BRS - Biochem Clinical Correlates Flashcards
1
Q
Which cells produce HCl of the stomach?
What is responsible for producing acidic gastric fluid?
A
- parietal cells of the stomach produce HCl
- H+-K+ ATPase (the proton pump) in the cell membrane is responsible for producing as much as 2 L of acidic gastric fluid per day.
2
Q
GERD:
pathology, symptoms, treatment
A
gastroesophageal refulx disease (GERD)
- results from reflux of HCl into the esophagus
- sxs: burning sensation in the chest, cough, SOB
- tx: proton pump inhibitors (PPI - omeprazole) to inhibit the H-K-ATPase/ “proton pump”
3
Q
what drug is used to treat glaucoma and altitude sickness?
A
carbonic anhydrase inhibitor (acetazolamide);
blocks the reaction pictured
4
Q
what can cause metabolic acidosis?
A
- accumulation of metabolic acids
- lactic acid or the ketone bodies, b-hydroxybutyric acid, and acetoacetic acid
- ingestion of acids or compounds that are metabolized to acids
- (e.g., methanol, ethylene glycol).
5
Q
what can cause METABOLIC ALKALOSIS?
A
- due to increased HCO3-, (accompanied by an inc. pH)
- Acid-base disturbances –> compensatory responses –> attempt to restore normal pH.
- E.g. a metabolic acidosis causes hyperventilation & the release of CO2, which tends to raise the pH.
- During metabolic acidosis, the kidneys excrete NH4+, which contains H+ buffered by ammonia:
6
Q
Glycoside digitalis:
mechanism of action, use
A
- MOA: inhibit the Na-K ATPase on cell membranes
- Tx: congestive heart failure
7
Q
how do labs measure the amount of glucose in urine?
(highly specific test)
A
using a dipstick to measure glucose in urine;
measures oxidation of glucose by GLUCOSE OXIDASE
8
Q
Gray Baby Syndrome:
define, physiology of infants –> pathology
A
- DEF: fetal shock-like syndrome (circulatory collapse); ashen-gray color, abdominal distention, vomiting, flaccidity, cyanosis, circulatory collapse, and death
- PHYS: infants have decreased ability to conjugate glucuronic acid onto drugs such as CHLORAMPHENICOL
- PATH: Admin of antibiotic during the neonatal period can result in elevated plasma levels of the drug
9
Q
Benedict test for reducing sugars:
- why used?
- what does it detect?
- when is this used routinely?
A
- why: bc dipsticks ONLY detect glucose; this is another test for reducing sugars
- what: ALSO detects the presence of glucose, sucrose, galactose, and fructose
- when: most newborn and infant urine is routinely screened
- screened for reducing sugars to detect inborn errors in metabolism
10
Q
Sorbitol:
def:
diffusion?
clinical correlate
A
- def: glucose is reduced to SORBITOL
- DOES NOT READILY diffuse out of cells
- CC: as sorbitol accumulates in cells –> causes osmotic damage to cells of the nervous system –> cataracts and neuropathy
11
Q
Leukocyte adhesion deficiency (LAD) II:
pathology, sxs
A
- Path: pts w/ this type of congenital deficiency –> deficiency in ability to glycosylate ligands for cell surface selectins, which mediate immune cell migration
- Sxs: prone to recurrent life-threatening infxns
12
Q
Heparin:
composition, MOA, use
A
- glycosaminoglycan
- important anti-coagulant found in the granules of mast cells
- tx myocardial infarction as well as preventing DVT during hospitalizations
13
Q
Influenza virus:
MOA
A
infects cells by binding its viral hemagglutinin to SIALIC ACID on the surface of epithelial cells
14
Q
Glycine:
function in the brain?
what antagnoizes it?
A
- Fxn: Glycine functions as INHIBITORY NEUROTRANSMITTER in the brainstem and spinal cord;
- Antagonist: RODENTICIDE STRYCHINE –> muscle spasm and twitching
15
Q
Glutamate:
MOA,
Antagonist
Implications
A
- MOA: Amino acid of highest concentration in brain and fxns as neurotransmitter in brain and spinal cord; EXCITATORY
- Antagonist: MEMANTINE, used for tx of Alzheimer disease
- Glutamate antagonism implicated in SCHIZOPHRENIA, in which drugs of abuse, like ketamine & phencyclidine, affects glutamate binding to its receptor
16
Q
Cholera toxin:
MOA, CC
A
it binds to the ganglioside GM1 receptor on cells and upon entry causes a potentially life-threatening water diarrhea
17
Q
CYSTIC FIBROSIS TRANSMEMBRANE REGULATOR
(CFTR):
where, mutation, CC
A
18
Q
Marfan Syndrome:
biochem/gross pathology; presentation
A
- biochem: mutations in gene for the highly alpha-helical fibrillary protein FIBRILLIN, which is a major component of fibrils found in extracellular matrix
- gross: patients have DEFECTIVE CONNECTIVE TISSUE, particularly in ligaments and aorta
- presentation: excessively long fingers and extremities; arachnodactyly, and predisposition to dissecting aortic aneurysms and valvular disease
19
Q
Creutzfeldt-Jakob disease (CJD)
pathology, presentation
A
- path: prion disease; results from transmission of a proteinaceous agent that is capable of altering the normal alpha-helical arrangement of prion protein->
- replacing it with beta-pleated sheets and smaller alpha helices; similar to pathogenic form –>
- resulting misfolding protein is resistant to degradation, w/ death of the affected neurons
- presentation: pronounced involuntary jerking movements (startle myoclonus), and rapidly deteriorating DEMENTIA
20
Q
A
21
Q
Heat shock proteins:
function, pathology
A
- fxn: group of chaperones
- path: mutations in such proteins –> leads to human disease
- Charcot-Marie-Tooth disease (MC cause of inherited neuromuscular diseases ; found to have mutations in HSPS
22
Q
alpha1- antitrypsin (AAT) deficiency:
path, presentation
A
- path: results in misfolded protein that gets trapped w/in the cell
- presentation: pts w/ decreased levels of this protease inhibitor manifest w/ cirrhosis and emphysema
23
Q
Huntington disease:
pathology, presentation
A
- path: expansion of a region of POLYGLUTAMINE REPEATS w/in the Huntington protein –> protein aggregates and forms intranuclear inclusions –> neuronal cell death
- presentation:
- progressive movement disorders
- dementia
24
Q
Bortezomib (Velcade)
purpose, function
A
- purpose: novel anticancer drug; used for treatment fo multiple myeloma and inhibits the proteasome
- function: thought is that cancer cells are more dependent on proteasomal degradation than normal cells for proliferation, metastasis, and survival
25
**Chediak-Higashi** syndrome:
pathology, presentation
* path: defect in the ability to transfer enzymes from lysosomes to phagocytic vesicles
* presentation: recurrent infections owing to a **lack of microbial killing, anemia,** and **thrombocytopenia**
26
**Sickle Cell Anemia:**
pathology, presentation
* path: mutation producing alterations in structure of hemoglobin
* beta chain of hemoglobin contains VALINE instead of GLUTAMATE at position 6
* Mutant hemoglobin (HbS), a hydrophobic amino acid replaces an AA w/ a negative charge --\>
* **allows deoxygenated molecules of HbS to polymerize** --\>
* RBCs contain large complexes of HbS --\> sickle shape
* presentation: causes HEMOLYSIS --\> anemia results
* painful vaso-occlusive crises
* end-organ damage may result
27
How does the affinity of hemoglobin for carbon monoxide differ from those of oxygen?
