Alcoholic, Metabolic, & Autoimmune Liver Disease - Franco

Question 1

Why is “primary biliary cirrhosis” a misnomer?

Describe this disease’s etiology.

Answer 1

There is generally little cirrhosis of the liver parenchyma

Usually autoimmune; IgM antimicrobial antibodies (AMA) target PDC-E2. (pyruvate dehydrogenase complex) on the canalicular

Question 2

Describe the epidemiology of PBC. Who is affected and at what age?

Answer 2

Almost entirely (caucasian) women, mean age 52 at presentation.

(look for a familial pattern)

Question 3

What are the expected lab findings in primary biliary cirrhosis?

What symptoms do the patients complain of?

Answer 3

Increased alkaline phosphatase (disease is cholestatic) and positive AMAs. Other autoimmune diseases may be copresent. Elevated cholesterol.

Lethargy and pruritus, some xanthomas/atheromas

Question 4

Why does primary biliary cirrhosis result in fat soluble vitamin deficiency?

What are the consequences of this?

Answer 4

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)

Question 5

What autoimmune diseases are most associated with primary biliary cirrhosis?

Answer 5

Sjogren’s disease > Thyroiditis > Rheumatoid Arthritis > many others…

Question 6

Why does primary biliary cirrhosis result in intense pruritis?

With this in mind, give three treatment options that relieve this symptom.

Answer 6

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)

Question 7

What gene causes hereditary hemochromatosis?

What chromosome is the gene located on?

Answer 7

HFE gene

Short arm of chromosome 6

Question 8

What does the HFE protein do?

Why does this cause hemochromatosis?

Answer 8

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

Question 9

What causes secondary hemochromatosis?

Answer 9

Ineffective hematopoiesis

Liver disease

Red cell transfusions

Iron-dextran injections

Long-term dialysis

Question 10

Who gets diagnosed with primary hemochromatosis?

What is the mutation?

Answer 10

Causcasians of northern european ancestry

C282Y/C282Y or

C282Y/H63D

Question 11

What symptoms are seen in hemochromatosis?

Answer 11

Liver function abnormalities

Lethargy

Hyperpigmentation

Diabetes

Impotence

Arthralgia

(AKA bronze diabetes)

Question 12

How does hemochromatosis present differently in women?

Answer 12

Typically presents later due to blood loss during menstrual cycle

Question 13

What tests are needed to diagnoses hereditary hemochromatosis?

Answer 13

• 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

Question 14

What stain is used with liver biopsys to see diagnose hemochromatosis?

How does iron appear with this stain?

Answer 14

Prussian Blue stain

Iron appears blue

Question 15

How should phlebotomy be used to treat hemochromatosis?

Answer 15

Ferritin <50

Initially weekly, but moved to quarterly after stable levels reached

Question 16

How is copper typically handled in a healthy human?

What is decreased in Wilson’s disease?

Answer 16

Bound to ceruloplasmin, excreted in bile, or excreted in urine

Ceruloplasmin levels are decreased and bile excretion is decreased

Question 17

How common is Wilson’s disease?

Who should Wilson’s disease be considered in?

Answer 17

30 cases per million

patients age 30-40 with liver problems

Question 18

Why is Wilson’s disease so difficult to diagnose?

Answer 18

Wide variety of neurological or psychiatric symptoms including:

Depression

Migraines

Insomnia

Psychosis

Movement disorders

Seizures

Question 19

What can lead to false negatives in Wilson’s disease diagnoses?

Answer 19

Wilson’s disease typically has ceruloplasmin levels less than 20mg/dL, but inflammation raises levels

Question 20

What are three physical signs of Wilson’s disease?

Answer 20

Urinary excretion of Copper

Kayser-Fleischer Rings

Increased copper concentration in liver biopsy

Question 21

What three therapies are available for Wilson’s disease?

How do they work?

Answer 21

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)

Question 22

What is Alpha-1 anti-trypsin?

What pathologies does alpha-1 anti-trypsin deficiency cause?

Answer 22

An elastase inhibitor

Hepatitis, cirrhosis, liver cancer, genetic emphysema

Question 23

What are three gene variations associated with alpha-1 antitrypsin?

How do their severitys compare?

Answer 23

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)

Question 24

How does alpha-1 antitrypsin cause disease in the lungs?

How does it cause disease in the liver?

Answer 24

Loss-of-function; A1AT does not inhibit elastase and tissue is generally destroyed, causing emphysema

Protein accumulation; A1AT misfolds and accumulates in hepatocytes

Question 25

How is Alpha-1 antitrypsin deficiency diagnosed?

Answer 25

Serum A1AT levels A1AT genotyping Liver biopsy to look for protein accumulation

Question 26

What is autoimmune hepatitis? What are some risk factors for autoimmune hepatitis?

Answer 26

inflammation of hepatocytes caused by autoantibodies in the serum female, with other autoimmune diseases

Question 27

What lab results are seen in autoimmune hepatitis? What is seen on histology in autoimmune hepatitis?

