PATHOPHYSIOLOGY – Exam 3
Hey everyone,
The following is a list of all the diseases discussed in this unit (quite a bit more
than last time). It is alphabetized, so you can look stuff up easily, and be able to compare
diseases with similar names. I believe all the information is accurate, but if you guys find
any glaring mistake, please send it out to the yahoogroup so that no one gets confused. I
am still trying to wrap my mind around all of Dr. White’s material, so you might find
more complete info in his notes, or in “Beeman’s”.
Forgive my random side notes, they are completely the product of being tired and
preferring to look crap up on google instead of actually study.
I hope this helps, and good luck!
-Pat Clements
Aceruloplasminemia Alkaptonuria
genetic recessive
lack of ceruloplasmin (a copper feroxidase, helps w/ Fe release)
iron accumulation  organ and tissue damage
often seen with other conditions (i.e. thalasemia and alcoholism)
- defective homogentisate oxidase
 accumulation of homogentisitc acid  urine
- urine turns black when it contacts O2.
- joint damage, cardiovasc/urinary damage
- red ochre to skin
Anderson’s Disease - defective branching enzyme (glycogenesis)
- causes irregular, long unbranched chain of glucose
(Think: you gotta go to Anderson’s to buy a saw to cut that long
chain)
Anemia
- morphologic classification (cell shapes, see specific examples)
- Kinetic classification:
- Decreased RBC production – improper marrow function
hypoplastic and aplastic anemia
*to remember, “plastic is something you make”
(__plastic disorders involve making RBC’s)
- Increased RBC destruction – i.e. hemolytic anemia
--causes hyperplasia – increased RBC production,
because RBC’s will have short lifespan.
- Ineffective erythropoiesis
- apoptosis of RBC precursors
- i.e. β-thalesemia (see for more information)
- anemia leads to increased iron uptake
(low circulating iron, and high reticuloendothelial stores)
- overactive hepcidin activity
** See iron deficiency anemia for more **
Anemia of Chronic Disease
- observed with infections, inflammation  cytokine mediated
- normal RBC size (though can be microcytic)
- Increased hepcidin  Fe trapped in MACs
also decreased iron absorbtion in gut (blocked ferroportin)
- poor response to supplemental iron
- low serum EPO
Angina
- partial loss of circulation to heart muscle
 chest pain, chronic condition
Arteriosclerosis
- hardening of the arteries (general term)
Atherosclerosis
-
form of arteriosclerosis
LDL goes into endothelium of arteries
reacts with oxygen free radicals (products of respiration)
modified LDL recognized by scavenger receptor on monocytes
become foam cells, with cholesterol ester droplets
(between endothelial and tunica media layers)
- inflammatory disease
Beri-beri
-
Thiamine deficiency
wasting disorder, leads to weakness and paralysis
carbohydrate metabolism is disrupted
test: transketolase (since TPP is a cofactor)
Branched chain keto aciduria
- aka Maple Syrup Disease
- lack of α-keto acid dehydrogenase complex
 no oxidative decarboxylation
-accumulation of α-keto intermediates
 can’t metabolize valine, isoleucine, leucine
- urine smells like maple syrup
- (Think: maple trees have branches)
- mental retardation
Cancer and RAS
Cholera
- mutant RAS = oncogenic
- unable to hydrolyze bound GTP
 signal always on  activates downstream cell growth
 uncontrolled cell growth = cancer
- caused by a toxin, produced by Vibrio cholera
- irreversibly modifies Gs subunit of adenylate cyclase
- stuck in GTP bound state (active)
 cAMP levels, PKA activation
 PKA regulated Cl- channel disrupted
 loss of water to intestine  diarrhea
Crigler-Najjar Syndrome
- rare, recessive
- extremely reduced/absent UDP-glucoronosyl transferase
 buildup of unconjugated bilirubin
Type I: Severe Jaundice
- may require liver transplant
- Kernicterus (brain damage  cerebral palsy & hearing loss)
Type II: Moderate Jaundice
- may respond to inducers (i.e. Phenobarbital)
Cystinosis
- defective cysteine transport
- produces crystals
 renal failure (crystals destroy kidneys)
Cystinuria
- cystine excretion (S=S)
Diabetes
- cells lose ability to sense the surplus of glucose and respond
 leads to increased glucagon synthesis
 increased lipolysis and glycogenolysis
-body response similar to starvation!
