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
