Fat-soluble vitamin deficiency and toxicity: Pathology review

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Fat-soluble vitamin deficiency and toxicity: Pathology review

NBME

NBME

Amino acid metabolism
Nitrogen and urea cycle
Citric acid cycle
Electron transport chain and oxidative phosphorylation
Gluconeogenesis
Glycogen metabolism
Glycolysis
Pentose phosphate pathway
Physiological changes during exercise
Cholesterol metabolism
Fatty acid oxidation
Fatty acid synthesis
Ketone body metabolism
Alkaptonuria
Cystinuria (NORD)
Hartnup disease
Homocystinuria
Maple syrup urine disease
Ornithine transcarbamylase deficiency
Phenylketonuria (NORD)
Essential fructosuria
Galactosemia
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Hereditary fructose intolerance
Lactose intolerance
Pyruvate dehydrogenase deficiency
Abetalipoproteinemia
Familial hypercholesterolemia
Hyperlipidemia
Hypertriglyceridemia
Glycogen storage disease type I
Glycogen storage disease type II (NORD)
Glycogen storage disease type III
Glycogen storage disease type IV
Glycogen storage disease type V
Mucopolysaccharide storage disease type 1 (Hurler syndrome) (NORD)
Mucopolysaccharide storage disease type 2 (Hunter syndrome) (NORD)
Fabry disease (NORD)
Gaucher disease (NORD)
Krabbe disease
Leukodystrophy
Metachromatic leukodystrophy (NORD)
Niemann-Pick disease type C
Niemann-Pick disease types A and B (NORD)
Tay-Sachs disease (NORD)
Cystinosis
Disorders of amino acid metabolism: Pathology review
Disorders of carbohydrate metabolism: Pathology review
Disorders of fatty acid metabolism: Pathology review
Dyslipidemias: Pathology review
Glycogen storage disorders: Pathology review
Lysosomal storage disorders: Pathology review
Carbohydrates and sugars
Fats and lipids
Proteins
Excess Vitamin A
Excess Vitamin D
Vitamin D deficiency
Vitamin K deficiency
Kwashiorkor
Marasmus
Iodine deficiency
Zinc deficiency
Beriberi
Folate (Vitamin B9) deficiency
Niacin (Vitamin B3) deficiency
Vitamin B12 deficiency
Vitamin C deficiency
Wernicke-Korsakoff syndrome
Fat-soluble vitamin deficiency and toxicity: Pathology review
Water-soluble vitamin deficiency and toxicity: B1-B7: Pathology review
Zinc deficiency and protein-energy malnutrition: Pathology review
Cell membrane
Cell signaling pathways
Cell-cell junctions
Cellular structure and function
Cytoskeleton and intracellular motility
Endocytosis and exocytosis
Extracellular matrix
Nernst equation
Osmosis
Resting membrane potential
Selective permeability of the cell membrane
Alport syndrome
Ehlers-Danlos syndrome
Marfan syndrome
Osteogenesis imperfecta
Primary ciliary dyskinesia
Adrenoleukodystrophy (NORD)
Zellweger spectrum disorders (NORD)
Cytoskeleton and elastin disorders: Pathology review
Peroxisomal disorders: Pathology review
DNA cloning
ELISA (Enzyme-linked immunosorbent assay)
Fluorescence in situ hybridization
Gel electrophoresis and genetic testing
Karyotyping
Polymerase chain reaction (PCR) and reverse-transcriptase PCR (RT-PCR)
Amino acids and protein folding
Cell cycle
DNA damage and repair
DNA mutations
DNA replication
DNA structure
Epigenetics
Gene regulation
Lac operon
Mitosis and meiosis
Nuclear structure
Nucleotide metabolism
Protein structure and synthesis
Transcription of DNA
Translation of mRNA
Adenosine deaminase deficiency
Lesch-Nyhan syndrome
Orotic aciduria
Bloom syndrome
Fanconi anemia
Li-Fraumeni syndrome
McCune-Albright syndrome
Xeroderma pigmentosum
Acute radiation syndrome
Purine and pyrimidine synthesis and metabolism disorders: Pathology review
Human development days 1-4
Human development days 4-7
Human development week 2
Human development week 3
Development of the digestive system and body cavities
Development of the fetal membranes
Development of the placenta
Development of the umbilical cord
Development of twins
Hedgehog signaling pathway
Ectoderm
Endoderm
Mesoderm
Development of the cardiovascular system
Fetal circulation
