron overload
– intermediate form of liver damage
o Excessive iron appears to be directly toxic to host
• CIRRHOSIS – result of years of subclinical progression
tissues by the ff mechanisms:
of the inflammatory and fibrotic processes.
Lipid peroxidation via iron-catalyzed free
radical reactions
Hemachromatosis
Stimulation of collagen formation
Interactions of reactive oxygen species
• Excessive accumulation of body iron – most are and of iron itself, leading to lethal injury or
deposited in parenchymal organs such as liver and predisposition to hepatocellular carcinoma
pancreas o Most common cause of secondary
• Results from a genetic defect causing excessive iron hemochromatosis: haemolytic anemias
absorption or as a consequence of parenteral associated with ineffective erythropoeisis
administration of iron Excess iron may result not only from
• Hereditary hemochromatosis – homozygous-recessive transfusions, but also from increased
inherited disorder absorption
• Secondary hemachromatosis – acquired forms of Transfusions alone (aplastic anemias) lead
hemochromatosis with known sources of excess iron to systemic hemosiderosis -> parenchymal
• Total body iron pool: 2-6gm in normal adults organ injury tends to occur in extreme
o 0.5 gram stored in Liver cases
98% in hepatocytes o Alcoholic cirrhosis – often associated with a
• In HH: total iron accumulation may exceed 50 gm, over modest increase in stainable iron within liver cells
1/3 accumulates in liver
• Ff features characterize this disease: Morphology
o Fully developed cases exhibit: (1)micronodular • Characterized principally by:
cirrhosis in all patients; (2) diabetes mellitus in o Deposition of hemosiderin in the following organs
75% to 80% of patients; and (3) skin pigmentation (in decreasing order of severity): liver, pancreas,
in 75 to 80% of patients myocardium, pituitary gland, adrenal gland,
o Iron accumulation is lifelong thyroid and parathyroid glands, joints, and skin
o Cirrhosis
Symptoms first appear in 5th to 6th decades
o Pancreatic fibrosis
of life
o Hemochromatosis gene located on the short arm • In the liver, iron becomes evident first as golden-yellow
of chromosome 6 at 6p21.3 close to the HLA hemosiderin granules in the cytoplasm of periportal
gene locus hepatocytes
o Stains blue with the Prussian blue stain
HFE gene – encodes an HLA class I-like
molecule that regulates intestinal • With increasing iron load, there is progressive
absorption of dietary iron. involvement of the rest of the lobule, along with bile duct
Most common HFE mutation: cysteine-to- epithelium and Kupffer cell pigmentation
tyrosine substitution at amino acid 282 • Iron is a direct hepatotoxin
• Inflammation is absent
• At this stage, liver is slightly larger than normal, dense, • HH can be diagnosed long before irreversible tissue
and chocolate brown damage has occurred
• Fibrous septa develop slowly leading to micronodular • Screening:
pattern of cirrhosis in an intensely pigmented liver o Demonstration of very high levels of serum iron
• Biochemical determination of hepatic iron concentration and ferritin
in unfixed tissue – standard for quantitating hepatic iron o Exclusion of secondary causes of iron overload
content o Liver biopsy, if indicated
o In normal individuals: iron content of unfixed liver • Screening of family members of probands is important
is less than 1000 ug per gram dry weight of liver o Heterozygotes for HH also accumulate excessive
o Adults with HH: over 10,000 ug iron per gram dry iron, but not to the degree required to cause
weightr significant tissue damage
o Hepatic iron concentrations in excess of 22,000 o Homozygotes may be identified before onset of
ug per gram – associated with fibrosis and clinical disease
cirrhosis • Identification of HFE gene opens the way for genetic
• Pancreas screening, limited by the heterogeneity of mutations in
o Intensely pigmented this disease
o Diffuse interstitial fibrosis • Patients with HH diagnosed in the subclinical,
o May exhibit some parenchymal atrophy precirrhotic stage and treated by regular phlebotomy
o Hemosiderin is found in both acinar and the islet have a normal life expectancy
cells and sometimes in the interstitial fibrous
stroma Wilson Disease
• Heart
