5 - Fatigue Flashcards
What are the thyroid hormones synthesized by the thyroid gland?
T4 (thyroxine), rT3 (reverse triiodothyronine), T3 (triiodothyronine)
These hormones play crucial roles in regulating metabolism and energy levels.
What are common causes of fatigue?
Lifestyle issues, physical conditions, mental and psychosocial issues, endocrine dysfunction, metabolic abnormalities, anemia, malignancy
Depression and endocrine dysfunction are among the most common etiologies.
What is myxedema?
Severe hypothyroidism with symptoms including weight gain, mental dysfunction, lethargy, depression, cold intolerance, deepening of voice, thickened dry skin, bradycardia, constipation
Myxedema is a clinical term used to describe severe hypothyroid symptoms.
What laboratory findings support the diagnosis of mild hypothyroidism?
Mild microcytic anemia, elevated TSH, low T4
These findings indicate a slowing of metabolic rate in the patient.
What is the most common cause of hypothyroidism in middle-aged females in the U.S.?
Hashimoto disease (Hashimoto thyroiditis)
Worldwide, inadequate iodine intake is the leading cause.
What are the key antibodies associated with Hashimoto thyroiditis?
Antithyroid peroxidase antibodies, antithyroglobulin antibodies
These antibodies are present in 90% of Hashimoto thyroiditis cases.
How is thyroid hormone synthesized?
Thyroid hormone is synthesized in the thyroid follicle; iodide is oxidized and reacts with tyrosine residues of thyroglobulin, forming MIT and DIT, which couple to form T4 and T3
TSH stimulates each step of this synthesis process.
What is the Wolff-Chaikoff effect?
High levels of iodide inhibit the organification of iodide, thus inhibiting thyroid hormone synthesis
This is a negative feedback mechanism useful in reducing thyroid gland activity.
What are the regulatory mechanisms for thyroid hormone secretion?
Hypothalamic-pituitary axis, TSH secretion regulated by TRH, influenced by factors like renal failure, starvation, sleep deprivation, depression, and steroid hormones
TRH sensitivity can modulate TSH secretion.
What distinguishes primary from secondary hypothyroidism based on TSH and T4 levels?
Primary hypothyroidism: high TSH and low T4; Secondary hypothyroidism: low TSH and low T4
This differentiation helps identify the underlying cause of thyroid dysfunction.
What is the role of deiodinases in thyroid hormone metabolism?
Convert T4 to the more active T3 in peripheral tissues
This conversion is crucial for the biological activity of thyroid hormones.
What are the clinical features of hypothyroidism?
Unexplained weight gain, fatigue, somnolence, constipation, thickening of skin, thinning of hair, cold intolerance, depression, bradycardia, diminished deep tendon reflexes
These symptoms can develop gradually and may be overlooked.
What is the importance of ultrasound in the evaluation of thyroid nodules?
Differentiates between ‘hot’ (functioning) and ‘cold’ (nonfunctioning) nodules; cold nodules may require biopsy to rule out malignancy
Nodules exceeding 1 cm generally warrant biopsy.
What is the significance of the pituitary gland’s function in thyroid hormone regulation?
Produces TSH in response to low T4 levels, indicating normal pituitary function in primary hypothyroidism
Elevated TSH levels suggest that the pituitary is responding appropriately to low thyroid hormone levels.
Fill in the blank: The thyroid gland secretes hormones in several forms, including _______.
[key learning term: T4 and T3]
True or False: Secondary hyperthyroidism is characterized by high TSH and high T4 levels.
False
Secondary hyperthyroidism is rare and involves low TSH and high T4 levels.
What molecule regulates TSH secretion?
Thyrotropin-releasing hormone (TRH)
TRH sensitivity can be modulated by factors such as renal failure, starvation, sleep deprivation, depression, and steroid hormones.
What are the essential biological processes involving thyroid hormones?
Normal growth into adult stature, development of the CNS, cellular growth, development, differentiation, regulation of metabolism, and homeostasis.
The actions of thyroid hormones include modulation of gene expression and nongenomic actions.
What is the response time difference between genomic and nongenomic actions of thyroid hormones?
Genomic actions take one to several days; nongenomic actions may be evident in minutes to hours.
How do thyroid hormones affect oxygen consumption?
