patoloji-ders-notlari

Title

Serdar Balcı

Inflammatory, Toxic, Alcoholic and Metabolic Diseases of Liver

Serdar BALCI, MD

DRUG- OR TOXIN-INDUCED LIVER DISEASE

Drug- or Toxin-Induced Liver Disease

• Liver is the major detoxifying organ
• Injury may result from;
• Direct toxicity
• Hepatic conversion of a xenobiotic to an active toxin
• By immune mechanisms
  • a drug or a metabolite acting as a hapten to convert a cellular protein into an immunogen
• Diagnosis depends on
  • Association of agent and liver injury in terms of time
  • Recovery on removal of the compound
  • Exclusion of other causes
• Should be in differential diagnosis list always
• Most important agent that produces toxic liver injury is alcohol

Drug-induced liver disease

• Common condition
• May manifest as
  • A mild reaction
  • Acute liver failure
  • Chronic liver disease
• Caused by:
  • Drugs or medicines
  • Herbal remedies
  • Dietary supplements
  • Topical applications (e.g., ointments, perfumes, shampoo)
  • Environmental exposures (e.g., cleaning solvents, pesticides, fertilizers)

Robbins Basic Pathology

Drug reactions

• Predictable
  • Dose-dependent
• Unpredictable (idiosyncratic)
  • Individual host variations
  • Immune response to drug-related antigen
  • The rate at which the agent is metabolized
• Both classes of injury may be immediate or take weeks to months to develop

Many drugs cause hepatic injury

**For updated information **

Predictable

• Acetaminophen
  • Most common cause of acute liver failure necessitating transplantation in the United States
  • Intentional suicidal overdoses are common, so are accidental overdoses
  • Codeine, alcohol upregulate P-450 system → acetaminophen is more toxic
• The toxic agent is not acetaminophen itself but toxic metabolites produced by the cytochrome P-450 system in acinus zone 3 hepatocytes
• These cells die, the zone 2 hepatocytes take over this metabolic function, in turn
• In severe overdoses the zone of injury extends to the periportal hepatocytes, resulting in fulminant hepatic failure

Idiosyncratic

• Chlorpromazine
  • causes cholestasis in individuals who metabolize it slowly
• Halothane
  • fatal immune-mediated hepatitis
• Sulfonamides
• α-methyldopa
• Idiosyncratic drug or toxin reactions involve a variable combination of
  • Direct cytotoxicity
  • Immune-mediated hepatocyte or bile duct destruction

Depending on the toxic material different zones may be affected

If the toxin is a metabolite of a drug then it may accumulate in zone 3 and most severe effect is seen in zone 3

Robbins Basic Pathology

Robbins Basic Pathology

**Acetaminophen overdose. Confluent necrosis is seen in the perivenular region (zone 3) **

Robbins Basic Pathology

ALCOHOLIC AND NONALCOHOLIC FATTY LIVER DISEASE

Fatty Liver Disease

• Alcohol
  • Steatosis
  • Steatohepatitis
  • Cirrhosis
• Nonalcoholic fatty liver disease (NAFLD)
  • Similar hepatic changes with alcohol
  • Associated with metabolic syndrome
    • insulin resistance, obesity, diabetes mellitus, hypertension, and dyslipidemia

Hepatocellular Steatosis

• Fat accumulation typically begins in centrilobular hepatocytes
• Small (microvesicular), large (macrovesicular)
• Later midlobule and then the periportal regions
• Macroscopically, the fatty liver with widespread steatosis
  • Large (weighing 4 to 6 kg or more), soft, yellow, and greasy

Fatty liver disease. Macrovesicular steatosis is most prominent around the central vein and extends outward to the portal tracts with increasing severity. The intracytoplasmic fat is seen as clear vacuoles. Some fibrosis (stained blue) is present in a characteristic perisinusoidal “chicken wire fence” pattern.