o Often enlarged • Autosomal-recessive
o Has hemosiderin granules within the myocardial • Marked by the accumulation of toxic levels of copper in
fibers producing a striking brown coloration to many tissues and organs, principally in the liver, brain,
the myocardium and eye
o Delicate interstitial fibrosis may appear • Normal: 40% to 60% of daily ingested copper (2 to 5
• Skin pigmentation mg) is absorbed in the stomach and duodenum and
o Attributable to hemosiderin deposition in dermal transported to the liver loosely complexed with albumin
macrophages and fibroblasts o Free copper dissociates and is taken up into
o Most results from increased epidermal melanin hepatocytes, where it is incorporated into an a2-
production globulin synthesized in the endoplasmic reticulum
o Combination of these pigments imparts a to form ceruloplasmin and resecreted into plasma
characteristic slate-gray color to the skin • Ceruloplasmin accounts for 90% to 95% of plasma
• Joint synovial linings copper
o Acute synovitis may develop due to hemosiderin • Circulating ceruloplasmin is desialylted as part of normal
deposition plasma protein aging
o Desialylated ceruloplasmin is endocytosed by the
• Excessive deposition of calcium pyrophosphate
liver, degraded within lysosomes, and its copper
damages the articular cartilage produces disabling is excreted into bile
polyarthritis referred to as PSEUDO-GOUT This is the primary route for copper
• Testes elimation
o Small and atrophic o Estimated total body copper: 50 to 150 mg
Atrophy secondary to a derangement in • Gene: ATP7B, on chromosome 13, encodes a 7.5 kB
the hypothalamic-pituitary axis transcript for a transmembrane copper-transporting
o Not usually significantly pigmented ATPase, located on the hepatocyte canalicular
membrane
Clinical Features • Majority of patients are compound heterozygotes
• More often a disease of males containing different mutations of the Wilson disease
• Rarely becomes evident before age 40 gene on each allele.
• Principal manifestations • Defective biliary excretion leads to copper accumulation
o Hepatomegaly in the liver in excess of the metallothionein-binding
o Abdominal pain capacity, causing toxic liver injury through copper-
o Skin pigmentation (particularly in exposed areas) catalyzed formation of reactive oxygen species.
o Deranged glucose homeostasis or frank diabetes • Once hepatic capacity for incorporationg copper into
mellitus due to destruction of pancreatic islets ceruloplasmin is exceeded sudden onset of critical
o Cardiac dysfunction (arrhythmias, illness.
cardiomyopathy)
o Atypical arthritis Morphology
• Some patients, the presenting complaint is • Fatty change: mild to moderate, with vacuolated nuclei
hypogonadism and occasionally, focal hepatocyte necrosis
• Classic triad: pigment cirrhosis with hepatomegaly, skin • Acute hepatitis can exhibit features mimicking acute viral
pigmentation, and diabetes mellitus hepatitis, except for the fatty change
o May not develop until late in the course of the • Chronic hepatitis exhibits moderate to severe
disease inflammation and hepatocyte necrosis, with
• Death: may result from cirrhosis or cardiac disease macrovesicular steatosis, vacuolated hepatocellular
o A significant cause of death is hepatocellular nuclei,
carcinoma o With progression, cirrhosis will develop
o Treatment for iron overload does not remove the • Massive liver necrosis
risk for this aggressive neoplasm o Rare manifestation
o Indistinguishable from that caused by viruses or • All individuals with the PiZZ genotype accumulate
drugs a1,AT-Z in the ER of hepatocytes
• Excess copper deposition – can be demonstrated by • Only 10% of PiZZ individuals develop clinical liver
special stains (rhodanine for copper, orcein stain for disease
copper-associated protein) o They exhibit lags in the ER protein degradation
• Demonstration of hepatic copper content in excess of pathway designed to degrade abnormally
250 ug per gram dry weight is most helpful for making a folded or unassembled polypeptidees
diagnosis • The intense autophagocytic response stimulated within
• Brain hepatocytes: chief cause of liver injury, possibly by
o Toxic injury primarily affects the basal ganglia (the autophagocytosis of mitochondria.
