Fat-soluble vitamin deficiency and toxicity: Pathology review

Chapters:

Watch video only

Case study0:00–0:55

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.

Vitamin deficiency0:55–2:11

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.

Digestive disorders2:11–3:34

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.

Absorption defects3:34–4:19

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.

Vitamin toxicity4:19–4:45

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.

Vitamin A 4:45–7:51

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.

Vitamin D 7:51–14:11

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.
Now, in all cases, vitamin D deficiency leads to impaired bone mineralization, meaning that osteoblasts don’t have enough calcium and phosphate to deposit into the organic matrix of the bone.
For your test, it’s important to remember that this manifests as rickets in children and osteomalacia in adults. So in children, because the growth plates haven’t closed yet, this leads to softening of the bones, impaired growth of bones, and bone malformations.
Whereas, in adults, where the epiphyseal plates have already closed, it only causes weakening and softening of bones, which makes them more prone to fractures.
With both rickets and osteomalacia, symptoms include diffuse bone and joint pain, proximal muscle weakness, bone fragility, and increased risk of fractures.
Because of low blood levels of calcium, there may also be muscle spasms and numbness. Rickets-specific symptoms include thin, soft skull bones, which is called craniotabes, delay in the closure of fontanelles, and bow legs, also known as genu varum.
There may also be an enlarged, prominent frontal bone. Additionally, rachitic rosary can be seen, which are little bumps that appear along the chest wall due to the widening of the junction between the ribs and costal cartilage in front of the rib cage.
Finally, those with severe vitamin D deficiency might also present with weakness, depression, confusion, and increased thirst or urination.
Moving on, vitamin D toxicity can be caused by excess supplement ingestion. But what’s high yield is that it can also present in individuals with granulomatous diseases, especially sarcoidosis.
That’s because epithelioid macrophages in the center of the granulomas have the enzyme 1-alpha-hydroxylase so they can activate vitamin D.
The test question will typically have the patient be a black female in her 20’s with bilateral hilar lymphadenopathy, erythema nodosum or red, hard, and painful nodules along the tibias, and an increased level of angiotensin- converting enzyme or ACE, which is produced by T cells on the periphery of the granuloma.
Regardless of the cause, vitamin D toxicity leads to hypercalcemia or elevated blood levels of calcium, which can present with symptoms like constipation, nausea, muscle weakness, depression, and anxiety.
And since there’s too much calcium in the blood, the kidneys try to excrete it into the urine, causing hypercalciuria, which is excess calcium in the urine.
What’s important to remember is that hypercalciuria leads to an excessive loss of fluid in the kidneys, which causes dehydration.
As a result, the combination of hypercalciuria and dehydration can lead to the formation of calcium oxalate kidney stones.
Okay, now let’s move on to vitamin K. Vitamin K is found in abundance in green leafy foods, like spinach, kale, and chard.
But what’s unique is that it is also synthesized by bacteria in our gastrointestinal tract, called the intestinal microbial flora, which further contributes to our overall intake.

Vitamin K 14:11–17:57

Now, the reason why vitamin K is so important is that it is involved in the activation of some factors of the coagulation cascade, including coagulation factors II, VII, IX and X, as well as the anticoagulation proteins C and S.
To do that, first, vitamin K in its dietary form, also called vitamin k quinone, needs to be converted into vitamin K hydroquinone by an enzyme, called quinone reductase.
Then, vitamin K hydroquinone acts as a cofactor to an enzyme called gamma glutamyl carboxylase, which converts the non-functional forms of II, VII, IX, and X into their functional forms.
After that, vitamin K turns into an oxidized form, called vitamin K epoxide, which gets recycled and converted back into vitamin K quinone by another enzyme called epoxide reductase.
For your exams, it’s important to understand this pathway since, as it turns out, the way the anticoagulant medication warfarin works is by blocking the function of epoxide reductase.
This in turn blocks vitamin K from getting recycled, so that factors II, VII, IX, and X don’t get activated. Now, for vitamin K deficiency, what you need to remember is that neonates are particularly susceptible because their intestinal flora is less able to make vitamin K endogenously, and transplacental passage is limited.
And to compound the problem, breast milk is relatively low in vitamin K. That’s why every newborn gets an intramuscular shot of vitamin K.
Another high- yield cause of vitamin K deficiency is prolonged use of broad spectrum antibiotics that kill the intestinal microbial flora.
And what’s even more important is to avoid combining these antibiotics with medications like warfarin that block vitamin K activity.
Now, individuals with vitamin K deficiency are more likely to develop bruises, bleed longer when cut, and are at risk for massive and uncontrolled bleeding in case of trauma.
Another commonly tested concept is that there’s a prolonged prothrombin time or PT, a mildly prolonged or normal partial thromboplastin time or PTT, and a normal bleeding time, which indicates normal platelet function.
That’s because, vitamin K deficiency leads to a reduced activity of factors of both the intrinsic pathway, such as factor IX, which is reflected by PTT, as well as factors of the extrinsic pathway, like factor VII, which is reflected by PT.
But what you need to remember is that factor VII has the shortest half life, so, when vitamin K levels get low, it’s the PT that rises first.
As the deficiency gets more severe, factors with longer half lives, like factor IX, start to decrease too, so PTT also rises.
In any case, bleeding time, which reflects platelet activity, stays normal.For vitamin K toxicity, the only thing you need to know is that it is so rare that you’ll probably never find it in your exams or even in real life!Okay, the last one is vitamin E.
We get most of it from various nuts, fruits, veggies, and oils, like sunflower seed oil. Vitamin E works primarily as a free radical scavenger.
What that means is it protects the polyunsaturated fatty acids within the cell membranes from peroxidation. For your exams, remember that this is especially important for red blood cells and neurons.So, vitamin E deficiency, which can once again result from inadequate dietary intake or fat malabsorption, typically presents with neuromuscular disease, like ataxia, due to degeneration of spinocerebellar tracts, impaired proprioception and vibratory sensation, due to the degeneration of the dorsal columns, and decreased tendon reflexes, due to the degeneration of peripheral nerves.

