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Case study: Hypervitaminosis A Unmasked Acute Viral Hepatitis

I will be interjecting throughout this case study paper, as it quite precisely demonstrates what I claim elsewhere in this blog-forum.   It is a long case study, and worth it to go all the way through.  My parts (particularly definitions) will be interspersed inside the quotes in [brackets], otherwise will be put in-between the quoted paper.

Hypervitaminosis A Unmasked Acute Viral Hepatitis

Abstract
A case of acute hypervitaminosis A complicating viral hepatitis is reported. Twenty days after presenting with hepatitis B, a 42 yr-old vegetarian developed acute hypervitaminosis A in the absence of recent, massive exposure to the vitamin. Findings included headache, confusion, skin desquamation,
[skin peeling] and hypercalcemia [high blood calcium]. Prior to developing hepatitis, he had ingested supplemental vitamin A without recognized ill effect.

That last sentence is directly contradicted by the authors later in this same paper.

Liver and serum vitamin A levels were both elevated; the liver biopsy showed abundant, lipid-filled Ito cells and perisinusoidal fibrosis. This case demonstrates that patients with excessive hepatic [liver] stores of vitamin A may develop hypervitaminosis A during acute, intercurrent liver disease.

To be clear, if one has excessive liver stores of Poison/"Vitamin A" and/or excessive levels of Poison/"Vitamin A" in the blood, then they are TOXIC with Poison/"Vitamin A".

Levels of retinal binding protein are reduced in hepatitis. This phenomenon may account for the findings in this case, since vitamin A is more toxic when not specifically bound to retinol binding protein.

Free-floating Vitamin A is toxic, this is in the literature.  Low retinol binding protein means that one is LESS PROTECTED against Poison/"Vitamin A" toxicity.  High retinol binding protein means that one is full of Poison/"Vitamin A" and at least the liver is still protecting the person from that one angle!

The size of the population at risk for this complication of hepatitis is unknown, but presumably it is growing with the widespread use of supplemental vitamin A.

Arctic explorers, after devouring polar beer liver, suffered lethargy, headache, vomiting and, a day later, skin desquamation (1). This disease, acute hypervitaminosis A, is now known to be caused by the enormous quantities of vitamin A stored in polar bear liver.

Might you know anyone who suffers from:

  • Fatigue (aka lethargy)
  • Headaches
  • Dry skin (this would come long before peeling/desquamation)

These are all good signs, each one by themselves, that Chronic Insidious Vitamin A Toxicity is present.  The dose makes the poison.  One whose poisoning is "less" will simply have "milder" symptoms.

Hypervitaminosis A is still observed but now usually presents as a chronic disease affecting several organs (2,3) including the liver (4-6). The reverse sequence, liver disease causing vitamin A toxicity, has not been described. The present patient, during the course of otherwise typical hepatitis B, developed a syndrome similar to that afflicting arctic explorers. He was found to have elevated hepatic stores of vitamin A. Current knowledge of vitamin A metabolism provides an explanation for this complication of hepatitis.

Case Report
A 42-yr-old previously healthy white male presented to the Veterans Administration Medical Center complaining of 2 wk of upper respiratory symptoms
[lung/breathing issues], myalgias [muscle pain], arthralgias [joint pain], nausea, anorexia [lack of appetite], and abdominal pain. Three days earlier he developed dark urine, acholic stools, and jaundice. He drank three beers a week but denied drug abuse, exposure to hepatitis, homosexual activity, and recent travel. He was a vegetarian and ingested vitamin C daily. Physical examination revealed an icteric, alert male with a liver span of 8 cm. Results of laboratory tests are shown in Table 1. He was sent home with a diagnosis of acute viral hepatitis and told not to ingest large supplements of vitamin C. Twenty days later he was brought to the hospital by friends because of increasing mental confusion and weakness. He described a 2-wk history of anorexia, nausea, and vomiting. For the past 2 days he had noted headache, fever, chills, and nonpruritic, scaling skin over his entire body.

It is very important to pay attention here.

