Biochemistry Diseases

Excess fluid in the interstitial space

Causes: 

- increased capillary pressure from venous obstruction, heart fail

• -increased capillary permeability from burns/allergy/toxin
• -decreased plasma protein because of diet, kidney loss
• -kidney disease which decreases GFR
• -Lymphatic Obstruction which decreases the return of protein

Na+ plasma concentration < 136 mmol/dL

Causes:-loss of sodium is greater than loss of water-decreased aldosterone concentrations-overhydration, use of antidiuretics, syndrome of inappropriate ADH secretion(SIADH) -renal failure causing low urine volume-dietary deficiency of sodiumEffects:-hypotonic plasma thus decreased osmolality-water goes into cells - swelling- weakness, convulsions, seizures - coma - death-pulmonary edema - respiratory distress

Na+ plasma concentration > 148 mmol/dL

Causes:

• -Dehydration, sweating, diarreah
• -diabetes insipidus
• -Adrenal tumor - excess aldosterone secretion

Effects:

• -increased plasma osmolality
• -water leaves cells - shrinkage
• -metabolic functions affected
• -irratability, convulsions, coma
• -low plasma volume affects cardiac/renal function

Blood volume depletion

Cause:

Dehydration

Effect:

Tiredness, lethargy, altered reflexes, blood pressure decrease, increased heart rate

Large blood volume

Cause:

overhydration

Effect: congestive heart failure, pulmonary edema, convulsions

Reduced number of functioning nephrons

Effects:

• -Decreased glomerular filtration rate
• -decreased H+ excretion 
• -decreased NH4+ excretion 
• -decreased bicarb regeneration

Renal loss of fluid (>3L/day)

Causes:

• -Psychogenic Polydipsia
• -diabetes insipidus
• -nephrogenic diabetes insipidus
• -osmotic diuresis
• -kidney disease because there is decreased transport of water and ions

compulsive intake of water

polyuria

• Impaired production/release of ADH
• disease where kidneys are unable to conserve water

polyuria

• Renal tubes do not respond to ADH
• Kidneys cannot reabsorb water

polyuria

• Plasma glu conc exceeds renal Tm for reabsorbtion
• (Tm maximal rate of transport)

• Cause:
• -excess glucose from diet but usually only in diabetics

• Effect:
• -large urine volume
• -decreased sodium reabsorption
• - glycosuria

Syndrome of inappropriate ADH secretion

• Cause:
• -ADH is continuously secreted

• Effect:
• -increased urine osmolality with sodium concentrations > 30mmol/L

decreased blood pH 

(< 7.3)

• Causes: 
• -lactic acidosis
• -ketoacidosis
• -impaited H excretion
• -exogenous acid
• -loss of bicarbonate
• -salicylate in blood (Aspirin)

Effect:

hyperventilation to lower pCO2

Increased blood pH

(> 7.3)

Causes:

• -loss of h
• -K deficiency
• -alkali ingestion
• -antacid
• -diuretics
• -vomiting (loss of HCl)
• -Cl deficieny (increased bicarbonate reabsorption)

• Effects:
• - hypoventilation to increase blood pCO2

Excess aldosterone secretion

• Cause:
• -Adrenal or pituitary malfunction

• Effect:
• -increase in sodium absorption leads to an increase in H+ secretion+excretion 
• -Metabolic Alkalosis

Low plasma concentration

• Cause:
• -diuretics (loop and thiazide)

• Effects:
• - excess H+ secretion causing metabolic alkalosis

High plasma K concentration

• Cause:
• -H+ goes into cells when blood is acidotic in order to buffer pH so K+ is removed from cells.