- symptoms: -elevated blood glucose
-chronic fatigue
-weight loss (even though adequate dietary intake)
-ketones in blood and urine
Type I - Juvenile
- no insulin produced by pancreas
 therefore can’t utilize glucose
Type II- Adult onset
- insulin is produced, but cells become resistant/desensitized
 tissues don’t respond to glucose or insulin
- related to obesity, as fatty adipocytes produce resistance proteins
- increased fat  insulin resistance  elevated insulin
required  elevated fasting blood glucose  diabetes
Dyslipidemia
- causes increased LDL-C and triglycerides, with decreased HDL
- LDL levels are main target for therapy,
though increasing HDL is also important.
- higher risk with age, smoking, diabetes, hypertension, family hist
- often accompanied by android body fat distribution (abodomen,
mostly in males, “apple shape”)
- primary dyslipidemia = genetic
- secondary dyslipidemia = result of another condition (~diabetes)
Type I - decreased LPL synthesis
- abnormal chylomicrons
- increased triglycerides
Type V - increased Apo C synthesis
- abnormal chylomicrons and VLDL
- increased triglycerides
* Other types were seen is later lectures, but I do not recall going
into any detail with them
End-stage kidney disorder (and RBC production)
- kidney damage leads to decreased erythropoietin synthesis
- therefore dec in RBC production.
Elevated NH3
- NH3 passes through blood brain barrier
- can cause coma and death
Enzymopathies
- inherited RBC disorders
- i.e. glucose 6-P dehydrogenase and pyruvate kinase deficiency
also porphyria
- enzymes could be involved in heme synthesis, reduction of
MetHb, protection from oxidation, ATP production, 2,3-BPG
Production.
Essential Fructose Uria
- lack of fructokinase
 fructose in urine (benign)
Farnesylation of RAS- adds farnesyl residue (cholesterol precursor)
- promotes membrane localization
- for RAS: into membrane  oncogenic
- therefore, this step would be a good anti-tumor target!
Gaucher’s Disease
- deficient glucocerebrosidase (β-glucosidase)
- can’t break ceramide- glucose bond
 accumulation of glucocerebroside
- bruising, enlarged liver and spleen, fatigue with anemia
 RBC’s swell with lipid deposits
 therefore, swelling in blood filtering organs
Gilbert’s syndrome - common, mild disorder
- reduced UDP-glucoronosyl transferase
 buildup of unconjugated bilirubin
Glucose 6-Phosphate Dehydrogenase Deficiency
- x-linked disorder, malaria resistance, enzymopathy
- enzyme catalyzes Gluc-6-P  6-phosphogluconate rxn.
-this produces the NADPH needed to reduce glutathione
- RBC’s more prone to oxidative damage
-oxidation of lipids and hemoglobin, spectrin destruction.
- causes hemolytic anemia and neonatal jaundice
- *malarial drugs could cause hemolytic attack
-SIDE NOTE: hemolytic attack could also be caused by fava
beans, made famous in the 1991 movie Silence of the Lambs,
where Anthony Hopkins was your favorite cannibalistic serial
killer, saying “I ate his liver with some fava beans and a nice
chianti”, then made the creepy “pft, pft, pft, pft” sounds.
Hartnup’s Disease
-
lack of niacin (vitamin B3)
Dermatitis, Dementia, Diarrhea (the 3 D’s)
genetic
inability of the body to produce niacin from tryptophan
Hemoglobin C disease
- see hemoglobinopathies
Hemoglobinopathies - inherited RBC disorders
- sickle cell / Hb C disease / thalesemia
- can be impaired Hb solubility, unstable Hb, increased or
decreased O2 affinity, imbalanced globin chain synthesis, wrong
subunits.
Hemolysis
- loss of RBC’s  causes erythropoiesis  increased iron uptake
Hemorrhage
- loss of RBC’s  erythropoiesis  increased iron uptake
Hereditary elliptocytosis / pyropoikilocytosis
- mutant spectrin subunits in RBC’s
- change cytoskeleton horizontal configuration
-elliptocytes and ovalocyte
Hereditary Hemochromatosis
- iron overload disorder
- defect leads to increased affinity for transferrin
 increased iron absorption
- iron becomes toxic for organs (i.e. liver and kidneys)
- increased hepcidin activity
(iron release inhibited  trapped in macrophages)
- ferratin becomes saturated
- more bound iron capacity (increased marrow hemosiderin)
- no available capacity (low reticuloendothelial stores)
- hypochromic RBC’s
- treat with phlebotomy
(if too much iron, take away RBC’s  erythropoiesis)
*in other words, give body a useful way to use excess iron!
