Clinical Correlations Flashcards
How does a patient present when they have too low of fatty acid catabolism?
Fatty acid catabolism is meant to provide alternative to glucose for ATP production during fasting/
Liver unable to conduct gluconeogenesis (low ATP)
Insulin responsive tissues keep burning glucose instead of fat during fasting
Fasting hypoglycemia with absence/low ketones and metabolic acidosis
How does a patient present when they have too high of fatty acid metabolism?
Fatty acid metabolism supposed to be shut off in fed state.
Insulin insufficiency (diabetes) lead to fatty acid mobilization in fed state
Hyperlipidemia with high concentration of ketones
What are disorders of Mitochondrial fatty acid import and how do patients present?
Defects in any part of carnitine shuttle affect muscle function because muscle uses FA even in fed state. Defects range from cramping to cardiomyopathy, death in infancy.
Fasting hypoglycemia
Genetic: CPTI and CPTII deficiency
Genetic/Nutritional: Primary carnitine deficiency - strict vegetarian diet so poor uptake and transport of carnitine
How do patients present with Beta-Oxidation disorders?
MCAD deficiency is most common FA degradation disorder - Medium Chain Acyl-CoA dehydrogenase
Results in hypoketotic fasting hypoglycemia
Accumulation of C6-C12 FA in urine, acyl-carnitines in blood
Zellweger Syndrome
Mutation in PEX gene. Peroxisome biogenesis disorder
Results in multiple developmental abnormalities. No peroxisomes in liver
Dx: Accumulation of very long chain fatty acids in blood
Refsum Disease
Alpha-Oxidation Deficiency. Peroxisome Biogenesis Disorder
Multiple developmental abnormalities
Dx: Accumulation of phytanic acid in blood
Primary Dyslipidemia
Abnormal Concentration of serum lipids.
Congenital disorders caused by mutations in lipoprotein metabolism - common in children, inherited by affected parent
What do defects in lipoprotein synthesis cause?
Hypolipidemia
What do defects in lipoprotein unloading cause?
Hyperlipidemia
Elevated TG and/or cholesterol
Risk of cardiovascular disease
Patient presents with corneal arcus. Family history of hypercholesteremia. Physical examination shows fatty deposit on Achilles tendon and knuckles. Lab shows 2x elevated cholesterol and normal TG. What lipoprotein is affected?
LDL because they mainly carry cholesterol.
This is Fredrickson IIa.
LDL could be elevated for many reasons such as
- Does not bind to receptor
- Receptor defective -> familial hypercholesteremia
- ApoB100 defective - familial defect ApoB100 or phenocopy of FH (detection of mutation)
What if a patient present with high TG and cholesterol? What lipoproteins could be affected?
LDL
VLDL
chylomicron remnants
What if a patient presents with elevated TG? What lipoprotein is impacted?
Chylomicrons and VLDL
What are secondary dyslipidemias?
Consequences of other metabolic disorders or disturbances.
Most frequent in adult
Often caused by poor diet, diabetes, alcohol abuse
Hypercholesterolemia
High LDL
Raises cardiovascular risk
Primary hypercholesterolemia - present in infancy
Secondary hypercholesterolemia - presents in adulthood, sedentary lifestyle, cholesterol rich diet, smoking
Statin drugs lower LDL by inhibiting endogenous cholesterol synthesis
Patient presents with complaints of sharp pain in upper right quadrant of abdomen and nausea. Jaundice, elevated serum bilirubin, elevated alkaline phosphatase.
Labs indicate cholestasis - flow of bile impaired. Bilirubin and AP not secreted into gut
Gallstones - contain cholesterol, bile acids, phospholipids, and bilirubin. Caused most often by precipitation of cholesterol
How does plasmalogen levels related to Alzheimer Disease?
Low levels of plasmalogen were found to be correlated with severity of AD.
Plasmalogen is an abundant phospholipid and enriched in CNS and brain
Gaucher Disease
Sphingolipid disorder and lysosomal storage disease.
Patient presents with splenomegaly and bone pain. Bone marrow biopsy shows Gaucher cells (macrophages filled with undegraded sphingolipids)
White blood cells show low glucocerebroside activity
How does a patient present with lysosomal storage diseases?
Congenital, progressive, and recessive disorders.
Generally involve the spleen since it is lysosomal rich.
Sphingolipidosis - accumulation of lipids often in brain
Mucopolsaccharidoses - Accumulation of acidic carbohydrate (GAG)
Less common - Pompe which is accumulation of glycogen
What do steroids, NSAIDs, and LOX inhibitors suppress?