putamen) atrophy and cavitation
o Develop eye lesions called Kayser-Fleishcer rings Morphology
green to brown deposits of copper in • Characterized by the presence of round-to-oval
Descemet’s membrane in the limbus of the cytoplasmic globular inclusions in hepatocytes
cornea o In routine H and E stains – acidophilic and
indistinctly demarcated from the surrounding
Clinical Features cytoplasm
• Rarely manifests before 6 years of age • Globules are also present in diminished size and
• Most common presentation: acute or chronic liver number in intermediate deficiency states
disease • Distinctive feature: the PAS-positive globules
• Neuropsychiatric manifestations, such as mild • Infrequently, fatty change and Mallory bodies are
behavioural changes, frank psychosis, or Parkinson present
disease-like syndrome, are the initial features in most of • Diagnostic a1-antitrypsin globules may be absent in
the remaining cases. young infant
• Biochemical diagnosis: based on a decrease in serum
ceruloplasmin, an increase in hepatic copper content, Clinical Features
and increased urinary excretion of copper • Neonatal hepatitis with cholestatic jaundice appears in
• Early recognition and long-term copper chelation 10-20% of newborns with the deficiency
therapy (as with D-penicillamine) can dramatically alter • Adolescence: presenting symptoms may be related to
the usual progressive downhill course hepatitis or cirrhosis
• Fulminant hepatitis or unmanageable cirrhosis – liver • The disease may remain silent until cirrhosis appears in
transplant middle to later life
• Hepatocellular CA may develop in 2-3% of PiZZ adults
a1-Antitrypsin Deficiency • Treatment and cure for severe hepatic disease:
orthotopic liver transplantation
• Autosomal recessive disorder • In patients with pulmonary disease: avoid cigarette
• Abnormally low serum levels of a1-antitrypsin smoking can accelerate the destructive lung disease
o Major function of this protein: inhibition of associated with a1-antitrypsin deficiency.
proteases, particularly elastase, cathepsin G, and
proteinase 3 Neonatal Cholestasis
• Leads to the development of pulmonary emphysema
lack of this protein permits tissue-destructive enzymes to • Prolonged conjugated hyperbilirubinemia in neonate
run amok • Affects approx 1 in 2500 live births
• Can also cause liver disease, mainly in neonates and • Major conditions causing it:
young adults o Cholangiopathies, primarily biliary atresia
• Most commonly diagnosed genetic liver disease in o A variety of disorders causing conjugated
infants and children hyperbilirubinemia in the neonate (collectively
called neonatal hepatitis)
a1-Antitrypsin o Table 18-10 pg 912
• Small, 394-amino acid plasma glycoprotein synthesized • Affected infants: jaundice, dark urine, light of acholic
predominantly by hepatocytes stools, and hepatomegaly
• Gene is located on human chromosome 14; very • Idiopathic neonatal hepatitis represents up to 50% of
polymorphic cases, biliary atresia another 20%, and a1-antitrypsin
• General notation: Pi for protease inhibitor and an deficiency represents 15%
alphabetic letter for the position on the gel; two letters
denote the genotype of the two alleles. Morphology
o Most common genotype: PiMM (occurs in 90% of • Morphologic features of neonatal hepatitis:
individuals) o Lobular disarray with focal liver cell necrosis
o Most common clinically significant mutation: PiZ o Panlobular giant cell transformation of
individuals have high risk for developing hepatocytes and formation of hepatocyte
clinical disease “rosettes”: radially arrayed hepatocytes
o Prominent hepatocellular and canalicular
Pathogenesis (di ko nagets wahahaha!) cholestasis
• Normal: The mRNA is translated and the protein is o Mild mononuclear infiltration of the portal areas
synthesized and secreted o Reactive changes in the Kupffer cells
• Deficiency variants: selective defect in migration of this o Extramedullary hematopoiesis
secretory protein from the ER to Golgi apparatus
o Most marked for the PiZ polypeptide INTRAHEPATIC BILIARY TRACT DISEASE
o Mutant polypeptide is abnormally folded, and
polymerizes, causing its retention in the ER Secondary Biliary Cirrhosis
o These antibodies are against the E2 subunit of
• Prolonged obstruction of the extrahepatic biliary tree the pyruvate dehydrogenase complex (PDC-E2),
• Most common cause of obstruction in adults: dihydrolipoamide acetyltransferase
extrahepatic cholelithiasis, followed by malignancies of o Enzyme complex is located on the inner face of
the biliary tree or head of the pancreas and strictures the inner mitochondrial membrane well-
resulting from previous surgeries shileded from circulating antibodies in
• Obstructive conditions in children: undamaged hepatocytes
o Biliary atresia
o Cystic fibrosis Pathogenesis
