Week 3

Question 1

Differentiate btw physiologic aging and disease

1. Body composition?
2. Body fat?
3. Temperature?
4. Body fluid regulation? (TBW vs thirst)
5. Senses; e,g Driving at night?
6. Heart murmur?
7. Memory
8. Difficulty swallowing
9. Respiration
10. Renal
11. Immune system
    * *Summary - presentation? End result?

Answer 1

Physiologic aging 
1. Body Composition Changes with aging
• Loss of lean body mass
• Decrease in skeletal muscle mass 
• Decrease in bone mass

2. Increase in total body fat
   • Not necessarily more weight
   • Accumulates in muscles and organs
   • Fat soluble drugs have longer half life (e.g DIAZEPAM)
3. Temperature
   • Risk increased for hyper- and hypothermia
   • Difficulty in mounting a fever response to infection
4. Body fluid regulation
   • Total body water decreased
   • Thirst sensation diminished

5. The senses 
• Dark adaptation decreases
• Near vision declines (presbyopia)
• High frequency hearing declines (presbycusis)
• Sense of smell declines after age 50
**Glaucoma and cataract is pathologic 

6. Aortic sclerosis
   - variable amount of calcification of cardiac skeleton
   - increased BP
   * *Normal part of aging

7. Forget something and retrace your steps slower
• SLOWER Storage and retrieval – recall 
• Decreased ability to multi task 
• Neuropathy
**Alzheimers is pathologic 

8. PRESBYESOPHAGUS may occur in aging
   - Hepatic metabolic function may decline
   ** Stricture, esophageal cancer, hiatal hernia are all pathologic
   Disease

9. Respiratory 
• Decreased elasticity 
• Decreased FEV1 
• Decreased O2 sat
**Smoking will have more rapid decline in FEV1 

10. Renal
    • Steady decline of function
    • Clinical: Drug metabolism!! Must review meds and calculate estimated GFR
    **e.g watch dose of gabapentin in elderly - decrease the dose
11. Immune system
    • Thymic involution- less naïve lymphocytes to respond
    to new threats **Thymus gland will SHRINK WITH AGE
    • Decreased T-cell proliferative response to mitogens
    • Decrease in some cytokines
    **In elderly, they don’t produce enough antibodies so need higher dose of flu shot

**Normal aging is HETEROGENOUS ( not everyone gets the same thing)
Marked by:
• Decrease in reserve capacity (homeostenosis)
• Diminished ability to respond to stress
= INCREASED VULNERABILITY

Question 2

How Disease present atypically in elderly

• *complications
  1. Pain
  2. Headache
  3. Abdominal pain
  4. Fever
  5. Weakness/fatigue
  6. Anorexia/weight loss

**General rule

Answer 2

Atypical presentation of Disease in elderly
**Complications; Delayed diagnosis, Increased risk of adverse outcomes

1. PAIN
   • Blunting of the sensation of pain may occur, and many
   elderly persons will minimize their complaints
   - Elderly with heart attack didn’t have any chest pain, just shortness of breath
   - Elderly person with shingles in chest can present with chest pain
2. Headache
   **Relatively uncommon as a NEW complaint
   • temporal arteritis
   • trigeminal neuralgia
   • herpes zoster
   • subdural hematoma
   • metastatic disease
3. Abdominal pain
   • Much more likely to be due to life-threatening
   disease in elderly patients!
   - Mesenteric ischemia
4. Fever
   • All conditions causing fever in younger
   persons may present without fever in elderly.
   • Pneumonia may present without fever or cough – just change in mental status or delirium***
5. Weakness/Fatigue
   • Apathetic hyperthyroidism; elderly just feel tired
6. Anorexia/weight loss
   **Malignancy and inflammatory disorders at top of list,
   BUT remember to consider other possibilities in elderly
   • Congestive heart failure or Chronic lung disease
   • Drug side effects
   • Depression
   • Memory loss
   • Hyperthyroidism

• *Don’t expect “textbook” presentations, expect more vague or nebulous complaints.
• acute confusion/Delirium
• “Weak and dizzy”
• refusal to eat and drink
• malaise and fatigue
• falls

Question 3

Important thing to remember when COMMUNICATING with the elderly

• patient hard of hearing?
• Alzheimer’s Patient?

Answer 3

Treat them with respect; address with Mr or Mrs not sweetie or darling
**Speak to patient directly

• In patient that can’t hear; don’t necessarily speak louder but DEEPEN YOUR VOICE
• In Alzheimer’s patient; Talk to both patient and family, ask YES OR NO questions
• Realize the human story behind each patient
• Recognize the difficulties that elderly patients may encounter in daily activities
• Develop empathy for elderly patients dealing with diseases

Question 4

More common congenital malformations in US by frequency (9)

**Infant death by birth defects

Answer 4

1. Club foot without CNS anomalies - 25.7%
   * *One of the highest because it can be positional
2. PDA (patent ductus arteriosus) - 16.9%
3. VSD (ventricular septal defects)
4. Cleft lip with or without cleft palate
5. . Spina bifida
6. Congenital hydrocephalus
7. Anencephalus
8. Limb reduction deformity (MSK)
9. Rectal and intestinal atresia

About 23.6% (almost a quarter) of infant death from CONGENITAL HEART DEFECTS

Question 5

**definition
- study of abnormal form?
- problem with generalized
growth and/or in the growth and
formation of one or more structures of
the body.

Answer 5

DYSMORPHOLOGY

DYSMORPHIC INDIVIDUAL

**Dysmorphology includes; genetics, embryology, clinical medicine

Question 6

Define

• **refers to an abnormality present at birth from any cause.
• 2 types
• what % of all newborns have a recognized major congenital anomaly
• what % of all births will be diagnosed with a congenital defect prior to age 6 yr

**Multiple malformations? (4)

Answer 6

Congenital anomalies or birth defects

Congenital malformation
- Physical or neurological defects that are present at the time of
delivery.
- Some problems will not become apparent until later in life.
- Divided into major and minor malformations*

• 3% of all newborns have a recognizable major congenital
  anomaly. **can’t lower number but can increase with drinking and smoking
• Up to 7% of all births will be diagnosed with a congenital
  defect prior to age 6 year.
  **Total 10% abnormal births; 63% single defect (e.g clubfoot), 25% SYNDROME (multiple defects)

Syndromes/Multiple malformation

1. Unknown 40%
2. Chromosomal 30%
3. Mendelian 25%
4. Teratogenic 5%

Question 7

Birth defects (3) - morphological alterations

1. • occur in 3-5% of newborns
   • Definition: defects that require medical or surgical intervention.
   • Will have a significant impact on the health of the infant
2. • variants that are of no serious medical or cosmetic significance and occur in less than 4% of the population
   • 3 or more minor anomalies increase suspicion for a possible major anomaly.
3. features that fall to the far end of the
   spectrum of normal minor anomalies or normal variants
   can serve as indicators of altered morphogenesis and
   clues to patterns of malformation

Answer 7

MORPHOLOGICAL ALTERATIONS
1. Major anomalies; e,g neural tube defects (anencephaly, spina bifida), Cleft lip/palate
2. Minor anomalies; e,g Down syndrome (brushfields spot, single palmar crease, palbebral slant
3. Normal variants
- Normal variants are features that fall to the far end of the
spectrum of normal minor anomalies or normal variants
can serve as indicators of altered morphogenesis and
clues to patterns of malformation
E.g of normal variants; flat nasal bridge, hydrocele, syndactylyl of 2nd and 3rd toes (problem with Fibroblast growth factor defect)

Question 8

Birth defects (3) - Congenital anomalies

• *3 types of problems in mrophogenesis
• process and examples

Answer 8

1. Malformation
   - process; intrinsically abnormal developmental process
   - eg; cleft lip, polydactyly
2. Deformation
   - process; mechanical compression
   - eg; clubfoot, plagiocephaly (lope sided head)
3. Disruption
   - process; breakdown of otherwise normal developmental process. *May have cut off blood supply
   - e.g; amniotic band amputation, porencephaly

Question 9

Identify congenital anomalies - group type

an abnormality of morphogenesis due to an intrinsic problem within the developing structure.

*MECHANISMS: altered tissue formation, growth or
differentiation due to genetic, environmental or a combination of
factors

• etiology ? (4)
• all etiology lead to?
• examples (look at table in notes)

Answer 9

MALFORMATION
** Primary structural defect resulting from an error in tissue formation

Etiology

• chromosome
• genetic
• teratogenic
• unknown

**All lead to morphogenic error - primary structural defect

E.g failure of Neural tube closure - spina bifida

• Give enough folic acid to overcome
• Taking methotrexate will cause spina bifida

Question 10

Identify congenital anomalies

** an abnormality of morphogenesis due to extrinsic force on a normally developing or developed structure.
MECHANISM: fetal constraint

Examples?
How to correct?

**ETiology (2)

Answer 10

DEFORMATION
**Best of 3 - can easily spring back

A. Plagiocephaly 
- asymmetric head 
- occurs pre or post natal 
**Corrected by HELMETS or POSITIONING 
B. Club foot 
- A club foot should be held in a cast, or strapped in a straighter position, soon after birth - until it is corrected past normal 

Etiology

1. Extrinsic (fetal constraint)
2. Intrinsic (fetal Akinesia)
   * *Lead to abnormal force - altered structure or position

Question 11

Identify condition - type of congenital abnormality
- an abnormality of morphogenesis due to a destructive force acting upon the developing structure.
MECHANISMS: cell death or tissue
destruction due to vascular, infectious,
or mechanical force

EtioloY??

Answer 11

DISRUPTION

• Occlusion of the omphalomesenteric artery may cause gastroschisis (body wall defect with herination)
• omphalocele; membrane covering
• gastrochisis; no membrane covering

Etiology

1. Vascular 2. Compressive 3. Tearing
   * *lead to vascular occlusion or abnormal force which LEAD TO TISSUE DESTRUCTION (asymmetric/unilateral limb reduction deficit)

Question 12

Identify vascular causes of congenital malformations (4)

Answer 12

1. Aberrant vessels
2. Vascular occlusion
   - vasculitis
   - thrombosis
   - embolism
3. Hypoperfusion
4. Vasoactive drugs
   - cocaine
   - amphetamines

Question 13

1. VASCULAR ACCIDENT can cause?
2. • Subclavian artery disruption
   • Absent pectoral muscle defect
   • Ipsilateral limb defects
3. **Considerations of multiple anomalies

Answer 13

1. PORENCEPHALY
   - Vascular accident (occlusion of a cerebral artery) may cause a porencephalic cyst
2. POLAND ANOMALY
   * pectoralis muscle don’t grow the way they should, ASYMMETRC breast development
3. Multiple anomalies - considerations
   - Can all the child’s abnormalities be explained on the basis of a single problem that leads to a cascade of subsequent structural defects?
   - Did one defective gene or group of genes cause the observed defects?

Question 14

Type of multiple anomalies

• a cascade of effects stemming from a single localized abnormality in early morphogenesis. – the single localized abnormality (1st defect) may be of the
  malformation, deformation or disruption type

2 examples

Answer 14

SEQUENCE

A. Malformation sequence - holoprosecencephaly ; small head, small space btw eyes, one nostril

B. Robin sequence

Question 15

Explain malformation sequences of holoproscencephaly vs robin sequence Vs potter sequence

Answer 15

1. Malformation sequence
   Primary malformation -
   i) Incomplete cleavage of prosencephalon; i) Holoprosencephaly ii) Synophthamia, ocular hypotelorism
   ii) Faulty biracial development; i) proboscis, cleft lip. II) Absent midfacial and anterior cranial base bones
   CYCLOPIA WITH PROBOSCIS
   - SONIC HEDGEHOG GENE programmed wrong - normally activated by cholesterol. Cholesterol lowering meds (statins) can cause holoproscencephaly*
   - lack of cholesterol can also lead to sex reversal
2. Robin sequence ; small chin push palate up - airway obstruction
   - Micrognathia (small chin)
   - Abnormal tongue position
   - U-shaped cleft palate
   - Possible airway obstruction
   ** 2 pathways lead to CLEFT PALATE
   I) Malformation - intrauterine mandibular hypoplasia - failure of tongue descent - cleft palate
   II) Deformation - mandibular constraint - failure of tongue descent - cleft palate
3. Potter sequence
   - die from respiratory failure because lungs didn’t grow enough
   A. Renal agenesis, amniotic leak, others - OLIGOHYDRAMNIOS - amino nodosum and pulmonary hypoplasia
   B. Fetal compression - pulmonary hypoplasia, altered facies, positioning defects of feet n hands, breech presentation

Question 16

Identify type of multiple anomalies

a combination of anomalies which occur together more frequently than by chance alone

• The underlying etiology is unknown
• Most cases sporadic

*Types (3)

Answer 16

ASSOCIATION

1. CHARGE Association
   - Coloboma of eye
   - Heart defects
   - Atresia of the choanne
   - Retardation of growth and development
   - Genital anomalies
   - Ear anomalies
2. VATER; vertebral defects, imperforate anus, tracheo-esophageal fistula, renal or radial ray defects
3. MURCS; mullerian duct, renal and
   cervical vertebral defects

Question 17

Identify type of multiple anomalies

anomalies of several different structures, all of which lie in the same body region during embryogenesis

Examples?

Answer 17

COMPLEX

1. OEIS Complex; (Omphalocele, exstrophy, imperforate anus, spinal defects)

Question 18

Identify type of multiple anomalies

multiple structural defects in one or more tissues thought to be due to a particular chromosomal, genetic, teratogenic or unknown insult that impairs multiple tissues

Example?

Answer 18

SYNDROME
**From Greek - “running together”

Cornealia de Lange Syndrome

• Short stature
• Mental retardation
• Limb defects
• Characteristic facies

Question 19

Steps involved in work up of genetic patient (5)

Answer 19

1. Collect an appropriate history
   A. Family history; pedigrees (3 gen, miscarriage, cause of death), consanguinity, ethnic origins

B. Pregnancy
I. Timing of conception, illness during pregnancy, medication used before and during pregnancy, use of alcohol, tobacco or illicit drugs, exposure to Xray or other radiation
II. Weight gain during pregnancy, quality of fetal movement, testing prior or during pregnancy; ultrasound, maternal serum screening, free cell DNA, amniocentesis or CVS, carrier testing

C. Medical history

• Review labor and delivery
• Feeding history
• Developmental milestone; Ask about regression
• Medical problems

2. Examine patient
   - observation ; estimate developmental age, look for asymmetry
   - measurements; growth parameters, parental head size, anything else that looks abnormal
3. Testing
   A. Chromosomes; routine, high resolution, microdeletion FISH, microarray CGH
   B. Molecular/DNA testing; disease specific (single gene vs multigene panel), WGS
   C. Metabolic studies; amino acids, organic acids, others
4. Establish a diagnosis
   - develop overall gestalt
   - standard references
   - follow overtime
   - for single defects; categorize the anomaly - malformation, deformation, disruption
   - multiple malformation; 60% will have diagnosis
5. Counsel patient and family
   - A communication process which deals with the human problems associated with the occurrence or risk of occurrence of a genetic disease in a family

Question 20

**Microdeletion syndromes (10)

Answer 20

1. Williams
2. Langer-Giedion
3. WAGR
4. Prader-Willi ** Ch 15
5. Angelman ** Ch 15
6. Smith Magines
7. Miller Dieker **Ch 17
8. Retinoblastoma **Ch 13
9. DiGeorge **Ch 22
10. VeloCardioFacial

Question 21

1. Who gives genetic counseling
2. Who can benefit from genetic counseling
3. When should you be referred for genetic counseling
4. What is necessary to provide genetic counseling

Answer 21

1. Who gives genetic counseling ; genetic counselors
   - Masters or PhD program with board certification
   - Trained to collect and assess information pertinent to potential genetic disease
   - Can provide patient education
   - Furnishes psychosocial support
   - Determine risk assessment.
   - Generally works under a physician guidance.
2. Who can benefit from genetic counseling
   - Known hereditary disease in family (carrier or presymptomatic testing)
   - Individual with suspected genetic disease
   - Individual with birth defects
   - Individual with unexplained mental retardation
   At risk individual because of ethnic background
    Advanced maternal age
   - Family history of early onset cancer
   - Recurrent pregnancy loss
   - Teratogen exposure
   - Consanguinity
    Individual with abnormal sexual development
   - Interpretation of abnormal prenatal tests
   - Couples seeking preconceptual counseling
3. When to be referred
   - Prior to conception, when there is a family history or other risk factor which increases the chance for an abnormal offspring
   - as soon as possible for newly diagnosed patients
4. What is necessary to provide genetic counseling
   - An accurate diagnosis
   - A complete family history (3 generations if possible more if indicated)
   - Current information on the condition
   - An unbiased approach to the family

Question 22

**Communication of risk

Mendelian vs empiric risk vs bayes theroem

Answer 22

Communication of risk
A. Mendelian Trait - calculated risk
B. Polygenic/Multifactorial Traits -empiric risk (observed)
C. Bayes Theorem - use of both calculated risk with observed data

1. Mendelian risk
   A. If this is a known dominant condition risk would be 50%.
   B. This is an X- linked trait and the risk for the fetus should be 12.5%
2. Empiric risk
   - If this is a family has a history of clefting with multifactorial inheritance, the recurrence risk would be 5-10%
3. Bayes theorem ** PPT
   - AD disease thrid child has 8/9 prob of not being a carrier and 1/9 chance of being a carrier

Question 23

1. Educational component of genetic counseling

2. Components

Answer 23

1. Educational component of genetic counseling
   - Use of visual aids (pictures of karyotype, pedigrees ,etc.)
   - Avoid jargon and technical terms
   - Elicit feedback to measure understanding
   - Be sensitive to cultural, religious, and ethnic background of family
   - Give both sides of the statistics
2. Components
   - Discuss all reproductive options
   - Avoid terms that are judgmental (example: many individuals who are deaf do not consider themselves as abnormal or to have
   a disease)
   - Provide the family with a written report which reviews information covered during the counseling
   - If possible give family information on parent support groups

Question 24

Reproductive options (6)

• *For couple at risk for offspring with genetic condition
• prior to pregnancy?

