Alcoholic, Metabolic, & Autoimmune Liver Disease - Franco Flashcards
Why is “primary biliary cirrhosis” a misnomer?
Describe this disease’s etiology.
There is generally little cirrhosis of the liver parenchyma
Usually autoimmune; IgM antimicrobial antibodies (AMA) target PDC-E2. (pyruvate dehydrogenase complex) on the canalicular
Describe the epidemiology of PBC. Who is affected and at what age?
Almost entirely (caucasian) women, mean age 52 at presentation.
(look for a familial pattern)
What are the expected lab findings in primary biliary cirrhosis?
What symptoms do the patients complain of?
Increased alkaline phosphatase (disease is cholestatic) and positive AMAs. Other autoimmune diseases may be copresent. Elevated cholesterol.
Lethargy and pruritus, some xanthomas/atheromas
Why does primary biliary cirrhosis result in fat soluble vitamin deficiency?
What are the consequences of this?
Biliary obstruction causes decreased bile salt excretion which reduces the ability for the GI tract to absorb lipids (and fat-soluble vitamins).
Vitamin D deficiency causes osteomalacia. Vitamin K deficiency causes prolonged bleeding (both uncommon)
What autoimmune diseases are most associated with primary biliary cirrhosis?
Sjogren’s disease > Thyroiditis > Rheumatoid Arthritis > many others…
Why does primary biliary cirrhosis result in intense pruritis?
With this in mind, give three treatment options that relieve this symptom.
The bile salts not excreted through the biliary tree accumulate elsewhere, eg in the skin and provoke itching.
Ursodeoxycholic acid (also improve labs and survival), cholestyramine (bind and remove more bile), diphenhydramine (anti-histamine and drowsy for nighttime relief)
What gene causes hereditary hemochromatosis?
What chromosome is the gene located on?
HFE gene
Short arm of chromosome 6
What does the HFE protein do?
Why does this cause hemochromatosis?
regulates the expression of transferrin
When iron levels in the blood are high, transferrin should be down-regulated; without functional HFE, transferrin levels stay high and iron accumulates
What causes secondary hemochromatosis?
Ineffective hematopoiesis
Liver disease
Red cell transfusions
Iron-dextran injections
Long-term dialysis
Who gets diagnosed with primary hemochromatosis?
What is the mutation?
Causcasians of northern european ancestry
C282Y/C282Y or
C282Y/H63D
What symptoms are seen in hemochromatosis?
Liver function abnormalities
Lethargy
Hyperpigmentation
Diabetes
Impotence
Arthralgia
(AKA bronze diabetes)
How does hemochromatosis present differently in women?
Typically presents later due to blood loss during menstrual cycle
What tests are needed to diagnoses hereditary hemochromatosis?
- Look at fasting transferrin saturation
- normal is <45%
- Genetic Testing
- if compound heterozygote, consider biopsy
- if homozygote, phlebotomy
- if homozygote over 40 or with elevated AST/ALT, biopsy
What stain is used with liver biopsys to see diagnose hemochromatosis?
How does iron appear with this stain?
Prussian Blue stain
Iron appears blue
How should phlebotomy be used to treat hemochromatosis?
Ferritin <50
Initially weekly, but moved to quarterly after stable levels reached
How is copper typically handled in a healthy human?
What is decreased in Wilson’s disease?
Bound to ceruloplasmin, excreted in bile, or excreted in urine
Ceruloplasmin levels are decreased and bile excretion is decreased
How common is Wilson’s disease?
Who should Wilson’s disease be considered in?
30 cases per million
patients age 30-40 with liver problems
Why is Wilson’s disease so difficult to diagnose?
Wide variety of neurological or psychiatric symptoms including:
Depression
Migraines
Insomnia
Psychosis
Movement disorders
Seizures
What can lead to false negatives in Wilson’s disease diagnoses?
Wilson’s disease typically has ceruloplasmin levels less than 20mg/dL, but inflammation raises levels
What are three physical signs of Wilson’s disease?