Hereditary Fructose Intolerance
- lack phosphofructokinase B
 can’t convert to it to DHAP
- liver failure, hypoglycemia
- Treat: avoid fructose
Hereditary Spherocytosis
- inherited disorder of the RBCs, membranopathy
- Defect cytoskeleton of RBC
-most often defect in spectrin subunits or ankyrin,
which interfere with interaction with Band-3
- cells lose flexibility as they pass through capillaries
- RBC’s  spherical, lose disc shape, membrane blebbing
- defect cells cleared by the spleen
 enlargement of spleen, and anemia
- therefore lots of precursor cells, but not many RBCs
visible, because they have shorter lifespan.
- can be confirmed using osmotic fragility test
Hexokinase deficiency
- enzyme from glycolysis, glucose  glucose 6-P rxn.
- therefore, decreased 2,3 BPG synthesis
- isotherm shift to the left (favors Hb O2 binding)
Homocystinuria
- lack cysathionine β-synthesase
(pyridoxal pyrophosphate dependent)
- increases serum homocysteine (toxic & immunogenic)
-ectopia lentis, osteoporosis, mental retardation
- Treat with B12, and methionine restricted diet
Homocysteinemia
- increased levels of homocystein (hcy)  inc. CHD risk
- also low folate levels are associated
Folate + B6 + B12 = lowered blood hcy levels.
- treat with vitamins and supplements
(folic acid, B6 and B12) (leafy green veggies, etc)
Hyperbilirubinemia
- Increased bilirubin (product of heme breakdown)
- Either too much made, or not being excreted properly
- Increased direct (conjugated
 hepatocellular disease or biliary obstruction
- Increased indirect (unconjugated)
 with a fever or starvation
Hypoxia
- i.e. due to high elevation
 erythropoiesis  increased iron uptake
- increased 2,3 BPG production
 HbO2 dissociation curve shift to the right
 decreased O2 affinity, to help release to tissues
21-Hydroxylase deficiency - disorder of steroid synthesis (from progesterone)
- can’t make glucocorticoids or mineral corticoids
- but can make androgens
 therefore overproduction of androgens
 faster maturation (virilization)
Infection and Inflammation - causes decreased iron uptake in the body
- interleukin 6 (IL6) leads the liver to produce Hepcidin
(a negative regulator of iron release)
- * bacteria need iron to reproduce, so decreasing Fe
uptake is a natural way to fight bacterial infection
Inherited Galactosemia
- lack of galactose-1-phosphate uridyl transferase
- recessive autosomal
- can’t properly metabolize galactose (GI problems with
milk consumption)
 accumulation of galactitol (toxic)
- cataracts, jaundice, liver enlargement
- Treatment: no galactose in diet (no ice cream for you!)
Iron deficiency anemia
- causes fatigue, anorexia, susceptibility to infection
- hypochromic RBC’s (low color, thin rim of Hb on edge)
- low Hb
- low iron stores (via hemosiderin)
- decreased ferritin
- increased transferrin (and increased transferrin receptor)
- decreased hemoglobin levels
- decreased mean corpuscular volume (MCV)
- increased DMT-1 (to absorb iron from the gut)
- Also, general anemia signs (inc EPO, inc 2,3 BPG)
Treat: Iron supplements, RBC’s will increase
Jaundice
- caused by excessive bilirubin in the blood
- common in infants
- gives skin and schlera (white of eye) a yellow tint
- can be neurotoxic if not treated
Prehepatic (hemolytic)
- RBC destruction  Hb release  can’t metabolize fast enough
[UDP-glucoronosyl transferase is rate limiting step]
- Increased unconjugated bilirubin (Indirect)
- liver enzymes are normal (since the problem is in the liver)
- bilirubin excreted in urine
Posthepatic (obstructive)
- interference with processed bilirubin delivery
- buildup of conjugated bilirubin (increased Direct bilirubin)
- bilirubin glucuronide excreted in stool (“putty” colored)
- slightly elevated liver enzymes (ALT, AST, AP)
[since liver is either being damaged, or is in distress]
Lead Poisoning
- inactivates ALA dehydratase (so ALA in urine)
- inhibits ferrochelatase (adding iron to protoporphyrin)
- also inhibits iron transport into mitochondria
Lipoprotein (a)
- variant of LDL increases CHD risk 3x  thrombogenic
- Treatment: restrict trans-fatty acids (hydrogenated oils)
- niacin and statins [to dec LDL, therefore dec impact of Lp(a)]
Marasmus
- see P.E.M.