Development of the ear
Development of the eye
Development of the face and palate
Pharyngeal arches, pouches, and clefts
Development of the gastrointestinal system
Development of the teeth
Development of the tongue
Development of the axial skeleton
Development of the limbs
Development of the muscular system
Development of the nervous system
Development of the renal system
Development of the reproductive system
Development of the respiratory system
Evolution and natural selection
Hardy-Weinberg equilibrium
Independent assortment of genes and linkage
Inheritance patterns
Mendelian genetics and punnett squares
Achondroplasia
Alagille syndrome (NORD)
Familial adenomatous polyposis
Hereditary spherocytosis
Huntington disease
Multiple endocrine neoplasia
Myotonic dystrophy
Neurofibromatosis
Polycystic kidney disease
Treacher Collins syndrome
Tuberous sclerosis
von Hippel-Lindau disease
Albinism
Alpha-thalassemia
Beta-thalassemia
Cystic fibrosis
Friedreich ataxia
Hemochromatosis
Sickle cell disease (NORD)
Wilson disease
Cri du chat syndrome
Williams syndrome
Angelman syndrome
Prader-Willi syndrome
Beckwith-Wiedemann syndrome
Mitochondrial myopathy
Klinefelter syndrome
Turner syndrome
Fragile X syndrome
Down syndrome (Trisomy 21)
Edwards syndrome (Trisomy 18)
Patau syndrome (Trisomy 13)
Hemophilia
Muscular dystrophy
Wiskott-Aldrich syndrome
X-linked agammaglobulinemia
Autosomal trisomies: Pathology review
Miscellaneous genetic disorders: Pathology review
Muscular dystrophies and mitochondrial myopathies: Pathology review
Bacterial structure and functions
Bacillus anthracis (Anthrax)
Bacillus cereus (Food poisoning)
Corynebacterium diphtheriae (Diphtheria)
Listeria monocytogenes
Clostridium botulinum (Botulism)
Clostridium difficile (Pseudomembranous colitis)
Clostridium perfringens
Clostridium tetani (Tetanus)
Actinomyces israelii
Nocardia
Staphylococcus aureus
Staphylococcus epidermidis
Staphylococcus saprophyticus
Streptococcus agalactiae (Group B Strep)
Streptococcus pneumoniae
Streptococcus pyogenes (Group A Strep)
Streptococcus viridans
Enterococcus
Bacteroides fragilis
Bartonella henselae (Cat-scratch disease and Bacillary angiomatosis)
Enterobacter
Escherichia coli
Klebsiella pneumoniae
Legionella pneumophila (Legionnaires disease and Pontiac fever)
Proteus mirabilis
Pseudomonas aeruginosa
Salmonella (non-typhoidal)
Salmonella typhi (typhoid fever)
Serratia marcescens
Shigella
Yersinia enterocolitica
Yersinia pestis (Plague)
Campylobacter jejuni
Helicobacter pylori
Vibrio cholerae (Cholera)
Moraxella catarrhalis
Neisseria gonorrhoeae
Neisseria meningitidis
Bordetella pertussis (Whooping cough)
Brucella
Francisella tularensis (Tularemia)
Haemophilus ducreyi (Chancroid)
Haemophilus influenzae
Pasteurella multocida
Mycobacterium tuberculosis (Tuberculosis)
Mycobacterium avium complex (NORD)
Mycobacterium leprae
Chlamydia pneumoniae
Chlamydia trachomatis
Gardnerella vaginalis (Bacterial vaginosis)
Mycoplasma pneumoniae
Coxiella burnetii (Q fever)
Ehrlichia and Anaplasma
Rickettsia rickettsii (Rocky Mountain spotted fever) and other Rickettsia species
Borrelia burgdorferi (Lyme disease)
Borrelia species (Relapsing fever)
Leptospira
Treponema pallidum (Syphilis)
Malassezia (Tinea versicolor and Seborrhoeic dermatitis)
Aspergillus fumigatus
Candida
Cryptococcus neoformans
Mucormycosis
Pneumocystis jirovecii (Pneumocystis pneumonia)
Sporothrix schenckii
Blastomycosis
Coccidioidomycosis and paracoccidioidomycosis
Histoplasmosis
Pediculus humanus and Phthirus pubis (Lice)
Sarcoptes scabiei (Scabies)
Acanthamoeba
Naegleria fowleri (Primary amebic meningoencephalitis)
Toxoplasma gondii (Toxoplasmosis)
Cryptosporidium
Entamoeba histolytica (Amebiasis)
Giardia lamblia
Babesia
Plasmodium species (Malaria)
Leishmania
Trichomonas vaginalis
Trypanosoma brucei
Trypanosoma cruzi (Chagas disease)
Diphyllobothrium latum
Echinococcus granulosus (Hydatid disease)
Ancylostoma duodenale and Necator americanus