• Effect:
• - competes at distal tubule with H+ for secretion causing acidosis

Decrease in blood pH due to increase in blood pCO2

• Causes:
• -Hypoventilation, COPD (emphysema), stroke, hypoxia
• -anaesthetics, opiates, spinal cord damage
• -poliomyelitis, epilepsy, resp muscle dystrophy/trauma
• -vomit, tumor, asthma, cystic fibrosis, pneumonia
• -Congestive Heart Failure, Respiratory Distress Syndrome (low surfactant)
• -toxic doses of aspirin

• Effect:
• -Kidneys increase excretion of H+ 
• -kidneys increase reabsorbption of bicarbonate and Na

Increase in blood pH due to decrease in blood pCO2

• Causes:
• -hyperventilation, salicylate intoxication, hysteria
• -anxiety, response to stress, oxygen tension,
• -above normal levels of aspirin stimulate resp center

• Effect:
• -kidney decreases H+ excretion 
• -decreases bicarbonate reabsorption

Low blood pH due to high Cl- plasma concentration

• Causes:
• -High Cl- concentration leads to decreased bicarbonate reabsorption in order to maintain electroneutrality

• Effect: 
• Acidosis

high blood pH due to low blood Cl- concentration

• Causes:
• low Cl- concentration leads to increased bicarbonate reabsorption in an attempt to maintain electroneutrality

• Effect:
• Alkalosis

No melanin synthesis leading to oculocutaneous albinism

leads to skin cancer, vision defects, photophobia

***Plasma Markers:

• CK-MB
• AST
• LDH
• Troponin I and T
• Myoglobin

***Plasma markers:

ALP (Alkaline Phosphatase)

***Plasma Markers:

• ALT (alanine transaminase)
• AST (aspartate transaminase aka SGOT)
• GGT (gamma-glutamyl transpeptidase)
• ALP (only in cirrhosis)

Plasma Markers:

Prostate specific antigen, specific proteins 

Inflammation of the pancreas

• Cause:
• -premature proteolytic activation of digestive enzymes

• Effect:
• -*Plasma Markers:
• Amylase
• Lipase

Mutant form of the Huntington protein binds and inhibits CBP protein activity

Cause:

• -Dominant- Negative loss of function mutation 
• -polyglutamin tract due to 5-CAG-3 repeat expansion

• Effect:
• -Mutant protein clumps and disrupts function leading to nueron cell death

Low androgen receptor function

• Cause:
• -mutation of androgen receptor gene causing loss of function 

• Effect:
• -low response to dihydrotestosterone

Autoimmune disease in which auto antibodies react with the U1 RNA component of the spliceosome

• Cause:
• -Autoimmune disorder in genes

• Effect:
• -Prevents normal splicing of mRNA in some genes
• -Fatigue, arthritis, fever, skin rashes, kidney problems

Beta globin gene makes additional splice sites in mRNA

• Cause: 
• -Gene mutation

• *Effect:
• -Abnormal beta globin protein

shorter calpain 3 mRNA that is missing exon 16 codons

Gene mutation that causes defective protein synthesis

difficulty breathing due to surfactant deficiency

• Cause:
• -low synthesis of surfactant
• -defect in ABC transporter
• -cell damage

• Effect:
• decreased amount of dipalmitoyl phosphatidyl choline (DPPC) secreted by Type II Alveolar Cells

genetic defect in cystic fibrosis transmembrane  conductance regulator (CFTR)

• Cause:
• -Genetic Mutation

• Effect:
• -Dehydration of respiratory and mucousal lining leading to thick mucous, diagnostic sweat test on forehead

Edema caused by insufficient protein in diet

• Cause:
• -Albumin produced in the liver is needed for specific transport and regulation of osmolality

• Effect:
• - plump belly

Inability to digest lactose after certain age

• Cause:
• -low lalactase enzyme synthesis

• Effect:
• -bloating and diarreah after ingestion of lactose

congenital inability to digest lactose

• Cause:
• -Autosomal recessive disorder where no lactase is made

• Effect:
• - can't consume normal milk as an infant

Cholesterol gallstone disease

• Cause:
• - decreased bile acids and phosphatidylcholine or increased biliary cholesterol secretion

• Effect:
• -gallstone

excess lipid in feces

• Cause:
• -lack of bile acids
• -defects in pancreatic enzymes
• -defective mucosal cells related to nutrient uptake
• -shortened bowel

