Exam 2 Clinical Correlates Flashcards
Type 2 diabetes
Emergence of insulin resistance, owing to a wide variety of causes; tissues do not respond to insulin as they normally would
Insulinoma
Periodic release of insulin from a tumor of the pancreatic β-cells, leading to hypoglycemic symptoms, which are accompanied by excessive appetite and weight gain
Hyperglycemia
Constantly elevated levels of glucose in the circulation owing to a wide variety of causes. Hyperglycemia leads to protein glycation and potential loss of protein function in a variety of tissues
Type 1 diabetes
No production of insulin by the pancreatic β-cells, caused by autoimmune destruction of the β-cells. Hyperglycemia and ketoacidosis may result from the lack of insulin
Maturity-onset diabetes of the young (MODY)
Forms of diabetes caused by specific mutations, such as a mutation in pancreatic glucokinase, which alters the set point for insulin release from the β-cells
Neonatal diabetes
One cause of neonatal diabetes is a mutation in a subunit of the potassium channel in various tissues. Such a mutation in the pancreas leads to permanent opening of the potassium channel, keeping intracellular calcium levels low, and difficulty in releasing insulin from the β-cells
Obesity
Understanding daily caloric needs can enable one to gain or lose weight through alterations in exercise and eating habits
Lactate production via anaerobic glycolysis in the muscle occurs during vigorous exercise
Increased physical activity, without increasing caloric intake, will lead to weight loss and increased exercise capacity. One effect of increased aerobic exercise is increasing the number and size of mitochondria in the muscle cells
Hyperthryoidism
Thyroid hormone is important in regulating energy metabolism; excessive T3 and T4 release enhances metabolism, leading to weight loss and a greater rate of heat production
Heart attack (MI)
The heart requires a constant level of energy, derived primarily from lactate, glucose, and fatty acids. This is necessary so that the rate of contraction can remain constant or increase during appropriate periods. Interference of oxygen flow to certain areas of the heart will reduce energy generation, leading to a MI
The lack of oxygen in the heart muscle is caused by severe ischemia due to clots formed within certain coronary arteries at the site of ruptured atherosclerotic plaques. The limited availability of oxygen to act as an electron acceptor decreases the proton motive force across the inner mitochondrial membrane of ischemic cells. This leads to reduced ATP generation, triggering events that lead to irreversible cell injury
Chronic obstructive pulmonary disease (COPD)
Can lead to inefficient energy production in the nervous system due to reduced oxygen delivery to the tissue
Dental caries
Effects of carbohydrate metabolism on oral flora and acid production
Lactic acidemia
Elevated lactic acid due to mutations in a variety of enzymes involved in carbohydrate and energy metabolism
Hereditary fructose intolerance
Lack of aldolase B, leading to an accumulation of fructose 1-phosphate after fructose ingestion. The increased levels of fructose 1-phosphate interfere with glycogen metabolism and can lead to hypoglycemia
Galactosemia
Mutations in either galactokinase or galactose 1-phosphate uridylyltransferase, leading to elevated galactose and/or galactose 1-phosphate levels. This can lead to cataract formation (high galactose) and intellectual disability (elevated galactose 1-phosphate levels) if not treated early in life
Anorexia nervosa
Patients who have been malnourished for some time may exhibit subclinical deficiencies in many vitamins, including riboflavin and niacin, factors required for energy generation
Congestive heart failure linked to alcohol use disorder
Thiamin deficiency, brought about by chronic alcohol ingestion, leads to dilation of the blood vessels, inefficient energy production by the heart, and failure to adequately pump blood throughout the body. The vitamin B1 deficiency reduces the activity of pyruvate dehydrogenase and the TCA cycle, severely restricting ATP generation
Arsenic poisoning
Arsenite inhibits enzymes and cofactors with free adjacent sulfhydryl groups (lipoic acid is a target of arsenite), whereas arsenate acts as a phosphate analog and inhibits substrate-level phosphorylation reactions
Leigh syndrome (subacute necrotizing encephalopathy)
Deficiencies of the pyruvate dehydrogenase complex (PDC), as well as of pyruvate carboxylase, are inherited disorders leading to lactic acidemia. In its most severe form, PDC deficiency presents with overwhelming lactic acidosis at birth, with death in the neonatal period. Even in less severe forms, neurologic symptoms arise due to the brain’s dependence on glucose metabolism for energy. The most common PDC deficiency is X-linked, in the α-subunit of the pyruvate decarboxylase (E1) subunit. Pyruvate carboxylase deficiency also leads to intellectual disability
Graves disease
An autoimmune genetic disorder caused by the generation of human thyroid-stimulating immunoglobulins. These immunoglobulins stimulate growth of the thyroid gland and excess secretion of the thyroid hormones T3 and T4.
