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GI 2 Pathology--Chapt. 18 and 19 > Chapter 18 part 3: Autoimmune hepatitis, Drugs, ALD, NAFLD, Hemochromatosis, Wilsons, a1AT > Flashcards

Chapter 18 part 3: Autoimmune hepatitis, Drugs, ALD, NAFLD, Hemochromatosis, Wilsons, a1AT Flashcards

1
Q

Autoimmune hepatitis

A
  • chronic progressive hepatitis often with a strong genetic predisposition (in Caucasians there is a frequent DRB1 allele association)
  • can be triggered by viral infections or drugs or may be a component of other autoimmune disorders (rheumatoid arthritis, Sjogren syndrome, or ulcerative colitis)
  • Entire histologic spectrum of hepatitis seen in AIH but CLUSTERS OF PERIPORTAL PLASMA CELLS are characteristic
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2
Q

Characteristic morphology of AIH

A

-CLUSTERS OF PERIPORTAL PLASMA CELLS

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3
Q

AIH–affects who? Classified how?

A
  • female predominance (78%) with high IgG but no serum markers of viral infection
  • classified on basis of patterns of autoAbs: Type 1 AIH and Type 2 AIH (Type 1 more common in US)
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4
Q

Type 1 AIH

A
  • shows autoAbs to nuclear (ANA), smooth muscle (SMA), actin (AAA), and soluble liver antigen-liver-pancreas (SLA-LP) Ags
  • associated with HLA-DR3!!!
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5
Q

Type 2 AIH

A

-exhibits autoAbs directed against the liver kidney microsome-1 (ALKM-1) and liver cytosol-1 (ACL-1) Ags

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6
Q

AIH symptoms

A
  • Acute onset of symptoms of liver failure occurs in 40%
  • symptomatic patients tend to show substantial liver destruction and scarring at the time of Dx
  • Untreated, 6-mo mortality can reach 40% and 40% of survivors develop cirrhosis
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7
Q

AIH Tx

A
  • Immunosuppression with transplantation for end-stage disease
  • AIH recurs in 20% of transplants
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8
Q

Drug and Toxin-induced Liver injury

A
  • Damage from toxin or drug should be considered in the differential Dx of any form of liver Dz (hepatocyte necrosis, hepatitis, cholestasis, fibrosis, or insidious onset of liver dysfunction)
  • Injury from drugs/toxins can be immediate or develop over weeks to months
  • Mechanisms include direct toxicity, hepatic conversion to an active toxin or immune-mediated injury
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9
Q

Acetaminophen

A

-in high doses is injurious due to production of toxic metabolite by CYP-450 system

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10
Q

Chlorpromazine

A

-causes cholestasis only in patients that are slow to metabolize it

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11
Q

Halothane

A

-in some people can induce a fatal AIH

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12
Q

Alcoholic Liver Disease

A
  • leading cause of liver pathology in most western countries; globally accounts for 3.8% of deaths
  • 3 overlapping forms of ALD: Hepatic steatosis (fatty liver), Alcoholic hepatitis, Alcoholic steatofibrosis
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13
Q

Hepatic steatosis (fatty liver)

A
  • marked by microvesicular lipid droplets within hepatocytes and can occur with even moderate alcohol intake
  • with chronic alcohol intake, lipid accumulates in macro vesicular droplets, displacing the nucleus
  • Liver becomes enlarged, soft, greasy, and yellow
  • little to no fibrosis (at least initially), and condition is reversible
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14
Q

Alcoholic hepatitis

A
  • ballooning degeneration and hepatocyte necrosis
  • also Mallory-Denk body formation (intracellular eosinophilic aggregates of intermediate filaments), neutrophilic reaction to degenerating hepatocytes, portal and periportal mononuclear inflammation and fibrosis
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15
Q

Alcoholic steatofibrosis

A
  • accompanied by stellate cell activation
  • Regenerative nodules can be prominent or obliterated by dense fibrous scar
  • End stage alcoholic cirrhosis resembles cirrhosis of any other cause
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16
Q