Answer 27

1. ALT, AST elelvation 2. Elevated gamma-globulin or IgG 3. Autoantibodies 1. Interface hepatitis 2. portal plasma cell infiltration

Question 28

What are the classifications of autoimmune hepatitis? Who does each type affect? What organelles are targeted? What antibodies are present?

Answer 28

* 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

Question 29

What are treatment options for autoimmune hepatitis? What might cause one to be prescribed over the other?

Answer 29

Prednisone (cytopenia, pregnancy, malignancy, short course) Prednisone and Azathioprine (post-menopause, osteoporosis, diabetes, acne, obesity, hypertension)

Question 30

How long should AIH be treated? What is the prognosis for AIH?

Answer 30

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

Question 31

Describe the 5 grades of **Inflammation** using the **Metavir** histological scoring system.

Answer 31

Inflammation: * 0: No activity * 1: Minimal * 2: Mild * 3: Moderate * 4: Severe

Question 32

Describe the 5 grades of **Fibrosis** using the **Metavir **histological scoring system.

Answer 32

Fibrosis: * 0: **No** fiborisis * 1: **Portal** fibrosis * 2: **Periportal** fibrosis * 3: **Septal** fibrosis * 4: **Cirrhosis**

Question 33

What is bridging fibrosis?

Answer 33

When fibrotic strands can be seen bridging (running between) portal triads, and to a lesser extent central veins.

Question 34

What is cirrhosis?

Answer 34

Thick bands of fibrotic tissue, bridging between portal triads and central veins, that **encircle** **nodules** of **functional** liver parenchyma.

Question 35

You obtain a liver biospy specimen. What stain would allow for easy detection of fibrosis?

Answer 35

**Trichome** stain - collagen is stained blue

Question 36

What is the difference in timing between hepatic necrosis and fibrosis?

Answer 36

Necrosis is **acute**. Fibrosis is **chronic** - takes **years** to develop in most cases.

Question 37

# Define: **Fulminant** liver failure What are the two most common causes of this?

Answer 37

**Acute **liver failure complicated by **coagulopathy** and **encephalopathy** Common causes: * Medications (acetaminophen) * Viral hepatits

Question 38

What is the amount of alcohol (in grams) contained in: 1. 12oz of beer? 2. 4oz of wine? 3. 1.5 of hard liquor?

Answer 38

1. 13.8g 2. 10.7g 3. 13.4g

Question 39

# Define the following for **men** and **women**: 1. Binge drinking 2. Heavy drinking 3. Excessive drinking

Answer 39

1. **Binge**: * Men: 5 or more drinks during **single occasion** * Women: 4 or more " " " " 2. **Heavy**: * Men: More than 2 drinks per day **on average** * Women: More than 1 " " " " " 3. **Excessive** includes: * Heavy drinking * Binge drinking * Or both

Question 40

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?

Answer 40

MEOS (Microsomal Ethanol Oxidizing System) Enzymes: 1. Alcohol Dehydrogenase (EtOH --\> Acetaldehyde) 2. Aldehyde Dehydrogenase (Acetaldehyde --\> Acetic Acid)

Question 41

Alcohol metabolism causes an **increase in NADH** levels. What metabolic consequences does this have on the body?

Answer 41

* Inhibits TCA cycle --\> reduced gluconeogenesis * Reduced FA oxidation In short: harder to derive short-term energy, even from bodily stores.

Question 42

Alcohol metabolism causes an **increased acetaldehyde**. What metabolic consequences does this have on the body?

Answer 42

* Activates **stellate cells** to form **collagen** (fibrosis!) * Microfilaments that maintain cell cytoskeletons are sheared * **Kupffer cells** produce **TNFalpha **(inflammation!)

Question 43

What cellular changes are seen in the hepatic pathogenesis of alchohol?

Answer 43

* Stellate cell activation (into "myofibroblasts") * Kupffer cell activation * Loss of sinusoid fenestrations * Loss of microvilli * Filling of the **Space of Disse** with dense ECM

Question 44

What is the Space of Disse? What cells reside in this space?

Answer 44

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.

Question 45

What percentage of heavy drinkers... 1. Develop fatty liver from a previously normal liver? 2. Develop alcoholic hepatitis from a previously fatty liver? 3. Develop cirrhosis from a previously fatty liver? 4. Develop cirrhosis from a liver that had alcoholic hepatitis?

Answer 45

1. **90-100%** 2. 10-35% 3. 8-20% 4. ~40%

Question 46

What three vessels make up a portal triad again?

Answer 46

1. Portal **vein** branch 2. Portal **artery** branch 3. Bile **duct** branch

Question 47

How can the **timing** of drinking alcohol contribute to the risk of developing ALD (alcoholic liver disease?)

Answer 47

Drinking alcohol on an **emtpy stomach** produces significantly ligher BACs than drinking following a meal, which places more stress on the liver.