Increase oxygen consumption in all tissues except the brain, gonad, and spleen by inducing transcription of genes for mitochondrial respiration and Na+-K+ ATPase synthesis.
What are the common symptoms of hypothyroidism?
Intolerance to cold, lethargy, weight gain, cool and dry skin.
What are the common symptoms of hyperthyroidism?
Intolerance to heat, weight loss, fatigue.
What causes hypothyroidism?
Autoimmune destruction (Hashimoto disease), iodine deficiency, congenital issues, decreased TRH or TSH, excess iodine (Wolff-Chaikoff effect).
What is the most common cause of hyperthyroidism in the United States?
Graves disease (thyrotoxicosis).
What is the mechanism behind Graves disease?
Increased production of thyroid-stimulating immunoglobulins mimicking TSH, binding to TSH receptors, stimulating excess thyroid hormone synthesis.
What is goiter?
Abnormal enlargement of the thyroid gland, occurring in hyperthyroidism, hypothyroidism, or euthyroid states.
What are goitrogens?
Foods that contribute to thyroid gland enlargement by disrupting hormone production through iodine uptake interference, e.g., legumes, raw cruciferous vegetables.
What is myxedema?
A form of severe hypothyroidism.
What is the best clinical indicator of thyroid function?
Measurement of TSH.
What is pyruvate kinase?
An enzyme that catalyzes the final step in glycolysis, generating 2 ATP per glucose molecule.
What are echinocytes?
Red blood cells with thorny projections.
What is the Coombs test used for?
To determine if there are antibodies against red blood cells leading to their premature destruction (autoimmune hemolytic anemia).
What laboratory findings indicate chronic extravascular hemolytic syndrome?
Normocytic anemia with elevated reticulocytes, possible splenomegaly, low haptoglobin, high total bilirubin (mostly indirect).
What is hereditary spherocytosis?
An inherited normochromic anemia caused by mutations in genes leading to red blood cell membrane defects.
What is the prevalence of pyruvate kinase deficiency?
Estimated prevalence of 1 in 300,000 live births, an autosomal recessive disorder.
What are the early signs of pyruvate kinase deficiency in infancy?
Prolonged neonatal jaundice associated with normochromic hemolytic anemia.
How is ATP availability maintained in red blood cells?
Red blood cells generate energy through glycolysis using glucose, as they lack mitochondria.
How does glycolysis generate energy from glucose?
Glycolysis occurs in the cytosol, converting glucose into pyruvate and generating ATP.
How is energy generated from glucose?
Glycolysis occurs in the cytosol. Glucose enters cells via GLUT transporters. Erythrocytes use GLUT1. Hexokinase phosphorylates glucose to glucose 6-phosphate, trapping it in the cell. Fructose 6-phosphate is formed and phosphorylated to fructose 1,6-bisphosphate by phosphofructokinase 1 (PFK1), using 2 ATP. This phase is known as the energy investment phase. PFK1 is the committed step enzyme. The molecule splits into dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. The energy-generating phase follows, oxidizing glyceraldehyde-3-phosphate using NAD+. Two substrate-level phosphorylation steps yield 4 ATP and 2 pyruvate. Pyruvate kinase catalyzes the formation of pyruvate from phosphoenolpyruvate, another regulated enzyme. The net yield is 2 ATP and 2 NADH with 2 pyruvate.
What is the net energy yield from glycolysis?
2 ATP and 2 NADH along with 2 pyruvate molecules.
What happens to pyruvate in aerobic conditions?
Pyruvate enters mitochondria, is converted to acetyl CoA, and oxidized to CO2 via the TCA cycle and electron transport chain to form ATP.
What is the oxaloacetate-malate shuttle?
NADH transfers electrons into mitochondria by reducing oxaloacetate to malate, which regenerates NAD+ for glycolysis.
How many ATP molecules can be produced from the complete oxidation of glucose?
Up to 36 ATP molecules in aerobic metabolism.
What is anaerobic glycolysis?
The process where pyruvate is reduced to lactate to regenerate NAD+ in the absence of oxygen.
How does pyruvate kinase deficiency affect red blood cells?
It causes decreased ATP production, affecting the Na+/K+ ATPase pump, leading to cellular dehydration and hemolysis.
What are the consequences of pyruvate kinase deficiency?