HIV treatment complication
One of the first drugs used to treat HIV was zidovudine (ZDV), formerly called AZT, a nucleoside analog reverse transcriptase inhibitor. This class of drugs can act as an inhibitor of mitochondrial DNA polymerase. Under rare conditions, it can lead to a depletion of mitochondrial DNA in cells, leading to a severe mitochondrial myopathy
Iron-deficiency anemia
Lack of iron for heme synthesis, leading to reduced oxygen delivery to cells, and reduced iron in the electron transfer chain, leading to muscle weakness
Cyanide poisoning
Cyanide binds to the Fe3+ in the heme of cytochromes a and a3, components of cytochrome oxidase. Mitochondrial respiration and energy production cease, and cell death rapidly occurs
Mitochondrial disorders
Many types of mutations, leading to altered mitochondrial function and reduced energy production, due to mutations in the mitochondrial DNA
Kearns–Sayre syndrome
Onset before 20 years of age, characterized by ophthalmoplegia, atypical retinitis pigmentosa, mitochondrial myopathy, as well as a cardiac conduction defect, cerebellar syndrome, or elevated CSF proteins
Deletion of contiguous segments of tRNA and OXPHOS polypeptides or duplication mutations consisting of tandemly arranged normal mtDNA and a mtDNA with a deletion mutation
Pearson syndrome
Systemic disorder of OXPHOS that predominantly affects bone marrow and pancreas
Deletion of contiguous segments of tRNA and OXPHOS polypeptides or duplication mutations consisting of tandemly arranged normal mtDNA and a mtDNA with a deletion mutation
MERRF (myoclonic epilepsy with ragged red fibers)
Progressive myoclonic epilepsy, a mitochondrial myopathy with ragged red fibers, and a slowly progressive dementia. Onset of symptoms: late childhood to adult
tRNALys
MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, and strokelike episodes)
Progressive neurodegenerative disease characterized by strokelike episodes that usually first occur in childhood and a mitochondrial myopathy
80%–90% mutations in tRNALeu
Leigh syndrome (subacute necrotizing encephalopathy)
Mean age of onset, 1.5–5 years; clinical manifestations include optic atrophy, ophthalmoplegia, nystagmus, respiratory abnormalities, ataxia, hypotonia, spasticity, and developmental delay or regression
7%–20% of cases have mutations in F0 subunits of the F0F1ATPase
LHON (Leber hereditary optic neuropathy)
Late onset, acute optic atrophy
90% of European and Asian cases result from mutation in NADH dehydrogenase (complex I)
Free-radical disease
Damage caused to proteins and lipids due to free-radical generation may lead to cellular dysfunction
Parkinson disease
Inability to convert tyrosine to DOPA; DOPA treatment can temporarily reverse tremors and other symptoms
Myocardial infarction
The lack of oxygen in the walls of the heart is caused by severe ischemia due to clots forming within certain coronary arteries at the site of ruptured atherosclerotic plaques. The limited availability of oxygen to act as an electron acceptor decreases the proton motive force across the inner mitochondrial membrane of ischemic cells. This leads to reduced ATP generation, triggering events that lead to irreversible cell injury. Further damage to the heart muscle can occur due to free-radical generation after oxygen is reintroduced to the cells which were temporarily ischemic, a process known as ischemic reperfusion injury
Chronic granulomatous disease
This disorder occurs due to a reduced activity of NADPH oxidase, leading to a reduction in the oxidative burst by neutrophils, coupled with a dysregulated immune response to bacteria and fungi
Respiratory distress syndrome of a newborn
Either mutation in surfactant, or lack of surfactant production in newborns; lungs have difficulty inflating and compressing
ALS