Question 48

What liver panel abnormalities are often seen in alcoholic liver disease?

Answer 48

* AST:ALT \>2-3 * ALT usually \< 300 * Alk Phos rarely raised * Low albumin * Prlonged INR (advanced disease)

Question 49

What **hematological** findings often are seen in alcoholic liver disease?

Answer 49

* Prolonged INR (would be seen with liver panel) * **Macrocytosis** / **anemia** * **Thrombocytopenia** (advanced disease)

Question 50

What drug class is useful for alcoholic liver disease? Name two examples.

Answer 50

Anti-inflammatory drugs 1. Glucocorticoids 2. Pentoxifylline

Question 51

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?

Answer 51

(Maddrey's) **Discriminant Function** **4.6\*(PT - PT_control) + T_bili** PT = prothrombin time PT_control = reference PT value (for given lab doing analysis) T_bili = Total bilirubin Values **\>32** have a **high** (30-50%) **1-month mortality** and thus have most potential benefit from steroid therapy.

Question 52

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

Answer 52

**Yes.** Use the discriminant formula. 4. 6\*(PT - PT_control) + T_bili 4. 6\*(19-12) + 12 **= 44** **44 \> 32**, so give steroids

Question 53

How effective ***is*** glucocorticoid therapy in alcoholic hepatitis patients?

Answer 53

* 6 month survival **with** therapy: ~84% * 6 month survival **without** therapy: ~45%

Question 54

Aside from the discriminant function, what other metric gives an estimate of survival in alcoholic hepatitis patients?

Answer 54

**Child-Turcotte-Pugh** score | (the lower, the better)

Question 55

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)

Answer 55

**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.

Question 56

NAFLD can be histologically subdivided into two categories. Name them and explain the difference.

Answer 56

* Non-alcoholic fatty liver (NAFL) * Hepatic steatosis * **No** inflammation * **No** hepatocellular injury (ballooning) * Non-alcoholic steatohepatitis (NASH) * Hepatic steatosis * Inflammation * Hepatocellular injury * +/- fibrosis

Question 57

Describe the stages in the progression of NAFLD.

Answer 57

* 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**)

Question 58

NAFLD has a strong association which what disorder? What findings are commonly seen?

Answer 58

**Metabolic Syndrome** * Obesity * Diabetes * Hypertriglyceridemia

Question 59

Describe the demographic etiology of NAFLD. Sex? Ethnicity? Age? Weight?

Answer 59

* Males \> Females * Hispanics \> Caucasians \> African Americans * Prevalence **and** severity increases with age * Risk increases with BMI

Question 60

What is the most common liver disease in children in the US?

Answer 60

NAFLD, with 18% of those children having NASH

Question 61

Do fats and cholesterol increase risk of NAFLD?

Answer 61

* Hypertriglyceridemia increases risk * 3x risk with TG \> 200 * Hypercholesterolemia does **not** increase risk

Question 62

Name some causes of steatosis and steatohepatitis.

Answer 62

* **Alchohol** * **Medications** * **Amiodarone** * **Steroids** * **HAART** * **Tamoxifen** * **Diltiazem** * **Nutritional** * Insulin resistance * Weight changes

Question 63

How does a fatty liver appear on ultrasound?

Answer 63

A fatty liver is **echogenic** - more dense than usual toward sound waves.

Question 64

1. How effective is weight loss in treating NAFLD? 2. What liver findings improve with weight loss? 3. What strategies to weight loss are effective?

Answer 64

1. **Very effective.** 2. Multiple studies have shown that weight loss improves both liver function test results and histological appearance. 3. Several methods have been shown to be effective, including: * Diet + exercise * Gastric banding * Anti-obestiy drugs (e.g. Orlistat)

Question 65

How much weight loss is required to improve steatosis in NAFLD? How much to improve inflammation in NAFLD?

Answer 65

**Steatosis**: Loss of **3-5%** of body weight **Inflammation**: Loss of up to **10%** of body weight may be required

Question 66

Other than weight loss, name two treatments for NASH. What elements of NASH are improved by these treatments?

Answer 66

* Pioglitazone * Vitamin E Both of these treatments were studied and found to yield an improvement in **histology**, **inflammation, and LFTs**. However, neither improved fibrosis.

Question 67

What is a notable side effect of pioglitazone?

Answer 67

Weight gain As this is itself a risk for NASH, a weight loss regimen should also be considered to more fully treat NASH.

Question 68

What is the mechanism of action of Pioglitazone? What is the drug's classical indication?

Answer 68

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.

Question 69

1. What should Vitamin E be used to treat? 2. What should it **NOT** be used to treat? 3. What dosage?

Answer 69

1. Used for **biopsy-proven** **NASH** 2. Not recommended for: * **NASH in diabetic pts** * NAFLD w/o liver biopsy * **NASH cirrhosis** * Cryptogenic Cirrhosis 3. 800 IU/day