Hepatic Inflammation and Fibrosis Flashcards
1
Q
Histological Scoring System: Metavir
A
- **Inflammation **(reversible)
- Grade 0: No activity
- Grade 1: Minimal
- Grade 2: Mild
- Grade 3: Moderate
- Grade 4: Severe
-
Fibrosis (irreversible)
- Grade 0: No fibrosis
- Grade 1: Portal fibrosis
- Grade 2: Periportal fibrosis
- Grade 3: Septal fibrosis
- Grade 4: Cirrhosis
2
Q
Hepatic Necrosis
- Definition:
- Can lead to ….
- Most common causes ….
A
-
Acute cell death
- Fibrosis in most cases takes years
- Can lead to acute liver failure (or fulminant liver failure)
- Most common causes are medications (acetaminophen) and viral hepatitis
3
Q
What is fulminant liver failure?
A
acute liver failure that is complicated by coagulopathy and encephalopathy
4
Q
Alcohol Content of Various Beverages:
A
5
Q
Alcohol Drinking Pattern Definitions:
- Binge Drinking
- Heavy Drinking
- Excessive Drinking
A
-
Binge Drinking:
- For women, 4 or more drinks during a single occasion
- For men, 5 or more drinks during a single occasion
-
Heavy Drinking:
- For women, more than 1 drink per day on average
- For men, more than 2 drinks per day on average
-
Excessive Drinking:
- includes heavy drinking, binge drinking or both
6
Q
- Whta catalyzes this reaction: Ethanol ⇒ Acetaldehyde
- What catalyzes this reaction: Acetaldehyde ⇒ Acetic acid
- What is the other function of CYP2E1?
A
- Ethanol ⇒ Acetaldehyde
- Alcohol Dehydrogenase (75-80%)
- Microsomal Ethanol Oxidizing System** **(20-25%), CYP2E1
- Acetaldehyde ⇒ Acetic acid
- Aldehyde Dehydrogenase
- Other function of CYP2E1:
- metabolism of acetaminophen
7
Q
Effects Of:
- Increased NADH
- Increased acetaldehyde
A
-
Increased NADH
- inhibition of TCA cycle; reduced gluconeogenesis
- reduced fatty acid oxidation
-
Increased acetaldehyde
- activates stellate cells to form collagen
- Microfilaments that maintain intracellular skeleton are sheared (ballooning)
- Kupffer cells produce tumor necrosis factor alpha (TNF α)
8
Q
ALD: Spectrum of Disease
A
9
Q
Risk Factors for ALD
A
-
Quantity of Alcohol
- >30 g/day in men
- > 20 g/day in women
- Outside of meals
- Binge drinking
- Hepatitis C
10
Q
Lab Abnormalities for ALD:
- Biochemistry
- Hematology
A
-
Biochemistry
-
AST/ALT ratio > 2-3
- If > 3, it is ALD (put your $ on it)
- ALT usually <300 IU/ml
- Rarely raised Alk Phos
- Low Albumin
- Bilirubin
-
AST/ALT ratio > 2-3
-
Hematology
- Prolonged INR (advanced disease)
- Macrocytosis / anemia
- Thrombocytopenia (advanced disease)
11
Q
How is alcoholic hepatitis treated?
A
-
Abstinence and lifestyle modification
- nutritional support
- 8-12 weeks to see improvement
-
Anti-inflammatory drugs
- glucocorticoids
- Pentoxifylline (inhibits TNFα)
- both are only used for alcoholic hepatitis
12
Q
How do you decide who to treat for alcoholic hepatitis?
A
-
Discriminant function
- 4.6 * (PT - PT CONTROL) + T BILI
- Patients with values > 32 have a 1-month mortality from 30%-50%
13
Q
What is the most common cause of elevated transaminases in the U.S.?
A
**Non-Alcoholic Fatty Liver Disease **(NAFLD)
14
Q
What is needed in order to diagnose NAFLD?
A
must obtain a history
15
Q
How is Non-Alcoholic Fatty Liver Disease categorized? (2)
A
-
Non-alcoholic fatty liver (NAFL)
- Presence of hepatic steatosis without inflammation or hepatocellular injury (ballooning of hepatocytes)
-
Non-alcoholic steatohepatitis (NASH)
- Presence of hepatic steatosis and inflammation with hepatocellular injury (ballooning of hepatocytes) with or without fibrosis
16
Q
What are the stages of NAFLD?
