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Some interesting studies about hair loss

biotin studies retinoids

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#1 Guest_Lee Harris_*

Guest_Lee Harris_*
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Posted 16 October 2008 - 08:26 PM

Hey ya'll. I am just about finished with a one month course of 40mg daily. A few days ago I started noticing that my nice thick hair was shedding at a much faster rate. Hairs falling out on my desk, computer, in the bathroom, etc.

I wasn't even aware that alopecia was a side effect of isotretinoin. No information in the medication insert, no info from my doctor, not even on the FDA website.

I came here, and have read through many of these posts on this thread and so my scholarly curiosity was aroused.

I did some research through my University's medical search tools and found some very interesting peer-reviewed journal studies that ya'll may be interested in... I haven't looked at the bulk of this thread so maybe ya'll are already aware of this but:

Below I have copy and pasted a study done by a team of Greek and Swiss researchers. Their goal was to measure the effects of isotretinoin on biotinidase levels. Biotinidase is the enzyme your liver produces to help break down biotin, which many of you have discovered may be related to the problem.

Some interesting notes, of 50 of the participants, 42 experienced hair loss. This is a staggering majority given that little information is out there about the side effect. Likewise, biotinidase levels were greatly curtailed, by as much as half, after only 30 days of isotretinoin treatment.

________________________________________________________________________________
_

The Effect of Isotretinoin on
Biotinidase Activity
Kleopatra H. Schulpisa Sophia Georgalac
Evangelos D. Papakonstantinoua Timos Michasc
George A. Karikasb aInstitute of Child Health and bPharmacokinetics Unit, Aghia Sophia Children’s Hospital, and cDermatological Clinic of Athens University, ‘A. Syngros’ Hospital, Kesariani, Athens, Greece
Received: June 22, 1998
Accepted: Nov. 4, 1998
Kleopatra H. Schulpis, MD, PhD
Institute of Child Health
Aghia Sophia Children’s Hospital
GR–11527 Athens (Greece)
Tel. +30 1 7708291, Fax +30 1 7700111
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 1999 S. Karger AG, Basel
http://BioMedNet.com/karger

Key Words
Cystic acne W Biotinidase W Isotretinoin W Biotin
Abstract

Background: Among the reaction and effects
of isotretinoin, mucocutaneous reactions, xerosis
and erythema of the skin as well as elevation
of liver enzymes and lipids except
high density lipoprotein have been reported.
Objective: Since biotinidase is mainly produced
in the liver and partial biotinidase deficiency
causes dermatological manifestations,
seborrheic dermatitis, alopecia etc.,
isotretinoin side effects in relation to biotinidase
activity were studied. Methods: Fortytwo
(n = 42) patients with severe cystic acne
had liver function tests, lipid estimations, serum
biotin as well as biotinidase activity evaluations
before (value 1) and on the 30th
day (value 2) of treatment with isotretinoin
monotherapy (Roaccutane 0.5 mg/kg/24 h).
The same laboratory tests were evaluated in
50 controls only once. Moreover, the effect of
isotretinoin on a known plasma biotinidase
activity was evaluated after incubation in vitro
with various concentrations of the drug.
Results: A statistically significant elevation of
liver enzymes and lipids, except high density
lipoprotein, was observed at the end of this
study. On the contrary, biotinidase activity
was found to be significantly decreased
as compared to the initial values (value 1 =
4.70 B 0.89 nmol/min/l, value 2 = 2.50 B
0.8 nmol/min/l, p ! 0.001) and to controls
(5.2 B 0.9 nmol/min/l vs. value 2 = 2.50 B 0.8
nmol/min/l, p ! 0.001). Additionally, biotin
levels showed no significant alterations and
the in vitro incubation of the enzyme with
various concentrations of the drug exhibited
no effect on its activity. Conclusion: It is suggested
that isotretinoin isomers-metabolites
act in the liver, resulting in low biotinidase
activity.