Pathogenesis of ALD

A
  • Only 10-15% of alcoholics develop cirrhosis suggesting other factors involved:
  • Gender: more women–related to pharmacokinetics and metabolism but estrogen also increases gut permeability to endotoxin, with subsequent Kupffer cell activation and increased proinflammatory cytokine production
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17
Q

Pathogenesis of ALD–Ethnic and genetic differences

A
  • African Americans have higher cirrhosis rates than Caucasian Americans, independent of alcohol consumption levels
  • Polymorphisms in metabolizing enzymes (e.g., aldehyde dehydrogenase) or cytokine promoters are associated with higher frequencies of alcoholic cirrohosis
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18
Q

Pathogenesis of ALD–Comorbid conditions

A

-Iron overload or viral hepatitis increases severity of ALD

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19
Q

Causes of steatosis

A
  • Impaired lipoprotein assembly and secretion
  • Increased peripheral catabolism of fat
  • Shunting of substrates away from catabolism and toward lipid biosynthesis
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20
Q

Causes of alcoholic hepatitis

A
  • Acetaldehyde generated from alcohol catabolism, inducing lipid peroxidation and acetaldehyde-protein adduct formation
  • Induction of cytochrome P-450 generating reactive oxygen species (ROS) and augmenting catabolism of other drugs to form potentially toxic metabolites
  • Impaired metabolism of methionine resulting in reduced glutathione levels that are protective for oxidative injury
  • Alcohol stimulating ET release from sinusoidal endothelium and causing vasoconstriction with diminished hepatic perfusion
  • Alcohol mediated release of bacterial endotoxin from the GI tract, causing increasing inflammatory response
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21
Q

Clinical features of Hepatic steatosis

A
  • associated with hepatomegaly and mild elevations of serum bilirubin and alkaline phosphatase
  • Abstention and adequate diet are sufficient treatments
22
Q

Alcoholic hepatitis

A
  • usually manifests acutely after a bout of heavy drinking
  • manifestations range from minimal to fulminant hepatic failure and include malaise, anorexia, and tender hepatomegaly
  • Bilirubin and alkaline phosphatase are elevated accompanied by neutrophilic leukocytosis–each bout incurs a 10-20% mortality and repeated incidents lead to cirrhosis in a 1/3 of patients
  • Typically adequate nutrition and abstention leads to a slow resolution
  • sometimes hepatitis persists and progresses to cirrhosis
23
Q

Alcoholic cirrhosis

A

-is irreversible; manifestations are similar to any other form of cirrhosis

24
Q

Prognosis of ALD

A
  • five year survival=90% for abstainers but drops to 50-60% for those who continue to drink
  • Death can result from hepatic coma, GI hemorrhage, intercurrent infection, hepatorenal syndrome, and or HCC
25
Q

Metabolic Liver Diseases

A
  • Nonalcoholic Fatty Liver Disease
  • Hemochromatosis
  • Wilson’s Disease
  • a1-Antitrypsin Deficiency
  • Cholestatic Diseases
26
Q

Nonalcoholic Fatty Liver Disease

A
  • group of conditions characterized by hepatic steatosis in the absence of heavy alcohol consumption
  • At the most pathologic end, NASH involves steatosis plus hepatocyte damage and inflammation
  • Rising incidence of NAFLD is attributed to increasing prevalence of obesity
  • NAFLD is strongly associated with the metabolic syndrome of dyslipidemia, hyperinsulinemia, and insulin resistance
27
Q

Pathogenesis of NAFLD

A
  • consequence of hepatocyte fat accumulation and increased hepatic oxidative stress leading to increased lipid peroxidation and ROS generation
  • Increased visceral adipose tissue also becomes dysfunctional with reduced adiponectin production and increased synthesis of pro inflammatory cytokines like TNF-a and IL-6
28
Q