o Choledochal cysts • Auto-immune etiology
o Syndromes in which there are insufficient o Includes aberrant expression of MHC class II
intrahepatic blie ducts molecules on bile duct epithelial cells and
• Secondary inflammation initiates periportal fibrosis, accumulation of autoreactive T cells around bile
which eventually leads to hepatic scarring and nodule ducts
formation, generating secondary biliary cirrhosis • Antibodies against other cellular components (nuclear
• Subtotal obstruction may promote secondary bacterial pore proteins, centomeric proteins, etc) are also
produced
infection of the biliary tree aggravates the
• Has extrahepatic manifestations of autoimmunity
inflammatory injury
• Enteric organisms (colifroms and enterococci) –
o Sicca complex of dry eyes and mouth (Sjogren
common culprits syndrome; Latin sicca meaning dryness)
o Scleroderma
Morphology o Thyroiditis
• End-stage obstructed liver: extraordinary yellow-green o Rheumatoid arthritis
pigmentation and is accompanied by marked icteric o Raynaud phenomenon
discoloration of body tissues and fluids o Membranous glomerulonephritis
• On cut surface: liver is hard, with finely granular o Celiac disease
appearance • Etiology and inciting triggers of primary biliary cirrhosis
• Histology: are not clear
o Coarse fibrous septae that subdivide the liver in a
jigsaw-like pattern Morphology
o Embedded in the septa are distended small and • Prototype of conditions leading to small-duct biliary
large bile ducts, contain inspissated pigmented fibrosis and cirrhosis
material • Focal and variable disease
• Cholestatic feature in the parenchyma may be severe, o Different degrees of severity in different portions
with extensive feathery degeneration and formation of of the liver
bile lakes • Precirrhotic Stage
• Once regenerative nodules have formed, bile stasis may o Portal tracts are infiltrated by a dense
become less conspicuous. accumulation of lymphocytes, macrophages,
• Ascending bacterial infection incites a robust plasma cells, and occasional eosinophils
neutrophilic infiltration of bile ducts o Terminal and conducting bile ducts are infiltrated
• Severe pylephlebitis and cholangitic abscesses may by lymphocytes; may exhibit noncaseating
develop granulomatous inflammation and undergo
progressive destruction
Primary Biliary Cirrhosis • The obstruction to intrahepatic bile flow leads to
progressive secondary hepatic damage
• Chronic, progressive, often fatal cholestatic liver o Portal tracts upstream from damaged bile ducts
disease, characterized by the destruction of intrahepatic exhibit bile ductular proliferation, inflammation,
bile ducts, portal inflammation and scarring, and the and necrosis of the adjacent periportal hepatic
eventual development of cirrhosis and liver failure parenchyma
• Primary feature: nonsuppurative, inflammatory o Parenchyma develops generalized cholestasis
destruction of medium-sized intrahepatic bile ducts • Relentless portal tract scarring and bridging fibrosis lead
• Primarily, a disease of middle-aged women to cirrhosis
• Female:male predominance in excess of 6:1 • Macroscopically:
• Age of onset: 20-80 years; peak incidence: 40-50 years o As disease progresses, bile stasis stains the liver
green
• Onset is insidious; presents with pruritus; jaundice
develops later
o Capsule remains smooth and glistening until a
• Hepatomegaly is typical fine granularity appears culminates in a well-
developed, uniform micronodularity
• Xanthomas and xanthelasmas arise owing to cholesterol
o Liver weight: first, normal to increased (due to
retention
inflammation); ultimately, liver weight is slightly
• Late features: stigmata of chronic liver disease
decreased
• Over a period of two or more decades: develop hepatic • Most cases, end-stage picture is indistinguishable from
decompensation, including portal hypertension with secondary biliary cirrhosis or the cirrhosis that follows
variceal bleeding and hepatic encephalopathy chronic hepatitis from other causes
• Serum alkaline phosphatase and cholesterol: elevated
• Hyperbilirubinemia: late development; signifies incipient Clinical Features
hepatic decompensation • Onset is extremely insidious, may be symptom free for
• 90% of patients: presence of circulating many years
“antimitochondiral antibodies” • Pruritis, fatigue, and abdominal discomfort develop,
followed by secondary features: xanthomas and
xanthelasmas, steatorrhea, and malabsorption-related • Arise from residual embryonic bile duct remnants
osteomalacia and/or osteoporosis • Occasionally, triangular bile duct hamartoma may lie
• Entry into end-stage of disease: general features of under Glisson’s capsule
jaundice and hepatic decompensation, including portal Polycystic Liver Disease
hypertension and variceal bleeding • Liver contains multiple diffuse cystic lesions