Answer 24

For couple at risk for offspring with genetic
condition. Prior to pregnancy: 
A. Elect to have no children or adopt 
B. Take risk- testing after birth 
C. Donor gamete to avoid defective genes

Question 25

Genetic counseling session

A 37 year old woman has recently married and considering starting a family. She is referred to genetics to discuss the potential genetic risks for older mothers.

Answer 25

Obtain a family history

Question 26

Genetic counseling issue s

1. Maternal age
2. Family hx cystic fibrosis
3. Family hx NTD
4. Jewish ancestry
   * *Screen by?

Answer 26

1. Maternal age
   - Pregnancy for women > 35 yo increases risk of Down syndrome as well as other aneuploidy disorders in fetus.
   - Counseling to explain chromosomes and their disorders - quote risk for age of 37 to be ~1 in 190 births.
   - Review prenatal screening & diagnostic testing available, discuss both risk and benefit of each procedure.
2. Family hx cystic fibrosis
   - Husband

Question 27

Identify liver disease

Morphology evidence of injured liver

a. Hepatocyte necrosis
b. Cholestasis
c. Fatty liver disease
d. Fibrosis and cirrhosis

**clinical and histology indistinguishable from? So how do you distinguish?

Answer 27

Drug and Toxin - induced Liver Disease

**
Drug-induced hepatitis clinically and histologically indistinguishable from viral- induced hepatitis

• • To distinguish
• VIRAL SEROLOGIC TEST

Question 28

Summarize types of drug reactions (2)

**give examples of each

Answer 28

1. Predictable (intrinsic)
   A. Hepatocellular damage is dose-dependent in “all” people
   B. ACETAMINOPHEN**, Amanita phalloides toxin, carbon tetrachloride
   and alcohol
2. Unpredictable (Idiosyncratic); some people take it and are fine, others are affected
   A. Depends on idiosyncrasies of the host response/metabolism
   B. Chlorpromazine can cause cholestasis
   C. Halothane may cause a fatal immune-mediated hepatitis

**May be immediate or may take months to develop

Question 29

Drug/toxin liver disease

1. Most common hepatotoxic causing acute liver disease
2. Chronic liver disease?

**What must you always perform to pick clinical hepatitis

Answer 29

1. Most common hepatotoxin causing ACUTE liver failure is ACETAMINOPHEN
   a. Toxic agent is a metabolite produced by cytochrome P-450 system in acinus zone 3 hepatocytes
2. Most common hepatotoxin causing CHRONIC liver disease is ALCOHOL

** Always perform a detailed drug and exposure history in patients with a clinical hepatitis

Question 30

3 forms of alcoholic liver disease and morphology

Answer 30

3 forms

1. Hepatocellular steatosis or fatty change
2. Alcoholic hepatitis (alcoholic steatohepatitis)
3. Alcoholic steatofibrosis including cirrhosis

A. Hepatocellular steatosis or fatty change

(1) Gross: soft, large (up to 4-6 kg), yellow, greasy liver
(2) Moderate intake causes microvesicular fatty change
(3) Chronic intake causes macrovesicular fatty change
(4) Continued intake causes centrilobular fibrosis possibly extending into the adjacent sinusoids

Question 31

Morphology or what alcoholic liver disease

(1) Gross: soft, large (up to 4-6 kg), yellow, greasy liver
(2) Moderate intake causes microvesicular fatty change
(3) Chronic intake causes macrovesicular fatty change
(4) Continued intake causes centrilobular fibrosis possibly extending into the adjacent sinusoids

Answer 31

Hepatocellular steatosis or fatty change

Question 32

What form of alcoholic liver disease

(1) . Gross; near normal sized liver
(2) Hepatocyte swelling (ballooning) and necrosis - swelling from accumulated fat, water and proteins in cytoplasm

**What is the characteristic finding? Also seen in what conditions?

Answer 32

Alcoholic hepatitis (alcoholic steatohepatitis)

• *MALLORY DENK BODIES
• clumped eosinophilic material in ballooned hepatocytes, composed of keratin 8 & 18, ubiquitin and other proteins. Characteristic of alcoholic liver disease but also seen in non-alcoholic fatty liver disease, Wilson disease, biliary tract diseases
• *Neutrophilic reaction
• infiltrate the hepatic lobules, accumulate around degenerating hepatocytes esp those with Mallory denk bodies
• Admixed with chronic inflammatory cells

Question 33

Morphology of what alcoholic liver disease
(1) Gross: brown shrunken diffusely nodular liver
(2) Begins with activation of portal fibroblasts and stellate cells (Ito cells) in Space of Disse
(3) Fibrosis
(a) Starts with sclerosis of central veins
(b) Spreads outward from centrilobular region in
Space of Disse
(c) Encircles individual and small clusters of
hepatocytes in the ‘chicken wire fence’ pattern
(d) Micronodules develop first (< 3 mm, Laennec cirrhosis),
typical for alcoholic liver disease
(e) With developing nodularity, cirrhosis becomes
established
(4) Regression is possible in early stages but as scarring disrupts vascular architecture, full restoration to normal is rare or impossible even with complete abstinence

Answer 33

Alcoholic steatofibrosis including cirrhosis

**FiRBOSIS
Regression is possible in early stages but as scarring disrupts vascular architecture, full restoration to normal is rare or impossible even with complete abstinence

Question 34

Pathogenesis of alcoholic liver disease 
A. How many develop cirrhosis 
B. Gender? 
C. Ethnic and genetic ; white vs black vs Asian 
D. Comorbid conditions

Answer 34

a. Only 10-15% of alcoholics develop cirrhosis. Many factors influence the development and severity of ALD
b. Gender; women more susceptible although most patients with ALD are men
C. Ethnic and genetics
- In US, cirrhosis rates higher in African Americans than in whites for same consumption. Asians who are homozygous for a variant of alcohol dehydrogenase (ALDH*2, very low activity) have alcohol intolerance
D. Co morbidity
- Fe overload, HBV and HCV infections severity of liver disease

Question 35

Summarize effects of alcohol on liver

1. Steatosis causes
2. Hepatitis causes
3. Fibrosis causes

**Result in release of ?

Answer 35

(1) Steatosis due to:
(a) Shunting of normal substrates from catabolism to lipid biosynthesis
(b) Impaired assembly and secretion of lipoproteins
(c) Increased peripheral catabolism of fat, releasing free f.a.s

2. Hepatitis due to:
   (a) Acetaldehyde causes lipid peroxidation and disrupts cytoskeletal and membrane function
   (b) Cytochrome P450 metabolism - ROS (reactive oxygen species) that damage membranes and change liver cell function
   (c) Altered methionine metabolism causes decreased glutathione
   Levels sensitizing liver to oxidative injury

(3) Fibrosis due to collagen deposition by proliferating and activated hepatic stellate or Ito cells

• *Causes release of bacterial endotoxins from the gut into the portal circulation - inflammatory response in the liver
• • Causes release of endothelins from sinusoidal endothelial cells - myofibroblast contraction and vasoconstriction - decreased perfusion

Question 36

Clinical - alcoholic liver disease

1. Minimum consumption that precipitate ALD
2. Excess consumption lead to ?
3. How do you get impaired digestion

Answer 36

a. 80 gm alcohol/day is considered the minimum consumption to precipitate alcoholic liver disease
b. Excess consumption leads to malnutrition & vitamin deficiencies
c. Chronic gastric and intestinal mucosal damage and pancreatitis leading to impaired digestion

Question 37

What form of ALD
**treatment and prognosis???

Clinical

(1) Minimal symptoms to fulminant hepatic failure, appears acutely after a bout of heavy drinking
(2) Labs: elevated bilirubin, alkaline phosphatase, serum transaminases (AST/ALT ratio >2) and leukocytosis
(3) Mortality: risk of death 10-20% with each episode
(4) Repeated episode - cirrhosis in a few years in 1/3 of patients

Answer 37

Alcoholic hepatitis

Treatment: adequate nutrition and alcohol withdrawal Prognosis: With nutrition and abstinence hepatitis will resolve in
some patients, in others it will persist and progress to cirrhosis

Question 38

What form of ALD
**Treatment

(1) May see hepatomegaly and mild increases in bilirubin and alk phos
(2) Severe hepatic dysfunction is rare

Answer 38

Steatosis

** Treatment: adequate diet and alcohol withdrawal

Question 39

What form of ALD
**Death due to?
Clinical
1. Only 10-15% of alcoholics
(2) See stigmata of portal hypertension (encephalopathy, possible caput medusae/esophageal varices/hemorrhoids, ascites, splenomegaly)
(3) See stigmata of impaired estrogen metabolism (palmar erythema, spider angiomata, gynecomastia and testicular atrophy in males)
(4) Labs: elevated transaminases, hyperbilirubinemia, variable elevation of alkaline phosphatase, hypoproteinemia (DECREASED albumin, globulin and clotting factors) and anemia

Answer 39

ALcoholic CIRHOSIS

**May develop cirrhosis WITHOUT clinical signs/symptoms
** Death may be due to hepatic coma, massive GI bleed, infection,
hepatorenal syndrome or liver carcinoma

Question 40

Identify liver disease

Pathogenesis; possible 2 hit model

a. Insulin resistance gives rise to hepatic steatosis
b. Hepatocellular oxidative injury results in liver cell necrosis and the inflammatory reactions to it

Answer 40

NAFLD - NONALCOHOLIC FATTY LIVER DISEASE

Spectrum of disorders with hepatic steatosis common to all
A. Isolated fatty liver (hepatic steatosis) ; no significant problems
B. Non-alcoholic steatohepatitis (NASH)
C. NASH cirrhosis (~11% over 15 years)
D. Small percentage may develop HCC with or without cirrhosis

Question 41

Morphology of NAFLD (3)

**Pediatric NAFLD?

Answer 41

A. Steatosis
(1) Involves > 5% of hepatocytes, by definition
(2) Microvesicular and macrovesicular change
(3) Minimal inflammation, cell death or scarring despite persistent
elevation of serum liver enzymes

B. Steatohepatitis (NASH)

(1) Histologic features same as alcoholic steatohepatitis, but may be less prominent: ballooning degeneration and necrosis, Mallory-Denk bodies and apoptosis. Unlike alcoholic hepatitis, inflammation is more mononuclear than neutrophilic
(2) Microvesicular and macrovesicular change

C. Steatofibrosis
(1) Same features and progression as alcoholic steatofibrosis but
with more prominent portal fibrosis
(2) Cirrhosis may develop remaining subclinical for years
(3) >90% of cases of “cryptogenic” cirrhosis now thought to be end-stage NAFLD

**Pediatric NAFLD increasingly recognized in obese children, histologic features differ from adults.

Question 42

Clinical of NAFLD

Steatosis vs NASH

Answer 42

a. Steatosis ; isolated fatty liver >80% of pts with NAFLD
(1) Usually asymptomatic
(2) Associated with metabolic syndrome: obesity, DM, insulin
resistance, hyperlipidemia
(3) None to minimal progression to cirrhosis
(4) No increased risk of death compared to general population
(5) Radiologic studies reveal fatty liver

b. NASH
(1) Asymptomatic to non specific symptoms (fatigue, RUQ pain)
(2) Elevated transaminases (90%) with AST/ALT ration <1
(3) ~11% progress to NASH cirrhosis and 7% of those to HCC
(4) Frequent cause of death; cardiovascular disease (because of association with metabolic syndrome)

Question 43

Fenger Hepatitis

1. 2 viral hepatitis virus that cause liver disease
2. Blood vs fecal oral transmission (by types)
3. What virus cause hepatitis as prominent feature following establishment of viremia
   * *transmission?

Answer 43

1. Hepatitis A and B
2. A. Blood transmission; Hep B,C,D
   B. Fecal oral transmission; A,E
   **Other routes; sexual transmission, mother to newborn transmission
3. YELLOW FEVER virus (Flavivirus) causes hepatitis as a prominent feature following the establishment of a viremia. Unlike those hepatitis viruses that are transmitted via the blood or the fecal- oral routes, yellow fever virus fall in the general category, arthropod borne viruses (arboviruses) and is transmitted by certain species of MOSQUITO

Question 44

Hepatitis virus types (5) - family - structure

** Other virus that cause hepatitis

Answer 44

1. Hep A virus; picornaviridae, hepatovirus genus; + polarity SS RNA
2. Hep B virus; Hepadnaviridae; partially DS DNA
3. Hep C virus; flaviviridae, hepacivirus genus; + polarity SS RNA
4. Hep D virus; deltaviridae; SS circular RNA
5. Hep E virus; Hepeviridae; + polarity RNA

Others;

1. EB virus; herpesviridae; DS DNA
2. Cytomegalovirus; herpesviridae; DS DNA
3. HSV; herpesviridae; DS DNA
4. Rubella virus (newborns); Togaviridae, genus rubivirus; + polarity RNA

Question 45

Hepatitis A

1. Incubation
2. Family, structure, aka?,
3. Replication cycle
4. Clinical features

Answer 45

Hepatitis A
1. short incubation (30-day avg), acute hepatitis, infectious hepatitis

2. Hepatitis A virus (HAV), Picornaviridae, Hepatovirus Genus(Enterovirus Type 72)
   a) virus particle very resistant, acid stable nonenveloped
   b) 27 nm particle, icosahedral symmetry
   c) SS + Polarity RNA genome
   d) grown in cell culture, no CPE, long replication cycle compared to other enteroviruses
3. Poliovirus replication cycle serves a prototype for + stranded RNA viruses
4. Clinical features;
   - sporadic outbreaks, short incubation, no carrier state, low mortality
   - children usually have mild disease,
   - adult have more severe (remember polio and EB viruses), especially in post-menopausal woman and patients with chronic liver disease

Question 46

Identify hepatitis type
Clinical features;
- sporadic outbreaks, short incubation, no carrier state, low mortality
- children usually have mild disease,
- adult have more severe (remember polio and EB viruses), especially in post-menopausal woman and patients with chronic liver disease

1. Epidemiology

Answer 46

Hepatitis A
Epidemiology
a) socioeconomic association, function of hygiene, high in mental institutions; Approximately 114 Million People Infected Worldwide In 2015

b) spread primarily fecal-oral route by contaminated food and water; high viral load in feces of infected individuals
* * 1o multiplication in GI tract epithelium and lymph nodes -> viremia -> liver, kidney spleen -> virus in feces, urine, blood in preicteric

c) With advent of HAV vaccine the rates of HAV have steadily declined in children living in high risk area of the country
d) Other target populations for administration of HAV vaccine include men having sex with men (MSM), injection and non-injection drug users, and international travelers

Question 47

IDENTIFY hepatitis type
spread primarily fecal-oral route by contaminated food and water; high viral load in feces of infected individuals
** 1o multiplication in GI tract epithelium and lymph nodes -> viremia -> liver, kidney spleen -> virus in feces, urine, blood in preicteric

1. Lab diagnosis
2. Immunity
3. Prevention and control
   - what is given 1-2 weeks after exposure?
   - vaccine types

Answer 47

Hepatitis A

1. Lab diagnosis
   a) immune electron microscopy detects virus
   b) anti HAV IgM (elevated)
2. Immunity
   - long term, does not protect against Hepatitis B or other hepatitis virus infections
3. Prevention and control
   a) pooled gamma globulin (given 1-2 weeks after exposure)
   b) vaccine- inactivated Hep A vaccine (HAVRIX or VAQTA) induces protective antibodies in 93% of volunteers, available since 1995,
   - Recommended for international travelers, MSM individuals using injected drugs and as of 1999 it is recommended for children living in high incidence states,
   - Two immunizations, first at one year, second 6 months later
   - TWINRIX(HepA and HepB combination); 4 Doses

Question 48

Hepatitis B

Infectious vs noninfectious particles
Structure and surface antigen? Core antigen?

