Hypervitaminoses and hypovitaminoses


      To register your attendance please type in your matricola number
Notice that your attendance will be registered only if you completed the reading, questions, and audios, and that you cannot interrupt and resume the session (but you can repeat it as many times as you like). Remember to press the [send] button before leaving this page! A confirmation message will appear at the end of this page.
      A comment section has been added at the end of this lecture. Adding a comment or question does not require registration with your matricola number, feel free to comment whenever you like.

      Insufficient dietary apport of vitamins and other essential nutrients (essential aminoacids, essential fatty acids, etc.) may be at the origin of disease. The elderly are at special risk, as are some fragile patients (e.g. onchological patients under chemotherapeutic treatment). Deficiency conditions may be in some cases observed because of reduced absorption, the typical example is avitaminosis B12 in patients suffering of atrophic gastritis or having undergone gastric surgery. Hypervitaminoses are observed for lipid soluble vitamins which are physiologically stored in our organism (usually in the liver), and are usually the result of excessive dietary supplementation: thus they are iatrogenic diseases. Vitamins and essential nutrients are many and the diseases due to their insufficient apport are difficut to diagnose; however, provided that the physician asks for the appropriate analysis, the laboratory can determine the concentration of all or almost all these substances and identify the selective deficit.

vitamin and its biological functionrecommended daily allowancedeficiency diseasenormal serum concentration
A (retinol)
vision, epitelium differentiation
0.5 - 1 mgreduced vision at dusk, skin and mucosal lesions20 - 50 μg/dL
D (calciferols)
calcium absorption
10 μgricketts, osteomalacia25 - 40 ng/mL of 25-hydroxy D3
3 - 10 mgoxidative damage of tissues; anemia>0.8 mg/dL
cofactor of carboxylation of Glu in coagulation enzymes
produced by intestinal microbiota
(deficiency may be simulated by
warfarin-like anticoagulants)
hemorragic syndrome- (measure PT, PTT)
Lipoic acid
cofactor of acyl transferases
- (deficiency uncommon)
B1 (thiamine)
cofactor of carboxylases
0.3-1.5 mgneurological symptoms (Beri-Beri,
Wernicke-Korsakoff syndrome)
- (urinary excretion >50 μg/day)
B2 (riboflavin)
precursor of FAD
0.5-2 mgskin and mucosal lesions, anemia- (urinary excretion >30 μg/day)
B3 (niacin, nicotinic acid)
precursor of NAD and NADP
6-20 mgpellagra
B5, W (pantothenic acid)
precursor of CoA-SH
B6 (pyridoxine)
cofactor of transaminases
0.5-2 mganemia, neuropathy-
B8, H (biotin)
cofactor of carboxylases
- (deficit uncommon)
B9 (folic acid)
cofactor of methyl-transferases and some redox reactions
30-400 μgmegaloblastic megalocytic anemia6-15 ng/mL
B12 (cobalamine)
cofactor of methyl-transferases
0.5-3 μgmegaloblastic megalocytic anemia
(pernicious anemia, Brill's disease)
>200 pg/mL
C (ascorbic acid)
redox cofactor
necessary for the biosynthesis of OH-Pro and OH-Lys in collagen
50 mgscurvy- (>0.1 mg/dL in the leukocyte / platelet fraction)

      Diagnosis of hypovitaminoses
      As a general rule hypovitaminoses cause diseases with quite uncharacteristic symptoms, thus their diagnosis is difficult. Exceptions to this rule are the macrocytic megaloblastic anemias of folate and B12 deficiency, ricketts, scurvy, and the hemorragic syndrome due to antivitamins K.
      Conditions that favor hypovitaminoses are:
- major catastrophes (famines, civil ware, refugees, etc.)
- increased requirement (e.g. folate during pregnancy)
- prolonged antibiotic therapy, which destroys the vitamin-producing intestinal bacterial flora
- malnutrition and malabsorption (e.g. etilism and Wernicke syndrome; athropic gastritis and pernicious anemia)
- reduced endogenous prodction for those vitamins that are partly produced by our body (e.g. nicotinamide and defects of Trp metabolism of Hartnup disease; ricketts due to insfficient exposure to sunlight; antibiotic therapy and vitamin K)
- assumption of antivitamins (warfarin anticoagulants and vitamin K; antibacterial and antiparasitic drugs acting as folate antagonists like trimetoprim)

      In the majority of cases the target organs of vitamin deficiencies are: (i) the skin and mucosae, which may present degenerative lesions and ulcerations; (ii) the central and peripheral nervous systems; (iii) the blood (anemia) and vessels (hemorragic syndromes). With the exception of the nervous system, these organs have rapid cell turnover. Measuring the concentration of vitamins in the serum, blood or urine is feasible, but if the patient is at risk for malnutrition and presents cutaneous, nervous or blood-related symptoms, administration of a multivitamin preparation is advisable, because the contraindications to this therapy are virtually non-existent. A very special case to consider, however, is pernicious anemia.