• Major cause of death: liver failure • Cysts are lined by cuboidal or flattened biliary epithelium
o Followed by massive variceal hemorrhage and and contain straw-colored fluid
intercurrent infection • Do not contain pigmented material
• Detached from the biliary tree
Primary Sclerosing Cholangitis
• Occasionally, liver cysts of biliary origin are identified,
more commonly in women
• Characterized by inflammation and obliterative fibrosis Congenital Hepatic Fibrosis
of intrahepatic and extrahepatic bile ducts, with dilation • Portal tracts are enlarged by irregular and broad bands
of preserved segments
of collagenous tissue, forming septa and dividing the
• There is “beading” of a barium column in radiographs of
liver into irregular islands
the intrahepatic and extrahepatic biliary tree • Variable numbers of abnormally shaped bile ducts are
o Due to irregular strictures and dilations of affected
embedded in the fibrous tissue
bile ducts
• Bile duct remnants are distributed along the septal
• Commonly seen in association with inflammatory bowel
margin
disease, particularly chronic ulcerative colitis o Sometimes, curved bile duct profiles are arranged
• Prevalence of primary sclerosing cholangitis in
in a concentric circle around portal tracts
ulcerative colitis patients: 4% • The increased number of bile ducts profiles are in
• Tends to occur in third through fifth decades of life
continuity with the biliary tree
• Males predominate, 2:1 • Anomaly arises because of persistence of a malformed
embryonic form of the biliary tree
Pathogenesis Caroli Disease
• Cause is unknown • Larger ducts of the intrahepatic biliary tree are
• Key events: segmentally dilated and may contain insipissated bile
o Secretion of proinflammatory cytokines by • Pure forms are rare
activated hepatic macrophages • Usually associated with portal tract fibrosis of the
o Followed by infiltration of T cells into the stroma congenital hepatic fibrosis type
immediately around bile ducts
Morphology Clinical Features
• Fibrosing cholangitis of bile ducts, with a lymphocytic • Von Meyenburg Complexes are common and usually
infiltrate, progressive atrophy of the bile duct epithelium, without clinical significance
and obliteration of the lumen • Polycystic liver disease may develop abdominal
• Onion-skin fibrosis – concentric periductal fibrosis tenderness or pain in stooping
around affected ducts o Occasionally, requires surgical intervention
o Followed by solid, cordlike fibrous scar o Slight female predilection
• In between areas of progressive stricture, bile ducts o Presentation common during pregnancy
become ecstatic and inflamed • Patients with congenital hepatic fibrosis rarely develop
o Result of downstream obstruction
cirrhosis
• As disease progresses, liver becomes markedly o May still face complications of portal
cholestatic culminates in biliary cirrhosis hypertension, particularly bleeding varices
• Caroli disease is frequently complicated by intrahepatic
Clinical Features cholelithiasis, cholangitis, and hepatic abscesses, also
• There is persistent elevation of serum alkaline portal hypertension
phosphatase o Has an increased risk of cholangiocarcinoma
• Progressive fatigue, pruritus, and jaundice may develop • Each of these 4 conditions appears to arise from
• Autoantibodies are present in less than 10% of patients intrinsic anomalies in the development of the smaller to
• Severely afflicted patients: symptoms associated with larger portions of the intrahepatic biliary tree
chronic liver disease such as weight loss, ascites, • (fig 18-33 pg 916) Well-documented association of
variceal bleeding, and encephalopathy autosomal-dominant polycystic kidney disease with
• Has increased risk for cholangiocarcinoma polycystic liver disease
• Definitive treatment: liver transplantation o Liver cyst in isolation or in abundance represent
the most frequent extra-renal manifestation of
Anomalies Of The Biliary Tree (Including Liver Cysts) autosomal-dominant polycystic kidney disease
and occur in most patients
• Lesions may be found during radiographic studies or at • Congenital hepatic fibrosis is strongly associated with
autopsy or may become manifest as the autosomal-recessive form of polycystic kidney
hepatosplenomegaly and portal hypertension in the disease
absence of hepatic dysfunction • Alagille syndrome – syndromatic paucity of bile ducts
• Four distinct lesions have been described o Uncommon autosomal-dominant condition
o Liver is almost normal, but portal tract bile ducts
Morphology are completely absent
Von Meyenburg Complexes o Cause by mutations in the gene Jagged1 on
• Close to or within portal tracts: small clusters of chromosome 20p, a cell-surface protein that
modestly dilated bile ducts embedded in a fibrous, functions as a ligand for the Notch