Answer 48

1. Hepatitis B virus (HBV) found in serum as a 42 nm particle(Dane particle): virus resists heat, and
   chemical disinfectants
   **DANE PARTICLES are the only INFECTIOUS virus particles
2. NONINFECTIOUS particles are also found in serum of infected individuals
   a. 22 nm particle (HBsAg aggregates)
   b. 27 nm particle (core antigen aggregates)
3. Dane particle, 42 nm, has an internal core structure surrounded by envelop
   Core structure (HBcAg) houses the following:
   A. PARTIAL double stranded DNA that serves as the viral
   genome
   B. Polymerase(reverse transcriptase) COMPLEX is also located in the virus core
   - Surface Ag, HBsAg (Australian Ag)constitutes the envelope proteins that surround core structure, Three sizes of HBsAg are synthesized; Large, Medium and Small
   - HBsAg form spherical particles which are aggregates of HBsAG, 22nm in diameter or filamentous 22 X 200 nm, this particle is not infectious (see above)
   C. Core Ags (HBcAg)aggregate to yield 27 nm particle, this particle is not infectious

Question 49

Hepatitis type
DANE PARTICLES are the only INFECTIOUS virus particles

1. Is virus grown in cell culture?
2. Complex antigen?
3. Antigen in core?

Answer 49

HEPATITIS B

1. Virus not grown in cell culture
2. HBsAg complex antigen, several antigenic determinants
   a. group specific antigen “a”
   b. subtype determinants d or y plus w or r
   c. four subtypes of HBV: adw, ayw, adr, ayr
   d. adw common with asymptomatic carriers, ayw associated with dialysis and drug addicts.
3. HBeAg (in core) - derived from HBc Ag; e antigen is the “infectivity” antigen, its presence in the serum indicates that infectious virus is present in the patient

Question 50

Identify hepatitis type
**Genome = partially double stranded DNA, located in core of virus (Dane Particle)

1. Polymerase complex located where?
2. Replication cycle occurs where?

Answer 50

Hepatitis B
1. Polymerase complex located IN CORE
- consists of DNA polymerase, linked to full length DNA strand, reverse transcriptase, Rnase H
- Enzymatic functions:
DNA Polymerase- Copies DNA template into a complementary strand, converts partially double stranded DNA into double stranded DNA
- Reverse transcriptase- Copies an RNA template into a strand of DNA; therefore a DNA-RNA is formed
- RNase H- Specifically degrades the RNA strand of the
DNA-RNA hybrid

2. Replication cycle occurs IN NUCLEUS AND CYTOPLASM
   - Viral attachment to cell receptor, followed by entry and viral uncoating
   - Partial DNA genome is converted to full double stranded DNA genome via DNA polymerase
   - DS DNA Genome is transcribed into viral RNA
   - Viral RNA serves two purposes (see diagram)
   a. Acts as messenger and is translated into proteins
   b. Serves as template for viral genome DNA synthesis

• • Viral genome synthesis requires reverse transcriptase to copy the RNA template into a complementary strand of DNA to form the RNA-DNA hybrid
• • RNase H degrades the RNA strand of the RNA-DNA and a viral DNA polymerase copies the full length strand of DNA to form the new genome, ie partially double stranded DNA
• *The – strand DNA serves as the template for transcription of mRNAs that are then translated into viral proteins, structural proteins and polymerase complex
• *The progeny virus particle is enveloped by a lipid bilayer with its associate HBsAgs (see diagram below for more complete view of replication scheme)

Question 51

Identify hepatitis type
1. Disease Characteristics: limited infection in some people, goes on to produce a chronic infection in others
2.Features: long incubation (60-day avg), gradual onset of
symptoms; most cases resolve, but some progress to a persistent disease or a chronic active disease, more severe disease than hepatitis A

• *Epidemiology
• people at increased risk of infection

Answer 51

Hepatitis B
Epidemiology
a)blood transfusions 0.3 - 3% most transfusion related serum hepatitis (80-90%) associated with “hepatitis C” at present time
b) virus can be isolated from saliva, semen, menstrual fluid, nasopharyngeal washings
c) HBV carriers, major source of spread, in US it is estimated that 750,000- 1,000,000 carriers exist
d) persons at increased risk of being infected with HBV;
1) parenteral drug users
2) heterosexual men and woman and homosexual men with multiple partners
3) household contacts and sexual partners of HBV carriers
4)infants born to HBV infected mothers
5) patients and staff in custodial institutions for developmentally disabled
6) recipients of certain plasma derived products
7) hemodialysis patients
8) health and public safety workers who contact blood
9) persons born in areas where HBV is endemic

Question 52

Identify hepatitis type

a) blood transfusions 0.3 - 3% most transfusion related serum hepatitis (80-90%) associated with “hepatitis C” at present time
b) virus can be isolated from saliva, semen, menstrual fluid, nasopharyngeal washings

1. Lab diagnosis
2. Immunity

Answer 52

1. Lab diagnosis
   a) enzyme immunoassay (EIA) and other antigen-antibody tests
   b) Blood banks test for HBsAg, anti-HBsAg and HBV DNA and possibly other antigen - antibody levels to determine if the patient is in chronic infection
   - The stage of HBV infection can be determined by monitoring the antibody and antigen levels within the patients serum. The presence of these antibodies and antigens over prolonged periods of time indicate that the individual may be a persistent carrier or a chronically active infected person (see diagram)
   c) Liver biopsy HbsAg in cytoplasm - less severe, HBcAg in nucleus more severe liver damage, both Ags not found in same cell
2. Immunity
   a) disease rarely fatal; immunity is longterm, IgM not significantly elevated
   b) will not protect against HAV, HCV or HEV
   c) partial immunity across HBV subtypes, “a” common determinant
   d) antibody to HBcAg first (IgM followed by IgG), then HBsAg antibodies develop in resolved cases, but IgG directed against HBsAg is not made in chronic active or persistent carriers (see diagram below)
   e) immune complex formation (viral antigens + specific antibodies) may be related to severity, vasculitis, cytotoxic T cells cause necrosis of the liver.

Question 53

Hepatitis type
** Prevention and control??
• Unresolved viral infection will have low levels of anti-Bs which indicate negative chronic active - lead to cirrhosis of liver

• what is preferred if person is allergic to yeast proteins, given to pregnant women
• types of vaccine? (2)
• when do you give HBIG?

Answer 53

Hepatitis B
Prevention and control
a) pooled gamma globulin of little value, hyperimmune HBIG protective, if given immediately after exposure, especially in neonates born to infected mothers need to test all pregnant women for HBV
b) monitor blood banks and addicts, all volunteers
c) non-blood spread? oral 50X dose to cause infection
d) original vaccine appeared effective; consisted of purified HBsAg, 92% protection,
**HEPTAVAX; preferred if personis allergic to yeast proteins, given to pregnant women
e) HBsAg produced in yeast expensive, very effective RECOMBIVAX, ENGERIX B
- HBsAg not glycosylated when produced in yeast, 5 yr duration in adults and longer ab levels in children- young adults
- Engerix has been approved for a 2 month immunization schedule, as well as the standard 6 month (0,1 and 6 months
** note: the preservative thimerosal has been used and is still used in vaccine preparations for adults.
However, the use of this mercury based compound in pediatric vaccines was questions by the American Academy of Physicians in 1999 and many hospitals discontinued immunization of newborns.
Now a thimerosal free vaccine is available from both SmithKline and Merck for pediatric use. Also Comvax is available, which combines Haemophilus influenza type B and hep B vaccines in a thimerosal free preparation
- TWINRIX, a combination of Havrix (HAV) and Engerix-B (HBV)

f) HBIG should be given IM to newborn of infected mother and vaccine ASAP, but within first 7 days, HB vaccine given to all newborns in endemic areas, Alaskan natives, and is now part of the pediatric immunization schedule (first dose within 24 hrs of birth)

**VACCINE SCHEDULE IN NOTES

Question 54

Hep B prevention and control cont’d

1. When is alpha interferon- peggylated effective?
   - is it first line?
   * nucleoside analogues?
2. Chronic hep B require 1 of 7 drug treatments?

Answer 54

1. alpha interferon-pegylated effective in a number of the more severe cases, however least effective when a very high level viremia is present
   - interferon may act by reducing virus load in blood, thereby allowing ones own immune system to keep infection in check
   - nucleoside analogues: entecavir, not recommended for mild cases of hepatitis B, severe cases may warrant more aggressive treatment
2. Chronic hepatitis B does require one of 7 drug treatments approved in the USA
   - Injectable interferon alpha
   - Pegylated Interferon*
   - Oral nucleoside analogue, Lamivudine
   - Nucleotide analogue, Adefovir
   - Nucleotide analogue, Enticavir*
   - Nucleotide analogue, Telbivudine
   - Nucleotide analogue, Tenofovir*
   * First line drug treatments

*** Drug resistance to nucleotide(side) drugs is always a concern

Question 55

Hep B lined to what cancer?

Identify 3 mechanisms how HBV-DNA is integrated into cellular DNA

Answer 55

HBV has been linked to Primary Hepatocellular carcinoma (PHC or HCC ). HBV carriers have 200 fold greater risk of PHC than uninfected individuals.

• *TAIWAN high HBV -> high PHC
• *PHC prevalent in sub-Saharan Africa and countries in Mediterranean basin

3 me aching so (HBV integrated into cellular DNA)

1. HBV DNA has a gene (HBx) which produces a transcription activation factor which not only activates viral genes, but also turns on cellular genes (oncogenes)
2. following integration of HBV genome into cell DNA they are juxtaposed next to a protooncogene which then is under the control of the regulatory element(s) of HBV
3. an alternative and more indirect mechanism for induction of HCC is the initiation of liver necrosis by HBV infection which is accompanied by chronic inflammation and hepatocyte regeneration. Cells are at greater risk of genetic changes (mutations)
   - Hepatitis C virus (HCV) may itself or in combination with HBV produce PHC
   * *Vaccine may eventually reduce PHC incidence

Question 56

Hepatitis type

Member of Flaviviridae; Genus
Hepacivirus
Icosahedral Capsid + envelop (E1 and E2 glycoproteins) Genome Composed of + stranded, non-segmented, single stranded RNA

**components?

**transmission? Incubation?

Answer 56

Hepatitis C 
1. 3 structural proteins; C, E1, E2
C - core protein 
E1  - Fusion Protein        
E2  - Receptor Binding

2. 5 Nonstructural proteins; NS1, NS2, NS3, NS4A&B, NS5A&B
   NS2 – Transmembrane Protein + Protease (NS3 N-Terminus) NS3 – Protease Cofactor(N-Terminus)+ RNA Helicase (C-Term.) NS4B-Transmembrane and ER membrane associated, morphogenesis
   NS5A-Viral replication
   NS5B- RNA Polymerase

• Transmitted primarily by blood or blood products like HBV),
• Incubation period 35-70 days, now that a diagnostic test is available to detect contaminated blood and blood products, IV drug use is becoming primary mode of transmission in developed countries

Question 57

Hepatitis type
Transmitted primarily by blood or blood products like HBV),
- Incubation period 35-70 days, now that a diagnostic test is available to detect contaminated blood and blood products, IV drug use is becoming primary mode of transmission in developed countries

1. Progression?
2. Symptoms? Are they worse or milder than Hep B?
3. Factors in reduction and discovery
4. Diagnostic test

Answer 57

1. Progression?
   - Progresses to chronic active liver disease in 1/2 of the acutely infected individuals; 10 -20% of those with chronic hepatitis show evidence of cirrhosis via biopsy
2. Symptoms? Are they worse or milder than Hep B?
   - Milder symptoms than Hep. B, less severe jaundice, lower transaminase elevation than HBV
3. Factors in reduction and discovery
   a. Blood screening for HBsAg by RIA, discarded HBsAg + blood
   b. Volunteer donors, eliminated those that have HepB
   c. After great reduction of HBV, serum hepatitis remained - nonA - nonB hepatitis which corresponds to HCV
4. Diagnostic test
   - Diagnostic test has been developed for HCV, even though the virus had not been cultured at even moderate levels
   - HCV antibodies can be detected in patients serum which reacts to the HCV viral protein.
   - EIA (enzyme immunoassay)- refined serological assay to detect circulating antibodies, (Ortho Diagnostics)
   EIA has also been used to determine time between post transfusion infection with HCV and seroconversion, 18 weeks average
   Confirmatory tests based on nucleic acid tests or immunoblot test

Question 58

Hep C

1. People at risk
2. What is beneficial in some patients relapse rate is high once treatment is stopped
   * *medications example (targets)

Answer 58

People at risk of acquiring HCV:

1) parenteral drug users
2) health care workers
3) hemodialysis patients
4) recipients of whole blood, blood cellular components or plasma- factor VIII now is treated to inactivate HIV, HBV and most likely HCV
5) sexual activity , person -person contact not shown to be major route of spread
6) Perinatal transmission also minor route
7) serum from donors of organs, tissue or semen intended for human use should be tested for anti-HCV by EIA

Alpha interferon is beneficial in some patients relapse rate is high once treatment is stopped

• *viral proteins- targets of three classes of antiviral drugs:
  1) protease inhibitor,
  2) NS5A Inhibitor
  3) NS5B Polymerase inhibitor
• Telaprevir (N3 protease inhibitor)
• Vitamin D May reduce viral replication
• Naringenin blocks progeny virus assembly
• Nucleoside analogues inhibit RNA Polymerase
• Most drugs treatment require co-administration with Peg-interferon
• HCV may cause HCC by indirect route (see mechanism c. under HBV section

Question 59

Hepatitis type
a.Virus structure corresponds to a 36 nm particle which contains circular, covalently-closed single-stranded RNA (1.7Kb), very high GC

**ENHANCE HEP B
a) antigen?
B) does it replicate on its own?
C) requirement for replication?
D) How does it enhance severity of Hep B infection
E) Diagnosis (3)

Answer 59

Delta agent (HDV) - enhances HBV infections

a)
- delta antigen (HD Ag)encoded by HDV binds to genomic RNA to yield virus core
- HBsAg, L,M,S, Donated by coinfecting HBV; HBsAgs + host lipids yield the outer envelop

b) a defective hepatitis virus, does not replicate on its own
c) requires HBV as a helper virus and therefore found in chronic HBV infection, HBV supplies its surface proteins (HBsAg), which surrounds the RNA-HDAg complex
d) Usually a severe clinically active disease is apparent, enhances severity of HBV infection

e) diagnosis:
1. HDAg in biopsy tissue
2. high titer of total antibody to HDAg
3. persistent IgM specific

F) alpha interferon has temporary benefits

Question 60

Hep type

b) Has a positive polarity, single stranded RNA genome
c) Transmitted usually in contaminated drinking water and food

1. Especially serious for?
2. Outbreaks?
3. Acute infections?
4. Evidence of?
5. Supportive treatment
6. Vaccine?

Answer 60

Hepatitis E Virus

• *Hepeviridae
  1. Especially serious for?
• Especially serious for pregnant women, about 20% to 30% fatality rate, immunocompromised

2. Outbreaks?
   - Outbreaks occur primarily in urban areas in developing countries and in rural areas in developed countries
3. Acute infections?
   - Acute infection in young adult, Lifetime immunity is established
4. Evidence of?
   - Some evidence of animal reservoirs
5. Supportive treatment
   - Supportive treatment-rest, fluids and nutrition, pregnant women and severe cases, as in immunosuppressed individuals,
   may require hospitalization
6. Vaccine?
   - No vaccine in US, China has developed vaccine

Question 61

1. New approaches to genetic recruitment

2. Genetics and type 2 DM

Answer 61

1. New approaches to genetic recruitment
   • Melanocortin 4 Pathway – POMC Deficiency, Leptin Receptor Deficiency, POMC Heterozygous Deficiency, Prader-Willi Syndrome
   • Presumed Clinical Trial - Setmelanotide
2. Genetics and type 2 DM
   • Genome-wide association studies (GWAS) have discovered > 260 genetic loci associated with type 2 diabetes and obesity
   • Next-generation sequencing studies ongoing
   • Pharmacogenetic studies for choice of glucose lowering therapy – 11 different drug classes

Question 62

1. You are working in a NYC newborn nursery – a child
   is born with ambiguous genitalia. What is the likely
   diagnosis? What are the genetic implications?
2. In the same nursery, a 1 week old male child is
   admitted with severe hypovolemia with marked
   hyperkalemia. What is the likely diagnosis? What
   are the genetic implications?
3. In your office, a 16 y/o presents with irregular
   periods (oligomenorrhea) and hirsutism. What
   genetic diagnosis should be considered?
4. Are all these presentations due to a mutation in the
   same single gene?

Answer 62

Congenital Adrenal Hyperplasia (CAH)

• Impaired cortisol synthesis 
• 90% 21-hydroxylase deficiency 
• Autosomal recessive 
• Incidence is 1/14,000 births world wide (classic)
- Yupik Eskimos of Alaska 1/280 
- Reunion Island 1/2000
• Nonclassic incidence 1-2/1000
- Some regions as high as 1-2/100 (e.g. NYC)

Question 63

CAH; classic vs nonclassic?