      Hypovitaminoses are rarely observed in the absence of specific risk factors, which include: (i) social emergency conditions (civil wars, refugees, etc.); (ii) old age or assumption of chemotherapy (these conditions may reduce appetite, and cause malnutrition); (iii) chronic intestinal diseases causing malabsorption; (iv) very special dietary habits (e.g. veganism and hypovitaminosis B12; use of white rice and Beri-Beri). By contrast, the "classical hypovitaminoses", which were historically observed in whole populations or groups (e.g. scurvy, pellagra, ricketts, etc.), due to poor diets are nowadays uncommon.

      Pernicious anemia (Brill's disease) is a potentially lethal disease caused by the deficiency of vitamin B12. This vitamin has a very low recommended daily intake, and is present mostly in food of animal origin. Every "common" diet contains a sufficient amount of this vitamin. The chemical structure of the vitamin is complex and intestinal absorption is mediated by binding to a specific transport protein produced by the gastric mucosa and called the "intrinsic factor". The complex of vitamin B12 and the intrinsic factor is absorbed by the gut via receptor-mediated endocytosis; a reservoir of vitamin B12 is stored in the liver.
      Pernicious anemia is only observed in some very special cases, including (i) patients suffering of athropic gastritis, gastric cancer, or having undergone to surgical resection of the stomach (e.g. because of cancer); these patients do not produce the intrinsic factor. (ii) Strictly vegan patients who refuse every food of animal origin, and do not make use of vitamin B12 supplementation. (iii) Newborns of mothers in the two above conditions (these babies may present congenital permanent neurological lesions).
      Oral supplementation of vitamin B12 is effective in case (ii), but not in case (i), where intramuscular administration is necessary.
      Diagnosis relies on the association of neurological symptoms and macrocytic anemia; a risk condition is always present. Confirmation is by determination of vitamin B12 concentration in the serum by radioimmunoassay, and by the Schilling test (measurement of the urinary excretion of radiolabeled vitamin B12). The intrinsic factor can be measured in gastric secretions. Achloridria is common but not diagnostic. Differential diagnosis is relatively easy because the possible causes of macrocytic anemia are limited: besides vitamin B12 deficiency they include folate deficiency, copper deficiency and, possibly, scurvy.

      Folate deficiency may be observed in pregnancy, due to the large demand of this vitamin by the fetus. Dietary supplementation with folate tablets during pregnancy is recommended.

      Diseases due to excess vitamin supply are iatrogenic and due to the patient taking excess vitamin supplementation. No normal diet can cause hypervitaminoses. Moreover, the majority of water-soluble vitamins are not stored in our body and thus any excess is disposed of by the kidney; in practice only liposolube vitamins (A, D, E, and K) are physiologically stored in the liver and can cause hypervitaminoses.

Questions and exercises:
1) Macrocytic and macroblastic anemia is observed in:
deficiency of folate or vitamin B6
deficiency of folate or vitamin B12
deficiency of vitamin B6 or B12

2) The normal blood concentration of vitamin A is:
150-750 pg/mL
25 - 40 ng/dL
20 - 50 μg/dL

3) Some vitamins can be produced in our body:
B6 from Trp; D from ergosterol; K by the intestinal microfauna
B12 from the heme; A from unsaturated fatty acids
C from glucuronic acid; panthetein from Cys

4) Wernicke neurological syndrome is due to a deficiency of:
vitamin B1
vitamin B2
vitamin B6

your score: 0
Attendance not registered because matricola was not entered.

You can type in a comment or question below (max. length=160 chars.); please specifiy that the subject of your comment or question is aminoacid metabolism:

All comments posted on the different subjects have been edited and moved to
this web page (for optimal reading try to have at least 80 characters per line)!

Thank you Professor (lecture on bilirubin and jaundice).

The fourth recorded part, the one on hyper and hypoglycemias is not working.
Bellelli: I checked and in my computer it seems to work. Can you better specify
the problem you observe?

This Presentation (electrolytes and blood pH) feels longer than previous lectures
Bellelli: it is indeed. Some subjects require more information than others. I was
thinking of splitting it in two nest year.

Bellelli in response to a question raised by email: when we compare the blood pH
with the standard pH we do not mean to compare the "normal" blood pH (7.4)
with the standard pH. Rather we compare the actual blood pH of the patient, with
the pH of the same blood sample equilibrated under standard conditions.
Thus, if we say that standard pH is lower than pH we mean that equilibriation with
40 mmHg CO2 has caused absorption of CO2 and has lowered the pH with respect
to its value before equilibration.