* Hemoglobin has about **250 times the affinity for carbon monoxide** than it does for oxygen.
* Path:
* Prolonged or heavy exposure to carbon monoxide results in **disorientation, headache, and potentially fatal asphyxiation.**
* Patients may have **‘‘cherry-red mucous membranes’’** due to the accumulation of carboxyhemoglobin.
28
**Osteogenesis imperfecta:**
pathology, presentation
* path: **synthesis of the Type I collagen;** widespread clinical consequence
* presentation: **BONE FRAGILITY** (w/ predisposition to **multiple childhood fractures)**, **hearing loss**, and distinctive **blue sclera**
29
**Ehlers-Danlos syndrome:**
pathology, presentation
* path: group of disorders characterized by a DEFECT in the synthesis or structure of collagen; Ehlers-Danlos type VI results from a **defect in the enzyme lysyl hydroxylase**
* presentation: **hyperextensible skin, laxity of joints, defects in large blood vessels**
30
**C-peptide levels:**
purpose,
* path: levels are used to differentiate the causes of high insulin in patients
* **C-peptide is elevated in cases of tumors of pancreatic Beta cells:** Low blood glucose/ due to inc levels of insulin via endogenous production
* **C-peptide is** NOT ELEVATED in surreptitious insulin administration (purposeful injection of insulin)
* think: commercial insulin preparations have purified away this contaminant
31
**Valacyclovir** and **Valganciclovir:**
function
* nucleoside analogs; valine ester **PRODRUGS** of the antiviral **acyclovir** (treating HSV types 1 and 2 and varicella-zoster infxns)
32
**ganciclovir** and **famciclovir**:
function
* **ganciclovir**: tx CMV retinitis in pts w/ AIDs
* a prodrug activated and converted by hepatic and intestinal enzymes to active drug and higher bioavailability and efficacy
* **famciclovir**: for shingles and recurrent outbreaks of HSV type 2
33
what is the optimal pH for **pepsin**?
Why?
* optimal pH for pepsin is **2**,
* reflecting its need as a digestive enzyme in the acidic gastric juice of the **stomach**
34
what is the optimal pH for **alkaline phosphatase**?
why?
optimal pH for alkaline phosphatase is **_9,_**
reflecting the basic pH environment in **_bone_**
35
**Isoniazid**:
use, function
* drug used in treatment of tuberculosis
* acetylated by an N-acetyltransferase
* **Fast** acetylators/metabolizers: clear the drug from blood about 300% faster than in the second group of individuals,
* **Slow** acetylators/poor metabolizers, in
whom the presence of drug is prolonged, causing *hepatotoxicity and neuropathy*
* *Km (affinity of isoniazid substrate) is normal, but the Vmax of ‘‘fast’’ N-acetyltransferase, is **three times normal.***
36
**Hypersensitivity to alcohol**:
pathology
* exists when drinking small amounts of alcohol causes
* *facial flushing and tachycardia (rapid heartbeat).**
* Alcohol dehydrogenase generates acetaldehyde, which is converted to acetate by **aldehyde dehydrogenase**. The latter enzyme exists in two forms, a high-affinity (low Km) form and a low-affinity (high Km) form.
* Those **sensitive to alcohol lack the high-affinity form**, resulting in excess acetaldehyde and, hence, vasodilation
37
**Physostigmine:**
pathology, use
* path: a competitive reversible inhibitor of acetylcholinesterase
* used to tx **glaucoma (**inc intraocular pressure) and **myasthenia gravis** (an autoimmune disease acting at the neuromuscular junction)
38
**Angiotensin-Converting Enzyme (ACE) inhibitors**:
examples, action
* captopril, enalapril, lisinopril
* MC used antihypertensive therapies that inhibit formation of angiotensin II, an octapeptide from angiotensin I
39
**EDTA** (ethylenediamine tetracetic acid):
path
* common noncompetitive inhibitor; result of chelation (metal binding) therapy
* resulting in removal of required divalent metal ions from active site of enzymes
* CC: blood of patients is collected with EDTA to **inhibit both calcium-activated proteases and the blood coagulation pathway**
40
**Nerve gas:**
path
* aka agents of chemical terrorism (tabun and sarin), **alkylphosphate insecticides** (malathion)
* path: **irreversible inhibitors of acetylcholinesterase**
* also called "suicide inhibitors", creating a reactive group irreversibly reacting in the active site, forming an extremely stable intermediate
41
how are **hemostasis and thrombosis** mediated?
* mediated by enzymes along cascading steps of
the blood coagulation pathways. Inherited **deficiencies of clotting factors result** in uncontrolled bleeding.
* **Factor VIII deficiency** causes **hemophilia A**, an X-linked disease rife in some European royal families
42
Where is CK-**MM** found?
Where is CK-**MB** found?
* CK-**MM**: makes up 99% of skeletal muscle distribution, and 75% of myocardium
* CK-**MB**: makes up 25% of myocardium, but it is not found in any other tissues;
* CK-MB is significant marker in a myocardial infarction (heart attack, MI)
* used in conjunction with another protein marker (**troponin**)
43
**Serum amylase**:
pathology
* elevated in cases of pancreatitis;
* the test to measure amylase is often ordered in patients to evaluate such a condition;
* however, serum lipase is another marker of **pancreatitis** that demonstrates higher sensitivity and specificity compared with **amylase**
44
**ACARBOSE**:
what, where, fxn
* **alpha-glucosidase inhibitor,**
* works in the intestine,
* fxn: to facilitate **better postdigestive blood glucose control**
* slowing down digestion of carbohydrates--\>
* lengthening the time it takes for carbs to be converted to glucose
45
**LACTASE DEFICIENCY:**
epi, pathology, sxs
* epi: occurs in 80% of Native, African, and Asian Americans
* path: lactose is NOT digested at a normal rate and accumulates in the gut --\> where it is metabolized by bacteria
* sxs: **bloating, abdominal cramps, watery diarrhea**
46
**STEATORRHEA:**
path
* occurs when excess lipids are excreted into the feces
* bc of lipid malabsorption from IMPAIRED LIPOLYSIS, MICELLE, OR CHYLOMICRON formation, or chylomicron transport
47
**ORLISTAT:**
fxn
* anti-obesity drug
* inhibits pancreatic and gastric lipase --\> 30% blockage of dietary fat from digestion and absorption, --\> **REDUCTION IN BODY WEIGHT in some patients**
48
**OLESTRA:**
fxn
* artificial fat, composed of a sucrose polyester and fatty acids
* NOT DEGRADED by gastric or pancreatic lipases and **PASSES THROUGH THE BODY UNDIGESTED** and unabsorbed --\>
* excress use in foods may interfere with absorption of fat soluble vitamins
49
**non-tropical sprue (ADULT CELIAC DISEASE)**
path, sxs
* path: causes reaction to gluten (a protein found in grains) \<-- from intestinal epithelial cells are DAMAGED --\> malabsorption results
* sxs: **steatorrhea, diarrhea, weight loss**
50
**ACHLORYDRIA:**
def, path
* def: lack of ability to produce HCl (usually due to autoimmune destruction of gastric parietal cells)
* path: **deficiencies in protein digestion and absorption**
51
**SECRETIN:**
fxn; clinical correlate
* Fxn: hormone that is released by **cells lining the duodenum** --\> bicarbonate is released from pancreas
* CC: FAILURE TO FULLY NEUTRALIZE the acidic gastric contents results in **PEPTIC ULCERS** in the duodenum
52
**HEREDITARY DEFICIENCY OF ENTEROKINASE:**
path, sxs, tx
* Deficiency of this important zymogen activator
* Sxs: diarrhea, failure to thrive, and hypoproteinemia
* Tx:
* managed during **infancy** with pancreatic enzyme supplementation.