• which has ambiguous genitalia?
• androgen excess?
• precocious puberty?
• short?
• onset in aldoscence
• high risk vs no risk of adrenal insufficiency

Answer 63

Congenital Adrenal Hyperplasia 
1. Classic 
• Large hyperplastic adrenals at birth 
• Ambigous genitalia (“adrenogenital syndrome”)
• Simple 25% (presentation 1) 
• Salt-wasting 75% (presentation 2)
- Crisis: Hypovolemic shock, hyperkalemia 
• High risk of adrenal insufficiency 
• Precocious puberty 
• Short stature

2. Nonclassic
• Mild (presentation 3) 
• No genital ambiguity 
• Onset usually in adolescence 
• Androgen excess
- Oligomenorrhea 
- Hirsutism 
- Acne
• No adrenal insufficiency

Question 64

1. Identify clinical forms of the following deficiency (3))

**Enzyme that convert progesterone to DOC and 17-OH-progesterone to 11-Deoxycortisol

2. Genetics (3)
3. In the 3 clinical forms form #1, identify enzyme activity in the deficiency

Answer 64

1. 
A. Salt-wasting classic CAH
- point mutations 75%
- gene deletion 12%
- large gene conversions 12% 
B. Simple (virilizing) classic CAH
C. Nonclassic CAH

2. Genetics
   • HLA linkage
   • 6p21.3
   • 21-hydroxylase genes
3. Enzyme Activity in 21-Hydroxylase Deficiency
   A. Salt wasting; 0%
   B. Simple virilizing classic; 1%
   C. Nonclassic; 20-50%

Question 65

Identify condition
Genetics ;HLA linkage, 6p21.3, 21-hydroxylase genes

1. Early recognition and treatment (3)
2. Prenatal diagnosis and treatment (4)
   * *Outcomes? Male vs unaffected female vs affected females

Answer 65

1. Early recognition and treatment (3) 
A. Newborn screening; all states since 2009 - screen 17OH-progesterone 
B. Effective treatment 
• Glucocorticoid treatment
• Mineralocorticoid treatment
• Genital reconstruction 
C. Genetic counseling 
• Birth of CAH child
• Adolescent transition to adult

2. Prenatal diagnosis and treatment (3)
   A. IRB-approved experimental protocol – outcome data
   B. Dexamethasone at confirmation of pregnancy at risk (20 mcg/kg) – crosses placenta – ideally before 6 weeks
   C. Chorionic villus sampling at 8 - 10 weeks
   • Karyotype
   • DNA analysis
   D. Amniocentesis; 16 weeks
   • Karyotype
   • DNA analysis
   • HLA typing
   • Amniotic fluid 17-OH progesterone
   E. Fetal DNA - on the horizon
   • Extracted from maternal blood
   • As early as 6 weeks
   • Would limit treatment to affected females

**OUTCOME
• Males - stop dexamethasone
• Unaffected females - stop dexamethasone
• Affected females - continue dexamethasone – to prevent genital virilization

Question 66

Identify condition
• A 30 y/o women presents with a thyroid nodule.
Her father had labile hypertension and died of a

Answer 66

MEN 2A and RET-Proto-Oncogene
**Mutiple endocrine Neoplasia; classic model for integration of molecular medicine into patient care

1. Type 1; 3 Ps, AUTOSOMAL DOMINANT
   A. Parathyroid neoplasia
   B. Pituitary neoplasia
   C. Pancreatic islet neoplasia
2. Type 2A; 2Ps AUTOSOMAL DOMINANT
   A. Thyrocalcitonin (Medullary carcinoma) - 100%
   B. Pheochromocytoma - 50%
   C. Parathyroid neoplasia - 10-20%

*MEN 2A variants
• Familial medullary thyroid carcinoma (FMTC); Local family with C609Y
• MEN 2A with cutaneous lichen amyloidosis (MEN-2A/CLA)
• MEN 2A with Hirschsprung disease

3. Type 2B; 1P 
A. Medullary thyroid carcinoma 100%
B. Pheochromocytoma 50%
C. No parathyroid disease
D. Marfinoid habitus nearly 100%
E. Intestinal ganglioneuromatosis and mucosal neuromas
nearly 100%

Question 67

What is the common condition between MEN 2A and MEN 2B
• Indolent 80%
• Rest aggressive, can metastasize early to liver,
bone, lung
• Death – airway obstruction, liver and lung metastases
• Aggressiveness dependent on type
• MEN 2B&raquo_space; Sporadic = MEN 2A > FMTC

Answer 67

Medullary Thyroid Carcinoma
• Neoplasm of parafollicular (C) Cells
• 2-8% Thyroid cancers
• Secretory: calcitonin, CEA, other peptides
• Sporadic 70%
• Familial – MEN 2A, MEN 2B, Familial MTC
• Hyperplasia → Nodular Hyperplasia → MicroCa → MacroCa

Question 68

1. Search for MEN 2A gene
2. RET proto-oncogene
   - discovered?
   - what receptor?
   - knocks out what?
   - interact with what factor?
   - what mutations

Answer 68

1. Search for MEN 2A gene 
• Well defined syndrome, large families 
• 1987 - Chromosome 10 (centromeric) Linked MEN 2A/ Hirschsprungs, MEN 2B 
• 1993 - RET Proto-oncogene  - 10q 
• Point mutations identified

2. RET proto-oncogene
   • 1985 – Discovered – REarranged during Transfection
   • Tyrosine kinase receptor
   • Constitutively active rearrangement in 10-35%
   Papillary Thyroid Carcinoma (PTC oncogene)
   • Knock outs: GI, Kidney, Sympathetic nervous system
   • Interacts with Glial Cell-Derived Neurotrophic
   Factor (GDNF)
   • GDNF Receptor alpha - complexes with RET to form
   complete receptor
   • Point Mutations – site of mutation determines extent of disease

Question 69

MEN 2A screening - Pre RET analysis

**frequency and age (3)

Answer 69

1. Pentagastrin-stimulated calcitonin
   Freq; yearly
   Age; 1-35
2. 24h urine metanephrine
   Freq; yearly
   Age; 5-50
3. Serum calcium
   Freq; biyearly
   Age; 20-40

Question 70

RET genetic testing

**MEN 2A or FMTC Kindred-known mutations (5)

Answer 70

1. Normal RET analysis
   • Excludes with nearly 100% certainty
   • No catecholamine or calcium screening
2. RET mutation
   • Thyroidectomy appropriate age (before 5 yr) (-or-)
   • Annual calcitonin and neck US until abnormal → thyroidectomy
   • Continue catecholamine and calcium screening
3. New or Established Kindred
   • Find Mutation
   • Screen All Possible Affected Members
4. Familial Medullary Thyroid Carcinoma
   • No known RET mutation occurs in 5-8% families
   • Annual calcitonin and neck US
   • Repeat genetic analysis when more mutations known
5. Sporadic medullary thyroid carcinoma
   • Absence of family history does not exclude mutation
   • 7% germline mutation
   • If no mutation, hereditary excluded with 99% certainty
   • Somatic RET mutations in 65%

Question 71

Identify condition (Norton cont’s LIVER 4)

• Caused by excessive iron absorption/accumulation, most of which is deposited in liver and pancreas, also heart, joints and endocrine organs
• Normal total body iron = 2 to 6 gm. 0.5 gm stored in hepatocytes.
• *Total body iron may exceed 50gm

Identify Primary (inherited) vs secondary causes

Answer 71

HEMOCHROMATOSIS
A. Secondary Hemochromatosis or Hemosiderosis
(1) Parenteral iron overload: transfusions, long-term dialysis, aplastic anemia, sickle cell disease, MDS, leukemias
(2) Ineffective erythropoiesis with increased erythroid activity: Beta thalassemia, sideroblastic anemia, pyruvate kinase deficiency
(3) Increased oral intake of iron
(4) Chronic liver disease: HBV, HCV, ALD, porphyria cutanea tarda; results in decreased hepcidin synthesis

b. Primary or Hereditary Hemochromatosis
(1) General
(a) Homozygous-recessive disorder with low penetrance
(b) Still one of the most common genetic disorders (c) M:F = 5-7:1, fewer women accumulate clinically relevant
amounts of iron within their lifetimes

Question 72

Identify condition
**Pathogenesis
(a) Defect in intestinal iron absorption → accumulation of 0.5-1.0 gm/yr
(b) Excess iron causes symptoms after ~ 20 grams have
accumulated

**How is Iron directly toxic to tissues (3)

Answer 72

Primary or Hereditary Hemochromatosis
**Iron is directly toxic to tissues via several mechanisms:
i. Lipid peroxidation via iron-catalyzed free radical rxns
ii. Activation of stellate cells and stimulation of collagen
formation
iii. Interaction of reactive oxygen species, Fe and DNA predisposition to hepatocellular carcinoma

Question 73

Hemochromatosis
1. What protein is the main regulator of iron absorption

2&3. Adult vs juvenile form of hemochromatosis

• which is more severe ?
• mutations?

Answer 73

1. HEPCIDIN ; **Main regulator of iron absorption
   (a) Inhibits release of iron from intestinal cells (enterocytes) and macrophages
   (b) Therefore, hepcidin lowers plasma Fe levels, deficiency of hepcidin causes Fe OVERLOAD
   (C) Other proteins (hemojuvelin [HJV], transferrin receptor 2
   [TFR2], and HFE [from the hemochromatosis gene]) regulate hepcidin
   (d) Decreased hepcidin synthesis due to mutations in hepcidin,
   HFV, TFR2 and HFE cause hemochromatosis

Adult form of hemochromatosis
(a) Almost always due to mutation in HFE gene on short arm of chromosome 6
(b) HFE gene product regulates hepcidin synthesis
(C) Cysteine-to-tyrosine substitution at aa 282 is present in 70-100% of pts with hereditary hemochromatosis
(D) High frequency of mutation but low penetrance

Juvenile hemochromatosis

(a) More severe than adult form
(b) Mutations in HAMP & HJV genes

Question 74

Identify MORPHOLOGY of condition
**hemosiderin deposition occur mostly where?

Clinical/diagnosis

(1) Symptoms rarely before fifth or sixth decade, later in women because menstrual blood loss counterbalances increased Fe absorption (Takes 40 years to accumulate 20gm of iron)
(2) Abdominal pain, hepatomegaly, increased skin pigment, cardiac dysfunction, hypogonadism, altered glucose metabolism & arthritis
(3) Classic tetrad of hepatomegaly/cirrhosis, skin pigmentation, diabetes mellitus (“bronze diabetics” - tan in winter) and cardiac dysfunction may not occur until late**
(4) Labs: highly elevated serum iron and serum ferritin levels
(5) Confirm diagnosis with genetic testing
(6) Rx: repeated phlebotomies and chelating agents promote recovery of tissue function giving normal life expectancy to PRE-CIRRHOTICS
(7) Death from cirrhosis, cardiac disease or HCC (15%)

Answer 74

HEMOCHROMATOSIS; Classic tetrad of hepatomegaly/cirrhosis, skin pigmentation, diabetes mellitus (“bronze diabetics” - tan in winter) and cardiac dysfunction (HF) may not occur until late**

Morphology of hereditary and secondary
(1) Hemosiderin deposition in LIVER, pancreas, myocardium, pituitary gland, adrenal gland, thyroid and parathyroid glands, joints and skin
(a) Liver with initial periportal hemosiderin distribution; then to
lobule
(b) Bile duct epithelial cells and Kupffer cells also involved
(c) WITHOUT an inflammatory response
(d) Liver is initially enlarged then shrinks
(e) Iron content of liver is 10-20X normal
(2) Cirrhosis

Question 75

Identify condition; general/pathogenesis?? Morphology?

• Due to mutation of the ATP7B gene located on chromosome 13, codes for a transmembrane copper-transporting ATPase
• Eyes show Kayser-Fleischer rings

**affect what part of brains?

Answer 75

WILSON DISEASE
General/pathogenesis
a. Accumulation of toxic copper levels primarily in liver, brain and eyes
b. Autosomal recessive
c. Due to mutation of the ATP7B gene located on chromosome 13, codes for a transmembrane copper-transporting ATPase d. Deficiency of the ATP7B protein → decrease copper transport into bile, impaired ceruloplasmin formation (Cu + alpha2globuin) and impaired secretion of ceruloplasmin into the blood
e. Most are compound heterozygotes with different mutations on each allele
f. Results in Cu accumulation in the liver (brain & eyes), decreased circulating
ceruloplasmin

Morphology

a. See mild to moderate macrovesicular fatty change, acute and chronic inflammation and cirrhosis
b. Hepatic copper content is helpful for diagnosis
c. Brain shows atrophy and cavitation of the basil ganglia
d. Eyes show Kayser-Fleischer rings

Question 76

Identify condition;
identify labs and treatment?

Clinical

a. Presentation is variable with average age of onset at 11 years
b. Most common presentation- acute or chronic liver disease
c. Neurologic symptoms: Parkinson disease-like movement disorders, psychiatric symptoms of depression, phobias, compulsive behavior, labile mood
d. Excess copper also causes hemolysis and pathologic changes in the kidneys, bones, joints and parathyroid glands
e. Because of vast range of genetic alterations, genetic testing is not a primary diagnostic tool

Answer 76

WILSON DISEASE

1. Labs
   - INCREASED hepatic Cu content (most sensitive and accurate test, >250 µg/gm dry weight)
   - INCREASED urinary Cu (most specific screening test)
   - DECREASED** serum CERULOPLASMIC levels

2. Treatment 
chelation therapy (D-penicillamine) or zinc-based therapy 

**Liver transplant in patients with hepatitis or cirrhosis may be curative

Question 77

Identify condition; general? Pathogenesis?

Morphology

a. Round to oval cytoplasmic inclusions, first seen in periportal hepatocytes
b. Inclusions are strongly positive with PASD stain yielding magenta granules
c. Young infants may show steatosis without PASD-positive granules
d. PiZZ patients may demonstrate neonatal hepatitis +/- Cholestasis, mild chronic hepatitis, fibrosis and cirrhosis (early or late)

Clinical
A. 10-20% of newborns develop neonatal hepatitis with jaundice b. If presenting in adolescence: hepatitis, cirrhosis or pulmonary disease
c. The disease may remain silent until cirrhosis develops in adulthood
D. Small percentage (2-3%) of PiZZ patients develop hepatocellular carcinoma
e. Rx: liver transplant AND NO SMOKING (to delay onset of lung disease)

Answer 77

Alpha1-antitrypsin deficiency
General
a. Autosomal recessive disorder of protein folding with very low alpha 1-AT levels
B. Gene located on chromosome 14
C. Most common genotype; PiMM (wild type, 90%)
D. Most common clinically significant mutation is PiZ
E. PiMZ genotype with intermediate levels of alpha 1-AT
F. PiZZ genotype with 10% of normal evils of alpha 1-AT

Pathogenesis
A. Mutant polypeptide alpha1-AT is abnormally folded, does not migrate from ER to Golgi apparatus causing ER stress and apoptosis
B. PiZZ individuals accumulate mutant alpha 1-AT Z in ER of hepatocytes

Question 78

Identify condition

• *General? Pathogenesis?
• how? Gender? Ages? Prevalence location?

Morphology
a. Interlobular bile ducts actively destroyed by lymphoplasmacytic
inflammation (with or without granulomas), “florid duct lesion”
b. Early disease is patchy throughout the liver
c. Eventual portal-portal septal fibrosis (bridging fibrosis)
d. Classic progression: widespread duct loss, cirrhosis, cholestasis
e. See feathery degeneration, ballooned, bile-stained hepatocytes, Mallory-Denk bodies, bile-stained liver
f. Alternatively, some develop portal htn rather than cholestasis
g. Little hepatocyte loss, often hepatocyte regeneration so liver is enlarged

Answer 78

PRIMARY BILIARY CIRRHOSIS; disorder of intrahepatic biliary tree
**Type of autoimmune cholangiopathies

General

a. Inflammatory destruction of small and medium-sized intrahepatic bile ducts
b. Disease of middle-aged women (F:M = 9:1)
c. Ages 30-70 years; peak incidence: 40-50 years of age
d. Highest prevalence: Northern Europe (England, Scotland) and northern U.S. (Minnesota)

Pathogenesis

a. Possible autoimmune disease with genetic and environmental factors also, trigger unknown
b. Patients may also have extrahepatic autoimmune diseases (Sjogren syndrome, scleroderma, rheumatoid arthritis, celiac disease, etc)
c. Anti-mitochondrial antibodies (AMA not ANA)*** in 95% of patients

Question 79

Identify condition? Treatment? Complication? What occurs with progression?

Clinical

a. Most cases diagnosed when asymptomatic with INCREASED alkaline phosphatase and GGT** which precipitates workup. Cholesterol may also be elevated.
b. + Anti-mitochondrial antibodies** (90-95% of patients)
c. Liver biopsy showing florid duct lesion confirms the diagnosis d. If symptomatic: Insidious onset of fatigue and pruritus

Answer 79

PRIMARY BILIARY CIRRHOSIS **type of autoimmune cholangiopathies

• Treatment; early therapy with ursodeoxycholic acid greatly slows progression
• Untreated; hyperbilirubinemia or portal htn as disease progresses
• Also with progression: skin hyperpigmentation, xanthelasmas, steatorrhea & osteomalacia and/or osteoporosis (from DECREASED absorption of vitamin D)

Question 80

Identify condition

Pathogenesis

a. Unknown but possibly immune mediated bile duct injury
b. Circulating autoantibodies include atypical MPO-ANCA in 65% anti-nuclear antibodies (ANA)** in 6%
* *General?
- associated with what condition?
- age? Gender?
* *Morphology
- large vs small ducts?
- how to diagnose>?

Answer 80

Primary Sclerosing Cholangitis
**Type of autoimmune cholangiopathies
General
a. Inflammation and obliterative fibrosis of intra- and extrahepatic bile ducts with dilation of preserved segment (“BEADED” appearance radiographically)
b. Associated with ulcerative colitis; **70% of PSC pts have ulcerative colitis, 4% of ulcerative colitis pts have PSC
c. Occurs in 20’s to 40’s, median age: 30 years
d. Males affected more than females (2:1)

Morphology

a. Large ducts: neutrophils and chronic inflammation. Inflamed areas develop strictures
b. Small ducts: concentric periductal fibrosis (“onion skin fibrosis”)
c. Diagnose with radiologic imaging of larger ducts
d. Liver then becomes cholestatic and cirrhotic

Question 81

Identify condition?

Risk for?
Treatment? (Specific vs nonspecific)

Clinical
a. Asymptomatic patients identified from persistent INCREASED alkaline phosphatase esp UC patients who are routinely screened
B. Symptomatic: fatigue, pruritis and jaundice
c. Ascending cholangitis, chronic cholestatic liver disease, cholelithiasis in dilated ducts, chronic pancreatitis, chronic cholecystitis

Answer 81

Primary Sclerosing Cholangitis
**Type of autoimmune cholangiopathies

• Risk of cholangiocarcinoma 0.6-1%/yr, 20% lifetime risk
• Non-specific treatment- cholestyramine for the pruritis and endoscopic dilation or stenting for symptom relief
• *Rx: liver transplant is curative in end-stage patients

Question 82

Identify anomalies of biliary tree

1. • Congenital dilations of the common bile duct
   • 80% present in childhood with abdominal pain, sx of biliary colic - F:M = 3-4:1

• *predispose to what?
• *increased risk for?