  1. Man goes to the VA Medical Center, doesn't feel good.
  2. Note his liver measurement, 8 cm. This will come up later.
  3. He was a vegetarian.  Note that it is called "retinol binding protein", and that enough protein is needed in the system to prevent Poison/"Vitamin A" toxicity.  He likely wasn't eating enough protein for the poisoning he was doing to himself.
  4. They STOPPED his Vitamin C...and 20 days later he is WORSE, not better.  Vitamin C (the ascorbate ion, aka ascorbic acid) is extremely PROTECTIVE against Vitamin A toxicity.  It doesn't prevent the toxicity from happening, yet it helps reduce many of the issues. Once it disappeared, he got decidedly worse.

He had been taking no medication. Physical examination revealed an icteric [signs of jaundice], lethargic, moderately tremulous man with normal vital signs except for mild postural hypotension. The liver span was 9 cm with a palpable edge. He had total body desquamation including palms and soles (Figure 1). He was oriented to time and place and did not have asterixis. He thought the President of the United States (in 1980) was “Kennedy.” He was admitted for evaluation. In addition to the laboratory results in Table 1, hemoglobin was 14.6, WBC was 17,100, platelets 237,000, BUN 67, creatinine 1.6, and amylase 69.

Note that his liver got BIGGER, and now his all of his skin is peeling.  His liver is quite unhappy.  Three weeks after he stopped the Vitamin C, mind you.

Initial therapy included intravenous hydration. He received a protein-free diet and lactulose for presumed hepatic encephalopathy. Over the next 2 days his sensorium began to clear, although he remained tremulous. The calcium decreased and renal function returned to normal. Because of total body desquamation, vegetarianism, and history of ingesting vitamin C, he was closely questioned regarding other vitamin intake. He then stated that for 10 yr he had taken one 25,000 IU vitamin A capsule daily plus one additional capsule daily when “under stress” or not feeling well. In addition, he ate carrot and raisin salad daily and large amounts of green, leafy vegetables. These sources provided an estimated daily vitamin A intake of between 50,000 and 75,000 III. The recommended daily allowance is 5000 IU. He also ingested 1000 IU of vitamin D daily and unknown quantities of vitamin E, B-complex, and bone meal.

Note daily carrot salad and large amounts of green leafy vegetables.  Vegetarian means a good possibility of protein deficiency.  These are not a good combination to prevent Poison/"Vitamin A" toxicity.

Poison/"Vitamin A" toxicity will cause hypercalcemia.
Vitamin D supplements will cause hypercalcemia.
Bone meal is a calcium supplement, basically.

This man presented with hypercalcemia.  Are you surprised?  I'm not.

In retrospect, he recalled that over the past year he had experienced cracked lips, dry skin, and excessive fatigue.

But wait...in the abstract above, the authors stated: "Prior to developing hepatitis, he had ingested supplemental vitamin A without recognized ill effect."

Yes, he did notice ill effects.

He steadfastly maintained he had taken only one vitamin A capsule since the diagnosis of hepatitis 3 wk previously. That capsule caused indigestion and severe heartburn which he attributed to the oil (to dissolve vitamin A) sealed within the capsule. To avoid these symptoms, he stopped taking vitamin A supplements 3 wk before admission. Serum vitamin A, obtained almost 4 wk after his most recent vitamin supplement, was 182 pg/dl (normal, 20-80).

So, he STOPPED Vitamin C AND he STOPPED Vitamin A.  Three weeks later, he is decidedly worse.

My interpretation of this is that he 1) lost the protective effect of the Vitamin C, and 2) his liver started dumping/detoxing Vitamin A into the system (because it wanted to rid itself of the poison it was storing).

His temperature rose to 101.2”F on the third hospital day.

Fever is a known acute Poison/"Vitamin A" toxicity symptom.

The following day, blood cultures drawn at admission grew Campylobacter fetus ssp intestinalis and Enterobacter aerogenes. The urine culture grew the same species of Enterobacter. He was treated with gentamicin and ampicillin, defervesced promptly, and remained afebrile for the subsequent hospital course. On the basis of antibiotic sensitivities, he was switched to oral tetracycline for 21 days.

