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 Arteriosclerosis Atherosclerosis - partial loss of circulation to heart muscle  chest pain, chronic condition - hardening of the arteries (general term) 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



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 - 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) - cystine excretion (S=S)



- 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 - 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


- 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. - lack of fructokinase  fructose in urine (benign)

Essential Fructose Uria

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 Hemorrhage - loss of RBC’s  causes erythropoiesis  increased iron uptake - 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 - enzyme from glycolysis, glucose  glucose 6-P rxn. - therefore, decreased 2,3 BPG synthesis - isotherm shift to the left (favors Hb O2 binding) - lack cysathionine β-synthesase (pyridoxal pyrophosphate dependent) - increases serum homocysteine (toxic & immunogenic) -ectopia lentis, osteoporosis, mental retardation - Treat with B12, and methionine restricted diet - 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) - 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 - 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

Hexokinase deficiency





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!) - 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

Iron deficiency anemia


- 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] - inactivates ALA dehydratase (so ALA in urine) - inhibits ferrochelatase (adding iron to protoporphyrin) - also inhibits iron transport into mitochondria

Lead Poisoning

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)] - see P.E.M. - defective muscle glygogen phosphorylase - can’t break down glycogen  increased glycogen deposition in muscle - 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)

Marasmus McArdle’s disease


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 - similar to Rickets - vitamin D deficiency  poor calcium uptake  demineralized bone - 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 - 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)




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


- 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 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)

Pyruvate kinase deficiency Rickets

- vitamin D deficiency - prevents adequate calcium absorption - bones of children are undermineralized, therefore become bowed - see hemoglobinopathies - 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 - [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

Sickle cell anemia Small Dense LDL


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. - narrowing of the arteries



- greasy, malodorous feces - indicative of pancreatic or biliary problems - caused by undigested fat in the stool - 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.”

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