Angiostrongylus (Eosinophilic meningitis)
Anisakis
Ascaris lumbricoides
Enterobius vermicularis (Pinworm)
Guinea worm (Dracunculiasis)
Loa loa (Eye worm)
Onchocerca volvulus (River blindness)
Strongyloides stercoralis
Toxocara canis (Visceral larva migrans)
Trichinella spiralis
Trichuris trichiura (Whipworm)
Wuchereria bancrofti (Lymphatic filariasis)
Clonorchis sinensis
Paragonimus westermani
Schistosomes
Viral structure and functions
Adenovirus
Hepatitis B and Hepatitis D virus
Cytomegalovirus
Epstein-Barr virus (Infectious mononucleosis)
Herpes simplex virus
Human herpesvirus 6 (Roseola)
Human herpesvirus 8 (Kaposi sarcoma)
Varicella zoster virus
Human papillomavirus
Parvovirus B19
BK virus (Hemorrhagic cystitis)
JC virus (Progressive multifocal leukoencephalopathy)
Poxvirus (Smallpox and Molluscum contagiosum)
Lymphocytic choriomeningitis virus
Hantavirus
Norovirus
Coronaviruses
Ebola virus
Dengue virus
Hepatitis C virus
West Nile virus
Yellow fever virus
Zika virus
Influenza virus
Human parainfluenza viruses
Measles virus
Mumps virus
Respiratory syncytial virus
Hepatitis A and Hepatitis E virus
Coxsackievirus
Poliovirus
Rhinovirus
Rotavirus
HIV (AIDS)
Human T-lymphotropic virus
Rabies virus
Eastern and Western equine encephalitis virus
Rubella virus
Prions (Spongiform encephalopathy)
Antimetabolites: Sulfonamides and trimethoprim
Antituberculosis medications
Cell wall synthesis inhibitors: Cephalosporins
Cell wall synthesis inhibitors: Penicillins
DNA synthesis inhibitors: Fluoroquinolones
DNA synthesis inhibitors: Metronidazole
Mechanisms of antibiotic resistance
Miscellaneous cell wall synthesis inhibitors
Miscellaneous protein synthesis inhibitors
Protein synthesis inhibitors: Aminoglycosides
Protein synthesis inhibitors: Tetracyclines
Azoles
Echinocandins
Miscellaneous antifungal medications
Anthelmintic medications
Anti-mite and louse medications
Antimalarials
Hepatitis medications
Herpesvirus medications
Integrase and entry inhibitors
Neuraminidase inhibitors
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Nucleoside reverse transcriptase inhibitors (NRTIs)
Protease inhibitors
Introduction to pharmacology
Enzyme function
Drug administration and dosing regimens
Pharmacodynamics: Agonist, partial agonist and antagonist
Pharmacodynamics: Desensitization and tolerance
Pharmacodynamics: Drug-receptor interactions
Pharmacokinetics: Drug absorption and distribution
Pharmacokinetics: Drug elimination and clearance
Pharmacokinetics: Drug metabolism
Adrenergic antagonists: Alpha blockers
Adrenergic antagonists: Beta blockers
Adrenergic antagonists: Presynaptic
Adrenergic receptors
Cholinergic receptors
Cholinomimetics: Direct agonists
Cholinomimetics: Indirect agonists (anticholinesterases)
Muscarinic antagonists
Sympatholytics: Alpha-2 agonists
Sympathomimetics: Direct agonists
Selective serotonin reuptake inhibitors
Atypical antidepressants
Monoamine oxidase inhibitors
Serotonin and norepinephrine reuptake inhibitors
Tricyclic antidepressants
Atypical antipsychotics
Typical antipsychotics
Anticonvulsants and anxiolytics: Barbiturates
Anticonvulsants and anxiolytics: Benzodiazepines
Lithium
Nonbenzodiazepine anticonvulsants
Psychomotor stimulants
Calcium channel blockers
cGMP mediated smooth muscle vasodilators
Class I antiarrhythmics: Sodium channel blockers
Class II antiarrhythmics: Beta blockers
Class III antiarrhythmics: Potassium channel blockers
Class IV antiarrhythmics: Calcium channel blockers and others
ACE inhibitors, ARBs and direct renin inhibitors
Thiazide and thiazide-like diuretics
Lipid-lowering medications: Fibrates
Lipid-lowering medications: Statins
Miscellaneous lipid-lowering medications
Positive inotropic medications
Adrenal hormone synthesis inhibitors
Mineralocorticoids and mineralocorticoid antagonists
Hypoglycemics: Insulin secretagogues
Insulins
Miscellaneous hypoglycemics
Hyperthyroidism medications
Hypothyroidism medications