Urinary excretion of Copper
Kayser-Fleischer Rings
Increased copper concentration in liver biopsy
What three therapies are available for Wilson’s disease?
How do they work?
D-penicillamine- chelates copper and induces cupruria
Trientine-chelates copper and induces cupruria
Zinc- blocks absorption and induces metallothionein
(wikipedia has no entries on cupruria, but it brings up a lot of entries in Spanish)
What is Alpha-1 anti-trypsin?
What pathologies does alpha-1 anti-trypsin deficiency cause?
An elastase inhibitor
Hepatitis, cirrhosis, liver cancer, genetic emphysema
What are three gene variations associated with alpha-1 antitrypsin?
How do their severitys compare?
M- main or WT
S- uncommon mutant
Z-common mutant
MM>MS>MZ>SS (no lung or liver disease)
SZ> null-null (lung disease)
ZZ (lung and liver disease)
How does alpha-1 antitrypsin cause disease in the lungs?
How does it cause disease in the liver?
Loss-of-function; A1AT does not inhibit elastase and tissue is generally destroyed, causing emphysema
Protein accumulation; A1AT misfolds and accumulates in hepatocytes
How is Alpha-1 antitrypsin deficiency diagnosed?
Serum A1AT levels
A1AT genotyping
Liver biopsy to look for protein accumulation
What is autoimmune hepatitis?
What are some risk factors for autoimmune hepatitis?
inflammation of hepatocytes caused by autoantibodies in the serum
female, with other autoimmune diseases
What lab results are seen in autoimmune hepatitis?
What is seen on histology in autoimmune hepatitis?
- ALT, AST elelvation
- Elevated gamma-globulin or IgG
- Autoantibodies
- Interface hepatitis
- portal plasma cell infiltration
What are the classifications of autoimmune hepatitis?
Who does each type affect?
What organelles are targeted?
What antibodies are present?
- Type 1 AIH
- affects adults
- targets the nucleus
- ANA (anti-nuclear antibody); ASMA (anti-smooth muscle antibody)
- Type 2 AIH
- affects children
- targets the microsome
- anti-liver-kidney microsomal antibody
What are treatment options for autoimmune hepatitis?
What might cause one to be prescribed over the other?
Prednisone (cytopenia, pregnancy, malignancy, short course)
Prednisone and Azathioprine (post-menopause, osteoporosis, diabetes, acne, obesity, hypertension)
How long should AIH be treated?
What is the prognosis for AIH?
ALT/AST/IgG return to normal values
Resolution of inflammation
good survival with treatment (80% at 20 years) vs 90% dead without treatment at 10 years
Describe the 5 grades of Inflammation using the Metavir histological scoring system.
Inflammation:
- 0: No activity
- 1: Minimal
- 2: Mild
- 3: Moderate
- 4: Severe
Describe the 5 grades of Fibrosis using the **Metavir **histological scoring system.
Fibrosis:
- 0: No fiborisis
- 1: Portal fibrosis
- 2: Periportal fibrosis
- 3: Septal fibrosis
- 4: Cirrhosis
What is bridging fibrosis?
When fibrotic strands can be seen bridging (running between) portal triads, and to a lesser extent central veins.
What is cirrhosis?
Thick bands of fibrotic tissue, bridging between portal triads and central veins, that encircle nodules of functional liver parenchyma.
You obtain a liver biospy specimen. What stain would allow for easy detection of fibrosis?
Trichome stain - collagen is stained blue
What is the difference in timing between hepatic necrosis and fibrosis?
Necrosis is acute.
Fibrosis is chronic - takes years to develop in most cases.
Define: Fulminant liver failure
What are the two most common causes of this?
**Acute **liver failure complicated by coagulopathy and encephalopathy
Common causes:
- Medications (acetaminophen)
- Viral hepatits
What is the amount of alcohol (in grams) contained in:
- 12oz of beer?
- 4oz of wine?
- 1.5 of hard liquor?