A familial form of ALS is due to mutations in SOD, leading to difficulty in disposing of superoxide radicals, leading to cell damage due to excessive ROS
Age-related macular degeneration
Oxidative damage occurs in the RPE, leading to first, reduced vision, and second, to blindness
Newborn hypoglycemia
Poor maternal nutrition may lead to inadequate glycogen levels in the newborn, resulting in hypoglycemia during the early fasting period after birth, in addition to some genetic disorders affecting glycogen and gluconeogenesis
Insulin overdose
Insulin taken without carbohydrate ingestion will lead to severe hypoglycemia, due to stimulation of glucose uptake by peripheral tissues, leading to insufficient glucose in the circulation for proper functioning of the nervous system
Glycogen storage diseases
Affect storage and use of glycogen, with different levels of severity, from mild to fatal
Glycogen synthase (GYS2)
Hypoglycemia, hyperketonemia, failure to thrive, early death
Glucose 6-phosphatase (Von Gierke disease) (G6PC)
Enlarged liver and kidney, growth failure, severe fasting hypoglycemia, acidosis, lipemia, thrombocyte dysfunction
Lysosomal α-glucosidase (Pompe disease): may see clinical symptoms in childhood, juvenile, or adult life stages, depending on the nature of the mutation (GAA)
Infantile form: early-onset progressive muscle hypotonia, cardiac failure, death before age 2 years. Juvenile form: later-onset myopathy with variable cardiac involvement. Adult form: limb-girdle muscular dystrophy-like features. Glycogen deposits accumulate in lysosomes
Amylo-1,6-glucosidase (debrancher): form IIIa is the liver and muscle enzymes, form IIIb is a liver-specific form, and IIIc a muscle-specific form (AGL)
Fasting hypoglycemia; hepatomegaly in infancy and some myopathic features. Glycogen deposits have short outer branches
Amylo-4,6-glucosidase (branching enzyme) (Andersen disease) (GBE1)
Hepatosplenomegaly; symptoms may arise from a hepatic reaction to the presence of a foreign body (glycogen with long outer branches). Usually fatal
Muscle glycogen phosphorylase (McArdle disease) (expressed as either adult or infantile form) (PYGM)
Exercise-induced muscular pain, cramps, and progressive weakness, sometimes with myoglobinuria
Liver glycogen phosphorylase (Her disease) (PYGL)
Hepatomegaly, mild hypoglycemia; good prognosis
Phosphofructokinase-I (Tarui syndrome) (PFKM)
As in type V; in addition, enzymopathic hemolysis
Phosphorylase kinase (PHKA2; PHKB; PHKG2; PHKA1)
Similar to type VI for liver-specific subunits; muscle fatigue for muscle-specific subunits
Phosphoglycerate mutase (PGAM2)
Similar to type V
Aldolas A (ALDOA)
Hepatosplenomegaly, hemolytic anemia
Blood transfusions
Blood typing is dependent on antigens on the cell surface, particularly the carbohydrate content of the antigen
Tay–Sachs disease
Lack of hexosaminidase A activity, leading to an accumulation of GM2 in the lysosomes
Sandhoff disease
Lack of both hexosaminidase A and B activity, leading to an accumulation of GM2 and globoside in the lysosomes
Jaundice
Lack of ability to conjugate bilirubin with glucuronic acid in the liver
Sphingolipidoses
Defects in ganglioside and sphingolipid degradation
Glucose 6-phosphate dehydrogenase deficiency
Lack of glucose 6-phosphate dehydrogenase activity leads to hemolytic anemia in the presence of strong oxidizing agents
Ethanol-induced hypoglycemia
Ethanol, combined with poor nutrition, leads to hypoglycemia because of excessive ethanol metabolism altering the NADH/NAD+ ratio in the liver
Asthma
A treatment to reduce bronchoconstriction is inhalation/administration of glucocorticoids. Systemic treatments stimulate gluconeogenesis, and can lead to hyperglycemia
Insulin overdose
Hypoglycemia as a result of insulin overdose because of insulin stimulation of glucose transport into muscle and fat cells