McArdle’s disease
- defective muscle glygogen phosphorylase
- can’t break down glycogen
 increased glycogen deposition in muscle
Membranopathies
- inherited disorders of the RBCs
- i.e. herediary spherocytosis, elliptocytosis, pyropoikilocytosis
- mostly related to changes in lipid:protein ratios, or changes that
affect membrane composition and fluidity.
- see herediary spherocytosis (case study from class)
Metabolic Acidosis - results from production of metabolic acids
- increases NH4+, which is excreted as glutamate
 urea production suppressed
Metabolic syndrome - diagnosed if 3 of the following are present:
- Abdominal obesity (men have waist measure >40 in)
(females >35 in)
- High triglycerides
- Low HDL
- High blood pressure
- High fasting blood glucose
Methemoglobin Anemia
- multiple causes, lead to decrease in ability to carry O2.
- defect methemoglobin reductase I/II
- deficiency of reductase enzymes
- Hb subunits mutated, so heme subunits make iron more
likely to become oxidized.
- inherited or acquired
(acquired through oxidant chemical exposure)
Myocardial Infaction (MI) - critical loss of circulation to the heart (coronary artery)
- caused by a white thrombus (platelet plug)
- heart tissue that dies cannot be recovered
- an acute crisis
- high risk patients will have their platelets targeted
(reduce clots)  use aspirin, etc
Niemann-Pick Disease (Type A)
- deficient in sphingomyelinase
-can’t break ceramide---P-choline bond
 accumulation of sphingomyelin in neurons and “foamy”
reticuloendothelial cells of liver, spleen, and bone marrow
- neuromuscular deterioration, mental retardation
Obesity
- classified if BMI is over 30 (overweight if BMI in 25-30 range)
- men’s girth (waist) >40 in
women’s
>35 in
- can predispose to chronic heart disease
- can lead to type II diabetes
- increased fat  insulin resistance  elevated insulin
required  elevated fasting blood glucose  diabetes
- increases inter-organ cycling of fat
 increased free fatty acids in blood
- increased caloric intake  increased fat storage
- diet and exercise, therapy, meds, and even surgery can help
Osteomalacia
- similar to Rickets
- vitamin D deficiency  poor calcium uptake
 demineralized bone
Pellegra
- lack of niacin (vitamin B3)
- Dermatitis, Dementia, Diarrhea (the 3 D’s)
Pernicious Anemia - lack of stomach glycoprotein (intrinsic factor)
 can’t absorb B12
- B12 deficiency
Phenylketonuria
- a buildup of phenylpyruvate (from phenylalanine metabolism)
(can’t make tyrosine)
- Treat: supplement tyrosine (Phe  tyr  OAA/AcoA)
- that way you won’t need phenylalanine
Polycythemia
- excessive blood cell production, especially RBC
- increased hematocrit
- increased WBC and platelets
- increased blood volume
Treat with phlebotomy
- primary = error in bone marrow
- secondary = due to EPO increase
(either environmental induced or faulty EPO synthesis)
Porphyrias
-
genetic or acquired (alcoholism, etc)
defect in heme biosynthesis
classified as either erythroid or hepatic (many hepatic)
can cause photosensitivity (byproduct buildup in skin)
hair growth
porphyrin in urine [red]
 excreted because it can’t be used to make heme
-urine glows under UV light!
Pregnancy (and iron)
- (Ok, so pregnancy is not really pathophysiology, please
don’t send me hate mail)
- tends to be less bound iron capacity
- but increased available capacity (cells could take in more Fe)
- iron is extremely important during pregnancy
Protein-Energy Malnutrition (P.E.M.), 2 types
- Starvation-induced (aka marasmus)
- gradual
- involuntary weight loss *diagnostic characteristic
- decreased blood proteins (albumin) ONLY after muscle mass
and fat has been depleted.
-Sidenote: In some parts of Mozambique, Marasmus is thought to
be caused by a malignant spirit sitting on the chest of a child.
- Trauma induced (acute catabolic insult, i.e. burns, surgery, etc)
- b/w 3-10 days
- systemic (not just to the injury site)
- increased Adrenocorticotropic hormone (ACTH)  inc cortisol
- increased glucagon, with decreased insulin sensitivity
- low blood protein evident with in 4-10 days
- no muscle wasting
- normal physical appearance
- large negative nitrogen balance (increased protein catabolism)
- Treatment: Hyperalimentation (though oral uptake is best
- Enteral tube feeding (tube into stomach)
- short term
- inexpsensive, allows body to regulate uptake
- Parenteral tube feeding (tube into veins)
- can be long term
- requires careful monitoring, as no uptake regulation
- Nutrient requirements for recovery
- Protein (to replace N)
1.2-2.0 gm/Kg body weight
- Carbs and lipids (for energy)
20-30 kcal/kg body weight
*don’t overfeed, it slows recovery from PEM
Pseudothrombocytopenia
- false low platelet count
- EDTA used in running CBC can cause platelets to clump
 clumps not picked up by machine
 patient appears to have low platelet count
Pyruvate kinase deficiency Rickets
inherited RBC disorder, enzymopathy
enzyme from glycolysis, PEP  pyruvate rxn.