Robbins Basic Pathology

Steatohepatitis

More with alcohol use than in NAFLD

Hepatocyte ballooning

Mallory-Denk bodies

Neutrophilic reaction

• Hepatocyte ballooning
  • Single or scattered foci of cells undergo swelling and necrosis
  • Start from centrilobular areas
• Mallory-Denk bodies
  • tangled intermediate filaments
  • eosinophilic cytoplasmic inclusions in degenerating hepatocytes

clustered inflammatory cells

necrotic hepatocyte

**Mallory-Denk body **

Robbins Basic Pathology

**keratins 8 and 18 **

**ballooned hepatocytes **

Robbins Basic Pathology

Neutrophil infiltration

Predominantly neutrophilic infiltration may permeate the lobule

Accumulate around degenerating hepatocytes, particularly those containing Mallory-Denk bodies

Lymphocytes and macrophages also may be seen in portal tracts or parenchyma

Steatohepatitis with fibrosis

First in the centrilobular region, central vein sclerosis

Perisinusoidal scar appears in the space of Disse of the centrilobular region

Spreads outward, encircling individual or small clusters of hepatocytes in a chicken wire fence pattern

Link to portal tracts

Condense to create central-portal fibrous septa

Liver takes on a nodular, cirrhotic appearance

Classic micronodular or Laennec cirrhosis

Course of Fatty Liver Disease

• Early
  • the liver is yellow-tan, fatty, and enlarged
• Later
  • Persistent damage
  • **Brown, shrunken, nonfatty organ composed of cirrhotic nodules that are usually less than 0.3 cm in diameter, smaller than is typical for most chronic viral hepatitis **
  • End-stage cirrhotic liver may enter into a “burned-out” phase
  • No fatty change and other typical features

Steatosis or fatty change imparts a yellow to orange cast to the liver parenchyma

Autopsy Pathology: A Manual and Atlas

Alcoholic cirrhosis

Diffuse nodularity. Average nodule size is 3 mm. Greenish because of bile stasis

Robbins Basic Pathology

Steatohepatitis leading to cirrhosis. Small nodules are entrapped in blue-staining fibrous tissue; fatty accumulation is no longer seen in this “burned-out” stage

Robbins Basic Pathology

Alcoholic liver disease

Steatosis, alcoholic hepatitis, and fibrosis may develop independently

Not necessarily represent a continuum of changes

Hepatocellular carcinoma arises in 10-20% of patients with alcoholic cirrhosis

Alcoholic liver disease

Robbins Basic Pathology

Causes of hepatocellular steatosis

• Shunting of substrates away from catabolism and toward lipid biosynthesis
  • Generation of excess reduced nicotinamide-adenine dinucleotide
    • metabolism of ethanol by alcohol dehydrogenase and acetaldehyde dehydrogenase
• Impaired assembly and secretion of lipoproteins
• Increased peripheral catabolism of fat

Causes of alcoholic hepatitis

• Acetaldehyde
  • metabolite of ethanol
  • induces lipid peroxidation and acetaldehyde-protein adduct formation
  • disrupt cytoskeleton and membrane function
• Alcohol directly affects
  • cytoskeleton
    • Mallory-Denk bodies
  • mitochondrial function
  • membrane fluidity
• Reactive oxygen species
  • oxidation of ethanol by the microsomal ethanol oxidizing system
  • neutrophils, areas of hepatocyte necrosis
• Cytokine-mediated inflammation and cell injury
  • TNF
  • IL-1, IL-6, IL-8
• Generation of acetaldehyde and free radicals is maximal in the centrilobular region, this region is most susceptible to toxic injury. Pericellular fibrosis and sinusoidal fibrosis develop in this area of the lobule.
• Concurrent viral hepatitis, hepatitis C, is a major accelerator of liver disease in alcoholics

Nonalcoholic Fatty Liver Disease (NAFLD)

