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
2
Q
Characteristic morphology of AIH
A
-CLUSTERS OF PERIPORTAL PLASMA CELLS
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)
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!!!
5
Q
Type 2 AIH
A
-exhibits autoAbs directed against the liver kidney microsome-1 (ALKM-1) and liver cytosol-1 (ACL-1) Ags
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
7
Q
AIH Tx
A
- Immunosuppression with transplantation for end-stage disease
- AIH recurs in 20% of transplants
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
9
Q
Acetaminophen
A
-in high doses is injurious due to production of toxic metabolite by CYP-450 system
10
Q
Chlorpromazine
A
-causes cholestasis only in patients that are slow to metabolize it
11
Q
Halothane
A
-in some people can induce a fatal AIH
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
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
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
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
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
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
18
Q
Pathogenesis of ALD–Comorbid conditions
A
-Iron overload or viral hepatitis increases severity of ALD
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
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
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
