Limjoco - Autoimmune & Alcoholic Liver Disease, NAFLD Flashcards
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!
Liver Autoimmune Hepatitis
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
Liver autoimmune hepatitis
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. Type 1
B. Type 2
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)
Liver Autoimmuine Hepatitis
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.
Liver Autoimmune Hepatitis
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
- Encephalopathy
- AIH-PBC (Primary Biliary Cirrhosis), AIH-PSC (Primary Sclerosing Cholangitis)
Lab findings of what disease?
- Elevated transaminases ALT, AST
- Serology
- Autoantibodies ANA, ASMA, anti-LKM-1
- Polyclonal serum immunoglobulins (esp. gamma globulins)
- Liver biopsy
Liver Autoimmune Hepatitis
What do the hepatocyes form on histology?
Bonus: What type of cells are characteristically found?
- Rosette Formation
- Bonus: Plasma cells (characteristic of, but not exclusive to, AIH)
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
- Fulminant hepatitis
- immunosuppression
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?
- Immunosuppression –> Prednisone
Azathioprine (Imuran)
Bonus: LIFELONG! needs to be continuously monitored
Fact:
Liver transplant
- 75% survive 10 yrs
- 20% AIH recurs in transplant
What are some examples of xenobiotics?
- Therapeutic agents, environmental toxins (“xeno”- “foreign”)
- Alcohol
- Drugs
- Steroids
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
Liver
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
Drug toxic reactions
Drugs like methotrexate and alcohol can cause the liver to become _____________
Steatohepatotic (cause steatohepatitis)
- What can occur with anabolic steroid use?
- What can occur with OCP use?
- Steroids - formation of bile plugs in the canaliculi
- OCPs - cholestatic feathery degeneration of the liver
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
In US today, acetaminophen overdose
- A predictable hepatotoxin
- See coagulative necrosis and ballooning degeneration
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
Alcoholic liver diease
Which type of hepatic steatosis is predominant in alcoholic liver disease?
Macrovesicular hepatic steatosis (microvesicular can also occur)
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
Hepatic Steatosis
Classic picture of alcoholic liver disease involves what bodies? along with what
Mallory-Denk (Mallory) Bodies
- Mallory bodies look “ropy” and thick
- Can also see Neutrophil satellitosis
What are the typical characteristics (2) of alcoholic hepatitis?
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
What does the histology slide of alcoholic liver disease show?
“Chicken wire” pericellular fibrosis (Alcoholic steatofibrosis)
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
What are some effects of alcohol on the body?
Effects of alcohol
- Steatosis
- Dysfunction of mitochondrial, cellular membranes
- Hypoxia
- Oxidative stress
What enzyme converts ethanol to acetaldehyde? (Requires NAD+ in hepatocytes)
Bonus: What enzyme converts acetaldehyde to acetate? (requires NAD+ in mitochondria)
Alcohol dehydrogenase
Bonus: Acetaldehyde dehydrogenase
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
Hepatocellular steatosis
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?
Alcoholic liver disease (Hepatitis)
Mnemonic -Another Scotch and Tonic
Diagnosis?
- After 15-20 years of drinking OR acutely after bout of heavy drinking
- Malaise, wt loss, anorexia, abdominal pain
Alcoholic Hepatitis
What are some factors that influence severity of alcoholic liver disease?
- 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
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
Alcoholic Cirrhosis
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)
Alcoholic cirrhosis
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”)
<<<<***FIBROSIS***>>>>
Stellate Cells
Severe alcoholic cirrhosis can lead to death from what causes?
- Hepatic coma
- Massive GI bleed
- Infection- sepsis
- Hepatorenal syndrome after alcoholic hepatitis
- Hepatocellular carcinoma (1-6% risk/year in cirrhotics)
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.
NAFLD - Non-Alcoholic Fatty Liver Disease
Criteria for what liver disease?
NAFLD
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
Liver Biopsy*
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!
Non-Alcoholic Steatohepatitis (NASH)
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. Steatosis
B. Steatohepatitis
Label the image:
1.
2.
3.
4.
- Ballooned hepatocytes
- Macrovesicular steatosis
- Apoptotic/Acidophil Body
- Lobular Inflammation
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
Non-Alcoholic Fatty Liver Disease
What is the Multiple-hit model for NAFLD Development?
Fatty deposition –> Multiple hits that likely interact: Diet, Genetic predisposition genes, Gut microbiome –> NASH
*(Two-Hit Model from 1998 now obsolete)
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
Insulin Resistance
Today, 90% of ____________ are considered “burned-out” NASH
Cryptogenic Cirrhosis
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)
Pediatric NAFLD:NASH
With NASH, patients have an increased risk for ________.
Objectives of treatment:
- Reverse steatosis
- Prevent cirrhosis
- Treat insulin resistance
Hepatocellular Carcinoma
