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D&T 4, Exam 3 (Liver) > Limjoco - Autoimmune & Alcoholic Liver Disease, NAFLD > Flashcards

Limjoco - Autoimmune & Alcoholic Liver Disease, NAFLD Flashcards

1
Q

What disorder?

  • A chronic, progressive hepatitis of unknown cause in which the immune system attacks the body’s own hepatocytes.
    • elevated transaminases ALT, AST
    • certain serum autoantibodies
    • necroinflammatory activity on liver biopsy
    • favorable response to immunosuppression
  • Untreated, can lead to cirrhosis and/or liver failure!
A

Liver Autoimmune Hepatitis

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2
Q

What disorder?

  • First described in 1940s, previously called “chronic active hepatitis,” “lupoid hepatitis”
  • Incidence is 1.9/100,000 - mostly white northern Europeans (unknown, but likely similar in the US?)
  • Mostly female (78%), but AIH can affect any age, sex
A

Liver autoimmune hepatitis

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3
Q

What type of Liver Autoimmune Hepatitis?

Depending on antibodies:

A. Middle-aged & older usually (but any age can be affected), more common in US

  • ANA, ASMA mainly
  • ASLA/LPAg, AMA also

B. Children & teens usually, southern Europe

  • Anti-LKM-1 (attacks CYP2D6 on plasma membrane of cell)
  • ACL-1 (anti-liver cytosol-1)
A

A. Type 1

B. Type 2

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4
Q

Etiology of what disease?

  • Unknown cause
  • Environmental triggers - drug or infection?
  • Genetic predisposition: North America / Europe: HLA-DR3 (DRB1*0301) and HLA-DR4 (DRB1*0401, China / Japan: HLA-DR4 (DRB1*0405)
A

Liver Autoimmuine Hepatitis

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5
Q

Clinical presentation of what disease?

  • Incidental finding - many subclinical, 25% no symptoms
  • Acute hepatitis 25-30% - flu-like symptoms, fatigue, jaundice, anorexia, hepatomegaly
  • Concurrent autoimmune conditions in 50% - thyroiditis, arthritis, Sjogren syndrome, etc.
A

Liver Autoimmune Hepatitis

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6
Q

Presentation of Liver Autoimmune Hepatitis:

  • May present as fulminant with __________
  • Overlap syndrome - clinical and histologic features of both autoimmune hepatitis with what two disorders?
  • Cirrhosis at presentation 6-85%
  • Considered a chronic disease, so duration of symptoms does not affect diagnosis or nomenclature
A
  • Encephalopathy
  • AIH-PBC (Primary Biliary Cirrhosis), AIH-PSC (Primary Sclerosing Cholangitis)
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7
Q

Lab findings of what disease?

  • Elevated transaminases ALT, AST
  • Serology
  • Autoantibodies ANA, ASMA, anti-LKM-1
  • Polyclonal serum immunoglobulins (esp. gamma globulins)
  • Liver biopsy
A

Liver Autoimmune Hepatitis

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8
Q

What do the hepatocyes form on histology?

Bonus: What type of cells are characteristically found?

A
  • Rosette Formation
  • Bonus: Plasma cells (characteristic of, but not exclusive to, AIH)
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9
Q

In those few who present with ________:

  • Mortality 40% in 6 months
  • Cirrhosis in 40% of survivors

Need to treat AIH****

  • Dramatic response to ____________ (90%)
  • Non-responders - present with cirrhosis, Type 2; may try other drugs
  • Early diagnosis, intervention vital
A
  • Fulminant hepatitis
  • immunosuppression
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10
Q

How is autoimmune hepatitis treated?

  • ___________ - remission in 80% (normalize AST, ALT, Igs)
  • Relapse in 50% w/ treatment withdrawal
  • Reinstate original treatment for remission

Bonus: Short term or Lifelong treatment?

A
  • Immunosuppression –> Prednisone
    Azathioprine (Imuran)

Bonus: LIFELONG! needs to be continuously monitored

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11
Q

Fact:

Liver transplant

  • 75% survive 10 yrs
  • 20% AIH recurs in transplant
A
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12
Q

What are some examples of xenobiotics?

  • Therapeutic agents, environmental toxins (“xeno”- “foreign”)
A
  • Alcohol
  • Drugs
  • Steroids
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13
Q

What organ:

  • major drug metabolizing, detoxifying organ, thus exposed to myriad therapeutic and environmental agents
    • Conversion of xenobiotic into active toxin
    • Through immune mechanisms
  • Can produce effects on the liver from:
    • Trivial (cholestasis) to severe (liver failure/fulminant hepatitis or chronic liver disease)
    • Attribute injury by showing temporal association or recovery on withdrawal
A

Liver

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14
Q

Types of what reactions?