• Metabolic syndrome
  • Having at least two of the following:
    • Obesity, insulin resistance, dyslipidemia, and hypertension
• Insulin resistance results in the accumulation of triglycerides in hepatocytes
  • Impaired oxidation of fatty acids
  • Increased synthesis and uptake of fatty acids
  • Decreased hepatic secretion of very-low-density lipoprotein cholesterol
• Fat-laden hepatocytes
  • highly sensitive to lipid peroxidation products generated by oxidative stress
  • damage mitochondrial and plasma membranes, causing apoptosis
• Most common cause of incidental elevation of serum transaminases
• Significant contributor to the pathogenesis of “cryptogenic” cirrhosis
• Pediatric NAFLD
  • Increasing problem as metabolic syndrome and NAFLD approach epidemic proportions
  • In children
    • Inflammation and scarring tend to be more prominent in the portal tracts and periportal regions
    • Mononuclear infiltrates rather than neutrophilic infiltrates predominate

Robbins and Cotran Pathologic Basis of Disease

Robbins and Cotran Pathologic Basis of Disease

Robbins and Cotran Pathologic Basis of Disease

Drug/Toxin-Mediated Injury with Steatosis

• Mitochondrial injury leading to diffuse, hepatocellular microvesicular steatosis
• Associated with severe and potentially fatal acute liver dysfunction
• Reye syndrome
  • <4 age
  • viral illness
  • Pernicious vomiting, irritability or lethargy and hepatomegaly
  • Serum bilirubin, ammonia, and aminotransferase levels are essentially normal at presentation
  • 25% progress to coma, accompanied by elevations in the serum levels of bilirubin, aminotransferases, and particularly ammonia
  • Death occurs from progressive neurologic deterioration or liver failure
• Reye syndrome has been associated with aspirin administration
• No definitive evidence that salicylates play a causal role in this disorder
• Aspirin is contraindicated in children and teenagers with febrile illnesses
• Similar mitochondrial dysfunction caused by
  • Tetracycline and valproate
  • Toxins in unripe ackee fruit, popular in Jamaica
  • Highly active antiretroviral therapy (HAART) regimens for HIV
    • same histologic injuries
    • but, spared significant morbidity

• Hepatocellular microvesicular steatosis
  • Electron microscopy of hepatocellular mitochondria
    • pleomorphic enlargement and electron lucency of the matrices
    • disruption of cristae and loss of dense bodies
• Cerebral edema
  • Astrocytes are swollen
  • mitochondrial changes similar to those seen in the liver
  • Inflammation is notably absent
• Skeletal muscles, kidneys, and heart also may reveal microvesicular fatty change and mitochondrial alterations

INHERITED METABOLIC DISEASES

Hemochromatosis

• Excessive accumulation of body iron
• Deposited in the liver, pancreas, and heart
• Most common form is an autosomal recessive disease of adult onset
  • mutations in the HFE gene
• Secondary iron overload
  • multiple transfusions, ineffective erythropoiesis (as in β-thalassemia and myelodysplastic syndromes), and increased iron intake

Hereditary Hemochromatosis

• Iron accumulates over the lifetime of the affected person
• Excessive intestinal absorption
• Total iron accumulation may exceed 50 gm, over one third of which is found in the liver
• Fully developed cases
  • cirrhosis (seen in all patients)
  • diabetes mellitus (in 75% to 80% of patients)
  • skin pigmentation (in 75% to 80%)

HFE gene

Located on the short arm of chromosome 6

Encodes a protein that is similar in structure to MHC class I proteins

Expression of the mutated HFE protein on small intestinal enterocytes leads to inappropriately upregulated absorption of iron and its binding to transferrin

HFE and the other genes involved in less common forms of hereditary hemochromatosis all regulate the levels of hepcidin, the iron hormone produced by the liver

Hepcidin normally down-regulates the efflux of iron from the intestines and macrophages into the plasma and inhibits iron absorption

When hepcidin levels are reduced there is increased iron absorption

Excessive iron directly toxic to tissues

Lipid peroxidation by iron-catalyzed free radical reactions

Stimulation of collagen formation

Direct interactions of iron with DNA

Hemochromatosis

• Deposition of hemosiderin
• Liver, pancreas, myocardium, pituitary, adrenal, thyroid and parathyroid glands, joints, skin, testis
• Liver
  • Golden-yellow hemosiderin granules in the cytoplasm of periportal hepatocytes, which stain blue with the Prussian blue stain
  • Progressive involvement of the rest of the lobule
  • Bile duct epithelium
  • Kupffer cells