* When patients become **adults**, they no longer need such supplementation, owing to the decreased anabolic demands and the autocatalysis of digestive enzymes
53
**CYSTINURIA:**
path, sxs
* PATH: transport of cysteine and basic amino acids is defective in both
the intestine and kidney.
* Cysteine cannot be resorbed from the glomerular filtrate and concentrates in the urine.
* Within the urine, the cysteine is oxidized to cystine, which can **crystallize**
* SXS: kidney stones
54
**HARTNUP DISEASE:**
path
transport of neutral amino acids is defective --\> resulting in potential **deficiencies of essential amino acids** because they are not absorbed from the diet.
55
what is the function of gamma-glutamyl transferase (GGT)?
what causes **elevated serum levels of GGT?**
* fxn: mediates rranslocation of amino acids in the g-glutamyl cycle
* elevated serum GGT in:
* **intrahepatic &** **posthepatic biliary obstructions --(indicating cholestasis**)
* pancreatic cancer and alcohol-induced liver disease
56
**RED BLOOD CELLS (RBCs):**
path
* **lack mitochondria** --\> **completely reliant on glycolysis as source of energy**
* deficiencies of glycolytic enzymes have a profound effect on RBC function
57
**Hereditary deficiency of GLUT-1**:
structure, sxs
* structure: an insulin-dependent transporter --\> decreased glucose in the **cerebrospinal fluid**
* sxs: manifest with intractable **seizures in infancy, developmental delay**
58
**Absence of A isoform of Aldolase:**
where is it found, presentation
* where: aldolase is found in RBCs and muscles
* presentation: **nonspherocytic hemolytic anemia**
* episodes of **Rhabdomyolysis** (destruction of muscle cells)
* following febrile illness
59
**Triose phosphate isomerase (TPI)**:
presentation
* neonatal-onset **hemolytic anemia** as well as progressive **neurologic involvement**
* children have progressive hypotonia with eventual diaphragm paralysis that requires ventilation, as well as **cardiomyopathy**
60
**enolase** inhibition
how, path
* enolase is INHIBITED BY FLUORIDE
* to prevent ongoing glycolysis in a patient's blood samples collected for sensitive **glucose tolerance tests,** blood is collected in tubes containing fluoride
61
**FETAL HEMOGLOBIN (HbF):**
structure,
and maternal-fetal interface
* composed of **two alpha subunits and two gamma subunits**, has a lower affinity for BPG than does HbA, and therefore, **HbF has a higher affinity for O2**.
* The difference in maternal and fetal hemoglobin **facilitates the unloading of O2 at the maternal–fetal interface** (i.e., the placenta).
62
**maturity-onset diabetes of the young (MODY):**
path, sxs
* path: type 2 is an autosomal dominant disorder involving mutations in the **glucokinase (GCK) gene**
* sxs: **nonprogressive hyperglycemia**; usually **asymptomatic** at diagnosis, and is usually managed with diet alone
63
**Phosphofructokinase deficiency**
type, path, sxs
* a form of **glycogen storage disease [TYPE VII]**
* path: glycogen accumulates in muscles --\> results in inefficiency use of glucose stores by RBCs and muscles
* Sxs: with **hemolytic anemia, muscle cramping**
64
**pyruvate kinase** deficiency:
path
* causes decreased production of ATP from glycolysis;
* RBCs have insufficient ATP for their membrane pumps, and a hemolytic anemia results
65
**ARSENIC:**
characteristics, pathology
* odorless and tasteless heavy metal, which has been used
throughout the centuries as a poison.
* path: it inhibits one of the subunits of the PDHC --\> resulting in **impaired production of acetyl CoA** and subsequent energy production via **oxidative phosphorylation**
66
**PDHC Deficiency**
**(PDHC =** pyruvate dehydrogenase complex)
path, sxs
* one of the MC neurodegenerative disorders associated with **abnormal mitochondrial metabolism.**
* sxs:
* Severe forms of the disease are lethal;
* mild forms exhibit ataxia and mild psychomotor delay and nonspecific symptoms (e.g., severe lethargy, poor feeding, tachypnea) related to lactate buildup
* (especially during times of illness, stress, or high carbohydrate intake.)
67
**Fluoroacetate**
**(rat poison)**
path, sxs
* path: reacts with oxaloacetate (OAA) to form fluorocitrate --\> Fluorocitrate inhibits **aconitase**, leading to the **accumulation of citrate**.
* Ingestion may result in **convulsions, cardiac arrhythmias, and eventually death.**
68
**fatal infantile mitochondrial myopathy**
path, sxs
* path: involves decreased activity of the mtDNA-encoded **respiratory chain complexes (I, III, IV, V)**
* sxs: patients have early progressive **liver failure** and **neurologic abnormalities, hypoglycemia,** and inc lactate in body fluids
69
**mutations in the mitochondrial encoded gene for**
**NADH:ubiquinone oxidoreductase (complex I)**
path
* results in the disorder **MELAS**.
* MELAS is an acronym for the clinical manifestations of the disease **mitochondrial encephalopathy, lactic acidosis, and stroke**
70
**mitochondrial DNA (mtDNA)**:
name, path, sxs
* name: **Leber's hereditary optic neuropathy** (LHON)
* path: have point mtuations in the gene for **cytochrome reductase**
* sxs: pts are typically males in their 20s and 30s who **develop loss of central vision**
71
**Kearns-Sayre syndrome:**
path, sxs
* path: mtDNA defect --\> mutations in the complex II of the ETC
* sxs: short stature, complete external **ophthalmoplegia, pigmentary retinopathy, ataxia, and cardiac conduction defects**
72
**LEIGH DISEASE:**
path, sxs
* path: **mtDNA** disorder (Mitochondrial DNA)
* sxs: present w/ lactic acidemia, developmental delay, seizure, extraocular, and hypotonia
* The disorder is usually **fatal by the age of 2 years**, with some patients exhibiting mutations in cytochrome oxidase
73
how do alcohol and certain drugs affect **cytochrome mono-oxidases**?
* Consumption of alcohol and certain drugs **_induces_** expression of various cytochrome mono-oxidases.
* Patients who abuse such substances are more **prone to the deleterious effects of ROS formed by these P-450 enzymes.**
74
**Chronic granulomatous disease** (CGD):
path, sxs
* path: results from a deficiency of NADPH oxidase and the inability to effectively kill engulfed microbes, especially bacteria.
* sxs: Patients with CGD present with **serious recurrent bacterial infections.**
75
**H2O2-MPO-halide system:**
fxn, path
* one of the most effective mechanisms for **killing bacteria within neutrophils.**
* However, patients with defects in this system have **near-normal immune function** because bacteria are killed, albeit slower, by superoxide produced by the action of **NADPH oxidase.**
76
**carbon tetrachloride** (CCl4):
use, mechanism
* use: **organic solvent** used in the **dry cleaning industry**
* mechanism: **P-450 cytochrome** system converts **CCL4 to the free radical species CCl3**.