sometimes hyalinized stroma transmembrane receptors
• Free of pigmented material
o Jagged1:Notch signalling pathway – regulates • The obstruction to blood flow and massive necrosis of
cell fate and involved in the development of liver, hepatocytes can lead to fulminant hepatic failure
heat, skeleton, eye, face, and kidney
o Patients exhibit extrahepatic features: peculiar Passive Congestion and Centrolobular Necrosis
facies, vertebral anomalies, and CV defects
o Can survive into adulthood; but at risk for hepatic • Considered together because they represent a
failure and hepatocellular CA morphologic continuum
o Both changes are commonly seen at autopsy
CIRCULATORY DISORDERS because there is an element of pretermed
circulatory failure with every death
IMPAIRED BLOOD FLOW INTO THE LIVER • The only clinical evidence of centrilobular necrosis or its
variants is mild to moderate transient elevation of serum
Hepatic Artery Compromise aminotransferases
• Parenchymal damage: can induce mild to moderate
• Thrombosis or compression of an intrahepatic branch of jaundice
the hepatic artery by embolism, neoplasia, polyarteritis
nodosa, or sepsis may result in a localized infarct that is Morphology
usually anemic and pale-tan or sometimes hemorrhagic • Right-sided cardiac decompensation leads to passive
• Hepatic artery thrombosis in a transplanted liver leads to congestion of the liver
infarction of the major ducts of the biliary tree and loss of o Liver is slightly enlarged, tense, and cyanotic with
the organ rounded edges
o Microscopically: congestion of centrolobular
Portal Vein Obstruction and Thrombosis sinusoids
o With time: centrolobular hepatocytes become
• Occlusive disease of the portal vein or its major radicles
atrophic results in markedly attenuated liver
produces abdominal pain, ascites, and other
cell cords
manifestations of portal hypertension (principally
• Left-sided cardiac failure or shock
esophageal varices which are prone to rupture)
o Ascites is often massive and intractable o May lead to hepatic hypoperfusion and hypoxia
• Acute impairment of visceral blood flow leads to • Hepatocytes in the central region of the
profound congestion and bowel infarction lobule undergo ischemic coagulative
necrosis (centrolobular necrosis)
• Extrahepatic portal vein obstruction may arise from:
• Hypoperfusion + retrograde congestion = centrolobular
o Banti Syndrome – subclinical occlusion of the
hemorrhagic necrosis
portal vein presents as variceal bleeding and
ascites o Liver has mottled appearance reflecting
o Intra-abdominal sepsis leading to pylephlebitis in hemorrhage and necrosis in the centrilobular
the splanchnic circulation regions known as nutmeg liver
o Thrombogenic disorders o Microscopically: sharp demarcation of viable
o Trauma periportal and necrotic pericentral hepatocytes,
o Pancreatitis that initiates vein thrombosis which with suffusion of blood through the centrilobular
region
propagates into the portal vein
• Uncommon complication of severe congestive heart
• Acute thrombosis of an intrahepatic portal vein radicle
failure: cardiac sclerosis
results in a sharply demarcated area of red-blue
o Pattern of liver fibrosis is distinctive, mostly
discoloration (infarct of Zahn)
o No necrosis; with severe hepatocellular atrophy centrilobular
and marked hemostasis in distended sinusoids
Peliosis Hepatis
• Idiopathic portal hypertension is a chronic, generally
bland condition of impaired portal vein inflow and
noncirrhotic portal hypertension • Rare condition in which sinusoidal dilation is primary
o May be associated with hypercoagulability of the • Most commonly associated with exposure to anabolic
blood, myeloproliferative disorders, peritonitis, or steroids, and rarely, oral contraceptives and danazol
chronic exposure to arsenicals o Pathogenesis is unknown
o Histologic manifestation: hepatoportal sclerosis • Clinical signs are generally absent
dense fibrosis of intrahepatic portal tracts with • Potentially fatal intra-abdominal hemorrhage or hepatic
obliteration of portal vein channels failure may occur
• Lesions usually disappear after cessation of drug
IMPAIRED BLOOD FLOW THROUGH THE LIVER treatment
• Most common cause: cirrhosis
• Physical occlusion of the sinusoids occur in a small but HEPATIC VENOUS OUTFLOW OBSTRUCTION
striking group of diseases
• Sickle cell disease: hepatic sinusoids may become Hepatic Vein Thrombosis and Inferior Vena Cava
Thrombosis
packed with sickled erythrocytes, both free within the
vascular space and phagocytosed by Kupffer cells
o Leads to panlobular parenchymal necrosis • Obstruction of a single main hepatic vein by thrombosis
• DIC: may occlude sinusoids is clinically silent
o Periportal sinusoidal occlusion and parenchymal • Obstruction of 2 or more major hepatic vein produces