- 13.8g
- 10.7g
- 13.4g
Define the following for men and women:
- Binge drinking
- Heavy drinking
- Excessive drinking
-
Binge:
- Men: 5 or more drinks during single occasion
- Women: 4 or more “ “ “ “
-
Heavy:
- Men: More than 2 drinks per day on average
- Women: More than 1 “ “ “ “ “
-
Excessive includes:
- Heavy drinking
- Binge drinking
- Or both
What is the name given to the metabolic pathway via which ethanol is metabolized?
What two enzymes form this pathway, and what reactions to they catalyze?
MEOS (Microsomal Ethanol Oxidizing System)
Enzymes:
- Alcohol Dehydrogenase (EtOH –> Acetaldehyde)
- Aldehyde Dehydrogenase (Acetaldehyde –> Acetic Acid)
Alcohol metabolism causes an increase in NADH levels. What metabolic consequences does this have on the body?
- Inhibits TCA cycle –> reduced gluconeogenesis
- Reduced FA oxidation
In short: harder to derive short-term energy, even from bodily stores.
Alcohol metabolism causes an increased acetaldehyde. What metabolic consequences does this have on the body?
- Activates stellate cells to form collagen (fibrosis!)
- Microfilaments that maintain cell cytoskeletons are sheared
- Kupffer cells produce **TNFalpha **(inflammation!)
What cellular changes are seen in the hepatic pathogenesis of alchohol?
- Stellate cell activation (into “myofibroblasts”)
- Kupffer cell activation
- Loss of sinusoid fenestrations
- Loss of microvilli
- Filling of the Space of Disse with dense ECM
What is the Space of Disse?
What cells reside in this space?
The connective tissue space between the liver’s hepatocytes and the layer of endothelial cells that border the sinusoids.
Stellate cells are found in the Space of Disse.
What percentage of heavy drinkers…
- Develop fatty liver from a previously normal liver?
- Develop alcoholic hepatitis from a previously fatty liver?
- Develop cirrhosis from a previously fatty liver?
- Develop cirrhosis from a liver that had alcoholic hepatitis?
- 90-100%
- 10-35%
- 8-20%
- ~40%
What three vessels make up a portal triad again?
- Portal vein branch
- Portal artery branch
- Bile duct branch
How can the timing of drinking alcohol contribute to the risk of developing ALD (alcoholic liver disease?)
Drinking alcohol on an emtpy stomach produces significantly ligher BACs than drinking following a meal, which places more stress on the liver.
What liver panel abnormalities are often seen in alcoholic liver disease?
- AST:ALT >2-3
- ALT usually < 300
- Alk Phos rarely raised
- Low albumin
- Prlonged INR (advanced disease)
What hematological findings often are seen in alcoholic liver disease?
- Prolonged INR (would be seen with liver panel)
- Macrocytosis / anemia
- Thrombocytopenia (advanced disease)
What drug class is useful for alcoholic liver disease?
Name two examples.
Anti-inflammatory drugs
- Glucocorticoids
- Pentoxifylline
What **formula **is used to estimate whether an alcoholic hepatitis patient would benefit from glucocorticoid therapy? Give the name and the formula itself.
What number is the suggested **threshold **and why?
(Maddrey’s) Discriminant Function
4.6*(PT - PTcontrol) + Tbili
PT = prothrombin time
PTcontrol = reference PT value (for given lab doing analysis)
Tbili = Total bilirubin
Values >32 have a high (30-50%) 1-month mortality and thus have most potential benefit from steroid therapy.
A 38yo male with a Hx of alcoholism presents with jaundice and malaise. His liver panel results are shown below. Would this patient benefit from glucocorticoid therapy?
- ALT 29
- AST 96
- ALK PHOS 98
- TOTAL BILI 12
- DIRECT BILI 8
- PT 19 SEC
- CONTROL PT 12 SEC
Yes. Use the discriminant formula.
- 6*(PT - PTcontrol) + Tbili
- 6*(19-12) + 12
= 44
44 > 32, so give steroids
How effective is glucocorticoid therapy in alcoholic hepatitis patients?