Loss of osmotic balance, loss of biconcave shape, formation of echinocytes, and extravascular hemolysis.
What other reactions in red blood cells require ATP?
- Conversion of glucose to glucose 6-phosphate
- De novo synthesis of glutathione
What is the role of glutathione in red blood cells?
It protects cells from oxidative stress.
How does a decrease in NADH affect red blood cells in pyruvate kinase deficiency?
It results in less lactate production and a buildup of methemoglobin, reducing oxygen delivery to tissues.
What is 2,3-bisphosphoglycerate (2,3-BPG)?
An allosteric regulator of hemoglobin that decreases oxygen affinity, facilitating oxygen release to tissues.
Why are only red blood cells affected in pyruvate kinase deficiency?
PKD affects the PKR isoform, which is unique to mature red blood cells, while other tissues maintain normal PK activity.
What characterizes pyruvate kinase deficiency?
It is a nonspherocytic hemolytic anemia presenting with prolonged jaundice, splenomegaly, and iron overload.
What is Wernicke encephalopathy?
Acute or subacute confusion or delirium due to thiamine deficiency.
What is Korsakoff syndrome?
Persistent and irreversible dementia associated with thiamine deficiency.
What is the role of thiamine pyrophosphate?
It is a cofactor for key enzymes in glycolysis and the TCA cycle.
What are the symptoms of chronic malnutrition in the case presented?
Extreme fatigue, disorientation, muscle wasting, and poor dentition.
What neurological findings were observed in the patient?
Lateral rectus gaze palsy, resting tremor, decreased sensation in lower extremities, and broad-based gait.
What is delirium tremens?
Sudden and severe mental changes due to severe alcohol withdrawal.
What is the clinical impression regarding the patient’s condition?
Chronic progressive deterioration over many months with generalized decline in health, possibly due to poor nutrition and alcohol abuse, suggesting generalized encephalopathy.
Consideration of head trauma, CNS mass lesions, infections, and metabolic disturbances.
What key laboratory tests were requested for the patient?
Laboratory studies including blood alcohol level, serum ammonia level, serum albumin, and prothrombin time.
A CAT scan of the head was also requested to exclude lesions.
What does a low serum albumin and prolonged prothrombin time indicate?
Markers of failing hepatic synthetic function in end-stage liver disease.
These findings support chronic liver disease and malnutrition.
What are the main symptoms of thiamine deficiency?
Wernicke encephalopathy and Korsakoff syndrome, leading to neuropsychiatric conditions.
Symptoms include behavioral disturbances, memory impairment, and ataxia.
What is the role of thiamine in metabolism?
Cofactor for alpha keto dehydrogenase complexes and transketolase, essential for energy metabolism.
Involves oxidative decarboxylation of alpha keto acids.
What is the function of the pyruvate dehydrogenase complex?
Catalyzes conversion of pyruvate to acetyl CoA, linking glycolysis to the TCA cycle.
Important for energy metabolism and ATP synthesis.
What happens to the TCA cycle during thiamine deficiency?
Activity of alpha ketoglutarate dehydrogenase is reduced, slowing down the TCA cycle.
Leads to insufficient ATP production and symptoms in high-energy tissues.
What is the consequence of branched-chain α-keto acid dehydrogenase deficiency?
Accumulation of leucine, isoleucine, and valine, leading to neurotoxic metabolites.
Associated with maple syrup urine disease (MSUD).
What is the function of transketolase in metabolism?
Catalyzes transfer of carbon units in the hexose monophosphate pathway, essential for synthesizing NADPH and ribose-5-phosphate.
NADPH is crucial for cholesterol and fatty acid synthesis.
Fill in the blank: Thiamine deficiency can lead to _______ syndrome.
Wernicke
This condition is characterized by neurological symptoms related to thiamine deficiency.
What laboratory findings suggest chronic liver disease in the patient?
Low serum albumin, mildly deranged PT/INR, and abnormal transaminases.
These findings indicate potential malnutrition and liver dysfunction.
True or False: Thiamine is a fat-soluble vitamin.
False
Thiamine is a water-soluble vitamin easily depleted from the body.
What is a potential complication of prolonged thiamine deficiency?
Korsakoff syndrome, which includes memory impairment and confabulation.
It is a permanent condition resulting from chronic thiamine deficiency.
What are the signs of Wernicke encephalopathy?