Eiconsanoid signaling!
What are some eicosanoids?
Prostaglandins - mediate inflammation and pain
Thromboxanes - facilitate blood clotting
Leukotrienes - mediate asthma and allergy
Acute Pancreatitis
Patient presents with abdominal pain, nausea, vomiting, pancreatic necrosis if advanced
Caused by alcohol, gallstones, infections. Premature activation of trypsin within the pancreas
Patient present with abdominal pain and cramping upon consuming gluten and nutrient deficiency.
Celiac Disease
Causes are incomplete digestion of gluten. due to loss of brush border peptidase, alpha-gliadin triggers inflammatory response, and a loss of villi and flat small intestines
Treat with gluten free diet
Hartnup Disease
Caused by deficiency in sodium dependent transporter of neutral amino acids across the intestine and kidney membranes.
Impacts the intestinal absorption of amino acids and kidney reabsorption of amino acids
Symptoms include pellagra like light sensitive rash (lack of tryptophan, precursor of niacin) and neutral amino acid aciduria
What lab test informs us about liver damage?
ALT - Alanine amintotransferase
Patient present with elevated levels of homocysteine in urine.
Homocystinuria
Caused by defect in cystathionine Beta-synthase which converts homocysteine to cystathionine
Cystathioninuria
Rare autosomal disorder in gene encoding cystathionine gamma-lyase which converts cystathionine to cysteine
Patient presents with elevated levels of cystathionine in blood and urine
Phenylketonuria
Caused by genetic defect in phenylalanine hydroxylase (more common) or in DHBtn reductase
Dx metabolites: Phenylpyruvate and phenylalanine
Symptoms include intellectual disability, recurrent seizures, and hypopigmentation
What is the mechanism of Phenylketonuria?
Accumulation of Phenylalanine competitively inhibits the transport of other amino acids across blood brain barrier and so interferes with neurotransmitter synthesis
Can impact formation of myelin, dopamine
Phe is competitive inhibitor of tyrosinase and so interferes with melanin (skin pigment)
What is the treatment for phenylketonuria?
Newborn screening
Low dietary Phe
Supplement with tyrosine
Why is aspartame toxic to people with phenylketonuria?
Aspartame is an artificial sweetener made of aspartate and phenylalanine
So when it is degraded, it releases Asp, Phe, and methanol
The Phe is toxic to people with PKU
Symptoms include elevated glycine, seizures, lethargy, and lack of muscle tone (hypotonia)
Glycine Encephalopathy
Mutations in glycine cleavage system
Known as nonketotic hyperglycemia
Familial Hyperinsulinemic Hypoglycemia Type 6 (HHF6)
Caused by rare mutation in GLUD1 that encodes GDH
Glutamate dehydrogenase become insensitive to GTP inhibition
Symptoms appear during high protein meal.
Leads to hyperammonemia - elevated ammonia levels, less N-acetylglutamate for urea cycle
Hypoglycemia - increased ATP promotes insulin releases
Propionic Acidemia
Loss of propionyl-CoA carboxylase
Accumulation of propionic acid because of increased propionyl-CoA (not being broken down)
Symptoms incudes metabolic acidosis leading to severe ketoacidosis, vomiting, rapid breathing, and lethargy
Methylmalonic aciduria
Caused by either defect in mutase or deficiency in Vitamin B12 results in accumulation of methylmalonate in serum and urine.
Mutase with Vit B12 converts L-methylmalonyl-CoA to succinylCoA
Vitamin B12
Water soluble
Bacteria is only source but can be found in animal products of ruminants
What are the types of Vitamin B12 deficiencies?
Actual B12 deficiency - Lack of B12 in diet
Functional B12 deficiency - Inability to absorb or metabolize B12
Pernicious Anemia - lack of intrinsic factor that binds B12 in ileum. Can cause organ specific autoimmune disease and is dx by presence of antibodies against the intrinsic factor
What is the biochemical basis of Vit B12 deficiency?
Non-functional methionine synthase causes trapping of THF as N5-methyl-THF. This leads to decrease in N5N10-methylene THF and blocks DNA replication
Folate can restore purine and thymidine synthesis but cannot prevent homocysteine synthesis
Non-functional mutase (catabolism of Ile, Val, Thr, Met) causes accumulation of methylmalonate and malonate. Folate cannot prevent methylmalonate accumulation.
What is the clinical basis of Vitamin B12 deficiency?