• Effect:
• -loss of lipids and lipid soluble vitamins (D,A,K,E)
• -strong smelling feces 
• -loss of vitamin A leads to night blindness

accumulation of phenylalanine(or phenylpyruvate) in  blood

• Cause:
• -genetic defect in the gene coding for phenylalanine hydrolase

• Effect:
• -can cause mental retardation, failure to walk or talk, seizures, hyperactivity, tremors, microcephaly, and failure to grow and thrive

Accumulation of branched chain amino acids and their toxic derivatives in the blood

• cause:
• -deficiency of branched chain alpha keto acid dehydrogenase, an enzyme that decarboxylates the branched chain amino acids

• effect:
• -urine smells like maple syrup or burnt sugar.
• -metabolic acidosis

• Effect:
• -results in the inability of PDH complex (E1) to decarboxylate pyruvate
• -it is anapoenzyme with no thiamine pyrophosphate cofactor bound (TPP)

-mild deficiency manifests as GI complaiants, weakness and burning feet sensation

severe deficiency results in Beri Beri and Wernike-Korsakoff syndrome

Thiamine deficiency presenting without edema

• Cause:
• -thiamine deficiency

• Effect:
• -inability of PDH to decarboxylate pyruvate because PDH is missing the cofactor TPP
• -results in advanced neuromuscular and cardiovascular disorders
• -delirium
• -muscle weakness and atrophy
• -memory loss
• -opthalmoplegia
• -peripheral vasodilation
• -increased venous returnto the heart

Thiamine deficiency presenting with edema

Thiamine deficiency associated with chronic alcohol abuse

• Cause:
• -thiamine deficiency due to alcohol abuse

• Effect:
• Initial/acute phase - delirium, mental derangement, ataxia, ophthalmoplegia

• late/chronic phase - anterograde amnesia, distinct pattern ofbrain damage (focal lesions)
• -this is also known as theirreversible stage

Dx - urinary thiamine excretion, transketolase (thiamine dependant enzyme) activity in RBC/whole blood before/after addition ofTPP and lactate/pyruvate levels post oral glucose load

Treatment - thiamine injection intramuscularly for 3 days then orally.  (before late stage)

severe congenital abnormality of PDH complex

• Cause:
• -Genetic mutation

• Effect: 
• -accumulation of pyruvate, lactate, alanine, and alpha ketoglutarate
• -mental retardation

Deficiency in CAT II (CPT II)

• Cause:
• -genetic disorder in generating CPT II 

•  Effect:
• -in infants, hypoglycemia, hypoketosis, hepatomegaly, and cardiomyopathy

Violent comiting after eating unripe ackee tree fruit

• Cause:
• -fruit contains hypoglycin, a strong irreversible inhibitor of medium/short acyl CoA dehydrogenases

• Effect:
• -low rates of beta oxidation thus causing cells to rely on carbohydrates as a main source of fuel leading to hypoglycemia

medium chain acyl CoA dehydrogenase deficiency

• Cause:
• -genetic inborn error

• Effect:
• -hypoglycemia because beta oxidation is impaired

decrease in red blood cells that occurs when your intestines cannot properly absorb vitamin B12 because there is a lack of intrinsic factor.

• effect:
• -can't absorb B12 and so Methylmalonyl CoA mutase can't function (neede for propionyl CoA digestion)
• -thus decreasing hematopoieses

Defect in biogenesis of perozisomes in all tissues

• Cause:
• -genetic defect

• Effect:
• -very long chain fatty acids (VLCFA) accumulate 
• -effects the liver and the brain

Impaired alpha oxidation of fatty acids

• Cause:
• -autosomal recessive genetic defect for peroxisomes

• Effect:
• -accumulation of phytanic acid
• -neurological issues

deficiency of Pyruvate Kinase

Cause: genetic defect

• Effect:
• -hemolytic anemia
• --mature RBC's lack mitochondria, they are completely reliant on glycolysis for ATP.
• --ATP is used to maintain proper electrolyte concentrations
• --pyruvate kinase deficiency will cause cell to rupture because of decreased ATP synthesis

deficiency of G6PDH

• Cause:
• -X-linked recessive disorder

• Effect:
• -decreases the cellular reduced glutathione pool
• --GSH is a major antioxidant in RBCs 
• ---required for maintenance of SH groups in proteins

