Liver DiseasesNon-alcoholic fatty liver diseaseHemochromatosisWilson diseaseα1-antitrypsin deficiencyNeonatal 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 diseaseHemochromatosisWilson diseaseα1-antitrypsin deficiencyNeonatal hepatitis

Liver abscesses

-Causes: EchinococcusAmebic infection-Usually present in immigrants from endemic regions-Pyogenic (secondary bacterial infection)Pathogenesis:1. via the portal vein 2. arterial supply3. ascending infection in the biliary tract (ascending

cholangitis)4. direct invasion of the liver from a nearby source5. penetrating injury

Liver abscesses, Clinical

• 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+ T-cell–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 Features1. Female predominance (78%)2. No serologic markers of viral

infection3. Elevated serum IgG and γ-globulin

levels4. 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/liver-pancreas 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

cells2. Hepatic conversion of a xenobiotic to an active

toxin3. 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.    Fibrosis5. 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

• 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

Pathogenesis ALCOHOLIC LIVER DISEASE

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 Morphology1. Hepatocyte ballooning2. Lobular inflammation3. 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

• 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

Parenteral iron overloadTransfusionsLong-term hemodialysisAplastic anemiaSickle cell diseaseMyelodysplastic syndromesChronic liver diseasePorphyria cutanea tarda

LeukemiasIron-dextran injectionsb-ThalassemiaSideroblastic anemiaIncreased oral intake of ironAfrican iron overload (Bantu siderosis)

II. HEMOSIDEROSIS

CAUSES OF HEMOCHROMATOSIS

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 40Females – after menopause !!!• 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 hepatitis3. Massive liver necrosis4. Chronic hepatitisSpecial staining: rhodamine stain for copper,

orcein stain for copper-associated proteinClinical Features 1. eye lesions called Kayser-Fleischer rings

or cataracts2. acute or chronic liver disease3. Neuropsychiatric manifestations(Parkinson)Rx: copper chelation therapy with D-

penicillamine 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