* This highly reactive species causes a chain reaction of lipid peroxidation, particularly in the liver, that leads to **hepatocellular necrosis.**
77
**amyotrophic lateral sclerosis (ALS)**
**aka Lou Gehrig's disease**:
path, sxs
* path: mutations in the intracellular forms of SOD (superoxide dismutase)
* sxs: characterized by **progressive ascending paralysis**, w/ eventual death from **RESPIRATORY FAILURE**
78
in which patients are **pathogens that produce catalse** of particular concern?
* patients LACKING NADPH OXIDASE are particularly susceptible to bacterial pathogens that produce catalase --\> bc hydrogen peroxide is the major killing agent in these individuals --\>
* therefore, infxns causing catalase-pos organisms --\> can be deleterious --\> bc the hydrogen peroxide is degraded
79
**glycogen synthase** genetic deficiency:
other name, path, tx
* name: Type 0 glycogen storage disease (GSD)
* path: inborn error of metabolism resulting in **fasting hypoglycemia with occasional muscle cramping**
* tx: can be managed with frequent meals and feeding of UNCOOKED CORNSTARCH to prevent overnight hypoglycemia
80
**Andersen disease**
path, sxs
* a **type IV GSD**, results from a genetic **deficiency of this branching enzyme**
* There is not an increased accumulation of glycogen, but rather, the **glycogen has very long outer branches.**
* Sxs: This structural abnormality leads to a reduced solubility of the glycogen, causing progressive scarring of the liver (cirrhosis), which leads to death at about 5 years of age. **Children fail to thrive**
81
**HERS DISEASE:**
path, sxs
* path: genetic deficiency of liver phosphorylase causes this type VI deficiency; partial deficiency
* sxs: extreme enlargement of the liver (Due to glycogen accumulation), pts can also present w/ mild hypoglycemia or no sxs at all
* (full deficiency is fatal)
82
**MCARDLE DISEASE:**
path, sxs
* path: muscle phosphorylase deficiency, type V GSD
* sxs: exercise-induced cramps, pain secondary to RHABDOMYOLYSIS --\> myoglobinuria --\> life-threatening **renal failure**
83
**CORI DISEASE:**
path, types, tx
* path: type III GSD, resulting from deficiency of debranching enzyme
* **type IIIa** is a deficiency of both liver and muscle enzymes and manifests with **hepatomegaly, hypoglycemia during fasting, and myopathy**
* tx: managed by small meals or continuous nasogastric feeding
* **type IIIb** is rarer; deficiency of lIVER enzyme only; NO muscular involvement
84
**POMPE DISEASE:**
path, types, sxs
* path: type II (2) GSD; lysosomal storage disease --\> accumulation of glycogen w/in the lysosome results in formation of large lysosomes (which ultimately comprises muscle cellular fxn)
* type IIa: infantile;
* sxs: muscle weakness (floppiness), w/ death by 2 years old secondary to heart muscle dysfxn
* milder IIb (juvenile)
* IIc (adult)
* IIb and IIc --\> delayed and progressive onset and are dominated by skeletal muscle weakness
85
**Phosphorylase kinase deficiency:**
path, sxs, types
* path: Deficiency of phosphorylase kinase is a type IX GSD.
* sxs: hepatomegaly, growth retardation, delayed motor development, and increased blood lipids.
* types:
* since phosphorylase kinase is a complex enzyme w/ multiple subunits --\> several diff't subtypes have been identified;
* MC form is **X-linked form**
86
**VON GIERKE DISEASE:**
path, sxs, tx
* path: Deficiency of glucose 6-phosphatase is a type I glycogen
storage disease (GSD)
* Failure to convert glucose 6-phosphate to glucose
--\> intracellular accumulation of glucose 6-phosphate and severe hypoglycemia
* sxs: lethargy, seizures, and brain damage. Patients often have hepatomegaly, increased bleeding (due to platelet dysfunction), and growth retardation.
* tx: Frequent meals and nighttime nasogastric feedings help control the disease.
87
**PEPCK deficiency**
**(**Phosphoenolpyruvate carboxykinase)
path, sxs
* path: rare but severe metabolic defect --\> absence of cytosolic form --\>
* sxs:
* **severe cerebral atrophy,**
* **optic atrophy,**
* **fatty infiltration of the liver and kidney, and**
* **intractable hypoglycemia.**
88
**Deficiency of F-1,6-bisphosphatase:**
path, sxs
* path: causes **neonatal hypoglycemia**
* This deficiency is typically only of the liver enzyme, and the muscular F-1,6-BP activity is normal.
* sxs:
* acidosis,
* irritability,
* tachycardia,
* dyspnea,
* hypotonia,
* moderate hepatomegaly
89
**deficiency of lactate dehydrogenase**:
type, sxs
* type: genetic
* sxs:
* muscle cramping
* myoglobinuria after intense exercise.
90
**Decreased production of insulin:**
path, name, sxs, tx
* path: usually caused by autoimmune destruction of pancreatic b cells,
* name: in type 1 (formerly called insulindependent) diabetes mellitus.
* sxs: hyperglycemia
* decreased uptake of glucose by cells
* increased output of glucose by the liver (due to low insulin and high glucagon levels in the blood).
* tx: use exogenous insulin to survive.
91
**decreased release of insulin:**
path, name, sxs
* path: either dec release from pancreas, or decreased sensitivity of tissues to insulin (insulin resistance)
* name: type II diabetes mellitus (formerly IDDM)
* sxs: **hyperglycemia**
92
**SULFONYLUREAS:**
use, MOA
* use: to manage type 2 diabetes mellitus
* MOA: stimulate the release of preformed insulin from the pancreatic islet cells to decrease serum glucose concentrations --\> preventing hyperglycemia
93
**GLUCAGONOMA:**
path, sxs
* path: tumor of the alpha cells of the pancreas (source of glucagon) --\> inc levels of glucagon circulating
* sxs:
* mild diabetes
* characteristic skin lesions
* anemia
94
**THIAZOLIDINEDIONES**:
examples, use, MOA
* ex: **Rosiglitazone, Pioglitazone**
* use: tx of type 2 diabetes
* MOA: induce genes that increase the cells' responsiveness to circulating insulin
95
**ORAL GLUCOSE TOLERANCE TEST:**
use, process, results
* use: used to diagnose diabetes
* process:
* pts drink liquid containing 75 g of glucose dissolved in water
* wait 2 hours, measure serum glucose
* results:
* Normal: \<139 mg/dL
* Prediabetes: 140-199 mg/dL
* Diabetes: 200 mg/dL
96
**fasting plasma glucose tests:**
use, process, results
* use: more often diagnostic for diabetes
* process:
* pt fasts for at least 8 hours
* tests are most reliable in the morning
* results:
* Normal: \<100 mg/dL
* Prediabetes: 100-125 mg/dL
* Diabetes: least two separate occasions, of more than 126 mg/dL
97
**BIGUANIDE:**
example, use, MOA
* ex: METFORMIN
* use: to manage type 2 diabetes mellitus;
* MOA: these work by inhibiting hepatic gluconeogenesis bc an AVERAGE person w/ type 2 diabetes has 3x the normal rate of gluconeogenesis --\>
* **decrease circulating glucose concentrations** in the postabsorptive state
98
**deficiency of fructokinase:**
name, diagnosis
* name: **benign fructosuria**
* diagnosis: autosomal recessive disorder (diagnosed incidentally)
* bc fructose accumulates in the urine
* **detached as a reducing sugar** that may give the indication of falsely high glucose readings
99
**lactose:**
what, where
* what: disaccharide
* where: found in milk or milk products;
* major dietary source of galactose
* found in many artificial sweeteners and as "filler" in some medications
100
**galactokinase deficiency**:
path, sxs
* path: results in inc levels of galactose in the blood and urine
* (galactosemia and galactosuria, respectively)
* sxs:
* cataracts in infants w/o appropriate dietary restriction
* otherwise, asymptomatic (unlike severe classic galactosemia)
101
**classic galactosemia**:
path, sxs, diagnosis
* path: serious disorder that results from a deficiency of
galactose 1-phosphate uridylyltransferase
* sxs:
* hepatomegaly, jaundice, hypoglycemia, convulsions, and lethargy.