necrosis may arise in pregnancy as part of liver enlargement, pain, and ascites called the Budd-
eclampsia Chiari syndrome
• Metastatic tumor cells may fill the hepatic sinusoids in o Caused by increased intrahepatic blood pressure
the absence of a mass lesion and an inability of the massive hepatic blood flow
to shunt around the blocked outflow tract
• Hepatic vein thrombosis is associated with primary • As the disease progresses, obliteration of the lumen of
myeloproliferative disorders, inherited disorders of the venule is easily identified by using special stains for
coagulation, antiphospholipid syndrome, paroxysmal connective tissue
nocturnal hemoglobinuria, and intra-abdominal cancers • Chronic or healed veno-occlusive disease:
• Occurance in pregnant women or those taking OCPs is o Dense perivenular fibrosis radiating out into the
usually through interaction with an underlying parenchyma, frequently with total obliteration of
thrombogenic disorder the venule
• 10% of cases: idiopathic in origin o Hemosiderin deposition is evident in the scar
• Separate distinction is made for inferior vena cave tissue
thrombosis at its hepatic portion (obliterative o Congestion is minimal
heptocavopathy)
o Frequently idiopathic HEPATIC DISEASE ASSOCIATED WITH PREGNANCY
o Nepal: endemic • Most common cause of jaundice in pregnancy: viral
• Mortality if untreated: high hepatitis (HAV, HBV, HCV, and HBV+HDV)
• Prompt surgical creation of a portosystemic venous o Pregnancy does not specifically alter the course
shunt: revese flow through the portal vein, improves of the liver disease, except hepatitis E viral
prognosis infection runs a more severe course in
• In the case of vena caval thrombosis, direct dilation of pregnant patients, fatality rates of 10-20%
caval obstruction may be possible during angiography • Unique and very small subgroup develop hepatic
• Chronic forms are far less lethal, over 2/3 of patients are complications directly attributable to pregnancy:
alive after 5 years preeclampsia, acute fatty liver of pregnancy, and
intrahepatic cholestasis of pregnancy
Morphology o Extreme cases of the first 2 conditions is fatal
• Liver is swollen and red-purple and has a tense capsule
• Microscopically: Preeclampsia and Eclampsia
o The affected hepatic parenchyma reveals severe • Preeclampsia
centrilobular congestion and necrosis o Affects 7-10% of pregnancies
• Centrilobular fibrosis: develops when thrombosis is o Characterized by maternal hypertension,
slowly developing proteinuria, peripheral edema, coagulation
• Major veins may contain totally occlusive fresh thrombi, abnormalities, and varying degrees of DIC
subtotal occlusion, or in chronic cases, organized • Eclampsia
adherent thrombi o When hyperreflexia and convulsions occur
• Thrombosis of obliterative hepatocavopathy may heal to o May be life threatening
leave only an incomplete membranous web protruding • Subclinical hepatic disease may be the primary
into the lumen of the inferior vena cava manifestation of preeclampsia, as part of a syndrome of
hemolysis, elevated liver enzymes, and low platelets
Veno-Occlusive Disease (Sinusoidal Obstruction HELLP syndrome
Syndrome) • Patients with hepatic involvement in preeclampsia may
exhibit modest to severe elevation of serum
• Occurs primarily in the immediate weeks following bone aminotrasnferases and mild elevation of serum bilirubin
marrow transplantation • Definitive treatment in severe cases: termination of
• Incidence: 25% in recipients of allogeneic marrow pregnancy
transplants; mortality: over 30% o Mild cases: managed conservatively
• Diagnosis: made on clinical grounds only (tender • Those who survived severe preeclampsia recover
hepatomegaly, ascites, weight gain, and jaundice) without sequelae
o High risk of liver biopsy in these patients
• Arises from toxic injury to the sinusoidal epithelium Morphology
o Cells round up and slough off the sinusoidal wall, • Affected liver in preeclampsia is normal in size, firm, and
embolizing downstream and obstructing pale, with small red patches due to hemorrhage
sinusoidal blood flow • Occasionally, yellow or white patches of ischemic
o Accompanied by passage of erythrocytes into the infarction can be seen
space of Disse and downstream accumulation of • Microscopically:
cellular debris in the terminal hepatic vein o Periportal sinusoids contain fibrin deposits with
o It is followed by proliferatin of perisinusoidal
hemorrhage into the space of Disse leads to
stellate cells and subendothelial fibroblasts in the periportal hepatocellular coagulative nerosis
terminal hepatic vein, with deposition of
• Blood under pressure may coalesce and expand to form
extracellular matrix
a hepatic hematoma
• Obliterative changes in the terminal hepatic vein are o Dissection of blood under Glisson’s capsule: may