A
- Fatty Liver (Hepatosteatosis) ⇒ (10% progress)
- Steatohepatitis (NASH) ⇒
- Steatohepatitis with Fibrosis (35% OF NASH) ⇒
- Cirrhosis (15% OF NASH)
17
Q
What is are the associated metabolic syndromes with NAFLD?
A
- Obesity (30-100%)
- Diabetes (15-50%)
- Hypertriglyceridemia (15-80%)
18
Q
NAFLD correlations:
- Prevalence
- Severity of disease
- Gender
- Race/Ethnicity
A
- Prevalence increases with age
- Severity of disease (including advanced fibrosis/cirrhosis) increases with age
- Males > Females
- Hispanics > Caucasians > African Americans
Note: Odds for NAFLD increase with higher BMI (obesity)
19
Q
_____ is the most common liver disease in children in the US
A
**NAFLD **the most common liver disease in children in the US
- NASH is present in 18% of these children
20
Q
What type of hyperlipedemia has the most impact on increased risk for NAFLD diagnosis?
A
- Hypertriglyceridemia rather than hypercholesteremia increases risk
- 3-fold greater risk with triglycerides > 200
21
Q
What are causes of steatosis and steatohepatitis?
A
- Alcohol
- Medications
- Nutritional
- Insulin resistance (IR)
- Abetalipoproteniemia
- Weight changes
22
Q
What medications cause steatosis and steatohepatitis?
A
- Amiodarone
- Steroids
- HAART
- Tamoxifen
- Diltiazem
23
Q
What are nutritional causes of steatosis and steatohepatitis?
A
- TPN
- Severe starvation
- Refeeding syndrome
24
Q
Development and Progression of NAFLD
A
25
What do you look for on ultrasound, when looking for a fatty liver?
* **fat is bright**
* normal tissue is dark
26
What are the therapeutic strategies for NAFLD?
1. **Lifestyle Modifications:**
* decrease oral intake
* active lifestyle
2. **Prevent/Treat Insulin Resistance**
3. **Reduce Oxidative Stress**
27
What was the AASLD statement on **weight loss for NAFLD patients**?
* **Loss of at least 3-5% of body weight necessary to improve steatosis**
* up to 10% may be needed to improve inflammation
28
What were the **results** for Pioglitazone vs. Vitamin E or Placebo for NASH?
* RESULTS (primary endpoint)
* vitamin E vs placebo; 43% vs 19% (p=0.001)
* pioglitazone vs placebo; 34% vs 19% (p=0.04)
* **Both reduced transaminases**
* **Both reduced inflammation**
* **Neither reduced fibrosis**
* Patients receiving pioglitazone gained more weight (4.7 kg)
29
What was the AASLD statement on **insulin sensitizing agents**?
* **Pioglitazone** can be used to treat patients with **biopsy-proven NASH**
* majority of patients that participated in clinical trials were non-diabetic and long-term safety and efficacy is not established
30
What was the AASLD statement on **Vitamin E**?
* **Vitamin E** at a dose of 800 IU/day **improves liver histology in non-diabetic patients with biopsy-proven NASH** and should be considered **first-line therapy**
* Until further data supporting its effectiveness becomes available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis or cryptogenic cirrhosis
31
How is Hereditary Hemochromatosis acquired?
Hereditary Hemochromatosis **(HFE gene)**
**Autosomal Co-dominance**
* **C282Y/C282Y** (homozygote)
* accounts for 82-90% of cases
* **C282Y/H63D **(heterozygote)
32
What is the **normal physiology and pathophysiology** for the HFE gene?
* **HFE regulates the absorption of iron from the small intestine**
* iron is absorbed and mobilized in plasma compartment by transferrin
* HFE **down-regulates transferrin** when iron supplies are adequate
* **A defective HFE gene** **fails to down-regulate transferrin** and iron continues to be absorbed from small intestine
* Iron deposits leads to development of free radicals
33
* What can **Parenteral Iron Overload** lead to?
* What causes Parenteral Iron Overload?
**leads to liver problems**
* Red cell transfusions
* Iron-dextran injections
* Long-term dialysis
34
What causes **Secondary Iron Overload**?
iron found in **kuppfer cells**
1. **Anemia caused by ineffective erythropoiesis**
* Thalassemia major
* Sideroblastic anemia
* Congential dyserythropoietic anemia
* Congential atransferrinemia
* Acerulopasminemia
2. **Liver disease**
* **Alcoholic liver disease**
* **HBV, HCV**
* **Nonalcoholic steatohepatitis**
3. Miscellaneous: excessive iron ingestion
35
* Which population is hemochromatosis most common?
* How often?