He was sensitive to gentamicin?  What if I were to tell you that gentamicin "depletes" liver Vitamin A, and it likely increased the detox/dumping of his liver Poison/"Vitamin A" stores, and that was probably what his "sensitivity" to it was?

By the tenth hospital day his neurologic status was normal, and the desquamation was improved. A liver biopsy was performed on the 16th hospital day. The hepatic vitamin A level was 3200 pg/g liver (normal <300) by the trifluoroacetic acid method (7). (This measurement was graciously performed by Wesley E. Jensen, Ph.D., Section of Gastroenterology, University of Chicago.)

This is now 36 days after his first visit to the VA hospital.  Liver biopsy is the GOLD STANDARD to diagnose Poison/"Vitamin A" toxicity.

Light microscopy of the biopsy specimen (Figure 2) revealed changes compatible with acute viral hepatitis in its late stage: liver cord disarray with occasional pseudotubular organization and mildly hydropic hepatocytes, a few acidophilic bodies, and scattered pigmented macrophages, some of which contained stainable iron. In addition, Masson trichrome stain revealed periportal and diffuse perisinusoidal fibrosis of mild degree. There were considerable numbers of fat droplets, both singly and in clusters, apparently within the sinusoids. On electron microscopy (Figure 3) three major findings were evident: (a) Many of the fat droplets seen by light microscopy were in Ito cells, which were abundant. (b) The perisinusoidal fibrosis consisted of a network formed by reticular and collagen fibers and a basement membrane-like material. (c) Kupffer cells were often enlarged, containing phagocytic vacuoles and lipid droplets.

The patient continued to improve and was discharged on the 19th hospital day. After discharge he experienced transient, universal alopecia including scalp hair, body hair, and mustache. By 3 mo after the onset of jaundice, hepatitis B surface antibody (anti-HB,) appeared. Aside from persistent fatigue, he felt fit and had resumed normal activities.

40 DAYS LATER, after he had stopped ALL Vitamin A supplements, this gentleman LOST ALL THE HAIR ON HIS ENTIRE BODY, including his mustache!!!  Hair loss and hair thinning are well-known side effects of Poison/"Vitamin A" toxicity.  Wondering why you're losing your hair?  Note the "persistent fatigue" too.

Discussion

Hypervitaminosis A has been frequently described, and vitamin A is a recognized hepatotoxin (2-4).

Please go and find any other "essential nutrient" that is considered a "recognized hepatotoxin".  You can't.  It's not a "vitamin" folks. It's a toxin.

The spectrum of hepatic injury resulting from chronic, excessive vitamin A ingestion ranges from mild elevations of liver enzymes (5) to hepatosplenomegaly with portal hypertension (4) to frank cirrhosis (6), depending on the dose and duration of exposure. Progressive hepatic damage occurs with continued vitamin ingestion (8).

Maybe you're familiar with the epidemic of "fatty liver disease", aka non-alcoholic fatty liver disease, aka NAFLD?  Here, let me introduce you:

The global NAFLD epidemic

Maybe you've noticed how conventional medicine can't seem to figure out what has been causing it?  Here's a hint:

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

Moving on...

The converse process, hypervitaminosis A resulting from (rather than causing) liver injury, has not been described. The present patient presented dramatically with hypervitaminosis A 20 days after the diagnosis of viral hepatitis B. Although a long-term user of supplemental vitamin A, he became intolerant to oil-containing vitamin A capsules at the onset of hepatitis.

Or maybe his body was simply trying to ask him to stop poisoning himself?

Despite the absence of recent vitamin ingestion, he returned with several features of acute hypervitaminosis A (9) including headache, skin desquamation, hypercalcemia, and confusion. He eventually experienced alopecia, a sign of more chronic toxicity (9).

Poison/"Vitamin A" toxicity doesn't ever fully go away unless it is properly depleted and detoxed out of the system.  His full-body hair loss and persistent fatigue are the signs of this happening.