Vitamin E 17:57–20:50

For your test, keep in mind that this presentation is extremely similar to that of Friedrich ataxia, as well as vitamin B12 deficiency.
Remember that vitamin B12 deficiency causes megaloblastic anemia which is a macrocytic anemia where the MCV larger than 100 fL.
There are megaloblasts, immature neutrophils with hypersegmented nuclei, and methylmalonic acid levels are increased. In contrast, vitamin E deficiency can lead to acanthocytosis, where red blood cell membranes form short protrusions or spikes, and hemolytic anemia, which is a type of normocytic anemia with an MCV between 80 and 100 fL, and hemolysis, or increased destruction of red blood cells.
Now, when there’s hemolysis, the bone marrow revs up and starts pumping out immature red blood cells called reticulocytes.
So for your exams, it’s important to know that there will be also an increased reticulocyte production index of over 2%.Now, vitamin E toxicity is relatively rare and results from high dose supplements.
It can often go on without any symptoms, but sometimes it may cause muscle weakness, fatigue, nausea, and diarrhea. What you need to know here is that in infants it is associated with an increased risk of necrotizing enterocolitis.
So keep an eye out for a preterm infant presenting with fever, diarrhea, vomiting, signs of respiratory distress, abdominal distention, abdominal tenderness, or even shock in the first week of life.
Another high- yield fact is that high doses of vitamin E may affect the effect of vitamin K, adding up to the anticoagulant effects of warfarin, and thus increasing the risk of bleeding.Alright as a quick recap… Fat soluble vitamins include vitamins A, D, K, and E.
Deficiency is mainly caused by inadequate dietary absorption or conditions with fat malabsorption, including digestive disorders and absorption defects.
Toxicity can be the result of excess intake of vitamin supplements, fortified foods, or medications. Vitamin A deficiency can present with night blindness, keratomalacia, Bitot spots, xerosis cutis, and immunosuppression, while toxicity can be acute or chronic.

Review20:50–22:30

Vitamin D deficiency is increasingly common in breastfed infants, those with inadequate sun exposure, and chronic liver or kidney disease, and can manifest as rickets in children and osteomalacia in adults.
Vitamin D toxicity can also be associated with sarcoidosis and causes hypercalcemia and hypercalciuria, increasing the risk for dehydration and kidney stones.
Vitamin K deficiency is common in newborns, increases the risk for bleeding, and causes an increased PT, a mildly increased or normal PTT, and normal bleeding time.
Vitamin K toxicity is extremely rare. Finally, vitamin E deficiency presents with neuromuscular symptoms similar to those of Friedreich ataxia and vitamin B12 deficiency, and acanthocytosis with hemolytic anemia.
Vitamin E toxicity is associated with an increased risk of necrotizing enterocolitis in infants and may affect vitamin K.Okay, back to our cases.
Naya is the 32- year- old female that came in for hip arthralgia, blurry vision and dry skin. These complaints, together with hepatosplenomegaly found on physical exam, should make you think of chronic vitamin A toxicity.
In her case, it was likely caused by the daily consumption of cod liver oil supplements, which are rich in vitamin A. On the other hand, Lorenzo, the 2- year- old boy, came in with genu varum and rachitic rosary, which is the classic presentation of rickets.

Summary22:30–23:10

That’s probably linked to the fact that he recently migrated from a sunny area, as well as his history of chronic kidney disease, causing vitamin D deficiency.
daily consumption of cod liver. Oil supplements, which are rich in vitamin A.
On the other hand, Lorenzo the two year old boy came in with Gina verum Andra. Kennick Rosary, which is the classic presentation of rickets.
That's probably linked to the fact that he recently migrated from a sunny area as well as his history of chronic kidney disease,
Fat-soluble vitamin deficiency and toxicity: Video | Osmosis