(Lipoproteins) Is the production of leptin an indirect cause of type 2 diabetes since
it works as a stimulus to have more adipose tissue that produces hormones?
Bellelli: in a sense yes, sustained increase of leptin causes the hypothalamus to adapt
and to stop responding. Obesity ensues and this in turn may cause an increase in the
production of resistin and other insulin-suppressing protein hormones produced by the
adipose tissue. However, this is quite an indirect link, and most probably other factors
contribute as well.

(Urea cycle) what is the meaning of "dissimilatory pathway"?
Bellelli: a dissimilatory pathway is a catabolic pathway whose function is not to produce
energy, but to produce some terminal metabolyte that must be excreted. Dissimilatory
pathways are necessary for those metabolytes that cannot be excreted as such by the
kidney or the liver because they are toxic or poorly soluble. Examples of metabolytes
that require transformation before being eliminated are heme-bilirubin, ammonia,
sulfur and nitrogen oxides, etc.

Talking about IDDM linked neuropathy can be the C peptide absence considered a cause of it??
Bellelli: The C peptide released during the maturation of insulin, besides being an indicator
of the severity of diabetes, plays some incompletely understood physiological roles. For
example it has been hypothesized that it may play a role in the reparation of the
atherosclerotic damage of the small arteries. Thus said, I am not aware that it plays a direct
role in preventing diabetic polyneuropathy. Diabetic neuropathy has at least two causes: the
microvascular damage of the arteries of the nerve (the vasa nervorum), and a direct
effect of hyperglycemia and decreased and irregular insulin supply on the nerve metabolism.
Diabetic neuropathy is observed in both IDDM and NIDDM, and requires several years to
develop. Since the levels of the C peptide differ in IDDM and NIDDM, this would suggest
that the role of the C peptide in diabetic neuropathy is not a major one. If you do have
better information please share it on this site!

In acute intermitted porphyria and congenital erythropoietic porphyria why do the end product
of the affected enzymes accumulate instead of their substrate??
Bellelli: First of all, congratulations! This is an excellent question.
Remember that a condition is which the heme is not produced is lethal in the foetus; thus
the affected enzyme(s) must maintain some functionality for the patient
to be born and to come to medical attention. All known genetic defects of heme
biosynthesis derange but do not block this metabolic pathway.
Congenital Erythropoietc Porphyria (CEP) is a genetic defect of uroporphyrinogen
III cosynthase. This protein associates to uroporphyrinogen synthase (which is present
and functional in CEP) and guarantees that the appropriate uroporphyrinogen isomer is produced
(i.e. uroporphyrinogen III). In the absence of a functional uroporphyrinogen III
cosynthase other possible isomers of uroporphyrinogen are produced together with
uroporpyrinogen III, mostly uroporphyrinogen I. The isomers of uroporphyrinogen
that are produced differ because of the positions of propionate and acetate side chains,
and this in turn is due to the pseudo symmetric structure of porphobilinogen. Only
isomer III can be further used to produce protoporphyrin IX. Thus in the
case of CEP we observe accumulation of abnormal uroporphyrinogen derivatives, which, as
you correctly observed are the products of the enzymatic synthesis operated by
uroporphyrinogen synthase.
The case of Acute Intermittent Porphyria (AIP) is similar, although there may be variants
of this disease. What happens is that either the affected enzyme is a variant that does not
properly associate with uroporphyrinogen III cosynthase or presents active site mutations
that impair the proper alignement of the phoprphobilinogen substrates. In either case
abnormal isomers of uroporphyrinogen are produced, as in CEP.
Also remark that in both AIP and CEP we observe accumulation of the porphobilinogen
precursor: this is because the overall efficiency of the biosynthesis of uroporphyrinogens is
reduced. Thus: (i) less uroporphyrinogen is produced, and (ii) only a fraction of the
uroporphyrinogen that is produced is the correct isomer (uroporphyrinogen III).

is it possible to take gulonolactone oxidase to synthesize vitamin C
instead of vitamin C supplement?
Bellelli: no, this approach does not work. The main reason is that
the biosynthesis of vitamin C, as almost all other metabolic processes, occurs intracellularly.
If you administer the enzyme it will at most reach the extracellular fluid but will not be
transported inside the cells to any significant extent. Besides, there are other problems
in this type of therapy (e.g. the enzyme if administered orally, may be degraded by digestive
proteases; if administered parenterally, may cause the immune system to react against a
non-self protein). In theory one could think of a genetic modification of the inactive human
gene of gulonolactone oxidase, but the risk and cost of this intervention would not be
justified. In addition to these considerations, except for cases of shipwreckage or
other catastrophes, a proper diet or administration of tablets of vitamin C is effective,
risk-free and unexpensive, thus no alternative therapy is reasonable. However, I express my
congratulations for your search on the biosynthesis pathway of ascorbic acid.

      Home of this course

Slides of this lecture