leads to buildup of intermediates
therefore increased 2,3 BPG synthesis
isotherm shift to the right (favors HbO2 release)
- vitamin D deficiency
- prevents adequate calcium absorption
- bones of children are undermineralized, therefore become bowed
Sickle cell anemia
- see hemoglobinopathies
Small Dense LDL
- elevation leads to 3x CHD risk
(more susceptible to macrophage uptake and oxidation)
-treat with NCEP diet (30-35% calories from fat)
-exercise, lose weight
-statins, niacin/fibrate
Scurvy
- [the one disease mentioned in every unit so far!]
- caused by lack of vitamin C, a cofactor for prolyl hydroxylase
- can’t properly synthesize collagen  unstable
 C.T. defects, bleeding gums, etc
Southeast Asian Ovalocytosis (SAO)
- inherited membranopathy
- K 56 E spectrin mutation
- RBC’s become oval-shaped
- homozygote = lethal
- heterozygote = malaria resistance
- prevalent in S.E. Asian population (duh!)
Splenectomy
- surgical removal of the spleen
- reduces ability to clear out RBC’s
 more abnormal shaped RBC’s in the blood
- this could be useful for someone with membranopathy
(i.e. spherocytosis)
- by not being able to filter out the abnormal RBC’s, anemia goes
away. However, the actual RBC abnormality is still there.
Stenosis
- narrowing of the arteries
Steatorrhea
- greasy, malodorous feces
- indicative of pancreatic or biliary problems
- caused by undigested fat in the stool
Stroke
- blockage of bloodflow in the brain
- caused by a white thrombus (platelet plug)
- high risk patients will have their platelets targeted (reduce clots)
-use aspirin, etc
Tay-Sach’s disease - neurologic degeneration, blindness, deaf, paralysis, death by 3 yr
- defect β-N-acetylhexosaminidase (Hexosaminidase A)
 gangliosides with GalNAc cannot be degraded
 lipid deposits form in neurons
Trauma (and clot risk)- Following severe injury, body upregulates platelet production
(senses need)
- High risk for clots in days following injury
- use anticoagulation treatment
Thalasemia
[example: woman in notes, starting p. 518]
- due to mutation in Hb alpha or beta chain (therefore α/β)
Mutant chains aggregate  form Heinz bodies
Beta form = most severe excess alpha chains
Compensate by gamma chains (fetal Hb)
Alpha form = milder than beta
Excessive beta chains, form B4 tetramers
-these are unstable, with high O2 affinity
- abnormal RBC’s in smear = microcytic
- hypochromic
- low hemoglobin
- iron overload disorder
- more bound iron capacity, but less available capacity
- increased iron absorption  increased serum iron
 transferrin saturation
- iron excretion in urine and feces
- classified as a hemoglobinopathy
- also, increased apoptosis of RBC precursors
 ineffective erythropoiesis
 imbalanced globin chain sythesis
- therefore, increased RBC production
- expanded bones (increased marrow to compensate)
- enlarged liver and spleen
- also can be an enlarged heart
Treat: Use an Fe chelating agent to remove excess Fe
i.e. Deferoxamine
Thrombocytopenia - low platelet count, can be detected with a CBC
(but watch out  see pseudothrombocytopenia)
- causes abnormal bleeding time
Thrombosis
- blood clot
- in CHD, rupture of thin fibrous cap
- higher risk if major plaque disruption, low blood flow
Urea cycle disorders - increased ammonia
- depletion of intracellular ATP
- can cause brain swelling
Van Gierke’s Disease- defective glucose-6-phosphatase
- after breaking off of glycogen, cannot convert G6P  glucose
Vitamin A deficiency- common in developing countries
- causes night blindness (eventually leading to total blindness)
keratinization of the skin and mucosal membranes
-**Golden Rice = genetically engineered rice to produce provitamin A (β-carotene), since rice is a staple food in many
developing countries.
Wernicke-Korsakoft - Thiamine deficiency
- associated with alcoholism
- test: transketolase (since TPP is a cofactor)
”It’s got to come out, of course.
But that doesn’t address the deeper
problem.”