* The infant may have difficultyfeeding, poor weight gain, and the development of cataracts. Infants are at increased risk for neonatal sepsis due to Escherichia coli.
* more serious complications: mental retardation and cirrhosis.
* dx: Neonatal screening tests typically detect the disorder early,
* tx: allowing for the elimination of all dietary galactose and preventing the development of more serious complications
102
**Deficiency of UDP-glucose epimerase:**
two forms, mgmnt
* The first is a **benign** condition, in which there is a deficiency in only leukocytes and erythrocytes.
* The second is **more serious** because it involves all tissues and has symptoms similar to classic galactosemia with the addition of hypotonia and nerve deafness
* mgmt: requires the elimination of dietary galactose.
103
**Galactitol:**
path
* like sorbitol, it accumulates in the cells --\> inc osmotic pressure and **promoting cell swelling --\>** leads to **damage of the nerves, lens of the eye, and liver cells**
* damage is caused when there is a defect in galactose metabolism
104
**deficiency of glucose 6-phosphate dehydrogenase:**
path, sxs
* path: causes **insufficient amounts of NADPH** to be produced under certain conditions (e.g., when strong oxidizing agents, such as some antimalarial drugs, are present)
* As a result, **glutathione is not adequately reduced** --\> unavailable to reduce compounds that are produced by the
metabolism of these drugs and to protect membranes from oxidative damage.
* sxs: RBCs lyse, and a **hemolytic anemia** can occur.
105
**Glycosaminoglycans:**
loc, characteristics, deficiency
* loc: important components of the **fluid in joints** (synovial fluid) and the **vitreous humor** of the eye
* characteristics:
* mucous and highly compressible bc water can be SQUEEZED OUT from between the chains
* deficiency:
* w/ osteoarthritis, pts have relative deficiency of these molecules --\>
* damage to the joint
106
**blood antigens:**
structures
* **O-linked glycoprotein** and lipid ceramides
* Most individuals produce a fructose linked to a galactose at the nonreducing end of the blood group antigen, the so-called H substance.
* Individuals with A blood group produce an N-acetylgalactosamine transferase, which transfers an N-acetylgalactosamine moiety to the H substance.
* Individuals with B blood group produce a galactosyltransferase that adds galactose to the H substance. Individuals with AB blood group produce both transferases, whereas individuals with O blood type produce neither and, therefore, have only the H substance at the nonreducing end
107
**I-cell disease:**
pathology; sxs
"I" stands for inclusion cells
* path: results from a defect in the addition of the mannose 6-phosphate tag on enzymes destined for the lysosome. As such, these hydrolytic enzymes end up being secreted from the cell. --\> Substrates within lysosomes accumulate, resulting in large
inclusion bodies, hence I-cells.
* sxs: skeletal abnormalities, joint impairment, coarse facial features, and psychomotor impairment culminating in **death by the age of 8 years**
108
**Total parenteral nutrition (TPN):**
define, use, fxn
* intravenous form of nutrition containing essential fatty acids requiring in the diet;
* used for **chronic illness,** infection, trauma, burn injuries, postsurgery recovery, starvation, and kidney or liver failure
* \*\*fxn: avoids the GI tract
109
what is considered **elevated triglycerides**?
what can this cause?
* elevated triglyceride \> 1000 mg/dL
* can cause **pancreatitis** (inflammation of the pancreas causing severe abdominal pain)
110
**chylous ascites**:
define, causes
* def: extravasation of milky chyle (lymph) w/ a triglyceride (TAG) level \> 200 mg/dL **into the peritoneal cavity of the abdomen**
* (fluid collection in peritoneum is ascites)
* causes:
* abdominal surgery
* abdominal trauma
* cancers (e.g. lymphomas, in which lymphatic system is obstructed)
111
**Primary carnitine deficiency:**
path
* deficiency of the plasma membrane carnitine transporter, leading to urinary wasting of carnitine.
* Subsequent depletion of intracellular carnitine impairs transport of long-chain fatty acids into mitochondria, **limiting fatty acid availability for oxidation and energy production.**
112
**CAT I deficiency**
(carnitine acyl transferase I):
causes
* results in **intermittent ataxia**,
* oculomotor palsy (cranial nerve [CN] III),
* hypotonia,
* **mental confusion**, and
* disturbance of consciousness.
113
**Medium-chain acyl CoA dehydrogenase (MCAD) deficiency:**
path
* **deficiency of one of the acyl CoA dehydrogenases,** which oxidizes fatty acids between 6 - 10 carbons long.
* The defect is manifested when serum glucose levels are low (hypoglycemia) because of fasting, infection, or increased amount of time between feedings.
* Fatty acids cannot be fully oxidized as an alternate form of energy in individuals with this disorder.
114
**Zellweger syndrome**
path, sxs
* **peroxisomal disorder** --\> accumulation of very-long-chain fatty acids because the peroxisome is not properly formed.
* Sxs:
* congenital craniofacial dysmorphism,
* psychomotor retardation, and
* seizures
* Death results in the first year of life
115
**Adrenoleukodystrophy**:
path
* path: a rare metabolic disorder.
* Very-long-chain fatty acids accumulate in the **brain** (causing demyelination) and in the **adrenal cortex** (causing degeneration) because of an inability to transport very-long-chain fatty acids into peroxisomes.
* Sxs: **psychomotor retardation** and **seizures.**
116
**STATINS:**
use, MOA
* use: to reduce the serum level of cholesterol
* MOA: **competitive inhibitors of HMG-CoA reductase**
* statins have been effective in regulating circulating cholesterol levels in patients with hypercholesterolemia
117
**GALLSTONES:**
composition, tx
* comp: made of cholesterol
* tx: **ursodeoxycholate** is used to inhibit formation of cholesterol gallstones;
* this is a hydrophilic bile salt that decreases content of cholesterol in bile
118
**ATHEROSCLEROSIS:**
path, what happens when occluded?
* path: the buildup of lipid-rich plaques in the intima layer of
arteries --\> Blood clots can form on these lipid-rich plaques, or part of the plaque may suddenly break loose, occluding a coronary or cerebral artery.
* When coronary artery is occluded --\> can cause MI (heart attack), --\> occlusion of a cerebral artery can cause an ischemic cerebrovascular accident (stroke).
119
**BILE ACID SEQUESTRANTS:**
example, mechanism
* e.x. Cholestyramine,
* **bind with bile acids in the intestinal lumen**. The insoluble complex of bile acid sequestrant and bile acid is eliminated in the stool.