-decrease in detoxification of free radicals and peroxisomes in formed cells

-most severe in RBC's because pentose phosphate pathway is the only pathway generating NADPH in RBC's

• oxidave stress (infections/favabeans/antimalarials/sulfa drugs)
• --> GSH converted to GS-SG for detoxification of oxidants
• --> increased requirement of NADPH to convert oxidized glutathione to the reduced form GSH 

• 2 outcomes:
• A)
• -->oxidants accumulate because deficiency in NADPH production
• --> damage of fatty acids containing double bonds (cell membrane)
• --> cell lysis
• B)
• --> denaturation of proteins due to GSH depletion
• --> formation of heinz bodies in RBC's

Leber Hereditary Optic Neuropathy

• Cause: 
• -mutation of mitochondrial NADH dehydrogenase (Complex I)

• Effect:
• - acute optic atrophy

Myoclonic Epilepsy and Ragged Red Fiber Disease

• Cause:
• -mutation in mitochondrial tRNA-lys

• Effect:
• -disrupts synthesis of proteins essential for oxidative phosphorylation
• -causes myoclonic epilepsy and ragged red fibers
• -causes dementia

Mitochondrial myopathy, Encephalomyopathy, Lactic Acidosis, and Stroke like episodes

• Cause:
• -mutation in mitochondrial tRNA-leu

• Effect:
• -in name
• --mitochondrial myopathies, encephalopathy, lactic acidosis, stroke like episodes

Administration of aminoglycoside drug leading to deafness

• Cause:
• -mutation in mitochondrial 12s rRNA and tRNA-ser

• Effect:
• -deafness

Type I glycogen storage disease 

effects LIVER and KIDNEYS

• Cause:
• -deficiency in glucose 6 phosphatase Type Ia (or glucose 6 phosphate translocase Type Ib)

• Effect:
• -high glycogen amount in the liver and the kidneys
• -normal glycogen structure
• -hepatonephromegaly
• -severe fasting hypoglycemia
• -lacticacidemia
• -hyperuricemia
• -hyperlipidemia
• -progressive renal disease

• Organs Effected:
• Liver- severe hypoglycemia
• hepatomegaly
• kidney disease
• early death if untreated
• treated by ingesting uncooked corn starch meal at night

Type II glycogen storage disease

effects LIVER and MUSCLE and HEART

• Cause: 
• -defective glycogen degradation in lysosome by acid maltase (alpha (1->4) glucosidase). 

• Effect:
• -lysosomal glygogen accumulation in heart, muscle, and liver
• -in severe cases lysomes can rupture
• -it is a glycogen storage disease, a lysosomal storage disease, and a muscular disease
• -weakness, progressive neuromuscular disorder
• -normal blood glucose levels

• infantile form is most severe
• -massive cardiomegaly, myopathy, hypotonia, hepatomegaly
• -cytosolic amount of glycogen is normal and has normal structure
• -early death in first year

• Late onset:
• -breathing problems

treated by enzyme replacement therapy

Type III glycogen storage disease

effects LIVER and MUSCLE

• Cause:
• -abnormal glycogen degradation due to deficiency of debranching enzyme
• -cannot cleave limit dextrin

• Effect:
• -abnormal glycogen structure with short outer branches 
• -mild hypoglycemia, 
• -muscle weakness and hepatomegaly, cardiomyopathy

Type IV glycogen storage

effects LIVER and MUSCLE

• Cause:
• -abnormal glycogen synthesisdue to deficiency of glycogen branching enzyme
• -branching enzyme normally forms a1-6 glucose bonds to form the glycogen branches

• Effect:
• -abnormal glycogen structure, long glucose chains with less branches
• -leads to scarring by the body's immune system
• -infantile hypotonia
• -infantile liver cirrhosis
• -death by 5 years of age