  • Predictable
    • Dose-dependent
    • Acetaminophen - accidental or intentional overdosing
  • Unpredictable/idiosyncratic
    • Immune-mediated destruction of liver cell/bile duct
    • Direct cytotoxicity
    • Chlorpromazine
    • Halothane
A

Drug toxic reactions

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15
Q

Drugs like methotrexate and alcohol can cause the liver to become _____________

A

Steatohepatotic (cause steatohepatitis)

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16
Q
  • What can occur with anabolic steroid use?
  • What can occur with OCP use?
A
  • Steroids - formation of bile plugs in the canaliculi
  • OCPs - cholestatic feathery degeneration of the liver
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17
Q

What is the is most common cause of acute liver failure needing transplantation?

  • Each year in the US, overdoses from this send 55,000 to 80,000 people to the ER. At least 500 people die from this (per CDC, FDA).
  • Daily dose - 4000 mg
A

In US today, acetaminophen overdose

  • A predictable hepatotoxin
  • See coagulative necrosis and ballooning degeneration
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18
Q

What disorder?

  • over a long period
  • results in a spectrum of pathologic liver changes
  • Leading cause of liver disease in most Western countries
  • In the world, causes 3.8% of deaths (8th highest risk factor for death)

​

Forms of liver injury:

  • Steatosis (fatty change)
  • Alcoholic (Steato-) Hepatitis (necroinflammatory changes)
  • Steatofibrosis
A

Alcoholic liver diease

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19
Q

Which type of hepatic steatosis is predominant in alcoholic liver disease?

A

Macrovesicular hepatic steatosis (microvesicular can also occur)

20
Q

What finding seen with alcoholic liver disease?

  • Liver may be enlarged
  • Soft, greasy on sectioning
  • Macrovesicular and microvesicular
  • Reversible w/ abstinence

–> Pathogenesis

  • Increased synthesis of lipid
  • Abnormal lipoproteins
  • Increased peripheral fat catabolism
A

Hepatic Steatosis

21
Q

Classic picture of alcoholic liver disease involves what bodies? along with what

A

Mallory-Denk (Mallory) Bodies

  • Mallory bodies look “ropy” and thick
  • Can also see Neutrophil satellitosis
22
Q

What are the typical characteristics (2) of alcoholic hepatitis?

A

Mallory/Mallory-Denk bodies

  • Thick, ropy perinuclear eosinophilic inclusions c/o cytokeratin intermediate filaments, other protein

Neutrophilic reaction

  • Infiltrate in areas of hepatic necrosis and produce free radicals
23
Q

What does the histology slide of alcoholic liver disease show?

A

“Chicken wire” pericellular fibrosis (Alcoholic steatofibrosis)

24
Q

FACT:

Pathogenesis of alcoholic liver

  • 80 grams of alcohol for short-term ingestion for one to several days ->> mild fatty change - reversible
  • 80 grams or more daily ->> severe liver injury
  • 160 grams or more daily x 10, 20 years ->> more severe liver injury
  • Only 10-15% of alcoholics develop cirrhosis- unclear why
  • NOTE: 20 grams/day for women
A
25
Q

What are some effects of alcohol on the body?

A

Effects of alcohol

  • Steatosis
  • Dysfunction of mitochondrial, cellular membranes
  • Hypoxia
  • Oxidative stress
26
Q

What enzyme converts ethanol to acetaldehyde? (Requires NAD+ in hepatocytes)

Bonus: What enzyme converts acetaldehyde to acetate? (requires NAD+ in mitochondria)

A

Alcohol dehydrogenase

Bonus: Acetaldehyde dehydrogenase

27
Q

What?

  • Shunting of normal substrates towards lipid synthesis
  • instead of catabolism -> more reduced NADH by alcohol dehydrogenase, acetaldehyde dehydrogenase -> more lipogenesis, less FA oxidation
  • Impaired assembly, secretion of LPs
  • Increased peripheral catabolism of fat -> FA s in circulation
A

Hepatocellular steatosis

28
Q

Findings of what disease?

  • Steatosis
  • Hepatomegaly
  • Labs: slightly elevated bilirubin, ALP, neutrophilia
  • AST>ALT 2:1 or more (in contrast to other chronic liver diseases)
    • *Mnemonic?
A

Alcoholic liver disease (Hepatitis)

Mnemonic -Another Scotch and Tonic

29
Q

Diagnosis?

  • After 15-20 years of drinking OR acutely after bout of heavy drinking
  • Malaise, wt loss, anorexia, abdominal pain
A

Alcoholic Hepatitis

30
Q

What are some factors that influence severity of alcoholic liver disease?

A
  • Gender - Women more susceptible - less AlcDH, more body fat proportionally, estrogen & LPS receptor K cells
  • Ethnic, genetic differences
  • African-American drinkers have higher cirrhosis rates than white Americans
  • Asians have ALDH2 variant and acetaldehyde
  • Co-morbid conditions
    • Synergistic with alcohol -> more severe effects
    • Iron overload
    • HCV, HBV infections
31
Q

What is the endpoint of alcoholic liver disease?