Answer 82

CHOLEDOCHAL CYSTS; uncommon

• Predispose pts to stone formation, stenosis, pancreatitis, obstructive biliary complications
• Increased risk of cholangiocarcinoma**

Question 83

Identify anomaly of biliary tree
1. Primary abnormalities are congenital malformations of biliary tree 2. Often associated with polycystic kidney disease 3. Increased risk of cholangiocarcinoma

**list 3 overlapping presentations

Answer 83

FIBROPOLYCYSTIC DISEASE

3 overlapping presentations

1. Von meyenburg complex; small bile duct Hamartomatous
2. Caroli disease/syndrome
3. Congenital hepatic fibrosis

Question 84

Identify anomaly of biliary tree

1. Autosomal dominant
2. Mutations in the Jagged gene on chromosome 20
3. See chronic cholestasis, pulmonary artery stenosis, butterfly-like vertebral arch defects and peculiar facies (broad forehead, wide-spaced eyes)
4. Portal tract bile ducts are ABSENT**
5. May survive into adulthood with increased risk of hepatic failure and hepatocellular carcinoma

Answer 84

ALAGILLE SYNDROME (Paucity of Bile ducts or Arteriohepatic dysplasia)

Question 85

Classification of circulatory disorders (3)

Answer 85

1. Impaired blood flow INTO the liver
2. Impaired blood flow THROUGH the liver
3. Impaired blood flow AWAY from the liver

Question 86

2 conditions of impaired blood flow INTO the liver

Answer 86

1. Hepatic artery compromise
   a. By thrombosis, embolism compression by tumor, PAN and sepsis
   b. Infarctions are rare due to dual blood supply except in transplanted liver
2. Portal vein obstruction and thrombosis
   a. Produces signs & symptoms secondary to portal htn; ascites uncommon
   b. Extrahepatic causes:
   (1) Intra-abdominal sepsis leading to pyelophlebitis
   (2) Hypercoagulable disorders
   (3) Tumors within the abdomen
   (4) Pancreatitis, pancreatic ca
   (5) Trauma, surgery
   (6) Idiopathic

Question 87

Conditions of impaired blood flow THROUGH the liver

1. Intrahepatic etiologies (4)
   - what is most common cause?
2. May lead to what?
3. What is; Primary dilation of sinusoids causing blood-filled cystic spaces, focal apoptosis of hepatocytes or sinusoidal endothelial cells

Answer 87

1. Intrahepatic etiologies:
   a. Cirrhosis (most common cause) **
   b. Sickle cell disease
   c. Disseminated intravascular coagulation
   d. Metastatic tumors; primary tumors (lung, breast, colon) that like to metastasize to the liver

2A. May see portal HTN

2B. May lead to massive necrosis of hepatocytes and acute hepatic failure

3. Peliosis hepatis
   a. Primary dilation of sinusoids causing blood-filled cystic spaces, focal apoptosis of hepatocytes or sinusoidal endothelial cells
   b. Associated with cancer, tuberculosis, Bartonella infection in AIDS patients, immunodeficiency, anabolic steroids, oral contraceptives and danazol
   c. May cause fatal intraabdominal hemorrhage or liver failure

Question 88

Impaired flow AWAY form liver (3)
1. identify morphology? And clinical?
- Due to obstruction of 2 or more hepatic veins
- Associated with myeloproliferative disorders, coagulopathies,
antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, intraabdominal cancer, pregnancy and oral contraceptive use

2. identify morphology? And clinical?
   - Associated with allogenic bone marrow transplantation
   - Also seen in cancer patients receiving chemotherapy
   - Due to toxic injury to sinusoidal endothelial cells
3. Morpholgy
   - right sided failure lead to passive congestion of centrilobular sinusoids
   - left sided failure or shock lead to hypoperfusion and hypoxia (INCREASED transaminases, mild to moderate jaundice)
   - combination of both leads to centrilobular hemorrhagic necrosis mottled appearance (“NUTMEG LIVER”)

Answer 88

1. Hepatic Vein Thrombosis (Budd-Chiari syndrome)
   * *Morphology
   (1) Enlarged red-purple liver with tense capsule
   (2) Severe centrilobular congestion and necrosis
   * *Clinical
   (1) High mortality if untreated
   (2) Treatment includes portosystemic venous shunts
2. Sinusoidal Obstruction Syndrome (Veno-occlusive Disease)
   **Morphology
   (1) Obliteration of terminal hepatic venules due to subendothelial
   swelling and collagen deposition
   (2) Acute disease: centrilobular congestion and necrosis
   (3) Progressive disease: obliteration of the venule lumen
   (4) Chronic disease: fibrous obliteration of the venule
   **Clinical
   (1) Tender hepatomegaly, ascites, weight gain and jaundice
   (2) Usually a clinical diagnosis (high risk with obtaining liver tissue)
   (3) Rx: ursodeoxycholate and anticoagulation in stem cell transplant pts
3. Passive congestion and centrilobular necrosis

Question 89

Identify condition of GVHD

1. Post bone marrow transplant; acute vs chronic
2. Post liver transplant; acute vs chronic

Answer 89

1. Post bone marrow transplant; acute vs chronic
   A. Acute (10-50 days post transplant)
   a. Donor lymphocytes attack epithelial liver cells
   b. Inflammation of parenchyma and portal tracts
   c. Necrosis of hepatocytes and bile duct epithelium

B. Chronic (>100 days post transplant)

a. Portal inflammation with fibrosis
b. ENDOTHELIITIS – subendothelial lymphocytes separate endothelium from basement membrane of portal and hepatic vein radicles

2. Post liver transplant; acute vs chronic
   A. Acute (cellular) rejection
   a. Mixed portal inflammation
   b. Bile duct and hepatocyte injury with ENDOTHELIITIS
   B. Chronic rejection; severe obliterative arteritis/cholangitis lead to ischemic changes and bile duct destruction

Question 90

Hepatic disease in pregnancy
**differentiate the 2 conditions
Morphology
(1) Periportal sinusoidal fibrin deposition + hemorrhage in the space of Disse → periportal coagulative necrosis
(2) May produce a hematoma that can rupture
(3) Labs: increased transaminases, mildly increased bilirubin
(4) Coagulopathy is evidence of advanced disease

**Treatment?

Answer 90

1. PREECLAMPSIA
   (1) Maternal hypertension, proteinuria, edema, and coagulation abnormalities
   (2) If sub-clinical hepatic disease is the primary manifestation then HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelets)
2. ECLAMPSIA = above features + hyperreflexia and seizures

***Treatment: deliver the baby if mature (>37 wks) or in severe cases

Question 91

Liver disease in pregnancy
a. Subclinical or mild hepatic dysfunction with elevated transaminases to hepatic failure, coma and death
B. Usually in second half of pregnancy (third trimester)

Morphology

(1) Microvesicular fatty change
(2) Severe cases look like viral hepatitis (portal inflammation, lobular disarray, reticulin collapse)

• *Clinical
• symptoms?
• is it mild or severe?
• how to Dx?
• treatment?

Answer 91

Acute fatty liver of pregnancy (AFLP)

Clinical

(1) May see bleeding, nausea, vomiting, jaundice and possible coma
(2) But most with mild disease
(3) Diagnosis via high index of suspicion + liver bx
(4) Rx: deliver the baby

Question 92

Identify liver disease in pregnancy

Labs; mildly INCREASED alkaline phosphatase & bilirubin (mostly conjugated)
Micro; mild Cholestasis without necrosis
**Itching can be bad, benign

Answer 92

Intrahepatic cholestasis of pregnancy

a. Hormonal state of pregnancy → decreased secretion of bile/bile salts
b. Pruritis +/– dark urine, acholic stools and jaundice in 3rd trimester
c. Micro: mild cholestasis without necrosis d. Labs: mildly INCREASED alkaline phosphatase & bilirubin (mostly conjugated)
e. Usually a benign condition
f. Mild ↑ in incidence of fetal distress

Question 93

Hepatic nodules and tumors
Differentiate the 2 nodular hyperplasias
1. Central scar with narrowed large vessels due to fibromuscular hyperplasia
2. Pathogenesis: conditions affecting intrahepatic blood flow (like FNH)

Answer 93

1. Focal nodular hyperplasia
   a. Well-demarcated area which can be several centimeters
   b. Mostly in young to middle-aged adults
   c. Central depressed gray-white stellate scar with radiating fibrous septa
   d. Central scar with narrowed large vessels due to fibromuscular hyperplasia
   e. Septa contains lymphocytic infiltrate and BD proliferation
2. Nodular regenerative hyperplasia
   a. Affects ENTIRE liver
   b. Spherical nodules WITHOUT dense fibrosis
   c. See nodules of plump hepatocytes with a rim of atrophic hepatocytes
   d. Pathogenesis: conditions affecting intrahepatic blood flow (like FNH)
   e. Associated with solid-organ (mostly renal) and BM transplantation
   f. Usually asymptomatic; can cause portal hypertension

Question 94

Benign liver neoplasms

1. What is the most common benign liver tumor
2. What is benign neoplasm from hepatocytes called? (List 3 subtypes)

Answer 94

1. CAVERNOUS HEMANGIOMAS- most common benign liver tumor
   a. Usually < 2 cm and just below the capsule
   b. Small and large vascular channels embedded in fibrous connective tissue
   c. Avoid biopsying this lesion
2. HEPATIC ADENOMA (LIVER CELL ADENOMA)
   - Benign neoplasms from hepatocytes
   - Subcapsular ones with possible rupture causing abdominal
   hemorrhage
   **Three subtypes
   A. HNF1- alpha INACTIVATED hepatocellular adenoma
   B. Beta catenin ACTIVATED hepatocellular adenoma
   C. INFLAMMATORY hepatocellular adenoma

Question 95

IDENTIFY subtypes of hepatic adenoma

1. Young women, oral contraceptive use.
   * *is there risk of malignancy?
2. Men and women, associated with OC and anabolic steroid use
   * *Is there risk of malignancy?
3. Men and women, associated with NAFLD
   * *any risk of malignancy?

Answer 95

1. HNF1- alpha INACTIVATED hepatocellular adenoma i. HNF-1alpha is a transcription factor
   ii. Young women
   iii. Sometimes associated with oral contraceptive use
   iv. Almost NO RISK for malignant transformation
2. Beta catenin ACTIVATED hepatocellular adenoma
   i. Neoplasia and malignancy in other organs
   ii. VERY HIGH RISK for malignant transformation
   iii. Should be resected even if asymptomatic
   iv. Men and women
   v. Associated with OC and anabolic steroid use
3. INFLAMMATORY hepatocellular adenoma
   i. Upregulation of C-reactive protein and serum amyloid A
   ii. Associated with NAFLD
   iii. Men and women
   iv. Intermediate risk for malignant transformation
   v. 10% have concomitant beta catenin mutation with predictably very high risk for malignant transformation

Question 96

Identify morphology of the 3 subtypes of liver cell adenomas

Answer 96

1. HNF1- alpha mutations - fatty, no cellular or architectural atypia
2. Beta catenin mutated - high degree of cytologic or architectural dysplasia, even with small areas of HCC
3. Inflammatory - areas of fibrotic stroma, mononuclear inflammation, ductural reactions, dilated sinusoids, telangiectatic vessels

Question 97

Malignant liver tumor
1, what is the most common liver tumor of young childhood (rarely occurs over the age of 3)
**Identify histology of 2 types

Answer 97

Hepatoblastoma
a. Most common tumor of young childhood (rarely occurs over 3 years of age)
b. Histology
(1) Epithelial type – fetal or embryonal cells with structures like a developing liver
(2) Mixed epithelial & mesenchymal type – areas of mesenchymal
differentiation with primitive mesenchyme, osteoid, cartilage or striated muscle

Question 98

Identify malignant liver tumor

Clinical

(1) Enlarging abdomen, vomiting and failure to thrive
(2) Frequent activation of WNT signaling pathway
(2) Often associated with familial adenomatous polyposis
* *Treatment? 5 yr survival percent?

Answer 98

HEPATOBLASTOMA

• Treatment: surgical resection and chemotherapy
• 5-year survival- 80%

Question 99

Identify liver malignancy 
Major etiologic factors
(a)  Chronic viral infection (HBV, HCV)**
(b)  Alcoholic cirrhosis **
(c)  NAFLD 
(d)  Metabolic diseases (hemochromatosis, Wilson disease) 
(e)  Metabolic syndrome 
(f)  Aflatoxins

**EPidemiology and pathogenesis?

Answer 99

HEPATOCELLULAR CARCINOMA (HCC)

1. High incidence HBV-prevalent areas (SE & E Asia, sub-Saharan Africa)
   (a) HBV infection begins in infancy (vertical transmission)
   (b) Younger onset of tumor, from 20 to 40 years of age
   (c) Cirrhosis present with 50%
2. Low incidence HBV non-prevalent areas (Americas, N Europe, Aust, NZ)
   (a) Associated with other chronic liver diseases (HCV, alcohol)
   (b) Later onset of tumor
   (c) Cirrhosis is present in 75-90% of cases

Question 100

Identify liver malignancy; most caused by chronic HBV, HCV and alcoholic cirrhosis

1. 2 early mutations?
2. Role of signalling through what pathway?
3. What is associated with viral hepatitis
4. Precursor lesions*** (3)

Answer 100

(a) Two most common early mutations: activation of β-catenin, inactivation of p53
i. Strongly associated with aflatoxin
ii. Usually not related to HBV infection
(b) Role for signaling through the IL-6/JAK/STAT pathway
(c) Chronic inflammation and cellular regeneration associated
with viral hepatitis

(d) Precursor lesions for HCC
i. Hepatic adenoma esp. with activated β-catenin: associated with NAFLD, sex hormone exposure
ii. Cellular dysplasia in chronic liver disease -
- Large cell change and small cell change
- Associated with HBV, HCV, alcohol, NAFLD, alpha-1AT, HH, PBC
iii. Dysplastic nodules found in cirrhosis
- low grade and high grade
- Associated with HBV, HCV, alcohol, NAFLD, alpha-1AT, HH, PBC

Question 101

The following lead to what condition ?

i. Hepatic adenoma esp. with activated β-catenin: associated with NAFLD, sex hormone exposure
ii. Cellular dysplasia in chronic liver disease -
- Large cell change and small cell change
- Associated with HBV, HCV, alcohol, NAFLD, alpha-1AT, HH, PBC
iii. Dysplastic nodules found in cirrhosis
- low grade and high grade
- Associated with HBV, HCV, alcohol, NAFLD, alpha-1AT, HH, PBC

**Morphology?

Answer 101

Hepatocellular Carcinoma (HCC)

Morphology
(1) Unifocal, multifocal or diffuse patterns
(2) Tumor paler than surrounding parenchyma
(3) Range from well-differentiated to anaplastic undifferentiated tumors
(4) Color reflects differentiation state: white - abundant stroma; yellow - predominantly fatty change; green - well-differentiated tumor cells are producing bile
(5) Intrahepatic metastases via vascular invasion or direct extension, more likely when tumor > 3cm
(6) Hematogenous spread is most common route for extrahepatic
metastases (esp. lung), late in disease

Question 102

Identify liver malignancy ; edematous (hypoalbuminemia) and CACHEXIA

(1) Ill-defined upper abdominal pain, malaise, fatigue, weight loss, possible awareness of hepatomegaly or abdominal fullness
(2) +/– jaundice, fever, variceal bleeding

• *
• levels of AFP
• what is most useful for diagnosis?
• how do they die?
• what is 5 yr survival %?

Answer 102

Hepatocellular carcinoma (HCC)
I. Elevated serum alpha fetoprotein levels in 50% of cases, not good for screening
II. Imaging and biopsy is MOST USEFUL in DIAGNOSIS
II. Death form; CACHEXIA, GI or esophageal bleed, liver failure with coma or rupture and fatal hemorrhage
III. 5 year survival for liver confined cancer; 31% with resection

Question 103

Identify liver malignancy

• 5% variant of HCC
• younger people
• better prognosis than HCC

Answer 103

FIBROLAMELLAR CARCINOMA

a. Occurs in young adults (20-40 years of age)
b. NO association with chronic liver disease
c. Single large, hard lesion with fibrous bands and cords of well-differentiated separated by lamellae of dense collagen bundles
d. BETTER prognosis than “regular” HCC (5 year survival 70+%)

Question 104

Identify liver malignancy

(1) Linked to liver fluke infestation particularly Clonorchis sp. & Opisthorchis sp.
(2) Also associated with chronic inflammatory diseases of the large bile ducts: primary sclerosing cholangitis, fibropolycystic liver disease, HBV, HCV, NAFLD
(3) Most cases are WITHOUT predisposing factors

**premalignant lesions?

Answer 104

Cholangiocarcinoma

** Premalignant lesions - Biliary intraepithelial neoplasias, low-grade to high- grade: BilIN-1, -2, -3

Question 105

Identify liver malignancy
**morphology of 2 forms?

Clinical

(1) Intrahepatic tumors not detected until late from symptoms of obstructed bile flow or liver mass
(2) Extrahepatic tumors present with biliary obstruction, cholangitis, RUQ pain
(3) Death usually within 6 -12 months

Answer 105

Cholangiocarcinoma
Morphology
1. Extrahepatic forms (80-90% of cases)
(a) Firm gritty gray nodules with abundant fibrous stroma within the bile duct wall
(b) Most are adenocarcinomas with/without mucin secretion
(c) Include Klatskin tumors: perihilar, at junction of R & L
hepatic ducts (50-60%); distal bile duct tumors (20-30%)

2. Intrahepatic forms (10-20% of cases)
   (a) Firm gritty texture 2° dense desmoplastic reaction
   (b) Most are well- to moderately differentiated sclerosing
   adenocarcinomas with dense collagenous stroma between malignant glands

**Both types
(a) Incite desmoplastic reaction
(b) Lymphovascular and perineural invasion are common routes
of metastasis

Question 106

What tumor types are more common than primary tumors?