Anorexia nervosa
The use of ketone bodies as an alternative energy source during prolonged fasting preserves muscle protein as reduced levels of glucose are now required by the nervous system
Weight loss
Maintenance of blood glucose levels during dieting occurs because of glycogenolysis and gluconeogenesis
MCAD deficiency
Lack of medium-chain acyl CoA dehydrogenase activity, leading to hypoglycemia and reduced ketone body formation under fasting conditions
Type I diabetes
Ketoacidosis; overproduction of ketone bodies due to lack of insulin and metabolic dysregulation in the liver
Carnitine deficiency
A primary carnitine deficiency is the lack of a membrane transporter for carnitine; a secondary carnitine deficiency is due to other metabolic disorders
Zellweger syndrome
A defect in peroxisome biogenesis, leading to a lack of peroxisomes, inability to synthesize plasmalogens, or oxidize very-long-chain fatty acids
TFP deficiency
A lack of mitochondrial trifunctional protein, leading to hypoglycemia, lethargy, hypoketonemia, and liver problems
Acute ackee fruit intoxication (Jamaican vomiting disorder)
Inhibition of an acyl CoA dehydrogenase activity by hypoglycin can lead to death due to severe hypoglycemia
Heart disease (FCH), familial combined hyperlipidemia
Familial combined hyperlipidemia, leading to elevated cholesterol and triglyceride levels in the serum. Levels of lipid in the blood, and symptoms displayed by patients, will vary from patient to patient
Respiratory distress syndrome of the newborn
Inability of lungs to properly expand and contract due to lack of surfactant, a complex mixture of lipids and apolipoproteins
Abetalipoproteinemia
Lack of microsomal triglyceride transport protein, leading to reduced production of VLDL and chylomicrons within the liver, and intestine, respectively
Cardiovascular disease (protection against future myocardial infarctions)
NSAIDs, such as aspirin, are used to block prostaglandin production via inhibition of cyclooxygenase. Low-dose aspirin provides potential protective effects for those with cardiovascular disease
Asthma
The use of inhalants containing corticosteroids, can control and reduce inflammation by inhibiting the recruitment of leukocytes and monocytes into affected areas. They also lead to a decrease in the synthesis of prostaglandins and leukotrienes
Metabolic syndrome
A combination of obesity, insulin resistance, and altered blood lipids leads to metabolic syndrome with an increased risk for type 2 diabetes and cardiovascular disease
Hypercholesterolemia
Defined by elevated levels of cholesterol in the blood, often leading to coronary artery disease
Familial hypercholesterolemia, type II
Defect in LDL receptor, leading to elevated cholesterol levels, and premature death due to coronary artery disease
Tangier disease
A mutation in the ABCA1 gene, leading to an inability to transport cholesterol from peripheral cells to HDL particles. This results in very low circulating HDL particles, and an increased risk of atherosclerotic disease in the patient
Hyperchylomicronemia
A mutation in either the lipoprotein lipase gene or apolipoprotein CII gene can lead to an inability to degrade the triglyceride in chylomicrons, leading to elevated triglycerides in the blood
Virilization
Excessive release of androgenic steroids, due to a variety of causes
Congenital adrenal hyperplasia (CAH)
CAH is a constellation of disorders due to mutations in enzymes required for cortisol synthesis. One potential consequence is excessive androgen synthesis, which may lead to prenatal masculinization of females. The different symptoms observed between patients are due to different enzyme deficiencies in the patients
Alcohol use disorder
Alcohol use disorder may occur, leading to damage of internal organs by acetaldehyde production.