Type V glycogen storage disease

effects ONLY MUSCLE

• Cause:
• -abnormal glycogen degredation in muscle due to deficiency in muscle phosphorylase
• -LIVER ISOZYME IS NORMAL

• Effect:
• -child appears tired/unmotivated for physical activity
• -temporary weakness and muscle cramping after exercise
• -can display rhabdomyolysis after forced exercise because of lack of ATP
• -Serum CK-MM is increased
• -NO raise in blood lactate after strenuous exercise as glycogen degradation is reduced
• -high levels of glycogen with normal structure in muscle
• -myoglobinemia and myoglobinuria

Type VI glycogen storage

effects LIVER

• Cause:
• -Abnormal glycogen degradation in the liver due to a deficiency of hepatophosphorylase.
• -the MUSCLE ISOZYME IS NORMAL

• Effect:
• -hepatomegaly and growth retardation
• -mild fasting hypoglycemia
• -high levels of glycogen with normal structure in the liver
• -less severe than Von Gierke's because gluconeogenesis is still functioning

Type VII glycogen storage disease

effects MUSCLE and RBC's

• Cause:
• -reduced activity of PFK-1 of the M isotype
• -LIVER ISOZYME IS NORMAL

• Effect:
• -clinically similar to McArdle's disease leadingto cramping
• -hemolysis is found due to 50% PFK-1 deficiency in RBC

Inability to digest fructose

• Cause:
• -deficiency of aldolase B in liver

• Effect:
• -ingestion of sucrose or fructose results in trapping of fructose 1 phosphate in liver cells
• -this leads to trapping of Pi which results in ATP deficiency, thus inhibiting gluconeogenesis
• -trapping of Pi also inhibits glyconeogenesis
• -this results in hypoglycemia

-HYPOGLYCEMIA results only AFTER eating FRUCTOSE or SUCROSE, NOT in a FASTED STATE

-urine analysis reveals that there is reducing sugar that is not glucose(fructose) present

Inability to convert fructose to F1P

• Cause:
• -deficiency of enzyme fructokinase in liver

• Effect:
• -after eating sucrose, fructose is not metabolized and is excreted in the urine
• -there are no toxic metabolites of fructose that accumulate in the liver thus they are asymptomatic
• clinitest will reveal that there is presence of a reducing sugar that is not glugose or galactose in the urine

• Galactokinase deficiency
• Inability to convert galactose to gal-1-P

• Cause:
• -galactosekinase deficiency

• Effect:
• -no accuulation of galactose 1-phosphate thus no developmental delay and no liver manifestations
• -manifestations are less severe than glassical galactosemia
• -urine is positive for galactose

• -Gal-1-P Uridyl transferase deficiency 
• -Inability to make UDP-Gal

• Cause:
• -deficiency in gal-1-phosphate uridyl transferase

• Effect:
• -results in the accumulation of galactose and Gal-1-P in liver and other tissues
• -accumulation in liver decreases rates of gluconeogenesis and glycogenolysis (due to trapping of Pi), resulting in profound hypoglycemia on feeding galactose or lactose
• -accumulation is toxic and deranges liver function causing hepatomegaly and jaundice

-HYPOGLYCEMIA results AFTER eating LACTOSE or GALACTOSE, does NOT OCCUR in the FASTED STATE

-gal-1-P accumulates in the lens, results in the formation of galacticol ehich is osmotically active, increases the water content of lens, causing cataracts or opacity of the lens

-gal-1-P accumulates in the brain resulting in neurological damage and some learning disability in children

-tested via heelprick right after birth, which measures levels of galactose or gal-1-P or activity of fal-1-P uridyl transferase