* Most common genetic disease in populations of **European** ancestry:
* **C282Y, H63D**
* Heterozygous state: 10% in Caucasians (C282Y/WT)
* Homozygous state in 0.5%- 1% (C282Y/C282Y)
* C282Y/H63D (compound heterozygote, 3%-5%)
36
What is the **clinical presentation** of hemochromatosis?
* **Liver function abnormalities - 75%**
* **Weakness and lethargy - 74%**
* **Skin hyperpigmentation - 70%** (bronze skin)
* Diabetes mellitus - 48%
* Arthralgia - 44%
* Impotence in males - 45%
* Electrocardiographic abnormalities - 31%
**Note:** All present at later age in women due to menstrual blood loss
37
What is the **formula** for a potential **diagnosis of hemochromatosis**?
38
What is the **treatment** for hemochromatosis?
**Phlebotomy**
* Goal serum **ferritin \< 50**
* Initially weekly phlebotomy
* Once quarterly thereafter
39
Describe human Cu metabolism:
40
What will cause you to consider Wilson's Disease?
* No one single finding is adequate for diagnosis
* Consider diagnosis in **any patient age 3-40:**
* Unexplained liver disease
* **Acute liver failure**
* Cirrhosis
* Neurological symptoms
* Psychiatric symptoms
41
What is **required** for a diagnosis of Wilson's Disease?
**Need 2 of 3:**
* Decreased CP
* Elevated urine Cu
* Kayser-Fleishcer rings
42
What are the neurological features of Wilson's Disease?
(P.S. long card)
* Movement disorders
* Drooling, dysarthria
* Rigid dystonia
* Dysautonomia
* Migraine headaches
* Insomnia
* Seizures
* Depression
* Neurotic behavior
* Personality changes
* Psychosis
43
How is **ceruloplasmin** (CP) affected in Wilson's Disease?
* 95% of homozygotes have level **\< 20mg/dL**
* _High CP levels occur in inflammation_ and may lead to _false negatives_
44
How is urinary **Cu excretion** affected in Wilson's Disease?
* Urine copper is derived from non-ceruloplasmin copper
* Rate of excretion in symptomatic patients may exceed 100 microgram/24hrs
45
What can be seen here?
**Kayser-Fleischer rings**
* Present in Wilson's disease (Cu deposition)
46
How is the **concentration of Cu** affected in Wilson's Disease?
* Normal hepatic copper content 50 μg/g dry weight
* **Homozygous WD \> 250 μg/g dry weight**
* **Heterozygous WD 20-250 μg/g dry weight**
* Obtain liver biopsy
47
What is used to treat Wilson's Disease?
* General chelator - **induces cupruria**
* **D-Penicillamine **(significant side effects)
* **Trientine**
* Metallothionein inducer, **blocks intestinal absorption of Cu**
* **Zinc**
48
* What is the function of alpha1 antitrypsin?
* What larger family of enzymes does it belong to?
* Where is it predominately produced?
* A1AT is an **inhibitor of the proteolytic enzyme elastase**
* It is part of a larger family of structurally unique protease inhibitors, referred to as **serpins**
* **Predominantly made in the liver**
49
What is the **prevalence of alpha1 antitrypsin deficiency**?
* **Most common cause of genetic liver disease in children**
* **Most common genetic disease leading to liver transplantation in children**
* **Most common cause of genetic emphysema in adults**
* In adults can cause hepatitis, cirrhosis, liver cancer
50
What are the two genes that are involved in A1AT deficiency?
**M and Z genes**
51
Contrast A1AT deficiency in the lungs and liver:
* **Lung**
* **Loss-of-function mechanism**
* The lack of A1AT allows **uninhibited PMN medicated proteolytic damage** to connective lung tissue
* **Liver**
* **Gain-of-function mechanism**
* Retention of **inefficiently secreted A1AT Z** molecule in endoplasmic reticulum **triggers a series of hepatotoxic events**
52
Consequences of the different genetic mutations of A1AT:
* PiMM
* PiMS
* PiMZ
* PiSS
* PiSZ
* Pi
* PiZZ
* PiMM, 100% activity, no lung or liver disease
* PiMS, 80% activity, no lung or liver disease
* PiMZ, 60% activity, no lung or liver disease
* PiSS, 50-60% activity, no lung or liver disease
* **PiSZ, 30-40% activity, causes lung disease only**
* **Pi null-null, 0% activity, causes lung disease only**
* **PiZZ, 10-15% activity, can cause both lung and liver disease**
* affects 1/1600-1800 live births
53
How is A1AT deficiency diagnosed?