** Clinical

Answer 106

Metastatic tumors of the liver

a. More common than primary tumors
b. Colon, breast, lung and pancreas are most common primaries
c. Multiple nodules with central necrosis
d. Clinical; Jaundice and INCREAST LFTs, possible hepatomegaly

Question 107

List 3 gallbladder disorders

Answer 107

1. Cholelithiasis
2. Acute and chronic cholecystitis
3. Gallbladder cancer

Question 108

1. Identify condition
   Clinical
   • Most patients without symptoms, ~ 70-80%
   • May see biliary colic pain (usually constant rather than “colicky”, RUQ +/- radiation to right shoulder or back
   • Complications: empyema, perforation, fistulas,
   cholangitis, obstructive cholestasis or
   pancreatitis
   • Small stones (<1cm) - obstruct
   *Large stones - erode into bowel - ILEUS

**2 types?

Answer 108

Cholelithiasis
• > 95% of biliary tract disease is associated
with cholelithiasis
• Affects 20,000,000 in US (25-50 tons); 700,000
cholecystectomies/yr in US
• 70-80% of stones are “SILENT”

**2 types
• Cholesterol stones (90% of Western cases)
• Pigment stones (bilirubin calcium salts)

Question 109

Prevalence/risk factors of cholesterol stones (4)

Answer 109

Cholesterol stones; Fat, Female, Forty, Fertile
1. Age and Sex
• Increases with age, seen in middle-age to older
persons
• Twice the prevalence in Caucasian women as men

2. Environmental – increase biliary cholesterol
   secretion
   • Estrogens (OCs and pregnancy) INCREASE cholesterol uptake and synthesis LEAD to INCREASED cholesterol stone formation
   • Obesity and rapid weight loss LEAD to INCREASED secretion
3. Heredity
   • Certain Native American groups (found in 75% of certain populations)
   • Positive family history
4. Conditions promoting bile stasis (prolonged
   fasting, TPN and spinal cord injury) LEAD to DECREASED cholesterol excretion LEAD to INCREASED cholesterol stones

Question 110

Pathogenesis and morphology of WHAT STONES?

**radiolucent

Answer 110

Cholesterol stones – Pathogenesis
• Form when cholesterol concentration exceeds
solubilizing capacity of bile (supersaturation)
forming solid crystals/stones
• Gallbladder hypomotility and INCREASED mucus secretion traps crystals promoting cholesterol stone formation

Morphology
• Form only in the GB
• Yellow and round to oval-shaped
• Most are RADIOLUCENT (NO shadow on x-ray)

Question 111

Back stones (radiopaque) and Brown stones (radiolucent)

• *What gallstones
  1. Risk factors
  2. Pathogenesis
  3. Morphology

Answer 111

PIGMENT STONES
1. Risk factors
• Hemolytic syndromes, ileal dysfunction/bypass
and biliary tree infections and parasites

2. Pathogenesis
   • Mixture of insoluble calcium salts form INCREASED unconjugated bilirubin from hemolysis
   • INCREASED unconjugated bilirubin with various bile tract
   infections (E. Coli, ascaris or clonorchis, opisthorchis)
3. Morphology
   • Black stones are formed in sterile bile - most (50-75%) are radiopaque (shadow on x-ray)
   • Brown stones - formed within infected intra- or extrahepatic ducts; radiolucent (NO shadow)

Question 112

Identify 3 types of condition

inflammation of gall bladder

Answer 112

Cholecystitis

1. Acute calculus cholecystitis
2. Acute acalculous cholecystitis
3. Chronic cholecystitis

Question 113

Identify condition of gall bladder

• 90% of cases due to a stone obstructing the
neck of the gallbladder or the cystic duct
• Pathogenesis:
- Chemical irritation leading to inflammation of the
obstructed GB because the
- Glycoprotein mucus layer disrupted → exposure of
epithelium to detergent action of bile salts

Answer 113

Acute calculous cholecystitis

Question 114

Identify condition of gallbladder

Pathogenesis:
• Ischemic compromise of GB mucosa secondary to
severe illness – cystic artery is an end-artery
• Other contributing factors:
- GB stasis
- INCREASED biliary sludge (viscous bile + mucus) →
obstruction

Answer 114

Acute acalculous cholecystitis
- NO stones 
- 10% of cholecystitis cases 
- Usually found in severely ill patients:
• Sepsis with hypotension
• Multisystem organ failure
• Immunosuppressed patients
• Severe trauma or burns
• Diabetes mellitus
• Infectious processes

Question 115

Identify condition of gallbladder

Morphology
A. Gross: enlarged, tense, red to violaceous to
possibly green-black and necrotic
• Serosa- hemorrhagic & fibrin covered
• Lumen- cloudy or turbid bile
• Wall- thickened and erythematous
B. Micro: acute inflammation, edema, vascular congestion, possible abcess

Answer 115

Cholecystitis
** Same in both acute calculous & acalculous
cholecystitis (except for presence/absence of
stones)

Question 116

Condition of gallbladder

Clinical
• May present with mild to moderate symptoms that
resolve or may present as an acute surgical
emergency
• Symptoms include RUQ or epigastric pain, fever,
anorexia, nausea, vomiting, fatty food intolerance
• Labs: mild to moderate leukocytosis, mild INCREASED alkaline
phosphatase
• Most episodes subside in 1-10 days
• 25% of cases will need surgery
• Recurrence is common in patients who recover without surgery

Answer 116

Acute calculous cholecystitis

Question 117

Condition of gallbladder

Clinical
• Insidious onset with symptoms obscured by
underlying disease
• Diagnosis rendered by high index of suspicion

Answer 117

Acute acalculous cholecystitis

• Incidence of perforation and gangrene higher in
acalculous than in calculous acute cholecystitis

Question 118

Condition of gallbladder

Morphology
• Serosa – smooth and glistening with possible dense fibrous adhesions from previous acute inflammation
• Lumen – green-yellow mucoid material, with or without stones
• Wall – thickened, gray-white wall
• Micro: variable chronic inflammation

Answer 118

Chronic cholecystitis

• May or may not be preceded by repeated bouts
of acute cholecystitis
• Associated with stones in 90% cases
• Symptoms similar to acute cholecystitis - nausea, vomiting & fatty food intolerance

• • The wall of the gallbladder is thickened and fibrotic due to chronic cholecystitis
• • The gallbladder mucosa is infiltrated by inflammatory cells

Question 119

1. Condition
   • Rare variant of chronic cholecystitis
   • Due to extensive dystrophic calcification in wall
   • INCREASED incidence of GB carcinoma
2. Complications of acute & chronic cholecystitis (4)

Answer 119

1. Porcelain gallbladder
2. Complications of acute & chronic cholecystitis:
   • Similar to cholelithiasis
   • Bacterial infection with cholangitis/sepsis
   • Perforation with abscess or peritonitis
   • Fistula formation with ileus

Question 120

Condition of gallbladder

• Most common extrahepatic biliary tree malignancy
• At least twice as common in women
• Occurs ~7th decade

**Pathogenesis?

Answer 120

GALLBLADDER CARCINOMA

Pathogenesis
• Gallstones – present in 95% cases, most important
risk factor
• 1-2% of patients with gallstones develop GB
carcinoma
• Underlying pathogenesis – chronic inflammation

Question 121

Condition of gallbladder
**Morphology?
Clinical
• Preoperative diagnosis in < 20% of patients
• Symptoms similar to cholelithiasis:
abdominal pain, anorexia, nausea, vomiting and jaundice
• Most with extensive disease at time of
diagnosis – extension into liver, bile ducts, LNs
• Rx: surgery & chemotherapy
• 5-year survival < 10%

Answer 121

Morphology:
• Mostly in the fundus or neck of the GB
• Most are adenocarcinomas
• Two patterns – infiltrating or exophytic
A. Infiltrating pattern more common
• Neoplastic cells invade the GB wall 
• Firm, poorly defined, may cause ulceration, perforation or fistula
B. Exophytic pattern
• Grows into lumen AND invades GB wall

• • The opened gallbladder contains a large, exophytic tumor that virtually fills the lumen
• • Malignant glands are seen lumen infiltrating a densely fibrotic gallbladder wall

Question 122

Toxicity

1. What dictates toxicity
2. What does LD50 mean?

Answer 122

1. What dictates toxicity
   - All substances are toxic
   - A Principle of Toxicology is the dose **DICTATES TOXICITY
2. What does LD50 mean? LD50 is the dosage (mg/kg body weight) causing death in 50% of the exposed animals
   - Comparisons made between agents may be based
   on calculated LD50
   - LD50 lethal dose in 50% of population*
   - Lower the LD50, more toxic the substance

Question 123

Identify toxicity
A colorless, odorless and tasteless gas; exposure not
detected by senses
** Number one cause of death from poisoning in the
US!!!!**
• Toxicity results from anoxia
• Death due to respiratory failure; Target organ is the
globus pallidus in the cerebellum

**major sources vs other sources

Answer 123

Carbon Monoxide (CO) 
• Major Sources ; incomplete combustion of fossil fuels e.g car exhaust, kerosene heaters and fires e.g home fires 

**Other sources; cigarette smoke, hemolytic anemia, biotransformation or pain removers e,g methylene chloride

Question 124

Describe mechanism of CO toxicity

• bind what to form?
• color of mucus membranes?

Answer 124

• CO binds to ferrous (Fe+2) iron in hemoglobin to
form carboxyhemoglobin (COHb); CHERRY RED color in mucus membranes
• CO binds 250x tighter to Fe+2 in hemoglobin than O2
- causes additional reduction in O2 carrying capacity
•O2 bound to COHb is released slower than from hemoglobin to further reduce O2 delivery to tissues
• Binds to other heme containing proteins

**Respiratory failure and death with COHb (%) at 70-80

Question 125

Symptom and treatment of CO positioning based on COHb (%)

Answer 125

1. 0-2.5 %; no effect, no treatment
2. 10-20%; mild headache, fatigue. Treat with fresh air
3. 40-50%; Coma, confusion. Tx 100% oxygen, hyperbaric oxygen

Question 126

Identify toxicity

• Rapid progression from onset of symptoms to death • Nausea, lightheadedness, hyperventilation, feelings of
suffocation, convulsions, coma
• Heart rate increased followed by decreased heart rate
• Death from respiratory failure, Brain damage in
recovered patients

Answer 126

Cyanide (CN) and CN releasing agents
• Exists as solid (salt form), liquid (HCN) or gas
- occupational exposure during mining, chemical synthesis, electroplating
- ingestion of apricot or peach pits, bitter almond
- excess dose of certain drugs, Laetrile
- fires

Question 127

Identify
**Mechanism of toxicity???

• Occupational exposure during mining, chemical
synthesis, electroplating
• Ingestion of apricot or peach pits, bitter almond
• Excess dose of certain drugs, laetrile
• Fires (evil twin in fires)

Answer 127

Cyanide (CN) and CN Releasing Agents
Mechanism of toxicity
• CN is a mitochondrial toxin, inhibits electron transport chain
• CN binds to ferric (Fe+3 ) iron of mitochondrial cytochrome oxidase; inhibit electron transport between cyt a and cyt a3
• Lethal dose - 50mg adults (1 tsp); 1.5mg in children

Question 128

**Identify steps in treatments
• Rapid progression from onset of symptoms to death • Nausea, lightheadedness, hyperventilation, feelings of
suffocation, convulsions, coma
• Heart rate increased followed by decreased heart rate
• Death from respiratory failure, Brain damage in
recovered patients

Answer 128

Cyanide (CN) and CN Releasing Agents
2 step process of treatment
Step 1; administer NITRITE (NaNO2 3% IV or amyl nitrite ampule)
- convert hemoglobin (Hb-Fe2+) to Hb-Fe3+
**Hb-Fe3+ (methemoglobin formed in blood) + CN- LEAD TO HbFe3+CN- (cyanomethemoglobin)

Step 2; administer THIOSULFATE

• cyanomethemoglobin + CN- + S2O32- LEAD TO SCN- via liver sulfotransferecase.
• *SCN- is less toxic and is the excreted.

Question 129

Identify toxicity
**Types

• Toxicology data for thousands of these compounds
is incomplete
• Human toxicity as well as environmental effects

Answer 129

Agricultural Pesticides
• Pesticides include insecticides, fungicides, herbicides, rodenticides, etc.
- toxicology data for thousands of these compounds is incomplete
- human toxicity as well as environmental effects

Question 130

Identify type of pesticide

Mechanism
• Inhibit acetylcholine esterase (humans and insects)
• Increase acetylcholine levels at receptors, exaggerate cholinergic effects

Answer 130

INSECTICIDES 
1. Organophosphate insecticides
• Diazinon  LD50 100-150 mg/kg
• Malathion LD50 1000-1375 mg/kg 
2. Carbamates Carbaryl (Sevin Dust) 

**DEATH due to RESPIRATORY FAILURE

Question 131

A. Organophosphate toxicity effects on

1. Bronchial tree
2. Salivary glands
3. Lacrimal glands
4. Bladder
5. GI
6. Eyes

B. Nicotinic symptoms?

C. Treatment of organophosphate posoning

Answer 131

• *Muscarinic (parasympathetic)
  1. Bronchial tree; wheezing, chest tightness, rhinitis, increased secretions, cough
  2. Salivary glands; Salivation
  3. Lacrimal glands; Lacrimation
  4. Bladder; Urination frequency increased
  5. GI ; Defecation, nausea, vomiting, cramps
  6. Eyes ; Miosis - blurred vision

B. Nicotinic (Sympathetic and Somatic
Motor neurons) Symptoms
• Muscle twitching (face), cramps, muscle weakness
• Elevated heart rate, blood pressure

C. Treatment for Organophosphates
• Atropine and pralidoxime (2-PAM)

Question 132

Identify type of pesticide

Mechanism of toxicity
-Inhibits acetylcholine esterase same as organophosphates
-BUT carbamoylated enzyme reactivates faster in
water than phosphorylated enzyme from
organophosphates
-Reactivation half life is 1 hr

**Treatment?

Answer 132

CARBAMATE Poisoning

• Atropine only
• DO NOT USE 2-PAM

Question 133

Identify treatment and diagnosis of toxicity

1. Mechanism of toxicity
   - free radicals (e.g O2)
   - lipid peroxidation
2. Symptoms
   A. Inhaled ; Acute irritation, shortness of breath, pulmonary
   edema; Chronic PULMONARY FIBROSIS
   B. Oral; Acute irritation and ulceration of mucous membranes
   C. Dermal and ocular; Acute Erythema, ulceration,
   Chronic Cataract formation

Answer 133

PARAQUAT

Treatment and Diagnosis
• Gastric lavage
• Early use of kaolin (Fuller’s Earth) limited use
• Hemodialysis or Hemoperfusion
• Qualitative test of sodium dithionite (1 ml of a 1% solution) in 2N sodium hydroxide form blue color

Question 134

Identify toxicity

• Component of Gasoline
• Acute toxicity ; CNS depression and or pulmonary irritation/edema
*Chronic toxicity; anemia, leukemia and lymphomas

Answer 134

Benzene
• Aromatic hydrocarbon used as a solvent
- componets of gasoline

Question 135

Identify toxicity

• Acute toxicity ; CNS depression without evidence of cancer

• Organic solvents
• *Biotransformation route determines toxicity

Answer 135

Toluene and Xylenes
• Organic solvents
• Toluene and xylenes are widely used in paint
thinners and glues

**Induce CNS depression without evidence of cancer. Aren’t oxides are very minor metabolites of toluene and xylenes due to rapid biotransformation at the benzylic methyl groups

Question 136

Heavy metal toxicity

A. Cumulative dose toxicity?
B. What functional groups does it interact with

Answer 136

A. Cumulative dose toxicity ; Metals, long half-life, poorly metabolized or excreted
B. Interact with Sulfur, Oxygen & Nitrogen functional groups

Question 137

Heavy metal antagonists or chelators
A. Detoxification requirement
B. Properties of Ideal chelating agent (6)

Answer 137

A. Detoxification requires use of a chelator

B. Properties of Ideal Chelating Agent

1. Chelator-metal complex has lower toxicity than metal
2. Chelator enhances excretion of metal
3. Able to complex metal at physiologic pH
4. Chelator not readily metabolized
5. Chelator has distribution in body similar to metal
6. Has greater affinity for metal than essential endogenous ligands (Calcium)

Question 138

Heavy metal antagonist and Chelators

1. Mechanism of Action
   - chelates lead & cadmium**
   * route of administration and excretion?
   * **ONLY ONE WITH NO SULFHYDRYL GROUP
2. Mechanism of Action- Sulfhydryl group binds to lead
   * treat what toxicity?

Answer 138

1. Calcium Disodium EDTA ** -metal displaces calcium within EDTA
   * * Route of Administration and Excretion
   - given parenteral (IV) and IM
   - RENAL excretion of metal-EDTA complex
   * *Used In SYMPTOMATIC LEAD POISONING. **contraindicated in renal disease
   - don’t be confused with disodium EDTA which is used for hypercalcemia
2. Succimer meso-2,3-dimercaptosuccinic acid; DMSA
   A. Mechanism of Action- Sulfhydryl group binds to lead
   B. Use
   -ORAL** administration
   -Treatment for lead toxicity (ASYMPTOMATIC)
   -Metal complex excreted in urine
   **Low compliance due to nausea and bad taste

Question 139

Heavy metal antagonist and Chelators

1. A. Action and Use
   I. Suflhydryl group complexes with: lead, arsenic, inorganic mercury
   II. Administered IM (prepared in peanut oil)
   III. Excretion
   -Metal-BAL complex is excreted in bile and urine (50-50)
   -Metal-chelate complex dissociates in acid urine
   B. Contraindicated in liver failure
2. **used in WILSON’s disease
   How?