* This **causes fecal loss of cholestero**l. As the body loses dietary cholesterol, the cells take up low-density lipoprotein (LDL) from circulation, which results in a lowering of circulating cholesterol.
120
**GEMFIBROZIL:**
class, fxn
* a member of the **fibrate** class of lipid-lowering agents,
* activates the transcription of lipoprotein lipase by activating the PPAR (peroxisome proliferator-activated receptors) family of receptors
* Therefore, the drug **decreases the level of VLDLs and other triglyceride-rich lipoproteins.**
121
**TANGIER DISEASE**
| (type, sxs, fxn)
* disease of **cholesterol transport**.
* sxs: characteristic **orange-colored tonsils**, a **very low HDL level**, and an **enlarged liver and spleen**.
* path: mutation in a transport protein, **cholesterol cannot properly exit the cell to bind to apo A (forming HDL).** This results in a very low HDL level
122
**LCAT DEFICIENCY:**
fxn
* **inability to convert cholesterol associated with HDL to cholesterol esters.**
* Ordinarily, these **cholesterol esters would be transferred to other lipoproteins**, which would then be **taken up by receptors in the liver**.
* Therefore, by inducing esterification of cholesterol, LCAT is important for the **continued removal of cholesterol
from the periphery.** Clinical manifestations include defects in the kidneys, red blood cells, and the cornea of the eyes
123
**type I diabetes:**
cause, path
* cause: due to a deficiency of insulin,
* path: caused by autoimmune destruction of insulin-producing cells in the pancreas. Insulin is required for glucose to be used by cells.
* Deficiency of insulin leads to a state known as **diabetic
ketoacidosis**,
* which manifests as a severely elevated serum glucose level, increased ketone body synthesis, and formation of acetone due to decarboxylation of acetoacetate
124
**respiratory distress syndrome (RDS):**
path
* occurs in newborn (**premature infant)** due to deficiency of surfactant in the lungs; --\> leads to decreased lung compliance
* primary phospholipid in surfactant: **Dipalmitoyl phosphatidylcholine (DPPC, aka lecithin) --\>** lowers surface tension at the alveolar air-fluid interface
* surfactant is normally produced at gestational week 30
125
**STEROIDS:**
examples, use
* ex: cortisone or prednisone
* use: for **inflammatory or autoimmune diseases** (such as RA), a debilitating inflammatory joint disease
126
**ASPIRIN:**
use, path
* shown to be **cardioprotective in myocardial infarction.**
* Although **PGI2** is also inhibited, the cardioprotective effect is mediated by **inhibiting TXA2.**
127
**ASTHMA:**
pathology, treatment
* path: causes severe breathing due to HYPERREACTIVITY AND NARROWING OF THE AIRWAYS (leukotrienes cause bronchoconstriction)
* tx: **leukotriene receptor antagonists** can be prescribed as tx
128
**3-b-Hydroxysteroid dehydrogenase deficiency**
(path, sxs)
* a disease resulting in **decreased production of aldosterone, cortisol, and androgens** (3-bhydroxysteroid dehydrogenase is required for production of all three types of steroids).
* Male infants manifest with **ambiguous genitalia** (owing to lack of androgens), and both males and females show salt wasting (owing to lack of aldosterone)
129
**17-a-hydroxylase deficiency:**
path, sxs
* disease resulting in **decreased production of cortisol** and androgens but increased production of aldosterone.
* Male and female teenagers are usually dx during puberty with"
* lack of secondary sexual characteristics.
* Increased aldosterone can cause excessive salt absorption
130
Hereditary deficiency of
**carbamoyl phosphate synthetase I (CPS I)**
(path, sxs)
* path: this deficiency causes an inability for nitrogenous waste (ammonia) to be metabolized via the urea cycle.
* Ammonia levels in such patients **rise, leading to brain damage, coma, or death, without strict dietary control.**
131
**ORNITHINE TRANSCARBAMOYLASE DEFICIENCY:**
type, sxs
* X-linked trait
* sxs: similar neurologic sequelae as CPS I deficiency
* (brain damage, coma, or death, without strict dietary control.
132
**Citrullinemia:**
cause, sxs
* results from a **deficiency of the enzyme argininosuccinate synthetase**, causing an elevation in serum levels of citrulline.
* sxs: w/o dietary management, the manifestations of this disease include **lethargy, hypotonia, seizures, ataxia, and behavioral changes.**
133
**arginocsuccinate aciduria:**
cause, sxs
* cause: results from a deficiency of the enzyme **argininosuccinate lyase** in the urea cycle,
* sxs: hyperammonemia with **grave effects on the CNS.**
134
**arginase deficiency:**
sxs, why?
* does NOT result in severe hyperammonemia;
* because:
* First, the formed arginine, containing two ‘‘waste’’ nitrogen molecules, can be excreted in the urine.
* Second, there are two isozymes, and in the event that the predominant liver enzyme is dysfunctional, the peripheral isozyme is inducible, leading to adequate restoration of the pathway.
135
**Type I primary oxaluria:**
cause
* results from the **absence of a transaminase**, which converts glyoxylate to glycine,
* sxs: renal failure due to excess oxalate in the kidney
136
**HISTIDINEMIA:**
path, sxs
* path: rare hereditary metabolic disorder, **histidase is defective** --\> can't convert histidine to urocanate --\> inc in histidine
* sxs: early cases assoc w/ mental retardation
* more recently, have not observed deleterious consequences
137
**methylmalonyl CoA mutase:**
path, sxs
* path: hereditary deficiency --\> accumulation of propionyl CoA, a substrate for the TCA cycle enzyme citrate synthase --\> leading to the condensation of propionyl CoA with oxaloacetate --\> accumulation of the TCA toxin, methyl citrate
* sxs: **failure to thrive, vomiting, dehydration, developmental delay, and seizures.**
138
**homocystinuria:**
path, sxs
* path: most often due to a defect in cystathionine b-synthase, --\> leading to increased homocysteine and methionine.
* sxs: Patients present with dislocation of the lens, mental retardation, and skeletal and neurologic abnormalities
139
**Maple surup urine disease:**
path, sxs, mgmt
* path: the enzyme complex that decarboxylates the transamination products of the branched-chain amino acids (the a-ketoacid dehydrogenase) is defective (Figure 12-10). Valine, isoleucine, and leucine accumulate.
* sxs:
* Urine has the odor of maple syrup.
* Mental retardation and poor myelination of nerves occur.
* mgmt: Dietary restrictions are difficult to implement because three essential amino acids are required.
140
**PHENYLKETONURIA (PKU):**
path, sxs, tx
* path: the conversion of phenylalanine to tyrosine is defective owing to **defects in phenylalanine hydroxylase.**
* A variant, nonclassic PKU, is a result of a defective enzyme in tetrahydrobiopterin synthesis.
* sxs:
* **musty odor urine** due to phenylketones building up (from phenylalamine accumulating)
* **mental retardation** occurs
* tx: restricting phenylalmine in the diet
141
**ALCAPTONURIA:**
path, sxs
* path: homogentistic acid (a product of phenylalanine and tyrosine metabolism) accumulates bc **homogentisate oxidase** is defective --\> homogentistic acid AUTO-OXIDIZES --\> products polymerize
* sxs
* polymerized products form **dark-colored pigments** accumulating in tissues
* assoc w/ **degenerative arthritis**
142
**ISOVALERIC ACIDEMIA:**
path, sxs, tx
* path: defect in **isovalerul CoA dehydrogenase** --\> preventing degradation of isovarleryl CoA during degradation of leucine
* sxs:
* \*pt has distinctive odor of **SWEATY FEET**
* neuromuscular irritability
* mental retardation
* tx: limiting the intake of leucine helps limit progression of sxs
143
what determines the amount of CREATINE excreted per day?
what is normal value?
what causes this to rise?