Behavioral disturbances, lateral gaze palsy, nystagmus, ataxia, and tremor.
These symptoms are indicative of thiamine deficiency affecting the CNS.
What are the major functions of the hexose monophosphate pathway?
Synthesis of NADPH and ribose-5-phosphate
Ribose-5-phosphate is required for nucleic acid synthesis, while NADPH is essential for cholesterol and fatty acid synthesis.
What is the role of NADPH in cellular metabolism?
Reducing power for the synthesis of cholesterol and fatty acids and maintenance of reduced glutathione
NADPH is required by the glutathione peroxidase-reductase system.
What does transketolase do in the hexose monophosphate pathway?
Catalyzes the transfer of 2-carbon fragments for monosaccharide interconversion
It is part of the nonoxidative branch of the pathway.
What are the two reactions catalyzed by transketolase?
- Transfers 2-carbons from xylulose 5-phosphate to ribose-5-phosphate forming glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate
- Transfers 2-carbons from xylulose 5-phosphate to erythrose 4-phosphate forming glyceraldehyde 3-phosphate and fructose 6-phosphate
How does transketolase connect glycolysis and the hexose monophosphate pathway?
Acts as a bridge by transferring 2-carbon fragments
This allows for the interconversion of monosaccharides.
What medical follow-up was arranged for the patient?
Medical follow-up and psychiatric services
Social service evaluation was conducted to improve living conditions.
Which cranial nerve palsy resolved first in the case evaluated?
6th cranial nerve palsy (ophthalmoplegia)
This resolution occurred before mental status changes and amnesia.
What condition is described as irreversible and leads to dementia after long-term alcohol abuse?
Korsakoff syndrome
It is associated with nutritional deprivation.
What is thiamine’s role in the conversion of pyruvate to acetyl CoA?
Necessary cofactor in the reaction catalyzed by pyruvate dehydrogenase
This enzyme links glycolysis with the TCA cycle.
What is the consequence of thiamine deprivation?
Can lead to beriberi quite rapidly
Thiamine is a water-soluble B vitamin.
In which part of the metabolic pathway is thiamine also a coenzyme?
TCA cycle as a coenzyme for alpha-ketoglutarate dehydrogenase
Which tissues are particularly susceptible to damage due to TCA cycle inhibition?
Tissues requiring significant amounts of ATP for energy
Includes the 6th CN nucleus, pons, cerebellum, and higher-level executive function.
What symptoms did the 2-year-old child present with?
Fever, vomiting, diarrhea, lethargy, cool extremities, tachycardia, weak cry
The child was evaluated at home by EMTs and showed signs of significant illness.
What was the initial glucose level found in the child?
30 mg/dL
This hypoglycemic level prompted immediate glucose replacement.
What is MCADD?
Medium-chain acyl CoA dehydrogenase deficiency, the most common fatty acid oxidation disorder
MCADD is significant in the context of fatty acid oxidation disorders.
What are fatty acids an energy source for?
Heart, skeletal muscle, gut, and indirectly for the brain during starvation
The brain and red blood cells depend exclusively on glucose.
What is the role of the carnitine shuttle?
Allows transport of long-chain fatty acids into the mitochondrial matrix for β-oxidation
This process is essential for fatty acid metabolism.
What is primary carnitine deficiency caused by?
Defective plasma carnitine transporter
Secondary carnitine deficiency can result from other metabolic disorders.
What are the cardinal symptoms of carnitine deficiency?
- Encephalopathy
- Cardiomyopathy
- Myotonic weakness
- Vomiting
- Confusion
- Muscle weakness
- Hypoglycemia
These symptoms typically manifest in infancy and childhood.
What should be included in newborn screening?
Inborn errors of metabolism, including fatty acid oxidation disorders
Early identification can prevent irreparable damage.
What is the differential diagnosis for hypoglycemia in a child?
- Sepsis
- Toxins
- Ketotic hypoglycemia
- Endocrine disorders
- Inborn errors of metabolism
Hypoglycemia can have various underlying causes.
What is indicated by elevated transaminases and CPK in the context of hypoglycemia?
Possibility of a disorder of fatty acid oxidation
These lab findings are crucial for differential diagnosis.
What is the hallmark of fatty acid oxidation disorders?