Assessments

USMLE® Step 1 questions

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Questions

USMLE® Step 1 style questions USMLE

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A 6-day-old boy is brought to the emergency department by his parents because of easy bruising. The infant was born at 38 weeks to a 23-year-old primigravida woman via normal vaginal delivery at home. This is his first medical evaluation. The patient’s mother took prenatal vitamins and maintained a healthy diet during pregnancy. Family history is unremarkable. Vitals are within normal limits. Physical examination reveals an alert infant. Examination shows multiple ecchymoses visible on upper and lower extremities. The remainder of the examination is unremarkable. Laboratory results are shown.
 
 Laboratory features 
 Laboratory value  Result 
 Platelet count    230,000/mm3 
 Bleeding time  5 minutes 
 Prothrombin time   27 seconds 
 Activated partial thromboplastin time  42 seconds 

Which of the following is the most likely cause of this infant’s presentation?

Transcript

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At the clinic, 32 year old Naya comes in with bilateral hip pain. She exercises regularly and has not changed anything in her routine recently. She mentions that she has recently also started to experience blurry vision, and has scheduled an appointment with her ophthalmologist. In addition, she mentions that her skin is unusually dry, which hasn’t improved with moisturizing cream. She takes several tablets of cod liver oil supplements daily. Physical examination reveals an enlarged liver and spleen. Next to her, 2 year old Lorenzo has been brought to the clinic by his mother for a yearly pediatric checkup. He was diagnosed with chronic kidney disease about one year ago in Italy. They then migrated to the United Kingdom. On examination, there is lateral bowing of the legs, as well as beading of the ribs along the anterior side of the chest.

