Transcript Liver Diseases

Liver Diseases
Non-alcoholic fatty liver
disease
Hemochromatosis
Wilson disease
α1-antitrypsin deficiency
Neonatal hepatitis
Associate Professor
Dr. Alexey Podcheko
Spring 2015
Intended Learning Outcomes:
• Liver Abscesses
• Drug-induced Liver Diseases
• Alcoholic Liver Diseases
• Metabolic Liver Diseases:
Non-alcoholic fatty liver disease
Hemochromatosis
Wilson disease
α1-antitrypsin deficiency
Neonatal hepatitis
Liver abscesses
-Causes:
Echinococcus
Amebic infection
-Usually present in immigrants from endemic regions
-Pyogenic (secondary bacterial infection)
Pathogenesis:
1. via the portal vein
2. arterial supply
3. ascending infection in the biliary tract (ascending
cholangitis)
4. direct invasion of the liver from a nearby source
5. penetrating injury
Liver abscesses, Clinical
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Associated with fever
Right upper quadrant pain and tender hepatomegaly
Jaundice
Rx: surgical drainage
Prognosis: if patients are elderly and have serious
coexistent disease, the mortality rate of patients with
large liver abscesses ranges from 30% to 90%.
• Rupture of Echinococcal cyst has severe clinical
consequences, including systemic spread of the
organism and resultant shock from massive immune
hypersensitivity response.
Morphology of Liver abscesses
• Size: Variable
(millimeters to many
centimeters)
• Quantity: Multiple
(Biliary) or single
(trauma)
• May produce empyema
or a lung abscess
• Rupture of subcapsular
liver abscesses can lead
to peritonitis or localized
peritoneal abscesses
• Echinococcal infection has a characteristic cystic structure; the
wall is laminated, and hooklets and intact organisms can be
identified
Autoimmune Hepatitis
• Definition: chronic and progressive hepatitis of unknown
etiology
• Pathogenesis: Type IV immunological reactions mediated by
IFN-γ produced by CD4+ and CD8+ T cells and by CD8+ Tcell–mediated cytotoxicity.
• Pathogenesis:
1. Genetic factors
2. Trigger factor- viral infections, certain drugs such as
minocycline, atorvastatin, simvastatin, methyldopa,
interferons, nitrofurantoin, and pemoline, and herbal products
(such as black cohosh).
• 3. Autoimmune hepatitis commonly occurs concurrently
with other autoimmune disorders, such as celiac disease,
systemic lupus erythematosus, rheumatoid arthritis,
thyroiditis, Sjögren syndrome, and ulcerative colitis.
Clinicopathologic Features
1. Female predominance (78%)
2. No serologic markers of viral
infection
3. Elevated serum IgG and γ-globulin
levels
4. Serologically exist 2 types :
Type 1 more common in USA,
associated with other AI diseases antinuclear (ANA), anti–smooth
muscle (SMA), anti–actin (AAA), and
anti–soluble liver antigen/liverpancreas antigen (anti-SLA/LP)
antibodies ()
Type 2 - more common in children anti–liver kidney microsome-1
(ALKM-1) antibodies, anti–liver
cytosol-1 (ACL-1) antibodies
Serious prognosis: high mortality -40%
within 6 months of diagnosis,
cirrhosis develops in at least 40% of
survivors
Clusters of plasma cells in
the interface of portal
tracts and hepatic lobules
Drug- and Toxin-Induced Liver
Disease
• The most common cause of fulminant hepatitis
in the United States is drug-induced liver toxicity
• Genetic variability is a critical factor
• Pathogenesis:
1. Direct toxicity to hepatocytes or biliary epithelial
cells
2. Hepatic conversion of a xenobiotic to an active
toxin
3. Immune mechanisms (hapten-immunogen)
• Drug reactions:
• predictable (dose-dependent) or unpredictable
(idiosyncratic –no relation with dose of the drug)
ALCOHOLIC LIVER DISEASE
• Excessive alcohol (ethanol) consumption is the leading cause of
liver disease
• Forms of alcoholic liver disease:
(1) hepatic steatosis (fatty liver disease),
(2) alcoholic hepatitis
(3) cirrhosis
Morphology
• Hepatic Steatosis (Fatty
Liver):
• macrovesicular steatosis
• there is little or no fibrosis
• fatty change is
completely reversible if
there is abstention from
further intake of alcohol.
Alcoholic Hepatitis (Alcoholic
Steatohepatitis)
1.