Hypoketotic hypoglycemia
This is a key finding in diagnosing these disorders.
Which fatty acid oxidation disorder is indicated by accumulation of octanoylcarnitine (C8)?
Medium-chain acyl CoA dehydrogenase deficiency (MCADD)
This finding is critical for diagnosis.
How is energy harvested from fatty acids?
Through β-oxidation in the mitochondria, producing acetyl-CoA
Acetyl-CoA enters the TCA cycle for further energy generation.
What stimulates the hydrolysis of triacylglycerols in adipose tissue?
Glucagon or epinephrine
This process releases free fatty acids into circulation.
What is the role of carnitine in fatty acid metabolism?
Transports long-chain fatty acids into mitochondria
Carnitine is essential for the activation and transport of fatty acids.
What is the significance of a normal insulin level in the context of hypoglycemia?
Excludes insulin hypersecretion or insulinoma
This finding helps narrow down the differential diagnosis.
What does an elevated anion gap indicate?
Presence of unmeasured anions in serum
Common causes include ketoacidosis, lactic acidosis, renal failure, and toxic ingestions.
What does lactic acidosis indicate in a child?
Hallmark of mitochondrial diseases
It can also be elevated in fructose intolerance and glycogen storage disorders.
What is the result of the carnitine shuttle process?
Long-chain fatty acids are converted to acylcarnitine and transported into mitochondria
This is essential for subsequent β-oxidation.
What is the first step in the carnitine shuttle?
Conversion of long-chain acyl CoA to acylcarnitine by CPT1
This step is rate-limiting and regulated by malonyl CoA.
What is the role of carnitine:acylcarnitine translocase (CACT)?
CACT transports acylcarnitine into the mitochondrial inner membrane
What does carnitine palmitoyltransferase 2 (CPT2) do?
CPT2 reactivates acylcarnitine back to long-chain acyl-CoA
What is the rate limiting step in fatty acid oxidation?
The CPT1 reaction
What negatively regulates CPT1?
Malonyl CoA
What is the committed step of fatty acid synthesis?
Formation of malonyl CoA by acetyl CoA carboxylase
What happens to fatty acids when malonyl CoA levels are high?
Long-chain fatty acids are prevented from entering mitochondria for β-oxidation
What are ketone bodies?
Water-soluble molecules derived from acetyl CoA produced by fatty acid β-oxidation
List the three types of ketone bodies.
- Acetoacetate
- β-hydroxybutyrate
- Acetone
When are ketone bodies used as energy sources?
During fasting, low carbohydrate diets, starvation, prolonged high intensity exercise, and certain disease states
What is the primary source of glucose during fasting?
Gluconeogenesis
What is the first step in ketone body synthesis?
Condensation of three acetyl CoA molecules to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA)
What enzyme cleaves HMG CoA to produce ketone bodies?
HMG CoA lyase
What is the characteristic smell associated with ketosis?
Fruity smell due to acetone
What enzyme converts ketone bodies back to acetyl CoA?
Succinyl CoA acetoacetate transferase
Which organ primarily regulates blood glucose levels?
The liver
What is the energy requirement for gluconeogenesis?
6 ATP to make one glucose molecule
What substrates are predominantly used in gluconeogenesis?
- Lactate
- Alanine
- Glycerol
What happens to pyruvate in a high energy state?
It is converted to oxaloacetate by pyruvate carboxylase
What occurs when someone with fatty acid oxidation disorder becomes ill?
They become dependent on gluconeogenesis for glucose synthesis
Why does a defect in fatty acid oxidation cause hypoglycemia?
The brain’s demand for glucose increases while fatty acid oxidation is impaired
What happens to medium-chain fatty acids in MCAD deficiency?
They accumulate and are esterified with carnitine
What is the result of elevated medium-chain fatty acids in the serum?
Elevation of dicarboxylic acids due to omega oxidation
How many types of fatty acid oxidation disorders exist?
More than 20
What are the three major classes of fatty acid oxidation disorders?
- Disorders of transport of fatty acid uptake and the carnitine shuttle
- Acyl dehydrogenase deficiencies
- Disorders of synthesis of ketone bodies
What are the three major classes of fatty acid oxidation disorders?
- Disorders of transport of fatty acid uptake and the carnitine shuttle
- Acyl dehydrogenase deficiencies
- Disorders of synthesis of ketone bodies
What are common symptoms of fatty acid oxidation disorders?