Based on the initial presentation, both Naya and Lorenzo seem to have some form of fat- soluble vitamin deficiency or toxicity. Fat- soluble vitamins include vitamins A, D, E, and K. Just like all vitamins, they need to be attained by diet. So, inadequate dietary consumption can be the cause of their deficiency. In a test question, some big clues are that the affected individuals often come from lower income countries or have an eating disorder like anorexia nervosa. Now, in the small intestine, fat- soluble vitamins are absorbed along with dietary fats, which means that anything affecting fat absorption can also affect the absorption of fat-soluble vitamins. Fat malabsorption typically presents with steatorrhea, meaning fatty, greasy, floating, voluminous, and terribly smelling stools. But a deficiency of fat-soluble vitamins might be the only clue you get for that. Now, causes of fat malabsorption can be broadly divided into two major groups: digestive disorders where the food can’t be broken down in the intestinal lumen, and absorption defects where the intestinal mucosa can’t take in the nutrients.

For your exams, the most common digestive disorders are exocrine pancreatic insufficiency and cholestasis. In exocrine pancreatic insufficiency, there’s a lack of pancreatic digestive enzymes, including lipase, which breaks down lipids. Now, what’s important to remember is that exocrine pancreatic insufficiency typically results from chronic pancreatitis, which is inflammation of the pancreas leading to the destruction of its exocrine portion. In adults, the greatest risk factor for chronic pancreatitis is alcohol abuse, whereas if you see chronic pancreatitis in a child, remember that the number one cause is cystic fibrosis. Fat digestion could also be affected by cholestasis, where not enough bile is reaching the intestine to emulsify fats and make them easier to absorb. Cholestasis can be hepatocellular, where hepatocytes don’t make enough bile, and commonly tested causes include increased estrogen like in pregnancy or oral contraceptive use. It could also be due to obstruction where something’s physically blocking bile flow. In a test question, think of obstructive cholestasis if you see a tumor in the head of the pancreas, primary sclerosing cholangitis, in an individual with a history of inflammatory bowel disease, or biliary atresia in a newborn.

Fat malabsorption can also be caused by absorption defects. Here we have diseases that cause damage to the small intestine mucosa, reducing the surface area available for absorption. These include celiac disease, which is an autoimmune condition where the gluten in food triggers the body’s immune cells to attack the intestinal mucosa. There’s also tropical sprue, which is thought to be the result of bacterial overgrowth in the intestines, and mostly affects tropical regions of the world, like the Caribbean, India, and Southeast Asia. Finally, there’s Whipple’s disease, which is caused by Tropheryma whipplei. Remember that Whipple’s disease also affects large joints, causing migratory arthralgias.

Okay, now, another high- yield fact for fat- soluble vitamins is that they can be stored in fat cells instead of getting excreted in the urine. And that is why their toxicity, also known as hypervitaminosis, is way more common than that of water- soluble vitamins. The number one cause of hypervitaminosis is excess intake of vitamin supplements, highly fortified foods, or medications containing a derivative of the vitamin.

Okay, now let’s dive into the various fat- soluble vitamins. Let’s start with vitamin A, also known as retinol, which is found mostly in fruits, leafy vegetables, as well as animal liver products, egg yolk, and dairy products. Normally, vitamin A is essential for the production of rhodopsin, which is an eye pigment found in the retina that allows us to see in dark or dim lighting. Other important functions of vitamin A include helping epithelial cells differentiate, and functioning as an antioxidant that helps boost the immune system.

Now, for clues of vitamin A deficiency, look for someone with inadequate consumption of fruits or vegetables or a condition causing fat malabsorption. The most classic symptom is night blindness, also known as nyctalopia, due to the decreased production of rhodopsin. Other high- yield eye manifestations include keratomalacia, which is the degeneration of the cornea, and Bitot spots, which are triangular, oval, or irregular foamy spots on the conjunctiva, resulting from squamous metaplasia and buildup of keratin debris in the cornea. Deficiency of vitamin A can also affect the skin, causing dryness, itchiness, and peeling with white flakes, also known as xerosis cutis, as well as the immune system, causing an increased susceptibility to infections.