Answer 139

1. British Antilewisite (BAL, DIMERCAPROL and 2,3-Dimercaptopropanol)
   * contraindicated in peanut allergy, liver disease. Dont take with acidifying agents like cranberry juice - can increase toxicity
2. Penicillamine
   **Oral agent - CHELATE COPPER
3. Mechanism sulfhydryl groups bind to metals
   -Metal-Penicillamine complex excreted in urine
   -Used in Wilson’s Disease**
4. Major Adverse effect agranulocytosis
   Penicillamine contraindications include renal insufficiency

Question 140

Identify metal
**symptoms of toxicity? Complications?

A. Exposure via Inhalation or Ingestion (most common)
B. Distribution and excretion
1. Distribution initially to RBC, kidney & liver
-erythrocytes contain >95% of WHOLE lead BLOOD LEVEL (bound to hemoglobin)***
2. Redistributes to bone and hair; storage in bone as tertiary lead phosphate (there for over 10 years and can’t get out)

Answer 140

LEAD

1. SYMPTOMS
   - Blood, Microcytic anemia, Basophilic stippling, hemolysis
   - Kidney Oliguric renal failure
   - Nerve: Memory loss, muscle weakness, lead palsy
   - GI: LEAD COLIC - Chronic (severe abdominal pain)
2. Lead ENCEPHALOPATHY
   - more common in children, CEREBRAL EDEMA, convulsions, coma & death

Question 141

1. 3 organs lead affects

2. Chelation therapy (3)

Answer 141

1. 3 organs lead affects ; nerves, hematopoietic, kidney
   A. Neurological (peripheral and central)
   - Lead accumulates in BRAIN; interferes with Ca dependent actions of Calcium
   - Peripheral neuropathy (more common in adults) demyelination and axonal degeneration
   **BRAIN IS THE MOST SENSITIVE ORGAN OF TOXICITY

B. Hematopoietic system (the most sensitive)
**HEMATOPOIETIC IS MOST SENSITIVE INDICATOR OF TOXICITY
I. LEAD interferes with heme synthesis; anemia due to shortened RBC life span and decreased heme synthesis
** delta aminolevulinate dehydratase in CYTOSOL
**Ferrochelatase In MITOCHONDRIAL
II. Lead inhibits δ-aminolevulinate dehydratase (cytosolic enzyme) and Ferrochelatase (mitochondrial enzyme) both enzymes are sulfhydryl dependent
III. Increased urinary δ-aminolevulinate and urinary coprophyrin III
IV. Increased RBC accumulation of protoporphyrin IX and nonheme iron

C. Kidney ; target proximal tubules

2. Chelation therapy (3)
   I. Calcium Disodium EDTA
   II. Succimer meso-2,3-dimercaptosuccinic acid; DMSA
   III. British Antilewisite (BAL)

Question 142

Identify metal

Mechanism of toxicity
Binds covalently to sulfhydryl groups and inactivate proteins

**Exist in what 3 chemical forms

Answer 142

MERCURY 
Exists in 3 Chemical Forms        
1. Elemental
2. Inorganic mercury salts
3. Organomercurials: most toxic

Question 143

Forms of mercury

1. Exposure
   a) Toxicity occurs mainly due to inhalation
   b) Ingested mercury -toxic due to low absorption (<0.01%), generally not toxic

**Target organs?

Answer 143

ELEMENTAL MERCURY

Target Sites
a) Nervous system: tremor, excitability, depression and irritability Hg0 crosses BBB and membranes prior to oxidation by catalase b) Excess salivation, gingivitis and erethism

Question 144

1. What are the target organs of inorganic mercury (4)

2. Target of organic mercury

Answer 144

1. INORGANIC mercury
   a) Binds Sulfhydryls causing graying of Mucous membrane along GI tract (ingestion)
   b) Kidney
   - proximal tubular necrosis
   - chronic exposure addition of glomerular damage
   c) GI pain, vomiting & hematochezia (ingestion only)
   d) Acrodynia and photophobia (chronic exposure)
2. ORGANIC mercury
   A. Alkylmercury methlymercury or dimethylmercury
   B. Target Organ
   -Nervous system causes ataxia, visual field constriction, and muscle tremor

Question 145

1. Identify condition
   - Environmental disaster occurring in Japan
   - Inorganic mercury released into environment and converted to methyl mercury
   - Chemical form detected in humans and animals was methyl mercury
2. Treatment of diff forms of mercury poisoning

Answer 145

1. MINAMATA DISEASE
   * *Balance Problems, permanent weakness, visual field constriction, numbness and ataxia.
2. Treatment
   I. Chelation Therapy for Elemental or Inorganic Mercury
   a. Penicillamine for low level exposure or asymptomatic
   b. Dimercaprol for high dose or symptomatic toxicity

II. Alkylmercury

a. Penicillamine, moderate success
b. Dimercaprol contraindicated, increases brain levels

Question 146

Identify metal
1. Target organs for inorganic arsenic
GI: splanchnic hyperemia, rice water diarrhea
Skin: hyperkaratosis, cancer
Cardiovascular: Arrhythmia
Nervous system: brain & peripheral neuropathy
Kidney: proximal tubular and glomerular

2. Chronic inorganic poisoning
   - Hyperkeratosis and skin cancer
   - Arrhythmia
   - Enlarged liver
   - Garlic odor to breath & sweat
   - Mee’s line in fingernails (6 weeks); horizontal lines in fingernails

**chemical form? Mechanism of cytotoxicity? Treatment

Answer 146

ARSENIC
**ARSINE GAS ONLY induces hemolysis

A. Chemical Form

1. Inorganic (As+3 and As+5)
2. Organic arsenicals
3. Arsine gas formed by industrial reduction of As in metals

B. Mechanism of Cytotoxicity

1. Pentavalent: Uncouple mitochondrial oxidative phosphorylation 2. Trivalent: binds to sulfhydryl groups
2. Arsine gas combines with hemoglobin, induces hemolysis

• • Chelation Treatment
    1. Dimercaprol combined with penicillamine PO
    2. Arsine gas chelation therapy ineffective

Question 147

Identify metal
A. EXPOSURE
1. Inhalation or ingestion

B. Target Organs

1. Inhalation causes pulmonary edema, EMPHYSEMA & renal damage
2. Ingestion causes only renal proximal tubular damage

• *Distribution and treatment
• what do you monitor?

Answer 147

CADIUM

Distribution

1. Cadmium accumulates in the liver and kidney
2. Cd is bound to Metallothionein, an inducible protein (induced by metal exposure)
   - Metallothionein has a high cysteine content
3. Cd-Mt complex is taken up by the kidney proximal tubule; Cd is cleaved from Metallothionein

Monitoring and Treatment

1. Urinary β2-microglobulin a marker of occupational exposure 2. Chelation therapy with calcium-disodium EDTA
   * *BAL IS CONTRAINDICATION - increase renal toxicity

CADMIUM TOXICITY
**ITAI ITAI DISEASE - accidental ingestion of cadmium in water and food. Chronic exposure + low calcium diet = renal damage, osteoporosis, bone pain (because Calcium was replaced by cadmium)

Question 148

Identify metal

Treatment 
Chelation Therapy          
1. Penicillamine Drug of Choice (ORAL) 
**Monitor for agranulocytosis 
2. Trientine Hydrochloride  (if you have agranulocytosis with #1)      
a) Alternative to penicillamine        
b) Orally effective
c) Major adverse effects is iron deficiency

Answer 148

COPPER

• *Wilson’s Disease
  1. Inappropriately high levels of copper
• *Defect in ATP7B protein
• impacts biliary copper excretion
• diminished copper incorporation with ceruloplasmin (low)
• *Normally copper is excreted in bile, but copper flux is low so not getting into bile

Question 149

1. Clinical importance of drug interactions (3)
2. Risk factors for drug interactions
   * *Patient factors (4)

Answer 149

Clinical Importance
A. Drug interactions cost over $1.3 billion per year.
B. OTC agents are a source of potential Drug-Drug Interactions esp for arthritis patients.
C. Various risk factors may predispose patient to increased likelihood of interactions.

Patient Factors

1. Multiple medications (the greater the number of concurrent medications, the more likely it is that the patient will have some type of drug-drug interaction)
2. Gender specific (oral contraceptives and antibiotics or St. john’s Wort)
   - Females; OCP + rifampin, abx or St. John’s wort
3. Extremes of age (pharmacokinetic and pharmacodynamic)
4. Major organ dysfunction (pulmonary, hepatic or renal disease)
5. Others; genetic polymorphisms, metabolic and endocrine dysfunction, other medical issues

Question 150

Differentiat pharmacokinetics vs pharmacodynamics

1. (DRUG A; sometimes called the precipitant drug) modifies the ADME of
   another drug (Drug B or object drug)
   For example, phenobarbital induces metabolism of diazepam (object)
2. Drug A modifies the effect of the object drug, even when serum
   concentrations of both drugs are normal
   Example: Aminoglycosides such as tobramycin can potentiate the effect of succinylcholine and tubocurarine causing prolonged neuromuscular blockade. Surgical respiratory depression is worsened when aminoglycosides are present along with succinylcholine or tubocurarine

Answer 150

A. Pharmacokinetics
1. ADME
Absorption, Distribution, Metabolism & Elimination
2. Pharmacokinetic interactions occur when the drug causing the interaction
(DRUG A; sometimes called the precipitant drug) modifies the ADME of another drug (Drug B or object drug)
**For example, phenobarbital induces metabolism of diazepam (object)
3. Involve alteration of drug disposition and are often difficult to predict

B. Pharmacodynamics- “what the drug does to the body”
1. Occur at the receptor site or further down transduction pathway
2. Drug A modifies the effect of the object drug, even when serum
concentrations of both drugs are normal
3. Can be antagonistic, additive or synergistic a) Example: Aminoglycosides such as tobramycin can potentiate the effect of succinylcholine and tubocurarine causing prolonged neuromuscular blockade. Surgical respiratory depression is worsened when aminoglycosides are present along with succinylcholine or tubocurarine
*Aminoglycoside antibiotics possess nondepolarizing neuromuscular blocking activity resulting in diminished presynaptic Acetylcholine release and decreased postsynaptic receptor activation
b) Benzodiazepine + Morphine additive CNS depressant effects.

Question 151

Drug-drug and drug-food interactions can occur at all phases of drug disposition.
**List all phases

Answer 151

Pharmacokinetics - ADME

Absorption
Distribution
Metabolism
Excretion

Question 152

Pharmacokinetics

1. Absorption altered by? (4)
2. formation of complexes (3)

Answer 152

Absorption
1. Can be altered by pH, transport, chelation, biotransformation

2. Formation of complexes
   a) Examples:
   (1) Antacids can bind with many drugs. When co-administered with a tetracycline, such as doxycycline, the antacid may bind to the antibiotic, causing decreased absorption of doxycycline and efficacy of both
   (a) Calcium, Magnesium or Aluminum in antacids binds with tetracycline causing decreased absorption

(2) Cholestyramine (resins) binds numerous medications (digoxin) decrease digoxin bioavailability
(3) Ferrous sulfate and calcium binds to mycophenolate mofetil causing a decreased effect of the immune suppressant, mycophenolate mofetil

Question 153

Drug interactions that affect

Absorption - Gastric emptying
Drugs that INCREASE vs DECREASE

Answer 153

Gastric emptying
a) Precipitant drugs that DECREASE gastric motility and may affect the rate, but not the extent of absorption of object drugs
Examples:
1) Anticholinergics such as amitriptyline may decrease gastric motility and thereby decrease the rate of absorption.
2) Opiates including morphine also slow gastric motility and a similar effect may be observed

b) Precipitant drugs that INCREASE gastric motility may result in a shorter time to peak and a greater peak effect, but may not change the net absorption, for object drugs
Examples:
- Some agents like metoclopramide specifically stimulate gastric motility.

Question 154

Drug interactions that affect

Absorption - Gastric pH

Answer 154

a) Precipitant drugs that increases gastric pH may reduce the absorption of object drugs that require an acidic environment in order to be absorbed.

• For example, H2 blockers (cimetidine, ranitidne) that increase stomach pH can cause decreased ketoconazole absorption.
• Proton pump inhibitors, including omeprazole, can cause decreased Atazanavir and itraconazole absorption.

Question 155

Drug interactions that affect

Absorption - Inhibition of transporters

• what is PGP ?
• Substrates for what are also substrates for PGP?
• effects of antibiotics on absorption?

Answer 155

Inhibition of P-glycoprotein (PGP) in the apical membrane of enterocytes will increase the absorption of drugs which are substrates of this transporter

What is PGP?
(a) ATP-dependent plasma membrane glycoprotein that functions for molecular transport; mechanism to protect body from harmful substances

(b) P-glycoproteins are part of a larger family of efflux transporters found in the gut, gonads, kidneys, biliary system, brain and other organs.

(c) They appear to have developed as a mechanism to protect the body from harmful substances. Using ATP as an energy source, they transport certain hydrophobic substances in the following directions:
(i) into the gut, urine, bile
(ii) out of the brain, reproductive organs and other organs

(d) Many substrates for CYP3A4 are also substrates for PGP.
(i) Examples
(a) If an object drug is a substrate for PGP and CYP3A4 and
ketoconazole (inhibitor of PGP/CYP3A4) is added, more of
the drug will be absorbed
(b) Grapefruit juice (inhibits CYP3A4) may significantly activate
PGP mediated efflux of object medications; this could
counter-act some of the CYP450 inhibition caused by
grapefruit juice

(e) Effect of antibiotics on absorption
(i) In some people, digoxin is partially converted to an inactive form by normal flora in the gut. Antibiotics, such as erythromycin, may reduce normal flora. Patients who take antibiotics and digoxin together may have higher serum digoxin levels because less digoxin is inactivated by normal flora.

Question 156

Drug interactions that affect

Distribution
1. Main mechanisms that affect distribution ?

Answer 156

The main mechanisms that effect the distribution of a drug are protein binding and inhibition or upregulation of membrane bound transporters, such as the P-glycoprotein efflux pump
a) PROTEIN BINDING

(1) Occurs between two drugs that are highly bound to protein in the plasma
(2) Highly protein bound (>90%) medications may be displaced from albumin sites by precipitant drugs, resulting in a subsequent increase in free levels of the object drug
(a) Warfarin is 99% bound to plasma protein. When another drug,
such as a sulfamethoxazole-trimethoprim, which is also highly bound to protein, is administered, displacement of only 1% of the warfarin will double the free fraction of warfarin thereby doubling the effective dose of the drug.
(3) In adults, redistribution and excretion of the object drug will occur; therefore, the effect may be transient or of little clinical importance UNLESS the medication:
(i) Has a small volume of distribution
(ii) Is slowly eliminated
(iii) Has a narrow therapeutic range

Question 157

Drug interactions that affect

METABOLISM

• *explain process of biotransformation reactions.
• WHat enzyme system plays major role?

Answer 157

Biotransformation reactions in general, produce metabolites that are usually inactive and more easily excreted from the body. Some drugs are actually metabolized to the active form. These are called “prodrugs”. Although the enzymes that metabolize drugs are located in most tissues of the human body, the primary metabolizing organ is the liver. High levels of these enzymes are also present in the GI, the lungs, the skin and the kidneys.

* Cytochrome P450 (CYP) enzyme system

Question 158

Drug interactions that affect

METABOLISM
Cytochrome P450 (CYP) enzyme system
** examples of enzymes
- induced by aromatic hydrocarbons in cigarette smoke.
- considered the most abundant and
clinically significant enzyme
- Substrates include SSRIs, pain relievers, beta blockers

2. Location of CYP enzymes
3. Types of isoenzymes

Answer 158

1. There are at least 42 known subfamily members of this system. Although there is crossover of specificity (one drug may bind to several different CYP enzymes), one can predict effect on specific subfamily
   members with the administration of specific drugs.
   **Examples
   (i) CYP1A2- induced by aromatic hydrocarbons in cigarette smoke. Cigarette smoke induces increased metabolism of the
   asthmatic agent theophylline in smokers
   (ii) CYP3A4- responsible for the metabolism of about 50% of all
   medically useful drugs. It is considered the most abundant and
   clinically significant enzyme
   (iii) CYP2D6- responsible for the metabolism of about 30% of all
   clinically useful medications. Substrates include SSRIs, pain
   relievers, beta blockers

(2) CYP enzymes can be found in the endoplasmic reticulum of hepatocytes, crypt cells and the enterocytes of villi in intestinal tract.
(3) Over 90% of oxidation by CYP450 enzymes can be attributed to 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 isoenzymes.

(4) Precipitant drugs may or may not be metabolized through the system even though they act as inducers or inhibitors.
(5) Note that there is inter-patient variability- some patients are more prone than others to drug interactions.