Fasting hypoketotic hypoglycemia, liver failure, hepatic encephalopathy
What distinguishes deficiencies in muscle-specific carnitine shuttle enzymes (CPT I and CPT II)?
Leads to rhabdomyolysis, cardiomyopathy, and elevation of serum creatine kinase during exercise
What is the recommended dietary approach for children with fatty acid oxidation disorders?
Low fat diet, avoid fasting for more than 10-12 hours, frequent carbohydrate-rich drinks
What clinical findings may indicate fatty acid oxidation disorders?
Accumulation of acylcarnitines, dicarboxylic acids, and acylglycines
What is the role of the carnitine shuttle in fatty acid metabolism?
Facilitates the transport of long-chain fatty acids into the mitochondria
What are the effects of prolonged fasting or GI illness in patients with fatty acid oxidation disorders?
Carbohydrate sources of energy are exhausted, leading to hypoglycemia
What laboratory findings can help distinguish fatty acid oxidation disorders?
Specific laboratory findings are detailed in Table 5.11
What is dystonia?
A movement disorder characterized by sustained or intermittent muscular contractions, repetitive movements, rigidity, and tremor
What are red ragged fibers?
Diagnostic finding for mitochondrial disorders, indicating subsarcolemmal accumulation of mitochondria
What is ubiquitination?
The addition of ubiquitin to a protein, affecting its activity, interactions, and labeling it for degradation
What is the significance of maternal inheritance in mitochondrial disorders?
Mitochondria are only passed on by the mother, leading to inheritance patterns that can reveal mitochondrial diseases
What is the typical structure of mitochondria?
Composed of two membranes: an outer membrane and an inner mitochondrial membrane, with a matrix that contains mtDNA
What is the primary function of the inner mitochondrial membrane?
Site of the electron transport chain responsible for oxidative phosphorylation
What is the mutation rate of mtDNA compared to nuclear DNA?
10-20 times greater
What is the consequence of the high mutation rate of mtDNA?
Gradual decline in mitochondrial efficiency throughout adulthood
What type of genetic material does mtDNA code for?
13 polypeptide chains involved in oxidative phosphorylation, as well as tRNA and rRNA
Fill in the blank: Fatty acid oxidation involves the progressive cleavage of _______ fragments from fatty acids.
2 carbon
True or False: Fatty acid oxidation disorders can be detected by newborn screening.
True
What biochemical findings suggest a mitochondrial disorder in a patient?
Elevated transaminases, ammonia, and lactic acid levels
What is the role of muscle biopsy in diagnosing mitochondrial diseases?
Confirms mitochondrial disease through deficient staining of cytochrome oxidase and presence of ragged-red fibers
What is the A3243G mutation associated with?
Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS)
What is the role of nuclear DNA in mitochondrial function?
Codes for the majority of proteins required for mitochondrial function, which are imported into the mitochondria
What are the implications of mitochondrial genetics having a high mutation rate?
Increased variability in clinical symptoms of mitochondrial diseases
What is the defining characteristic of the genetics of mtDNA?
It is characterized by maternal inheritance.
Mitochondria are only passed on by the mother, as sperm mtDNA is removed during transport through the male reproductive tract.
What is homoplasmy?
The process by which all mtDNA molecules are composed of a pure population of normal mtDNA or a pure population of mutant mtDNA.
Contrast with heteroplasmy, which involves a mixture of mutant and normal mtDNA.
What is heteroplasmy?
When there is a mixture of mutant and normal mtDNA in the same cell.
This can lead to variability in manifestations of mitochondrial disorders.
Which tissues have very high ATP requirements?
- Cardiac muscle
- Skeletal muscle
- Central nervous system (CNS)
These tissues require higher oxidative phosphorylation for cell viability.
What happens when the number of normal mtDNA drops below the threshold level in a heteroplasmic cell?
Respiration and ATP synthesis may be insufficient, leading to cell death.
How do mitochondrial diseases typically arise?
Due to chronic disruption in aerobic energy production.
This leads to unmet cellular energy needs and clinical phenotypes.
What are the characteristic clinical features of defects in mtDNA?
- Maternal inheritance pattern
- Variability among family members and in affected tissues
- Late onset of the disease with lactic acidosis
Why does lactic acidosis typically occur in mitochondrial disorders?