Now, for vitamin A toxicity, think of an individual with excess intake of vitamin A. This is usually in the form of supplements. But for your exams, what’s high yield is that vitamin A is also given in severe cases of measles. A vitamin A derivative, called isotretinoin, is also administered orally to treat severe acne, while another metabolite, called all-trans retinoic acid, or ATRA for short, is used in acute promyelocytic leukemia or APL. Now, symptoms vary depending on whether the toxicity is acute, meaning that it occurs over a few hours or days, or chronic, in which case it lasts for months or years. Acute toxicity typically presents with blurry vision, nausea, vomiting, and vertigo. In contrast, chronic toxicity can present with hair loss, dry or peeling skin, hepatosplenomegaly or liver and spleen enlargement, and arthralgias or joint pain. For your exams, a highly tested fact is that chronic toxicity can also cause elevated intracranial pressure. Some clues to this might be a persistent headache, cerebral edema, and papilledema, or swelling of the optic disk.

Another high- yield fact examiners want you to know is that excess vitamin A, during the first trimester of pregnancy, can be teratogenic and affect the baby. So before prescribing medications that contain a derivative of the vitamin, such as isotretinoin, make sure that there are two negative pregnancy tests and that the individual applies two contraception methods.

Alright, next up is vitamin D. Now, active vitamin D starts out as one of two metabolically inactive molecules. Either vitamin D2, which comes from plants, fungi and yeast, and vitamin D3 which can either come from fish, milk, or plants in our diet, but can also be made by our own skin cells when they are exposed to UV rays from the sunlight. Both vitamin D2 and D3 first get to the liver, where the enzyme 25-hydroxylase turns them into 25-hydroxy-vitamin D. This can then travel to the proximal tubules of the kidneys and meet the enzyme 1-alpha-hydroxylase, which turns them into 1,25-hydroxy-vitamin D. And that’s the active form of vitamin D. Now, what’s especially important to note is that activation of vitamin D can be triggered by parathyroid hormone when calcium or phosphate levels are low. More specifically, parathyroid hormone, low calcium, and low phosphate cause the renal cells in the proximal tubule to increase their synthesis of 1-alpha-hydroxylase. The effects of activated vitamin D include stimulating bone resorption at high levels and bone mineralization at low levels. Vitamin D also promotes calcium and phosphate absorption in the small intestine, as well as calcium and phosphate reabsorption in the kidneys. So, remember that active vitamin D ultimately leads to an increase in blood levels of both calcium and phosphate. Make sure you don’t confuse that with parathyroid hormone, which stimulates calcium reabsorption, while inhibiting phosphate reabsorption in the kidney, resulting in an increase in calcium, but a decrease in phosphate levels.

Causes of vitamin D deficiency once again include inadequate dietary intake and fat malabsorption. Regarding inadequate intake, newborn infants, especially premature ones who are exclusively breastfed are at high risk for vitamin D deficiency, and that’s a high yield fact! That’s because breast milk typically doesn’t contain adequate amounts of vitamin D. For that reason, it’s important that breastfed infants receive oral vitamin D drops. Okay, but what’s unique about vitamin D deficiency is that it can be also caused by inadequate exposure to UV light. In a test question, look for individuals who have recently immigrated from a sunny area to an area without a lot of sun. Also, keep in mind that for unknown reasons, individuals with darker skin tone seem to be at higher risk. Another cause of vitamin D deficiency is chronic liver disease, due to the liver's inability to turn vitamin D2 and D3 into 25-hydroxy-vitamin D. The same goes for chronic kidney disease, where the kidneys can’t turn 25-hydroxy-vitamin D into 1,25-hydroxy-vitamin D. In addition, vitamin D deficiency has been linked to the use of medications like phenytoin, an anticonvulsant that’s metabolized by the same liver and kidney hydroxylase enzymes that are needed for the synthesis of vitamin D.

Sources

  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
  4. "Sarcoidosis and calcium homeostasis disturbances—Do we know where we stand?" Chronic Respiratory Disease (2019)
  5. "Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline" (1998)