  • Develops slowly in 10-15% of patients
  • Gross: Liver is shrunken, diffusely nodular, firm
  • Microscopic: Nodules of hepatocytes surrounded by fibrous bands
A

Alcoholic Cirrhosis

32
Q

What disorder?

  • At autopsy, see in ~10% alcoholics
  • Complications from portal HTN
  • Malnutrition – alcohol is major source of calories
  • Clinical - malaise, weakness, anorexia, wt loss; jaundice, ascites, edema
  • Laboratory Findings
    • Increased serum AST, ALT, bilirubin; variable ALP, anemia, low protein (globin, albumin, clotting factors)
A

Alcoholic cirrhosis

33
Q

Alcoholic Cirrhosis:

  • Liver biopsy
  • 20% of cirrhotics have other disease
  • Clinically silent cirrhosis

What is the most important consequence of injury, inflammation?

  • Results in ABNORMAL VASCULATURE
  • Any degree indicates progressive liver injury
  • Due to activated ___________ in centrilobular sinusoids
  • Perisinusoidal, pericellular fibrosis (“chicken-wire”)
A

<<<<***FIBROSIS***>>>>

Stellate Cells

34
Q

Severe alcoholic cirrhosis can lead to death from what causes?

A
  • Hepatic coma
  • Massive GI bleed
  • Infection- sepsis
  • Hepatorenal syndrome after alcoholic hepatitis
  • Hepatocellular carcinoma (1-6% risk/year in cirrhotics)
35
Q

What disorder?

  • Most common chronic liver disease in the US today. Affects 3-5% US population
  • Growing worldwide with spread of obesity, type 2 diabetes, and metabolic syndrome.
A

NAFLD - Non-Alcoholic Fatty Liver Disease

36
Q

Criteria for what liver disease?

A

NAFLD

37
Q

NAFLD:

  • Imaging tests reveal fat accumulation in liver
  • But current non-invasive tests lack sensitivity, specificity

What is the Gold Standard Test for grading & staging of disease assess efficacy of new treatments?

Grade = degree of inflammation, necrosis, steatosis

Stage = degree of fibrosis

A

Liver Biopsy*

38
Q

What disorder?

  • More progessive form of spectrum of diseases under NAFLD
  • Hepatic manifestation of METABOLIC SYNDROME
  • Insulin resistance is central to pathophysiology
  • Most common cause of elevated liver enzymes today!
A

Non-Alcoholic Steatohepatitis (NASH)

39
Q

Associated with NAFLD:

A. Greater than 5% fat cells in liver parenchyma

  • Elevated liver enzymes
  • Without inflammation, cell death, fibrosis

B. Steatosis + necroinflammatory changes of hepatitis

A

A. Steatosis

B. Steatohepatitis

40
Q

Label the image:

1.

2.

3.

4.

A
  1. Ballooned hepatocytes
  2. Macrovesicular steatosis
  3. Apoptotic/Acidophil Body
  4. Lobular Inflammation
41
Q

What disease?

Clinical Manifestations

  • Fatigue, right upper quadrant pain- hepatomegaly
  • NO history of significant alcohol consumption

Lab Findings

  • Elevated serum ALT and ASP in 90%
  • AST/ALT ratio <1 (as opposed to Alcoholic Steatohepatitis in which ratio usually 2 or more
A

Non-Alcoholic Fatty Liver Disease

42
Q

What is the Multiple-hit model for NAFLD Development?

A

Fatty deposition –> Multiple hits that likely interact: Diet, Genetic predisposition genes, Gut microbiome –> NASH

*(Two-Hit Model from 1998 now obsolete)

43
Q

Individuals with _________ :

  • More visceral fat that is also dysfunctional
  • Decreased adiponectin - hormone that promotes insulin sensitivity
  • Increased release cytokines TNF-alpha, IL-6, with additional “hits”
  • Promote fat cell apoptosis (fat-laden cells & oxidative stress –> mitochondrial, cell membrane damage) –> progression to NASH
A

Insulin Resistance

44
Q

Today, 90% of ____________ are considered “burned-out” NASH

A

Cryptogenic Cirrhosis

45
Q

What disorder?

  • More diffuse steatosis
  • More portal fibrosis (otherwise same as adult)
  • Mononuclear inflammatory cells in portal and lobule (vs. neutrophils in lobule in adult)
A

Pediatric NAFLD:NASH

46
Q

With NASH, patients have an increased risk for ________.

Objectives of treatment:

  • Reverse steatosis
  • Prevent cirrhosis
  • Treat insulin resistance
A

Hepatocellular Carcinoma

D&T 4, Exam 3 (Liver) (19 decks)

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