* amt of creatine excreted per day depends on BODY MUSCLE MASS and KIDNEY function
* normal = 15 mmol for average person
* path:
* in cases of kidney failure, CREATINE RISES, so does Blood Urea Nitrogen
144
ACETAMINOPHEN:
tx for overdose
* drug that is commonly ingested at an overdose level.
* Normally, glutathione plays a major role in detoxifying this potential hepatotoxic and lethal agent.
* \*\*As stores of GSH dwindle, the patient moves from malaise and vomiting --\> jaundice, gastrointestinal bleeding, encephalopathy, and finally death.
* **N-Acetylcysteine (NAC)** is a medication that replenishes levels of GSH during acetaminophen toxicity.
145
**NITRATES**
ex, use, MOA
* ex: nitroglycerin, nitroprusside, isosorbide dinitrate
* use: control of blood pressure in select patients
* MOA: these agents release NO once they are in the bloodstream
146
Normal GABA activity?
What drugs stimulate GABA, and what is their use?
* Normal GABA: promotes **neuron inhibition** by PROMOTING entry of chloride into the neuron
* drugs that stimulate GABA: benzodiazepine, topiramate, lamotrigine, tigabine)
* stimulate GABA activity
* tx seizures and other hyperspastic disorders
147
Histidine binds to which receptors in the stomach? Effects?
What drug affects this?
* Binds to H1 receptors found in stomach --\> STIMULATE release of GASTRIC ACID
* USE: Blockers of H1 are used in tx of **GASTRIC REFLUX**
148
Where are H2 receptors located?
Associated drugs?
* H2 receptors are located on **basophils** and stimulate their degranulation during the allergic response
* H2 receptor blockers are used to tx **ALLERGIC CONDITIONS**
149
**SELECTIVE SEROTONIN REUPTAKE INHIBITOR (SSRI):**
fxn, use
RECALL: serotonin is an important stimulatory NT involved in mood
* fxn: promote serotonin's actions; 1st line agents
* use: to treat DEPRESSION
150
**CARCINOID TUMORS:**
path, sxs
* path: these tumors overproduce the neurotransmitter serotonin ---\> accumulation of the primary metabolite 5-hydroxyindole acetic acid (5-HIAA)
* these tumors can metastasize to the liver --\> can cause carcinoid syndrome
* sxs:
* carcinoid syndrome: diarrhea, flushing, wheezing, cardiac valve damage
151
Drugs to tx HYPERTHYROIDISM (GRAVE'S DISEASE):
examples, MOA
* drugs: propylthiouracil and methimazole,
* MOA: **inhibit the iodination of tyrosine residues** as well as the coupling reaction.
152
**ALBINISM:**
path, effects
* path: **defect in the conversion of tyrosine to melanin**, . The disorder results from a deficiency of the enzyme **tyrosinase** (which converts tyrosine to melanin) or in defects in tyrosine transport.
* effects:
* with partial or full **absence of this pigment in the hair, skin, or eye**
* Lack of melanin **increases the risk** for developing skin cancer.
153
**PARKINSON DISEASE:**
path, sxs
* path: dopamine levels are decreased because of a **deficiency
in conversion of dopa to dopamine**
* sxs:
* tremors,
* difficulty initiating voluntary movement,
* a masked face with a staring expression, and
* a shuffling gait.
* OF NOTE: the infantile forms of the disease have been found to be due to defects in tyrosine hydroxylase
154
what are the approaches to tx for neuropsychiatric disorders such as depression and PARKINSON DISEASE?
Inhibition of MAO and COMT
(monoamine oxidase) and catecholamine O-methyltransferase, respectively
155
**PHEOCHROMOCYTOMAS:**
path, dx
* path: these pts overproduce adrenally synthesized catecholamines
* dx: have increased levels of VMA (vanillylmandelic acid)
* urinary levels of VMA are used to diagnose these tumors
156
**METHOTREXATE:**
structural analog, MOA, use
* structural analog: of FOLIC ACID that inhibits DIHYDROFOLATE REDUCTASE
* MOA: INHIBITS PURINE SYNTHESIS to slow down cell proliferation
* use: cancer tx, or autoimmune diseases like rheumatoid arthritis
157
**TRIMETHOPRIM:**
analog, fxn
* analog: a folate analog that binds specifically to bacterial dihydrofolate
reductase
* fxn: It is a potent antibacterial compound often used in conjunction with
sulfonamides, which also inhibit the same pathway in bacteria.
158
**SPINA BIFIDA and ANENCEPHALY:**
epi, prevention
* the most common neural tube defects,
* are reduced by supplementation with folic acid before conception and during the first trimester of pregnancy
159
**Overactivity of PRPP synthetase:**
path, sxs
* path: owing to a lack of feedback inhibition, is an X-linked disorder resulting in overproduction of nucleotides. The condition leads to increased degradation as well,
* sxs:
* **hyperuricemia**
* **gout**
* **kidney stones**
160
**Mycophenolic acid:**
path, use
* path: a powerful immunosuppressant and a reversible inhibitor
of **IMP dehydrogenase**. The drug limits the formation of nucleic acids in
activated and **proliferating immune cells**
* use: treating **autoimmune disease** as well as to prevent transplant rejection.
161
**HYDROXYUREA:**
MOA, use
* MOA: antineoplastic agent that INHIBITS ribonucleotide reductase
* use: to tx chronic myelogenous leukemia (CML), polycythemia vera, and essential thrombocytosis.
162
**LESCH-NYHAN SYNDROME**:
MOA, sxs
* MOA: X-linked recessive disorder, is caused by a defective HGPRT. Purine bases cannot be salvaged (i.e., reconverted to nucleotides). The purines are converted instead to uric acid, which increases in the blood.
* Sxs:
* Mental retardation
* self-mutilation are characteristics of the disease
163
**adenine phosphoribosyl transferase (APRT):**
MOA, sxs
* MOA: autosomal recessive mutations --\> inability of cells to salvage the purine base adenine
* sxs:
* develop nephrolithiasis with renal colic,
* hematuria,
* recurrent urinary tract infections,
* and dysuria.
164
**Deficiency of purine nuceloside phosphorylase (PNP):**
MOA, sxs
* MOA: accumulation of both dATP and dGTP in lymphoid tissue, which is toxic to immune cells --\> present with decreased numbers of T cells and lymphopenia.
* Sxs:
* Neurologic symptoms, including mental retardation and
* muscle
spasticity, and
* autoimmune disease are present
165
**adenosine deaminase (ADA) deficiency**:
MOA, sxs
* MOA: leads to severe combined immunodeficiency (SCID). As in PNP
deficiency, both dATP and dGTP accumulate.
* Sxs:
* natural killer (NK)-cell deficiency
* marked lymphopenia
166
**ALLOPURINOL**:
MOA
* MOA: an inhibitor of xanthine oxidase, is used in the treatment of gout.
* More recently, febuxostat, a novel nonpurine analog inhibitor of xanthine
oxidase, has been used.