secondary to sinusoidal damage alternative name: lead to hepatic rupture
sinusoidal obstructive syndrome
• 70-85% of patients recover spontaneously Acute Fatty Liver of Pregnancy
• Treatment: largely supportive
• Present in later half of pregnancy, usually in the 3rd
Morphology trimester
• Characterized by obliteration of hepatic vein radicles by • Symptoms are directly attributable to incipient hepatic
varying amouns of subendothelial swelling and fine failure, including bleeding, nausea and vomiting,
reticulated collagen jaundice, and coma
• Acute disease, there is striking centrolobular congestion • Can progress within days to hepatic failure and death
with hepatocellular necrosis and accumulation o • Primary treatment: termination of pregnancy
hemosiderin-laden macrophages
• Chronic graft-versus-host disease (more than 100 days
Morphology after)
• Diagnosis rests on biopsy identification of the o Portal tract inflammation
characteristic microvesicular fatty transformation of o Selective bile duct destruction
hepatocytes o Eventual fibrosis
• In severe cases: lobular disarray with hepatocyte • Portal vein and hepatic vein radicles may exhibit
dropout, reticulin collapse, and portal tract inflammation
endothelitis subendothelial lympocytic infiltrate lifts
• Diagnosis depends on:
the endothelium from its basement membrane
o High index of suspicion
• Cholestasis seen in both acute and chronic
o Confirmation of microvesicular steatosis using
• Acute cellular rejection
special stains for fat (oil-red-O or Sudan black) on
o Characterized by infiltration of a mixed population
frozen tissue sections
of inflammatory cells into portal tracts, bile duct
Electron microscopy can ale be used for
and hepatocyte injury, and endothelitis
steatosis
• Chronic rejection
Intrahepatic Cholestasis of Pregnancy o Severe obliterative arteritis of small and large
arterial vessels results in ischemic changes in the
liver parenchyma
• Onset of pruritus in the 3rd trimester, followed by
o Bile ducts are progressively occluded due to
darkening of urine and occasionally light stools and
direct attack or obliteration of their arterial supply
jaundice heralds the development of this syndrome
• Both may lead to loss of the graft
• Serum bilirubin (conjugated mostly) rarely exceeds
5mg/dl
Nonimmunologic Damage to Liver Allografts
• Alkaline phosphatase may be slightly elevated
• Liver biopsy: mild cholestasis without necrosis
• Revascularization and prefusion of the donor liver may
o Altered hormonal state of pregnancy appears to
result in preservation injury
combine with biliary secretion defects to o Attributable to generation of oxygen radicals in a
engender cholestasis
hypoxic organ with insufficient reserves of oxygen
• Generally a benign condition scavengers to prevent damage
o But mother is at risk for gallstones and o Leads to sinusoidal endothelial injury and Kuppfer
malabsorption cell activation, neutrophil adhesion, platelet
o Incidence of fetal distress, stillbirth, and aggregation, and local cytokine release
prematurity is modestly increased • Hepatocyte ballooning and cholestasis follow, with
variable degrees of centrilobular necrosis
HEPATIC COMPLICATIONS OF ORGAN OR BONE
MARROW TRANSPLANTATION • Severe injury: portal tracts are damaged cause
inflammation, bile duct proliferation, and fibrosis
Drug Toxicity After Bone Marrow Transplantation • Hepatic artery thrombosis – sufficiently severe vascular
insult to cause severe compromise in the transplanted
• Describes a syndrome of hepatic dysfunction following liver
the cytotoxic therapy administered to patients just prior • Portal vein thrombosis may be insidious and present
to bone marrow transplantation only as variceal hemorrhage weeks to months later
• Affects up to one half of patients • Bile duct obstruction – from stricture at the anastomosis
• Characterized by weight gain, tender hepatomegaly, with the native common bile duct
edema, ascites, hyperbilirubinemia, and a fall in urinary
sodium excretion TUMORS AND TUMOR-LIKE CONDITIONS
• Onset: days immediately following the transplantation
• The most common hepatic neoplasms are metastatic
• A spectrum of centrolobular necrosis and inflammatory carcinomas
changes is encountered culminates in veno-occlusive • Important in the differential diagnosis of hepatic masses
disease are
• Clinical outcome is directly related to the severity of liver 1. whether there is underlying liver disease, especially
toxicity cirrhosis, in which there is a greater risk for primary
• Persistent severe liver dysfunction: fatal outcome, hepatocellular carcinoma
succumbs to septicemia, pneumonia, bleeding, and/or 2. whether the mass is solitary or multiple
multiorgan failure
Benign Tumors
Graft-Versus-Host Disease and Liver Rejection