Jaundice
Altered liver function leads to a reduced ability to conjugate and solubilize bilirubin, which leads to bilirubin deposition in the eyes and skin, giving them a yellow pallor (Jaundice). This is an indication of liver disease
Liver Fibrosis
Excessive damage to liver, often due to alcohol metabolism, particularly acetaldehyde accumulation, leading to extensive collagen secretion and loss of liver function
Viral hepatitis
Infection of the liver by viral hepatitis may lead to liver failure
Pyridoxamine deficiency
The lack of vitamin B6 affects many systems, such as heme synthesis, glycogen phosphorylase activity, and neurotransmitter synthesis, leading to possibly dementia, dermatitis, anemia, weakness, and seizures
Hepatic encephalopathy
Liver failure leading to brain dysfunction, caused by the liver’s inability to rid the body of toxins, including ammonia
Ammonia toxicity
Ammonia accumulation interferes with energy production and neurotransmitter synthesis in the brain, altering brain function
OTC deficiency
Most common urea-cycle defect, leading to elevated blood ammonia and orotic acid levels, and will lead to mental impairment if not treated
CPS1 deficiency, argininosuccinate synthetase deficiency, argininosuccinate lyase deficiency, and arginase deficiency
Mutations in urea-cycle enzymes, leading to various degrees of hyperammonemia and inability to synthesize urea. Can be distinguished by the type of urea-cycle intermediates that accumulate in the blood
PKU
Classical PKU is due to a defect in phenylalanine hydroxylase, whereas nonclassical PKU is due to a defect in dihydropteridine reductase (or an inability to synthesize tetrahydrobiopterin). Both forms of PKU will lead to intellectual disability if treatment is not initiated at an early age
Alkaptonuria
Alkaptonuria is due to a defect in homogentisate oxidase, leading to an accumulation of homogentisic acid. Arthritis may develop later in life
Tyrosinemia
Tyrosinemia type 1 is a defect in fumarylacetoacetate hydrolase, leading to liver failure and early death. Tyrosinemia type 2 is a defect in tyrosine aminotransferase, leading to skin lesions and neurological defects
Cystathionuria
Defect in cystathionase, leading to an accumulation of cystathionine. No major complications result from this mutation
Homocysteinemia
A defect in cystathionine β-synthase leads to accumulation of homocysteine, which can result in cardiac and neurological complications in the patient
Primary oxaluria type 1
Defect in glycine transaminase leading to oxalate accumulation, and renal failure due to stone formation within the kidney
Maple syrup urine disease
A defect in the branched-chain α-keto acid dehydrogenase, leading to an accumulation of the α-keto acids of the branched-chain amino acids, resulting in intellectual disability
Cystinosis
A defect in the transport protein that carries cystine across lysosomal membranes, with three forms of diseases. Cystine accumulates in lysosomes, interfering with and ultimately destroying their function and affecting different organs
Thiamin deficiency
A thiamin deficiency leads to accumulation of α-keto acids because the enzymes that catalyze oxidative decarboxylation reactions will not function in the absence of this vitamin. This will interfere with energy production and lead to a ketoacidosis
Colon cancer
Colon cancer can be treated by drugs which block the action of thymidylate synthase, blocking DNA synthesis by reducing the supply of dTTP
Pernicious anemia
Pernicious anemia is due to the lack of intrinsic factor, which leads to a B12 deficiency. The B12 deficiency indirectly interferes with DNA synthesis. In cells of the erythroid lineage, cell size increases without cell division, leading to megaloblastic anemia
Alcohol-induced megaloblastic anemia
Alcohol-induced malnutrition, which can lead to folate and/or B12 deficiencies. The folate and/or B12 deficiency will lead to the development of megaloblastic anemia
Neural tube defects
A lack of folate derivatives leads to reduced methylation in the nervous system, altering gene expression and increasing the risk of neural tube defects
Gout
Painful joints because of the precipitation of uric acid in the joint space
PNP deficiency
A defect in a purine salvage enzyme, leading to a loss of T-cell function, with near normal B-cell function and a partial immunodeficiency disease. Purine nucleosides will accumulate
Lesch–Nyhan syndrome (lack of HGPRT activity)
The loss of HGPRT activity leads to the accumulation of purines and uric acid, with intellectual disability and self-injury resulting in severe cases. Gout will also appear in these individuals
Hereditary orotic aciduria
A defect in UMP synthase, leading to orotic acid accumulation and delay in growth
ADA deficiency
The loss of ADA activity leads to SCID, with a loss of both T- and B-cell function. dA and derivatives of dA accumulate in the blood and blood-based cells
Cancer
The use of drugs that interfere with DNA replication will destroy rapidly dividing cells at a faster rate than normal cells