**Accumulation of iron results in a rusty brown liver **

Autopsy Pathology: A Manual and Atlas

Robbins Basic Pathology

Iron is a direct hepatotoxin, and inflammation is characteristically absent

Liver typically is slightly larger than normal, dense, and chocolate brown

Fibrous septa develop slowly

Cirrhosis in an intensely pigmented (very dark brown to black) liver

Dry weight:

Normal iron content of unfixed liver tissue <1000 µg/g dry weight

Clinically evident iron overload of hereditary hemochromatosis exhibit >10,000 µg/g dry weight of iron

>22,000 µg/g dry weight are associated with the development of fibrosis and cirrhosis

Wilson Disease

Autosomal recessive

Accumulation of toxic levels of copper

Liver, brain, and eye

Loss-of-function mutations in the ATP7B gene

Chromosome 13, encodes an ATPase metal ion transporter that localizes to the Golgi region of hepatocytes

Normal copper physiology

Absorption of ingested copper (2 to 5 mg/day)

Plasma transport in complex with albumin

Hepatocellular uptake, followed by binding to an α2 -globulin (apoceruloplasmin) to form ceruloplasmin

Secretion of ceruloplasmin-bound copper into plasma, where it accounts for 90% to 95% of plasma copper

Hepatic uptake of desialylated, senescent ceruloplasmin from the plasma, followed by lysosomal degradation and secretion of free copper into bile

• without ATP7B activity

  • copper cannot be passed on to apoceruloplasmin and cannot be excreted into bile

• Copper accumulates progressively in hepatocytes

• Toxic injury by

• promoting the formation of free radicals

• binding to sulfhydryl groups of cellular proteins

• displacing other metals in hepatic metalloenzymes

• By the age of 5 years

  • Copper begins to escape from the overloaded, damaged hepatocytes into the circulation
  • Free copper generates oxidants Red cell hemolysis
  • Deposited and damage to
  • Brain, cornea, kidneys, bones, joints, and parathyroid glands
  • Urinary excretion of copper increases markedly

• Hepatocellular carcinoma is quite uncommon in Wilson disease

• Kayser-Fleischer rings

• May mimic other liver diseases
  • Fatty liver diseases
  • Viral hepatitis
  • Acute and chronic hepatitis
  • Excess copper deposition can often be demonstrated by special stains
    • rhodanine stain for copper, orcein stain for copper-associated protein
  • Hepatic copper content in excess of 250 µg/g dry weight is most helpful for making a diagnosis
• Basal ganglia, putamen
  • Atrophy and even cavitation
  • Hepatolenticular degeneration
• Kayser-Fleischer rings
  • Green to brown deposits of copper in Descemet membrane in the limbus of the cornea

α1-Antitrypsin Deficiency

Autosomal recessive disorder

Abnormally low serum levels

The major function of AAT is the inhibition of proteases

Pulmonary emphysema

Hepatic disease results from retention of mutant AAT in the liver

AAT synthesized predominantly by hepatocytes

Most allelic variants produce normal or mildly reduced levels of serum AAT

Homozygotes for the Z allele ( PiZZ genotype) have circulating AAT levels that are only 10% of normal levels

PiMZ heterozygotes have intermediate plasma levels of AAT

The PiZ polypeptide contains a single amino acid substitution that results in misfolding of the nascent polypeptide in the hepatocyte endoplasmic reticulum

Mutant protein cannot be secreted by the hepatocyte, it accumulates in the endoplasmic reticulum and triggers unfolded protein response, lead to induction of apoptosis

Marked cholestasis with hepatocyte necrosis in newborns

Childhood cirrhosis

Chronic hepatitis or cirrhosis that becomes apparent only late in life

Hepatocellular carcinoma develops in 2% to 3% of adults with PiZZ genotype, usually but not always in the setting of cirrhosis

The treatment and cure for the severe hepatic disease are orthotopic liver transplantation

α1-Antitrypsin deficiency

Round to oval cytoplasmic globules composed of retained AAT

Glycoprotein stains with PAS

Robbins Basic Pathology