* **Serum A1AT levels**
* **A1AT phenotypes**
* **Liver biopsy**
54
What type of stain is needed to visualize A1AT deficiency?
Periodic Acid-Schiff Base stain
55
**Autoimmune Hepatitis**
* **Definition:**
* **What is found in the serum?**
* Type of onset; **Gender preference?**
* Incidence:
* **Associations:**
* Definition: **Hepatocyte inflammation**
* **Autoantibodies** in serum
* Insidious or acute onset; **F/M 4:1**
* 20-30 cases per million population
* **50% have other autoimmune disorders**
56
**Autoimmune Hepatitis**
* Labs:
* Characterized by ....
* Labs:
* **ALT, AST elevation,** occ. \> 1000
* **Elevated gamma-globulin or elevated IgG**
* **Autoantibodies**
* Characterized by **interface hepatitis, portal plasma cell infiltration**
57
How is AIH subclassified based on serological markers? (2)
1. **Type 1** (Classic, 80-90%, _adults_)
* Organelle: _nucleus_
* **ANA** (anti-nuclear antibody)
* **ASMA** (anti-smooth muscle antibody)
2. **Type 2** (anti-LKM 1 hepatitis, _children_)
* Organelle: _microsome_
* Anti-liver-kidney microsomal antibody
58
What conditions are associated with AIH?
* **Thyroid disease**
* Rheumatoid arthritis
* Diabetes
* Sjogren’s syndrome
* Polymyositis
* IgA deficiency
* Idiopathic thrombocytopenia
* Urticaria
* Vitiligo
* Addison’s disease
* Inflammatory Bowel Disease
59
What is used to treat AIH?
* Single Therapy
* **Prednisone**
* Combination
* **Prednisone + Azathioprine**
60
What are the only two times steroids are used for liver therapy?
1. **Alcoholic hepatitis**
2. **Autoimmune hepatitis**
61
What are the **endpoints and prognosis** of AIH therpay?
* Treatment endpoints: normal ALT, AST, IgG, gamma-globulin, resolution of inflammation on biopsy
* Treated patients
* Response 65% within 18 months
* Response 80% within 3 years
* 20-year survival is 80%
* Untreated patients
* 50% dead within 3 years
* 90% dead within 10 years
62
What is **Primary Biliary Cirrhosis** (PBC)?
* Chronic, progressive, cholestatic liver disease
* **Destruction of intrahepatic bile ducts**
* Probable autoimmune pathogenesis
63
**PBC:**
**Epidemiology**
* 25-400/million
* 3500 new cases/year
* **90-95% women**
* **Predominantly Caucasian**
* **Mean age 52** at presentation, range 30-65
64
What is the **autoimmune pathogenesis** of PBC?
* **High prevalence of serum autoantibodies** (antimitochondrial antibodies, AMA)
* present in 95%
* **Elevated IgM**
* _Association with other autoimmune diseases_
* Increased familial incidence of disease
* 6% family history of PBC
65
What is the **target site** in PBC?
* Major target antigen of the AMA’s are a multi-enzyme complex **(pyruvate dehydrogenase complex,** **PDC)**
* One antigen, **PDC-E2** appears to predominate
* The PDC-E2 which AMA’s target are **located on the membrane of the biliary epithelial cells**
66
How do **asymptomatic** PBC patients present?
* **Raised Alkaline Phosphatase**
* **AMA+**
* Investigation for other autoimmune disease
67
**PBC:**
**Signs and Symptoms**
* Asymptomatic - 25%
* **Fatigue - 65%**
* **Pruritus - 55%**
* ****due to bile salt deposition
* bottom of feet most affected
* Hepatomegaly - 25%
* Splenomegaly - 15%
* Jaundice - 10%
* Xanthelasma - 10%
68
How do **fat soluble vitamins** become deficient in PBC?
* **Decreased bile salt excretion, steatorrhea**
* **Correlates with duration and severity of liver disease**
* **Vitamins A, D, E, K**
* vitamin D (8-23%): osteomalacia, fractures, regular bone densitometry
* vitamin K (7-8%): prolonged PT
* _Vit K supplementation will work_
69
What disorder is most commonly associated with PBC?
**Sjogren's/Sicca Syndrome**
70
How are the biochemistry labs affected in a patient with PBC?
* **Alkaline Phosphatase:** 3-4 x normal in \>90%
* _Bilirubin usually rises late_
* **Cholesterol elevated in 85%**
* _Not associated with heart disease_
71
What is the characteristic **histological** finding in PBC?
**Florid duct lesion**
* Lymphocytes and mononuclear cells causing inflammatory changes around bile ducts