Hepatocyte swelling
and necrosis
2. Mallory bodies:
cytokeratin intermediate
filaments -eosinophilic
cytoplasmic clumps in
hepatocytes (found in
NAFLD, PBC, Wilson
disease, chronic
cholestatic syndromes,
and hepatocellular
tumors)
3. Neutrophilic reaction:
accumulate around
degenerating hepatocytes
4. Fibrosis
5. Bile stasis
Alcoholic Cirrhosis
• The final and irreversible form of
alcoholic liver disease
• may develop in 1 or 2 years in some
cases.
• Morphology:
• Cirrhotic liver is yellowtan, fatty, and
enlarged,
• Transformed into a brown, shrunken,
nonfatty organ, sometimes less than 1
kg in weight.
• MICRONODULAR
• Ischemic necrosis and fibrous
obliteration of nodules eventually create
broad expanses of tough, pale scar
tissue
• A.k.a. “Laennec cirrhosis”
• Bile stasis
• Mallory bodies
Pathogenesis ALCOHOLIC LIVER
DISEASE
• 10% to 15% of alcoholics develop
cirrhosis
• 80 gm of alcohol over one to several
days generally produces mild,
reversible hepatic steatosis
• More prone females, African Americans
• Co-morbid conditions: Iron overload,
Malnutrition and deficiencies of
vitamins
Pathogenesis ALCOHOLIC LIVER
DISEASE
• Alcohol directly affects microtubules
and mitochondria
• Generation of excess reduced
nicotinamide adenine dinucleotide
(NADH + H+) causes steatosis
• Acetaldehyde induces lipid peroxidation
and acetaldehyde-protein adduct
formation
• Release of bacterial endotoxin from the
gut
Clinical Features of ALCOHOLIC
LIVER DISEASE
• Hepatic steatosis: hepatomegaly, elevated bilirubin
and alkaline phosphatase, AST:ALT>2
• Alcoholic hepatitis: malaise, anorexia, weight loss,
tender hepatomegaly, hyperbilirubinemia, elevated
alkaline phosphatase, and a neutrophilic
leukocytosis
• Alcoholic cirrhosis: micronodular type of
cirrhosis!!! similar to other forms of cirrhosis:
hypoproteinemia (globulins, albumin, and clotting
factors)
“Metabolic” Liver Disease
• Group of liver diseases is attributable to
disorders of metabolism, either acquired or
inherited.
• Non-alcoholic fatty liver disease
• Hemochromatosis
• Wilson disease
• α1-antitrypsin deficiency
• Neonatal hepatitis
NONALCOHOLIC FATTY LIVER
DISEASE
• NAFLD is a group of conditions that have in common
the presence of hepatic steatosis (fatty liver), in
individuals who do not consume alcohol, or do so in
very small quantities (less than 20 g of ethanol/week).
• The most common cause of chronic liver disease in
the United States
• Affects more than 30% of the population
• Variants:
• 1. hepatic steatosis
• 2. steatosis accompanied by minor, non-specific
inflammation
• 3. non-alcoholic steatohepatitis (NASH)
• NASH may progress to cirrhosis in 10% to 20% of
cases
NASH Morphology
1. Hepatocyte ballooning
2. Lobular inflammation
3. Steatosis
More than 70% of obese
individuals have some form of
NAFLD.
It is the most common cause of
so-called cryptogenic
cirrhosis, namely cirrhosis of
“unknown” origin.
Pathogenesis.
A “two-hit” model :
(1) hepatic fat accumulation
(2) hepatic oxidative stress
macrovesicular
NASH Clinical Features
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Generally asymptomatic
Obesity, insulin resistance, and diabetes
Biopsy - fat accumulation in the liver
Serum AST and ALT are elevated in about 90%
of patients with NASH
• The AST/ALT ratio is usually less than 1, in
contrast to alcoholic steatohepatitis in which the
ratio is generally above 2.0 to 2.5.
• Fatigue and right-sided abdominal discomfort
HEMOCHROMATOSIS
• Excessive accumulation of body iron, most of
which is deposited in parenchymal organs such as
the liver and pancreas.
• Total body iron pool 2 to 6 gm. In hemochromatosis,
total iron accumulation may exceed 15 gm/liver
• Primary or hereditary hemochromatosis is a
homozygous-recessive inherited disorder
that is caused by excessive iron absorption.