Megaloblastic anemia - Impairment of DNA synthesis causes production of marge, immature, hemoglobin poor red blood cells in bone marrow
Demyelination
Atherosclerosis - high homocysteine
Dx metabolites: methylmalonate, methylmalonyl-CoA, and homocysteine
Maple Syrup Urine Disease
Deficiency in branched chain keto acid dehydrogenase (BCKDH)
Dx metabolites: High branched chain amino acids in blood and high branched chain ketoacids in the urine
Symptoms include maple syrup odor of urine (branched chain alpha keto acids) and brain edema
Tyrosinemia II
Inborn error in tyrosine degradation pathway. Loss of tyrosine aminotransferase which converts tyrosine to 4-hydroxyphenol pyruvate
Symptoms include keratitis and photophobia
Treat with diet low in Phe and tyrosine
Patient presents with black urine and joint destruction. Patient has elevated levels of homogentisate and alkaptone
Alkaptonuria
Loss of homogentisate oxidase
Treatment with nitisinone - inhibits conversion of 4-hydroxyphenopyruvate to homogentisate
Tyrosinemia I
Inborn error in tyrosine degradation
Loss of fumarylacetoacetate hydrolase
Dx Metabolites: Succinylacetone
Early Step Urea Cycle Enzyme Deficiencies
More severe
Deficiency in either carbamoyl phosphate synthetase I or ornithine transcarbamoylase
Resuls in severe hyperammonemia
Late step urea cycle enzyme deficiencies
Less toxic
Citrullinemia - loss of argininosuccinate synthetase. Dx metabolite is citrulline
Argininogsuccinic Aciduria - loss of argininosuccinate lyase. Dx metabolite is argininosuccinate
Hyperargininemia - loss of arginase, Dx metabolite is arginine
How are patients with early urea cycle disorder treated?
Protein restriction
Removal of ammonia ions independent of urea formation - phenylbutyrate and benzoate form water soluble conjugates with glutamine and glycine
Liver transplant
How are patient treated with late urea cycle disorders?
Dietary intervention - supplement with arginine
Removal of ammonia ions independent of urea formation - phenylbutyrate and benzoate form water soluble conjugates with glutamine and glycine
What can indicate kidney impairment?
Changes in serum creatinine
How do patients with creatine metabolism disorders present?
Children present with hypotonia
Variety of neurological symptoms - seizures, intellectual disability
Treat with creatine
Parkinson’s Disease
Degeneration of dopaminergic neurones
Usually in people over 60
Loss of involuntary muscle control
Relief by administration of DOPA
Oculocutaneous albinism type I (OCA1)
Most common
Loss of function of tyrosinase so inability to synthesize melanin in skin, hair, and eyes
Complications include impaired vision and early appearance of skin tumors
Pellagra
Diets lows in niacin, tryptophan, or cofactors required for niacin synthesis
Hartnup - Uptake of certain amino acids from blood and reabsorption by kidney blocked. pellagra can result, treated with high protein/niacin diet.
Dry PEU - Marasmus
Patient starves for glucose and protein
Wet PEU, Edema - Kwashiorkor
Starves severely for protein
Labs may show low albumin, transferrin, white blood cell count. Patient may present with lethargy and weakness
Cachexia
Involuntary Weight Loss. Comorbidity of cancer and other wasting diseases (COPD, heart disease, kidney disease)
Type II Diabetes
Inadequate insulin response
Patient complains of thirst and frequent urination and increased dizziness. Physical exam shows patient is overwieght with signs of dehydration
Acanthosis nigricans in neck region. High blood sugar and serum insulin is elevated
Treat by suppressing gluconeogenesis, lipolysis
Type I Diabetes
Inadequate insulin secretion
Patient experiences thirst and frequent urination. Dehydration, dizziness, and abdominal pain. Insulin level is low
Treat with insulin
What are common complications of diabetes?
Hyperglycemia - damages blood vessels and starves tissues
Retinopathy - leads to blindness
Nephropathy - chronic renal failure
Neuropathy - numbness
What are molecular causes of insulin resistance?
Inhibitory phosphorylation of IRS proteins
Loss of FoxO1a inhibition
Low PDK1 activity
How does a patient present with Hyperinsulinemia?
Hypoketotic hypoglycemia
Inappropriately high insulin
Supress fatty acid metabolism
What are biochemical markers for Diabetes Management?
Glycated Hemoglobin - HbA1c - less than 5.7%
C Peptide - indicates endogenous insulin production
Beta cell specific antibodies - glutamic acid decarboxylase antbodies indicate autoimmune reaction against beta cells