Question 159

Drug interactions that affect

METABOLISM
Enzyme INDUCTION vs Enzyme INHIBITORS
**Examples

Answer 159

Enzyme Induction

a) Synthesize new enzyme and speed up oxidation and clearance of object drug
b) This may increase drug levels if the object drug has active metabolites. Cyclophosphamide, a prodrug, must first be metabolized to its active form, phoramide mustards, before it can exert its effect. At the same time, acrolein is formed, which is implicated in the drug’s bladder toxicity
c) ***Remember the MAJOR inducers: phenytoin, rifampin & carbamazepine

Enzyme Inhibitors
a) Quick onset, drug interaction can occur within 24 hours
b) An enzyme inhibitor (cimetidine) reduce drug metabolism of theophylline causing increased drug concentrations that may lead to an increased therapeutic response and/or toxicity
c) **Remember the MAJOR inhibitors: ketoconazole, cimetidine,
erythromycin, grapefruit juice (due to naringin)

Question 160

Drug interactions that affect

METABOLISM

• *Genetic polymorphism
  1. Low vs high CYP 2D6 in what populations
  2. Good vs poor metabolizes via CYP 2C19
  3. Do poor or good metabolized have a greater response to meds

Answer 160

Genetic polymorphisms

a) Low CYP 2D6 7.5% of North Americans and 1% Asian and slightly higher than 8% in African Americans
b) 20% Asian and African Americans and 3-5% white Americans are poor metabolizers via CYP 2C19
b) Poor metabolizers will have a greater response to medications

Question 161

Drug interactions - metabolism

**Types os CYP450 Isoenzymes, substrates, inhibitor, inducer

Answer 161

• **PPT
  1. CYP1A2
  2. CYP2C9
  3. CYP2C19
  4. CYP2D6
  5. CYP3A4

Question 162

Drug interactions

Elimination
1. Renal tubular secretion or altered tubular reabsorption
a) Drugs may compete for tubular secretion, resulting in an increase of the object drug.
**examples?
B) Some drugs that cause altered tubular reabsorption may also cause drug interactions
(1) Example?

Answer 162

a) Drugs may compete for tubular secretion, resulting in an increase of the
object drug.
i. Probenecid inhibits tubular secretion of penicillins. This interaction could be used to increase penicillin’s effect
ii. Methotrexate and sulfomethoxazole compete for tubular
iii. Methotrexate and omeprazole omeprazole inhibits H+, K+-ATPase secretion. This can result in methotrexate toxicity. This is a dose dependent phenomenon, only seen with higher doses
blocking the active secretion of methotrexate by the kidney. Results in diminished methotrexate excretion, higher serum methotrexate levels and toxicity.

b) Some drugs that cause altered tubular reabsorption may also cause drug interactions
(1) Example
i. Trimethoprim can cause an increase in distal renal
tubular absorption of potassium (similar to amiloride) , which
may result in hyperkalemia; more common HIV (higher dose)

Question 163

Drug interactions

Elimination - P glycoprotein (PGP)
- responsible for renal excretion of what drug?

Answer 163

a) Also found in high concentrations in the brush border of the proximal renal tubule epithelium

b) Responsible in part for renal excretion of digoxin
(1) Quinidine inhibits the tubular secretion of digoxin via
PGP. This may result in digoxin toxicity when these medications are used in combination**

Question 164

Elimination

Alterations in urine pH
a) Unionized drugs are often reabsorbed into the blood stream
b) Low pH causes an acidic drug to be in its unionized form; vice
versa for basic drugs
*examples
1. Acetozolamide and urine pH
2. Aspirin and acetazolamide

Answer 164

(1) Carbonic anhydrase inhibitors (such as acetazolamide) increase urine pH. The increased pH causes an increased reabsorption of quinidine and a subsequent increase in plasma levels of quinidine and cause cardiotoxicity.
(2) Aspirin when taken with acetazolamide increases aspirin
toxicity
i. Lower blood pH due to metabolic acidosis, increases entry of salicylate into brain, increased unionized drug
ii. Higher amount of unionized salicylate will be filtered by the kidneys due to lower blood pH.

Question 165

Drug interactions are NOT a class-wide effect

• *Identify greater potential and less potential for interactions based on drug class
  1. Macrolides
  2. H2 blockers
  3. HMG CoA reductase inhibitors

Answer 165

1. Macrolides
   A. Greater potential; erythromycin, clarithromycin (inhibit P450)
   B. Less potential; azithromycin
2. H2 blockers
   A. Greater potential; cimetidine (inhibits P450)
   B. Less potential; Ranitidine
3. HMG CoA reductase inhibitors
   A. Greater potential; lovastatin (prodrug), atorvastatin (active metabolite)
   B. Less potential; Praastatin, fluvastatin

Question 166

Conclusions of drug interaction

Answer 166

1) Potential for many drug interactions exists, but they won’t necessarily happen in every patient
2) Various factors influence the potential for interactions
3) Patients at high risk for drug interactions may benefit from a certain drug within a class (ranitidine vs. cimetidine)
4) Stress to your patients the importance of using one pharmacy to assist in screening for drug-drug interactions. Most have national online databases to track all drugs prescribed for an individual.

Question 167

Principles of treatment to drug poisoning/overdose

3
* *Most common poisonings in kids <5yr vs people >18yrs

Answer 167

A. Initial Exam

1. Identify toxin and estimate dose
2. Estimate time since exposure
3. Physical status
4. Most common poisonings in children < 5 yr. of age: Fe containing vitamins, Pesticides, OTC cold remedies, cleaning supplies
5. Most common poisonings in people >18 yr. of age: analgesics, sedatives/Hypnotics substance abuse, Antidepressants, alcohol

B. Supportive Care

1. Death due to respiratory failure and/or cardiovascular complications
2. Respiratory depression worsened by overdose of barbiturates, opiates and alcohol

C. Terminate Exposure to Toxin

1. Prevent further absorption via route of exposure
   - carbon monoxide
2. Enhance elimination
   - alkalinize urine for acidic drugs
3. Use antidote or antagonist if available

Question 168

Methods to terminate exposure to a toxin 
A. Emesis 
- use of what? 
- use of emetic? 
- contraindications? 

**Emesis contraindicated in the home for the following products ? (4) - rationale

Answer 168

A. EMESIS

1. Mechanical
2. Syrup of Ipecac
   a) action on chemoreceptor trigger zone (CTZ)
   b) direct stimulant on GI tract to induce vomiting
3. Use of Emetic
   a) OTC agents (Acetaminophen, aspirin) many drugs in pill or tablet form, Fe-containing vitamins
   b) Pesticides
4. Contraindications
   a) Corrosive agents
   b) Petroleum distillates risk of pneumonitis > systemic toxicity c) Loss of gag reflex
   d) Occurrence of Convulsions
   - Tricyclic antidepressants
   - Strychnine
   - Gamma hydroxy butyrate

• • Emesis contraindicated in the home for the following products ? (4) - rationale
    1. Ammonia - caustic substances
    2. Drain cleaner or electric dishwasher cleansers - caustic substance
    3. Kerosene, motor oil - pulmonary hydrocarbon pneumonitis
    4. Furniture polish - pulmonary hydrocarbon pneumonitis

Question 169

Methods to terminate exposure to a toxin 
B. Lavage
- aids in ? 
- used in what patient?
- contraindication? 
- not effective in what ?

Answer 169

B. LAVAGE WITH ACTIVATED CHARCOAL

1. Aids in removal of unabsorbed toxin
2. Can be used in comatose patient
3. Contraindicated with corrosives, caustics or sharp objects
4. Ineffective for acids, alkalis, some pesticides, metals or petroleum distillates

**LOOK AT TABLE for agents well absorbed by activated charcoal
- Acetaminophen Amphetamines Aspirin Benzodiazepines
Barbiturates Nicotine Carbamazepine Theophylline Digoxin Strychnine Phenothiazines Malathion

Question 170

A.
3 examples of antagonist
1. Opiate antagonist
2. Benzo antagonist

B. Methods to enhance excretion

Answer 170

A. Antagonists

1. Naloxone opiate antagonist reverse respiratory depression
2. Flumazenil benzodiazepine antagonist
3. Atropine

B. Methods to enhance excretion
** SODIUM BICARBONATE; -Enhance excretion of acidic drugs

Question 171

**Identify toxin

• • Major toxicity is aspiration and chemical pneumonitis
• what is the best indicator of aspiration potential?

Answer 171

PETROLEUM DISTILLATES
A. Ingestion most likely in children < 3 yr. of age
B. Most common agent ingested include furniture polish, kerosene, gasoline
C. Major toxicity is aspiration and chemical pneumonitis
D. Viscosity, surface tension and volatility of compound predict risk of aspiration

1. Viscosity, low viscosity increases potential to flow into airways
   * Best indicator of aspiration potential is VISCOSITY**
   - LOW VISCOSITY (GASOLINE), HIGH ASPIRATION RISK
   - HIGH VISCOSITY (MINERAL OIL), LOW ASPIRATION RISK
2. Surface tension, low surface tension allows rapid spread from mouth to trachea
   - LOW SURFACE TENSION (SIPHONING GASOLINE), HIGH ASPIRATION RISK
3. Volatility, highly volatile causes rapid displacement of oxygen alveoli
   - HIGH VOLATILITY (GASOLINE), HYPOXIA

Question 172

Identify toxin

• *Most deaths due to cardiac arrest
• Primary targets are lung, CV, CNS

*Treatment?

Answer 172

AEROSOL PROPELLANTS
A. Intentional or accidental inhalation of aerosol products (paint, glue, cooking oil, static guard etc.)
-Propellants used: propane, isobutane, butane, benzene, and toluene

B. Primary target organs are the lung, cardiovascular system and CNS

1. Heart, tachycardia and arrhythmias
   - Most deaths due to cardiac arrest
2. CNS, lethargy, depression, memory loss
3. Pulmonary, irritation, bronchospasm, hypoxia, permanent damage due to contents
   - spray paints, static guard or cooking spray
4. Gasoline contains BENZENE LEUKEMIA
5. Toluene in correction fluid ophthalmic nerve and auditory nerve damage
6. Huffing during Pregnancy increased fetal death, low birth weight

TREATMENT
-no antidote, treat symptoms

Question 173

IDENTIFY toxin

• GI: Initial vomiting, gastric pain, diarrhea, gastric scarring - FIRST STAGE
• SECOND STAGE - lethargy but no vomiting
• Cardiac and Hepatic damage - THIRD STAGE (organ failure)
• FOURTH STAGE - scarring causing pyloric obstruction
• *How is toxicity calculated?
• what is the toxic dose?

**Treatmnet (3)

Answer 173

IRON TOXICITY

1. Ingestion of iron containing multi-vitamins- children
2. The toxic dose is calculated based on the amount of ELEMENTAL IRON;
3. Chewable or liquid vitamin preps have better iron absorption
4. Minimally Toxic dose >20 mg/kg elemental Fe **
5. Chelation therapy with deferoxamine if plasma iron 350 µg/dl
6. Emesis to remove iron tablets, lavage with bicarbonate or phosphate

Treatment

1. Emesis
2. Lavage; bicarbonate to decrease absorption
3. Chelation ; DEFEROXAMINE

Question 174

Examples of elemental iron calculation
IS IT TOXIC?
1.  What is the toxic dose if ten tablets each containing 100 mg, Ferrous gluconate were ingested by a 10
kg child?

2. What if it were ferrous sulfate (anhydrous)?

Answer 174

1. Ferrous gluconate
   11 mg elemental iron x10 = 110 mg
2. ferrous sulfate (anhydrous)?
3. 8 mg elemental Fe x 10 = 368 mg

*** Ferrous sulfate toxic 36.8 mg/kg while gluconate is
not a toxic level

REMEMBER THAT Minimally Toxic dose >20 mg/kg elemental Fe

Question 175

Identify toxin drug

TARGET ORGANS

1. Liver, cause centrilobular necrosis
2. Kidney, proximal tubular necrosis
   * mostly in cough and cold preps

**Mechanism of toxicity

Answer 175

ACETAMINOPHEN
A. Sources
Over- the- Counter Analgesics, Headache remedies, Cold and flu products

Mechanism of Toxicity
Acetaminophen metabolized by P450 to toxic metabolite: N-acetyl-benzoquinoneimine also called NAPQI
-NAPQI is hepatotoxic metabolite
-metabolite detoxified by glutathione conjugation
-N-acetyl-benzoquinoneimine covalently binds to proteins -damage first to centrilobular region, highest P450 level

Question 176

Number 1 cause of drug induce liver failure in US

1. Symptoms of toxicity
2. Treatment - WHAT IS THE ANTIDOTE? HOW CAN IT BE GIVEN
3. Interaction with alcohol
   - alcohol induce what?
   - how does alcohol increase toxicity of this drug?
   Increase what enzyme? Decrease what enzyme?

Answer 176

Symptoms of Toxicity

a. Acetaminophen is associated with a delayed appearance of hepatic toxicity
b. Hepatic toxicity appears as rise in ALT after 48 hr

Treatment

1. Emesis, Lavage with activated charcoal
2. ANTIDOTE N-acetylcysteine (oral - 100% to liver, also IV) **
   - Precursor for glutathione synthesis, increase intracellular glutathione levels
   * *You don’t give glutathione IV

Interaction of Alcohol and Acetaminophen

1. Hepatotoxicity with THERAPEUTIC doses of acetaminophen
2. Alcohol induces CYP 2E1
3. Alcohol metabolism DIMINISHES NADPH
   - cofactor in maintaining glutathione in reduced state -glutathione in oxidized state cannot detoxify free radicals or conj with drugs
4. Alcohol decreases level of reduced glutathione capable of reacting with NAPQI
   - alcohol INCREASE NADH: NAD diminishes glucuronidation

Question 177

IDEntify toxin

METABOLISM

1. Follows zero order kinetics at toxic levels (usually for arthritis at zero order)
2. As dose increases conjugation by glycine and glucuronide becomes saturated

**Sources?

Answer 177

SALICYLATES (ASPIRIN)

SOURCES

1. Over the counter analgesics
2. Topical for muscle ache (methyl salicylate)
3. Wart remover (salicylic acid)

METABOLISM

1. Follows zero order kinetics at toxic levels
2. As dose increases conjugation by glycine and glucuronide becomes saturated
3. Salicylic acid, glycine and glucuronide conjugates excreted in urine

Question 178

Identify toxicity
Mechanism
- HYPERVENTILATION; stimulate respiratory centers in the medulla
- uncoupled oxidative phosphorylation (thermogenic?); stimulate CO2 production

• *Stages of toxicity (4)
• resp?
• renal?
• *Treatment (4)

Answer 178

SALICYLATE (not ASPIRIN that is the active metabolite)
STAGES OF TOXICITY ; Resp alkalosis, renal compensation, resp acidosis, metabolic acidosis

1. Stimulate respiration induces RESPIRATORY ALKALOSIS
2. Compensatory increased renal bicarbonate excretion occurs
3. METABOLIC ACIDOSIS (occurs mostly in children)
   - salicylates interfere with carbohydrate metabolism producing an accumulation of organic acids
4. BODY TEMPERATURE, ELECTROLYTE AND FLUID ABNORMALITIES
   - fever predominantly in children (105oF)
   - dehydration (sweating and hyperventilation)
   - increased bicarbonate excretion
   - hypokalemia

TREATMENT

1. Remove aspirin from stomach by Emesis, lavage and/or charcoal 3. Correct electrolytes, fluid and temperature
2. Alkalinize urine
   - enhance salicylic acid excretion

Question 179

Identify the following alcohol toxicities
1. Metabolized to ACETONE (CNS depressant) and acetic acid
Symptoms? Treatment?
2. ** Toxic metabolites formaldehyde and formic acid **
- formic acid leads to blindness
3. Target organ is the Kidney renal failure, oliguria, deposit oxalate crystals **

• *Treatment? (3)
• what treat ethylene glycol?

Answer 179

ALCOHOLS
A. ISOPROPYL ALCOHOL
1. Metabolized to acetone (CNS depressant) and acetic acid
2. Symptoms are respiratory depression, lethargy, gastritis, ketoacidosis,
3. Ketones in urine without glucose (don’t confuse with DKA)
4. Treat symptoms, no antidote

B. METHANOL

1. Major target for irreversible toxicity is the eye (blindness) -formic acid (mitochondrial toxin) CAUSE BLINDNESS
2. Toxic metabolites formaldehyde and formic acid
3. Metabolic acidosis due to formic acid

C. ETHYLENE GLYCOL

1. Induces inebriation, CNS depression nausea and vomiting
2. Target organ is the Kidney renal failure, oliguria, deposit oxalate crystals**
   - OXALATE CRYSTALS (found in spinach) DEPOSIT IN LUMEN OF KIDNEY

TREATMENT FOR METHANOL AND ETHYLENE GLYCOL

1. Ethanol; complete alcohol dehydrogenase, greater affinity than other alcohols
2. FOMEPIZOL for ethylene glycol
3. Correct acidosis
   * *Emesis or lavage

Question 180

A two year old boy is brought into the emergency room. His parents describe his symptoms as stomach pain, nausea, vomiting and chills. An X-ray of the stomach indicates 10 opaque oval looking shapes. When interviewed, he says he ate some candy he found in his parents’ bathroom.

1. What tests should be run immediately?
2. What treatment would you suggest having the following data: ALT 10 U/l; BUN 15 mg%; plasma iron 350 µg/dl

Answer 180

1. LTFs
2. Iron toxicity
   * DEFEROXAMINE

Question 181

Mr. H. Hour was brought into the emergency room by his wife. He is coughing, has a headache, appears to be congested, has stomach pain and sees halos of light around everyone. He has had a cold for the past week and decided to drink a pint of a corn liquor his friend had called “hair of the dog”; it was made by someone he met while out in the rural areas of the Smoky Mountains. What potential toxic substances could be contained in “Hair of the Dog” that are consistent with his symptoms?

1.  What potentially toxic substances could be
   contained in the corn liquor?
2.  What do his symptoms suggest is the toxic
   agent?

Answer 181

1. Could be methanols or lead

2. Seeing halos - METHANOL