167
**GOUT:**
MOA, sxs, tx
* MOA: results from accumulation of uric acid with the formation of uric acid crystals in the joints, especially the first metatarsophalangeal joint (podagra).
* sxs: painful arthritis
* tx: multiple agents like allopurinol.
168
**hereditary orotic aciduria:**
path, sxs, tx
* orotic acid is excreted in the urine because **UMP synthase is defective.** Pyrimidines cannot be synthesized, and therefore--\>
* **sxs: growth retardation occurs.**
* Tx: Oral administration of uridine bypasses the metabolic block and provides a source of pyrimidines
169
**Thymidylate synthase:**
MOA, tx
* MOA: inhibited by the antineoplastic agent 5-fluorouracil
(5-FU). 5-FU is converted by thymidylate synthase to 5-FdUMP, which remains bound to the enzyme, as a suicide inhibitor.
* Tx: 5-FU is an important agent in the **treatment of cancers such as breast and colon cancer.**
170
Effect of lead on **d-ALA dehydrogenase;**
## Footnote
**sxs**
* **inhibited** by heavy metal ions such as lead.
* sxs
* This inhibition results in the **anemia** seen in patients with lead poisoning.
* Accumulation of lead leads to **abdominal pain and encephalopathy with cognitive and motor impairment.**
171
**JAUNDICE:**
MOA, cause
* MOA: results from a deficiency in the liver’s ability to conjugate or transport bilirubin. Jaundice refers to the **yellow color of skin and eyes** that results from the deposition of bilirubin.
* Cause: hemolytic anemia, primary liver disease, obstruction of the
biliary system, and congenital deficiencies of the enzymes responsible for the metabolism of bilirubin
172
**Crigler-Najjar syndrome:**
MOA, type 1, type 2
* MOA: deficiency of bilirubin uridine diphosphate gluconyl transferase (UDP-GT).
* Type I: Type I results from a complete absence of the gene, with severe hyperbilirubinemia that accumulates in the brain of affected newborns, causing a toxic encephalopathy (kernicterus).
* Type II: Type II, a benign form, results from a mutation causing a partial deficiency of the gene.
173
**GILBERT SYNDROME:**
epi, MOA, sxs
* epi: relatively common and benign disorder (2% to 10% of the population)
* MOA: that results from decreased activity of (uridine diphosphate-glucuronate) UDP-GT.
* sxs: Occasional bouts of mild jaundice with increased physiologic stress occur during hemolysis or hepatocellular injury.
174
**ANOREXIA NERVOSA:**
pathology
* characterized by **self-induced weight loss.**
* Individuals frequently affected include **young, affluent, white women,** who despite an emaciated appearance, often claim to be ‘‘fat.’’
* It is partially a **behavioral** problem; those afflicted are obsessed with losing weight.
175
**KWASHIORKOR:**
epi, pathology, sxs
* epi: commonly occurs in children in developing countries where the
diet, adequate in calories, is low in protein.
* path: **A deficiency of dietary protein** causes a decrease in protein synthesis and eventually inhibits regeneration of intestinal epithelial cells, further compounded by malabsorption.
* sxs: **Hepatomegaly** and a **distended abdomen** are often observed.
176
**MARASMUS:**
pathology, sxs
* path: a diet deficient in both **protein and calories**
* sxs: persistent startvation ultimately results in **death**
177
**Normal versus Obese person:**
body composition
* A normal person (Table 15-4) refers to a 70-kg individual with a fuel reserve of 30% by weight. The increased reserve of the obese individual is mostly fat.
* Complete fasts indicate one can live without food, but with water, for about 60 days (theoretically, a 70-kg person has 21 kg of fuel reserve, divided as 15 kg of fat and 6 kg of protein.
* This approximates 165,840 calories of energy. The daily metabolic need of such a person is about 2620 calories per day, for a survival time of 63 days).
* Death ensues when essential proteins (e.g., from brain, heart) start to be used for energy
178
**HEPATIC ENCEPHALOPATHY:**
path
* severe liver disease cannot detoxify ammonia and thus develop **hepatic encephalopathy** from the accumulation of **ammonia in the CNS.**
* **Lactulose** is used to treat this condition and **reduces ammonia** by either increasing bacterial assimilation of ammonia or reducing deamination of nitrogenous compounds
179
what are the transaminase common diagnostic markers of liver damage found in serum?
**ALT**: alanine aminotransferase
**AST**: aspartate aminotransferase
Both are cytosolic transaminases released from dying cells upon insult
180
blood urea nitrogen (**BUN)**;
use
widely used measure of the kidney's functional ability to excrete the nitrogenous waste produced by the body
181
**Erythropoietin (EPO):**
production, use
* produced by: produced by recombinant DNA technology
* use:
* is used in the management of **anemia resulting from kidney failure, hemolytic anemia, or anemia associated with chemotherapy.**
* It is also a **blood doping** agent in endurance sports such as cycling, rowing, and long-distance running
182
**Methylxanthine:**
examples, MOA
* ex: caffeine, theophylline
* MOA: these inhibit phosphodiesterase --\> inc cellular levels of cAMP
183
**Androgen insensitivity syndrome** (formerly know as testicular feminization);
path, sxs
* path: mutations in the steroid receptor for androgens; X-linked disease
* sxs:
* lack of masculinization of genitalia of chromosomally male
individuals,
* giving them the phenotypic appearance of females.
184
**COSYNTROPIN TEST**:
use, process, results
* use: to evaluate **hypothalamic-pituitary-adrenal (HPA)** axis
* process:
* synthetic form of ACTH, is administered
* serum cortisol levels are measured at 30 and 60 min
* results:
* **adrenal insufficiency**
* requiring the administration of **exogenous corticosteroids**
185
**SYNDROME OF INAPPROPRIATE ADH (SIADH)**
path, cause
* path: overproduction of ADH --\> dilutional hyponatremia, reduced serum osmolarity, and inability to dilute the urine
* cause:
* can be caused by **trauma to the head,** or
* **from ectopic production of ADH by lung tumors**
186
MC tumor of pituitary,
sxs?
* **Prolactinoma** is the MC tumor of the pituitary
* Sxs:
* double vision (owing to compression of the optic chiasm)
* amenorrhea
* galactorrhea
* Hyperprolactinemia can result from **drugs that inhibit dopamine's action;** incl some of the **antipsychotic medications** used for schizophrenia
187
**thyroid stimulating hormone (TSH):**
test use, elevated versus low levels
* test use: **used to screen pts for THYROID DISEASE**
* elevated: suggest LOW LEVELS OF THYROID HORMONE (HYPOTHYROIDISM)
* low levels: suggest INC LEVELS (HYPERTHYROIDISM)
188
**OPIOIDS**:
use, ex
* use: pharmacologic agents that **mimic the effects of endogenous
endorphins** --\> used for pain control; however, they have significant addictive potential
* ex: morphine
189
**hypothyroidism:**
path, effects, sxs
* the stimulatory effect of thyroid hormone on the oxidation of fuels is diminished.
* As a consequence, the generation of ATP is reduced,
* effects:
* The reduced BMR is associated with diminished heat production, causing cold intolerance and decreased sweating.
* With less demand for the delivery of fuels and oxygen to peripheral tissues, the circulation is slowed, causing a reduction in heart rate and, when far advanced, a **reduction in blood pressure.**
* sxs: due to dec in ATP --\>sense of weakness, fatigue, and hypokinesis.
190