Morphology of NAFLD

A
  • Hepatocytes are filled with fat vacuoles in the absence of inflammatory infiltrates (steatohepatitis)
  • Varying degrees of fibrosis present
29
Q

Clinical features of NAFLD

A
  • Patients with simple steatosis are generally asymptomatic with little risk of progression to cirrhosis
  • With NASH, individuals can be symptom free, although many report fatigue, malaise, or RUQ discomfort
  • serum transaminase levels are elevated in 90% of patients and there is increased risk for cirrhosis and HCC
  • Bc of association bw NASH and metabolic syndrome, cardiovascular disease is a frequent cause of morbidity and mortality
  • Tx targeted at correcting associated obesity, hyperlipidemia and insulin resistance
30
Q

Natural history of NAFLD phenotypes

A

-Isolated fatty liver shows minimal risk for progression to cirrhosis or increased mortality whereas NASH shows increased overall mortality as well as increased risk for cirrhosis and HCC

31
Q

Hemochromatosis

A
  • excessive iron accumulation in parenchymal cells of various organs–esp liver and pancreas; 2 types:
  • Hereditary hemochromatosis (primary)
  • Hemosiderosis (secondary hemochromatosis)
32
Q

Hereditary hemochromatosis

A
  • primary hemochromatosis

- homozygous recessive heritable disorder caused by excessive iron absorption

33
Q

Hemosiderosis

A
  • secondary hemochromatosis
  • denotes disorders associated with parenteral iron administration (e.g., repetitive transfusions, ineffective erythropoiesis, increased iron intake, or chronic liver disease)
34
Q

Pathogenesis of hemosiderosis

A

-tissue damage from direct iron toxicity via free radical formation with lipid per oxidation, stimulation of collagen formation by hepatocyte stellate cells and/or iron and ROS-DNA interactions

35
Q

Total body iron content is regulated by

A
  • intestinal absorption
  • Hepcidin exerts greatest effect by controlling expression of ferroportin, an iron efflux channel on intestinal epithelium and macrophages
  • hepcidin lowers plasma iron, whereas hepcidin deficiency causes iron overload
  • Other proteins involved in iron metabolism (e.g., hemojuvwelin [HJV], transferrin receptor 2 [TFR2] and HFE) do so largely by modulating hepcidin levels
36
Q

Adult form of hemochromatosis is almost always caused by

A
  • mutations of HFE gene
  • More than 70% of patients have a cysteine-to-tyrosine substitution at amino acid 282 (C282Y) that inactivates HFE and reduces hepcidin expression
  • frequency of C282Y heterozygosity is 11% (homozygosity occurs with 0.45% frequency)
  • Disease penetrance is low and genetic condition alone does not invariably lead to hemochromatosis
37
Q

Morphology of hemochromatosis

A
  • Iron accumulates as hemosiderin in various tissues–in decreasing order: liver, pancreas, myocardium, endocrine glands, joints and skin
  • Cirrhosis and pancreatic fibrosis are chief additional morphologic changes
38
Q

Clinical features of hemochromatosis

A
  • micronodular cirrhosis
  • DM and skin pigmentation in 75-80%
  • Iron accumulation is lifelong but injury caused by excessive iron is gradual so symptoms usually appear after 40 yrs
  • Male predominance (6:1) bc of iron loss in women (menstruation, pregnancy) that delays iron accumulation
39
Q

Hemochromatosis and death

A
  • from cirrhosis (and/or HCC) and cardiac involvement
  • Regular phlebotomy is sufficient Tx
  • Early Dx can therefore enable normal life expectancy and screening of genetic probands is important
40
Q

Figure 18-5 Normal iron absorption

A
  • HFE (protein product of HFE one), HJV and TFR2 regulate hepatocyte hepcidin synthesis
  • Hepcidin then binds to ferroportin on enterocytes leading to internalization of complex and ferroportin degradation
  • Ferroportin degradation reduces iron efflux from enterocytes
  • Through these regulatory interactions normal iron absorption is maintained
41
Q