• Secondary H. (hemosiderosis) accumulation of iron in tissues, which may
occur as a consequence of parenteral
administration of iron
HEMOCHROMATOSIS: General features
(1) micronodular cirrhosis in all patients;
(2) diabetes mellitus in 75% to 80% of
patients
(3) skin pigmentation in 75% to 80% of
patients
(4) symptoms usually first appear in the fifth
to sixth decades of life
(5) Males predominate (5 to 7 : 1) with
slightly earlier clinical presentation
CAUSES OF HEMOCHROMATOSIS
II.
HEMOSIDEROSIS
Parenteral iron overload
Transfusions
Long-term hemodialysis
Aplastic anemia
Sickle cell disease
Myelodysplastic syndromes
Chronic liver disease
Porphyria cutanea tarda
Leukemias
Iron-dextran injections
b-Thalassemia
Sideroblastic anemia
Increased oral intake of iron
African iron overload (Bantu
siderosis)
Pathogenesis
• HFE protein transfers iron from endosomes
into cytoplasm of enterocytes. The adult
form of hemochromatosis is almost always
caused by mutations of HFE
• The main regulator of iron absorption is the
protein hepcidin . Deficiency in hepcidin
causes iron overload.
• Iron Toxicity:
(1) lipid peroxidation via iron-catalyzed free radical
reactions,
(2) stimulation of collagen formation by activation of
hepatic stellate cells
(3) interaction of reactive oxygen species and of iron
itself with DNA, leading to lethal cell injury or
predisposition to hepatocellular carcinoma.
Morphology hereditary
hemochromatosis
(1) deposition of hemosiderin in
the following organs (in
decreasing order of severity):
liver, pancreas, myocardium,
pituitary gland, adrenal gland,
thyroid and parathyroid glands,
joints, and skin (detected by
the Prussian blue histologic
reaction or by atomic
absorption analysis of tissue);
(2) cirrhosis
(3) pancreatic fibrosis
(4) heart is often enlarged
Clinical Features of Hemochromatosis
• Hemochromatosis is one of the most common
hereditary diseases and inborn errors of
metabolism (1:220 in European descents)
• Classic triad: cirrhosis with hepatomegaly+skin
pigmentation+ diabetes mellitus
• Males and rare before age 40
Females – after menopause !!!
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Hepatomegaly
Abdominal pain
Skin pigmentation (particularly in
sun-exposed areas)
Diabetes mellitus
Cardiac dysfunction (arrhythmias, cardiomyopathy)
Atypical arthritis
Hypogonadism (e.g., amenorrhea in the female,
impotence and loss of libido in the male).
WILSON DISEASE
• Autosomal recessive disorder caused by
mutation of the ATP7B gene, resulting in
impaired copper excretion into bile and a
failure to incorporate copper into
ceruloplasmin
• Primary route of copper elimination is
excretion through bile
• Accumulation of toxic levels of copper in
many tissues and organs, principally the
liver, brain, and eye
Morphology:
1. Fatty change (steatosis)
2. Acute hepatitis
3. Massive liver necrosis
4. Chronic hepatitis
Special staining: rhodamine stain for copper,
orcein stain for copper-associated protein
Clinical Features
1. eye lesions called Kayser-Fleischer rings
or cataracts
2. acute or chronic liver disease
3. Neuropsychiatric manifestations(Parkinson)
Rx: copper chelation therapy with Dpenicillamine or Trientine
Kayser-Fleischer rings
α1-ANTITRYPSIN DEFICIENCY
• Autosomal recessive disorder due to low
levels/activity of α1-antitrypsin
• a1-Antitrypsin is synthesized predominantly by
hepatocytes
• α1-antitrypsin deficiency is the most
commonly diagnosed genetic hepatic disorder
in infants and children
• Pathogenesis:
• The accumulated α1AT-Z(mutated form) in the
endoplasmic reticulum triggers a series of events,
including an autophagocytic response,
mitochondrial dysfunction, and possible activation
of pro-inflammatory NF-κB, causing hepatocyte
damage
Morphology
• 1. round-to-oval
cytoplasmic globular
inclusions in hepatocytes
(α1-antitrypsin globules),
which in routine H&E stains
are acidophilic and
indistinctly demarcated
from the surrounding
cytoplasm (PAS positive)
• 2. fatty change and Mallory
bodies
• The diagnostic may be
absent in the young infant;
steatosis may be present as
a tip-off to the possibility of
α1-antitrypsin deficiency.
PAS positive inclusions with alpha-1-antitrypsin deficiency
Neonatal hepatitis caused by α1-antitrypsin deficiency. Note the severe
cholestasis and multinucleated giant cells