Hepatic Inflammation and Fibrosis Flashcards
Histological Scoring System: Metavir
- **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
Hepatic Necrosis
- Definition:
- Can lead to ….
- Most common causes ….
-
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
What is fulminant liver failure?
acute liver failure that is complicated by coagulopathy and encephalopathy
Alcohol Content of Various Beverages:
Alcohol Drinking Pattern Definitions:
- Binge Drinking
- Heavy Drinking
- Excessive Drinking
-
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
- Whta catalyzes this reaction: Ethanol ⇒ Acetaldehyde
- What catalyzes this reaction: Acetaldehyde ⇒ Acetic acid
- What is the other function of CYP2E1?
- 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
Effects Of:
- Increased NADH
- Increased acetaldehyde
-
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)
ALD: Spectrum of Disease
Risk Factors for ALD
-
Quantity of Alcohol
- >30 g/day in men
- > 20 g/day in women
- Outside of meals
- Binge drinking
- Hepatitis C
Lab Abnormalities for ALD:
- Biochemistry
- Hematology
-
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)
How is alcoholic hepatitis treated?
-
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
How do you decide who to treat for alcoholic hepatitis?
-
Discriminant function
- 4.6 * (PT - PT CONTROL) + T BILI
- Patients with values > 32 have a 1-month mortality from 30%-50%
What is the most common cause of elevated transaminases in the U.S.?
**Non-Alcoholic Fatty Liver Disease **(NAFLD)
What is needed in order to diagnose NAFLD?
must obtain a history
How is Non-Alcoholic Fatty Liver Disease categorized? (2)
-
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
What are the stages of NAFLD?
- Fatty Liver (Hepatosteatosis) ⇒ (10% progress)
- Steatohepatitis (NASH) ⇒
- Steatohepatitis with Fibrosis (35% OF NASH) ⇒
- Cirrhosis (15% OF NASH)
What is are the associated metabolic syndromes with NAFLD?
- Obesity (30-100%)
- Diabetes (15-50%)
- Hypertriglyceridemia (15-80%)
NAFLD correlations:
- Prevalence
- Severity of disease
- Gender
- Race/Ethnicity
- 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)
_____ is the most common liver disease in children in the US
**NAFLD **the most common liver disease in children in the US
- NASH is present in 18% of these children
What type of hyperlipedemia has the most impact on increased risk for NAFLD diagnosis?
- Hypertriglyceridemia rather than hypercholesteremia increases risk
- 3-fold greater risk with triglycerides > 200
What are causes of steatosis and steatohepatitis?
- Alcohol
- Medications
- Nutritional
- Insulin resistance (IR)
- Abetalipoproteniemia
- Weight changes
What medications cause steatosis and steatohepatitis?
- Amiodarone
- Steroids
- HAART
- Tamoxifen
- Diltiazem
What are nutritional causes of steatosis and steatohepatitis?
- TPN
- Severe starvation
- Refeeding syndrome
Development and Progression of NAFLD
What do you look for on ultrasound, when looking for a fatty liver?
- fat is bright
- normal tissue is dark
What are the therapeutic strategies for NAFLD?
-
Lifestyle Modifications:
- decrease oral intake
- active lifestyle
- Prevent/Treat Insulin Resistance
- Reduce Oxidative Stress
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
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)
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
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
How is Hereditary Hemochromatosis acquired?
Hereditary Hemochromatosis (HFE gene)
Autosomal Co-dominance
-
C282Y/C282Y (homozygote)
- accounts for 82-90% of cases
- **C282Y/H63D **(heterozygote)
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
- 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
What causes Secondary Iron Overload?
iron found in kuppfer cells
-
Anemia caused by ineffective erythropoiesis
- Thalassemia major
- Sideroblastic anemia
- Congential dyserythropoietic anemia
- Congential atransferrinemia
- Acerulopasminemia
-
Liver disease
- Alcoholic liver disease
- HBV, HCV
- Nonalcoholic steatohepatitis
- Miscellaneous: excessive iron ingestion
- 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%)
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
What is the formula for a potential diagnosis of hemochromatosis?
What is the treatment for hemochromatosis?
Phlebotomy
- Goal serum ferritin < 50
- Initially weekly phlebotomy
- Once quarterly thereafter
Describe human Cu metabolism:
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
What is required for a diagnosis of Wilson’s Disease?
Need 2 of 3:
- Decreased CP
- Elevated urine Cu
- Kayser-Fleishcer rings
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
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
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
What can be seen here?
Kayser-Fleischer rings
- Present in Wilson’s disease (Cu deposition)
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
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
- 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
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
What are the two genes that are involved in A1AT deficiency?
M and Z genes
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
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
How is A1AT deficiency diagnosed?
- Serum A1AT levels
- A1AT phenotypes
- Liver biopsy
What type of stain is needed to visualize A1AT deficiency?
Periodic Acid-Schiff Base stain
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
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
How is AIH subclassified based on serological markers? (2)
-
Type 1 (Classic, 80-90%, adults)
- Organelle: nucleus
- ANA (anti-nuclear antibody)
- ASMA (anti-smooth muscle antibody)
- Organelle: nucleus
-
Type 2 (anti-LKM 1 hepatitis, children)
- Organelle: microsome
- Anti-liver-kidney microsomal antibody
- Organelle: microsome
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
What is used to treat AIH?
- Single Therapy
- Prednisone
- Combination
- Prednisone + Azathioprine
What are the only two times steroids are used for liver therapy?
- Alcoholic hepatitis
- Autoimmune hepatitis
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
What is Primary Biliary Cirrhosis (PBC)?
- Chronic, progressive, cholestatic liver disease
- Destruction of intrahepatic bile ducts
- Probable autoimmune pathogenesis
PBC:
Epidemiology
- 25-400/million
- 3500 new cases/year
- 90-95% women
- Predominantly Caucasian
- Mean age 52 at presentation, range 30-65
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
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
How do asymptomatic PBC patients present?
- Raised Alkaline Phosphatase
- AMA+
- Investigation for other autoimmune disease
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%
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
What disorder is most commonly associated with PBC?
Sjogren’s/Sicca Syndrome
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
What is the characteristic histological finding in PBC?
Florid duct lesion
- Lymphocytes and mononuclear cells causing inflammatory changes around bile ducts