Dysfunction in the electron transport chain leads to decreased ATP production and increased NADH levels, causing a buildup of pyruvate and lactate.
What histological feature is associated with many mitochondrial disorders?
Ragged red fibers (RRFs).
These fibers are indicative of mitochondrial disease but are observed in only 30% of cases.
What laboratory findings indicate liver dysfunction in mitochondrial disease?
- Elevated ammonia
- Elevated liver enzymes
- Hepatomegaly
What is the mainstay of treatment for mitochondrial disease at this time?
Supportive therapy, including vitamins and supplements for mitochondrial support.
What is the clinical spectrum of mitochondrial disease characterized by?
Variability due to different tissue functions and energy requirements.
What factors contribute to the penetrance and clinical severity of mitochondrial disorders?
The number of defective mitochondria transmitted during early cell division in the embryo.
What is metabolic stroke in the context of mitochondrial disorders?
Damage to the brainstem and cortex that is nonthrombotic.
May be explained by nitrous oxide deficiency and microvascular damage.
What are the key laboratory findings in mitochondrial disorders?
- Hepatomegaly
- Elevated transaminases
- Elevated ammonia levels
- Lactic acidosis
What is the role of ATP in the urea cycle?
The urea cycle requires ATP for proper function, and reduced ATP production in mitochondrial disease leads to dysfunctional urea synthesis.
What are ragged red fibers and what do they indicate?
They are muscle fibers with mitochondrial proliferation indicative of mitochondrial disorders.
What is the effect of age on mtDNA mutations?
The number of mtDNA mutations increases with age, leading to a decline in oxidative phosphorylation.
What is the clinical presentation of tissue damage in mitochondrial diseases?
Damage is most prominent in high-energy tissues such as the brain, heart, and skeletal muscle.
What does a lack of cytochrome C oxidase staining indicate?
It is indicative of a mtDNA defect.
What is the significance of elevated TSH in a patient?
It indicates primary thyroid gland failure, likely Hashimoto thyroiditis.
What is the most appropriate initial diagnostic study for fatigue and depression in a female patient?
Thyroid-stimulating hormone.
What elevated level is key to diagnosing encephalopathy in adults?
Elevated ammonia level
Normal BUN in conjunction with elevated ammonia is crucial for diagnosis.
Is hypoglycemia after vigorous exercise a symptom of hypothyroidism?
No
Hypoglycemia after exercise relates to disorders of energy mobilization.
What does a nonketotic hypoglycemic episode after fasting in an infant indicate?
Fatty acid oxidation disorder
Characteristic finding in such cases.
What does the presence of ketone bodies like β-hydroxybutyrate indicate?
Not increased in nonketotic hypoglycemia
This finding is associated with other metabolic disorders.
What condition is indicated by prolonged neonatal jaundice due to hemolysis?
Pyruvate kinase or glucose 6-phosphate dehydrogenase deficiency
Suggestive of hemolytic processes.
What is Wernicke encephalopathy associated with?
Alcoholism, malnutrition, and thiamine deficiency
Treatment involves glucose and thiamine administration.
What is Tarui disease caused by?
Mutations in the PFKM gene
Leads to total loss of PFK activity in muscle.
What is the result of irreversible membrane injury in pyruvate kinase deficiency?
Chronic hemolytic anemia
This leads to bilirubin accumulation and gallstone formation.
What suggests mitochondrial disease in a patient?
Clinical features and family history
Mitochondria have their own genome coding for essential proteins.
What does hypoketotic hypoglycemia indicate in a patient?
Mitochondrial HMG-CoA synthase deficiency
Normal fatty oxidation in cultured cells supports this diagnosis.
What is the treatment for Wernicke-Korsakoff syndrome?
Thiamine (vitamin B1) and glucose
Thiamine is a cofactor for several key metabolic enzymes.
What does a high TSH level indicate?
Primary hypothyroidism
Indicates a failing thyroid gland.
What is the next confirmatory test for hypothyroidism after TSH?
Free thyroxine (T4) levels
Decreased FT4 levels confirm hypothyroidism.
True or False: Antithyroid peroxidase antibody indicates hypothyroidism.
False
Its presence indicates Graves disease and hyperthyroidism.