-urine test detect presence of galactose

Chronic disease of joints

• Cause:
• -involves damage to the functioning extracellular matrix

• Effect:
• -Degeneration of joints

Chronic autoimmune disease

• Cause: 
• -involves dammage to the functioning ECM

• Effect:
• -autoimmune destruction

Instable collagen due to poor hydroxylation

• Cause:
• -Lack of vitamin C which is coenzyme for prolyly/lysyl hydrogenase

• Effect:
• -Bleeding gums, hemorrhages, poor wound healing

defect in collagen synthesis

• Cause:
• -Genetic defects in hydroxylases/oxidases/peptidases

• Effect:
• -Hypermobile joint, fragile skin/vessels

Abnormal collagen formation leading to weak bones

• Cause:
• -Mutation of type Ia1 or Ia2 gene
• -Dominant- Negative loss of function mutation

• Effect:
• -Weak and brittle bones

Osteogenesis Imperfecta Type I

• Cause:
• -Genetic defect in collagen synthesis (usually type I)

• Effect:
• -Long bone fractures as infant, blue sclera, normal or near normal height possible hearing loss as adule

Osteogenesis Imperfecta Type II

• Cause:
• -Genetic defect in collagen synthesis (usually type I)

• Effect:
• -Death in utero or neonatal stage due to respiratory problems, underdeveloped lungs and small rib cage

Mutation in fibrillin 1 protein gene that antagonizes the normal gene product

• Cause:
• -Haploinsufficiency syndrome with fibrillin gene

• Effect:
• -Tall, slender, joints flexible, valve/aortic problems can lead to heart failure, defective eye and skeleton

Genetic deficiency of alpha 1 antitrypsin

• Cause:
• -Genetic Defect

• Effect:
• -Neutrophil elastase is unihibited and degrades elastin of the lungs leading to emphysema and liver injury 

deficiency of iduronidase can't degrade heperan sulfate or dermatan sulfate

• Cause:
• -X-linked genetic disorder

• Effect:
• -Coarseness of facial features, ear and respiratory problems, underdeveloped lungs and small rib cage

• -deficiency of Iduronidase sulfatase
• -cant degrade heparan sulfate or dermatan sulfate

• Cause:
• -Genetic Defect

• Effect:
• -Coarseness of facial features, ear and respiratory problems, underdeveloped lungs and small rib cage + corneal clouding

other types of Mucopolysaccharidosis

• Cause:
• -Genetic defects

Shingolipidosis, deficiency of beta- hexosaminidase A

• Cause:
• -Genetic defect

• Effect:
• -Accumulation of GM2 (deficiency of the enzyme beta-hexosaminidase), cherry red macula, onion shell inclusions, weakness, seizures, blindness, death by 5

sphingolipidosis, deficiency of alpha- galactosidase A

• Cause:
• -X-linked genetic disorder

• Effect:
• -Accumulation of ceramide trihexoside in vascular endothelium, kidney failure, heart failure, stroke, anhidrosis, weakness, fatigue, angiokeratomas (red purple skin rash with bathing trunk distribution), acroparesthesia (burning lower extremities)

Sphingolipidosis, decifiency of beta-glucocerebrosidase

• Cause:
• -Genetic Defect

• Effect:
• -Accumulation of glucocerebrosides, crumpled tissue paper appearance of cytoplasm, retardation, adult form shows no brain damage but hepatosplenomegaly and long bone osteoporosis

Sphingolipidosis, deficiency of acid sphingomelinase

• Cause:
• -Genetic Defect

• Effect:
• -Accumulation of shingomyelin in spleen, liver, and brain 
• -Type A: classic infantile, ab swelling, cherry macula, retardation, and death by  3
• -Type B: visceral, chronic organ damage no neuro probs but live only to early adulthood 

• -intracytosolic inclusions due to defective enzyme transport 
• -deficiency of n-acetyl glucosamine-1-phosphotransferase
• -aka mucolipidosis II

• Cause:
• -Genetic Defect

• Effect:
• -Absence of mannose-6-P marker which is needed for lysosomal transport, similar defects as Hurlers, enlarged heart valves, restricted joint movement

Sphingolipidosis

Genetic Defect

Sphingolipidosis

Genetic Defect

Sphingolipidosis

Genetic Defect

Sphingolipidosis

Genetic Defect

Sphingolipidosis

Genetic Defect