- 6 month survival with therapy: ~84%
- 6 month survival without therapy: ~45%
Aside from the discriminant function, what other metric gives an estimate of survival in alcoholic hepatitis patients?
Child-Turcotte-Pugh score
(the lower, the better)
A 42yo obese female with a history of diabetes mellitus present with jaundice and malaise. Her liver panel shows elevated transaminases. She undergoes a liver biopsy, which is consistent with alcoholic hepatitis. However, she denies alchohol use entirely. What is the most likely diagnosis, and how common is this disorder?
(Hint: She’s not lying)
Non-Alcoholic Fatty Liver Disease (NAFLD)
- Histology can mimic ALD
- Many lipid vacuoles (hepatic steatosis)
- Most common causes of elevated transaminases in U.S.
- Most common chronic liver disorder in U.S.
NAFLD can be histologically subdivided into two categories.
Name them and explain the difference.
- Non-alcoholic fatty liver (NAFL)
- Hepatic steatosis
- No inflammation
- No hepatocellular injury (ballooning)
- Non-alcoholic steatohepatitis (NASH)
- Hepatic steatosis
- Inflammation
- Hepatocellular injury
- +/- fibrosis
Describe the stages in the progression of NAFLD.
- Fatty Liver (Hepatosteatosis)
- 10% progress to:
- Steatohepatitis (NASH)
- 35% of NASH pts progress to:
- Steatohepatitis with Fibrosis
- Which can further progress to:
- Cirrhosis
- (15% of pts with NASH)
NAFLD has a strong association which what disorder?
What findings are commonly seen?
Metabolic Syndrome
- Obesity
- Diabetes
- Hypertriglyceridemia
Describe the demographic etiology of NAFLD.
Sex?
Ethnicity?
Age?
Weight?
- Males > Females
- Hispanics > Caucasians > African Americans
- Prevalence and severity increases with age
- Risk increases with BMI
What is the most common liver disease in children in the US?
NAFLD, with 18% of those children having NASH
Do fats and cholesterol increase risk of NAFLD?
- Hypertriglyceridemia increases risk
- 3x risk with TG > 200
- Hypercholesterolemia does not increase risk
Name some causes of steatosis and steatohepatitis.
- Alchohol
-
Medications
- Amiodarone
- Steroids
- HAART
- Tamoxifen
- Diltiazem
- Nutritional
- Insulin resistance
- Weight changes
How does a fatty liver appear on ultrasound?
A fatty liver is echogenic - more dense than usual toward sound waves.
- How effective is weight loss in treating NAFLD?
- What liver findings improve with weight loss?
- What strategies to weight loss are effective?
- Very effective.
- Multiple studies have shown that weight loss improves both liver function test results and histological appearance.
- Several methods have been shown to be effective, including:
- Diet + exercise
- Gastric banding
- Anti-obestiy drugs (e.g. Orlistat)
How much weight loss is required to improve steatosis in NAFLD?
How much to improve inflammation in NAFLD?
Steatosis: Loss of 3-5% of body weight
Inflammation: Loss of up to 10% of body weight may be required
Other than weight loss, name two treatments for NASH. What elements of NASH are improved by these treatments?
- Pioglitazone
- Vitamin E
Both of these treatments were studied and found to yield an improvement in histology, inflammation, and LFTs. However, neither improved fibrosis.
What is a notable side effect of pioglitazone?
Weight gain
As this is itself a risk for NASH, a weight loss regimen should also be considered to more fully treat NASH.
What is the mechanism of action of Pioglitazone?
What is the drug’s classical indication?
Insulin Sensitizing Agent
Typically used to treat diabetes, but it is effective against NASH in non-diabetic patients as well. The NASH use is still experimental and long-term effects are not established.
- What should Vitamin E be used to treat?
- What should it NOT be used to treat?
- What dosage?
- Used for biopsy-proven NASH
- Not recommended for:
- NASH in diabetic pts
- NAFLD w/o liver biopsy
- NASH cirrhosis
- Cryptogenic Cirrhosis
- 800 IU/day