Figure 18-5–Hemochromatosis

A
  • In hereditary hemochromatosis, HFE, HJV or TFR2 gene mutations lead to reduced hepcidin synthesis
  • The resulting decreased hepcidin-ferroportin interaction allows for increased ferroportin activity and increased iron efflux from enterocytes, giving rise to systemic iron overload
42
Q

Wilson Disease

A
  • autosomal recessive, caused by mutations of the ATP7B gene coding for a canalicular copper-transporting ATPase
  • copper absorption and delivery to liver is normal but:
    1) copper excretion into bile is reduced
    2) copper is not incorporated into ceruloplasmin
    3) ceruloplasmin secretion into blood is inhibited
  • this causes copper accumulation in liver causing heating injury through ROS generation; also spills over into circulation of nonceruloplasmin-bound copper causes hemolysis and pathology in other sites–esp cornea and brain!!
43
Q

Morphology of Wilson Disease

A
  • Liver damage from minor to severe–fatty change, acute and chronic hepatitis (with Mallory-Denk bodies), cirrhosis and/or (rarely) massive necrosis
  • CNS toxicity–esp basal ganglia with atrophy, cavitation
  • All pts with neurologic involvement get eye lesions called Kayser-Fleischer rings–green brown copper deposits in Descemet membrane of corneal limbus
44
Q

Clinical features of Wilson Disease

A
  • variable age of onset and presentation
  • acute or chronic disease before age 40 most common manifestation
  • Neuropsychiatric disorders also occur, including mild behavioral changes, frank psychosis and Parkinson-like symptoms
  • Biochemical Dx is based on decreased serum ceruloplasmin, increased hepatic copper content and increased urinary copper excretion
45
Q

Serum copper levels and Dx of Wilson disease? Tx?

A
  • Serum copper levels are of NO DIAGNOSTIC VALUE!!

- Copper chelation is standard therapy; liver transplantation may be necessary

46
Q

Alpha-1 antitrypsin deficiency

A
  • autosomal recessive marked by very low serum levels of this protein
  • a-1 AT normally inhibits neutrophil proteases released at sites of acute inflammation (elastase, cathepsin G, and proteinase 3)
  • Deficiency leads primarily to emphysema because activity of destructive proteases is not curtailed as well as hepatic disease caused by hepatocellular accumulation of misfolded protein
47
Q

Pathogenesis of a1-AT deficiency

A
  • a1-AT synthesized primarily by hepatocytes
  • gene is extremely polymorphic with more than 75 isoforms designated alphabetically based on gel migration mobilities
  • most common genotype (90%) is designated as protease inhibitor (Pi)MM
  • Most mutations result in no or only moderate reductions in a1-AT levels and have no clinical manifestations; but PiZZ homozygotes (most common disease genotype) have circulating a1-AT levels below 10% of normal
48
Q

PiZZ homozygotes in a1-AT deficiency–mechanism of disease

A
  • occurs bc PiZ has a single glutamic acid to lysine substitution resulting in protein misfolding and preventing egress from ER–this triggers the ER stress response including autophagy, mitochondrial dysfunction and proinflammatory NF-KB activation all causing hepatocyte damage
  • Additional genetic or environmental factors modify pathogenesis bc only 10-15% of PiZZ homozygotes develop overt liver disease
49
Q

Morphology of a1-AT deficiency

A

-PAS-positive (diastase-resistant) cytoplasmic globules in periportal hepatocytes; hepatic manifestations range from cholestasis to hepatitis to cirrhosis

50
Q

Clinical features of a1-AT deficiency

A
  • Neonatal hepatitis with cholestatic jaundice occurs in 10-20% of newborns with a1-AT deficiency
  • Later presentation may be due to acute hepatitis or complications of cirrhosis
  • HCC in 2-3% of PiZZ homozygous adults
  • Smoking accenuates lung emphysematous damage
  • Tx=Liver transplant

GI 2 Pathology--Chapt. 18 and 19 (8 decks)

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