Liver and serum vitamin A levels confirmed the clinical diagnosis. In retrospect, the patient probably had mild, unrecognized chronic hypervitaminosis A prior to his acute illness; he had noted dry skin, cracked lips, and fatigue for the year preceding admission.

The metabolism of vitamin A has been studied in viral hepatitis. Both vitamin A and retinol binding protein, its specific serum carrier, are low in acute hepatitis (10-13). Furthermore, retinol binding protein varies inversely with bilirubin, SGOT, and alkaline phosphatase during the course of hepatitis (12,13). The present case is unusual because serum vitamin A was high, not low, during hepatitis.

Current knowledge of vitamin A metabolism (14) suggests an explanation for this paradox. After absorption from the gut, vitamin A is esterified with long-chain fatty acid and transported to the liver in chylomicrons. The retinyl esters are stored in hepatocytes and specialized sinusoidal cells, the Ito cells (15). Retinol binding protein is produced in hepatocytes and regulates vitamin A release from the liver. The vitamin enters serum as the free alcohol, retinol, which circulates with retinol binding protein as an equimolar complex. Of note, retinyl esters normally comprise 5% or less of the total serum vitamin A and, when present, circulate bound nonspecifically to lipoproteins.

In hypervitaminosis A the metabolic situation differs. Mallia et al. (16) showed elevated levels of lipoprotein-bound retinyl esters in rats made toxic with vitamin A, while levels of retinol remained normal (16).

That statement right there shows that Poison/"Vitamin A" toxicity can exist in the liver, demonstrated via elevated "storage" forms of retinyl esters in the blood, while the standard, normal "blood test for Vitamin A" (aka serum retinol) looks totally NORMAL.  This is how the problem has stayed hidden for so long...there are almost no labs that run retinyl ester testing, and doctors & patients aren't going to get a liver biopsy unless something is REALLY wrong.  Thus, no one finds the problem.  Is this by design?

Retinol binding protein levels fell despite the elevation of total serum vitamin A. Smith and Goodman found a similar pattern in 3 patients with chronic hypervitaminosis A (17). They demonstrated an excess of total vitamin A relative to retinol binding protein, a difference largely accounted for by elevated levels of lipoprotein-bound retinyl esters. These findings suggest toxicity occurs when excessive amounts of vitamin A circulate that are not bound to retinol binding protein. Thus, retinol binding protein seems to prevent vitamin A toxicity in two ways, by regulating the interaction of plasma vitamin A with target cells and by controlling release of hepatic vitamin A.

We propose that two pathological processes combined to cause acute hypervitaminosis A in the present case. First, the patient had chronic vitamin A overload as suggested by his past dietary history and proven by his elevated vitamin A stores. Second, he developed acute viral hepatitis, a form of liver injury associated with low serum levels of retinol binding protein. This fall may have been even steeper than usual because albumin, another liver-derived serum protein, also fell markedly. As a result, high levels of vitamin A circulated in the presence of low levels of retinol binding protein, the pattern associated with toxicity. Massive release of vitamin A from necrotic liver probably did not contribute to the problem because vitamin A levels are usually low during hepatitis and because Ito cells are not known to be harmed by hepatitis viruses.

This complication of hepatitis requires the presence of excessively large body stores of vitamin A. Such stores can result from the daily ingestion of only 35,000 IU, or 7 times the recommended daily allowance (18). An intake of this magnitude is easily achieved because capsules containing 25,000 IU are available over-the-counter. Moreover, the vitamin is used therapeutically for a variety of dermatologic conditions (9) and some workers have suggested a role for the vitamin in both cancer therapy and prevention (19). These latter developments have been reported in the lay press and will undoubtedly influence many individuals to use vitamin A supplements. In noting these facts, we suspect that the population with abnormally large hepatic stores of vitamin A is growing. Thus, the process described in this paper and other manifestations of hypervitaminosis A may be seen more frequently in the future.

Please, read that last part again.

Dr. Garrett Smith, the "Nutrition Detective"
Licensed Naturopathic Physician (NMD) in Arizona
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