Effect of Isotretinoin on
Biotinidase Activity
Skin Pharmacol Appl Skin Physiol
1999;12:28–33
29

Introduction
The use of orally administered isotretinoin
(13-cis-retinoic acid) has transformed the
management of patients with severe nodulocystic
acne. Isotretinoin has marked effects on
sebaceous glands and on sebum production
and composition [1, 2]. Of more significance
among the reactions of the drug, mucocutaneous
reactions, generalized itchiness and xerosis,
increased skin fragility and exfoliation
of palms and soles are encountered as adverse
effects of the drug [2]. Thinning of the hair
tends to be more frequent in patients receiving
isotretinoin whereas the usual ocular complications
are mild and benign in nature [3–
6]. Dyslipidemia, muscular and skeletal complications,
minor transient abnormalities of
liver function have also been reported [7–9].
Furthermore, biotinidase (EC 3.5.1.12)
cleaves the biocytin moiety (lysyl biotin) and
other small peptides present in biotin-dependent
carboxylases [10]. The enzyme permits
free biotin to recycle and to be claimed from
dietary proteins. Biocytin, the lysine Â-aminoamide
of biotin, is thought to be the natural
substrate of biotinidase and probably arises
from the proteolysis of the biotin-dependent
carboxylases, in all of which biotin is bound to
the apocarboxylases via the Â-amino group of
·-lysine residue [11, 12]. Profound biotinidase
deficiency causes dermatological manifestations
similar to biotin deficiency probably as a
consequence of impaired intestinal absorption,
cellular salvage and renal reclamation of biotin
as well as neurological manifestations including
seizures, hence little free biotin is metabolically
available [12, 13]. Since inherited biotinidase
deficiency has been reported to induce
skin lesions and conjunctivites, changes which
are also characteristic side effects of retinoids,
it is speculated that these findings of acquired
biotinidase deficiency of isotretinoin-treated
patients should be investigated.
Thus, the aim of this study was the evaluation
of serum biotin levels as well as biotinidase
activity in patients with cystic acne before
and after 30 days’ treatment with isotretinoin.
Additionally, a preliminary in vitro experiment
of isotretinoin effects on biotinidase
activity was also carried out.
Patients and Methods
Patients
Forty-two patients with severe cystic acne (22 M,
20 F), mean age 18.6 B 1.9 years, participated in the
present study. Fifty medical students of comparable
age and sex were the controls.

Methods
The study was approved by the Greek Ethical
Committee. All patients and controls underwent laboratory
examinations, complete blood counts, liver
function tests, including SGOT, SGPT, alkaline phosphatase,
ÁGt, total protein and lipids before (value 1)
and after day 30 (value 2) of treatment with isotretinoin
monotherapy (Roaccutane Roche 0.5 mg/kg/24 h
per os). Moreover blood (3.0 ml) was drawn for the
estimation of biotin serum levels and biotinidase activity
at the same intervals of this study (value 1 and value
2). These laboratory tests were evaluated in controls
only once. Biotinidase Assay. A fluorometric assay for the
determination of biotinidase activity was carried out,
according to Ebrahim and Dekisnamur [14]. Human
serum was dialyzed against 50 mM phosphate buffer,
pH 7.0 and stored at –20° C prior to use. The reaction
was performed by adding dissolved serum sample to a
reaction mixture containing 0.1 M sodium acetate
buffer, pH 5.5, 5 mM EDTA, and 0.5 mM biocytin to a
final volume of 0.5 ml. After 1-hour incubation at
37° C, 50 Ìl of perchloric acid 60% was added to stop
the reaction. The precipitated protein was removed by
centrifugation. To 0.45 ml of the supernatant, after
alkalination, 0.5 ml of fresh made buffer (containing
0.5 M sodium carbonate, pH 9.5, 0.1% 1,2-diacetyl
benzene and 3 mM 2-mercaptoethanol) was added.
After 25 min at room temperature the samples were
read in a Perkin-Elmer LS3 fluorometer at 546 nm.
Biotinidase activity was tested in triplicate under light
protection when treated with isotretinoin (final concentration
0.1–0.5 mM). The evaluation was carried
out after incubation at 37 ° C and gentle shaking (drug,predissolved in ethanol absolute p.a.), against a blank
identical to control, a reference sample containing isotretinoin
only plus an ethanol reference blank (maximum
isotretinoin absorbance at 354 nm). Pure isotretinoin
was purchased from Roche Hellas Ltd.
Biotin Assay. An enzyme-linked method was used
to determine the biotin levels in serum, as previously
described by Nyalala et al. [15].
Statistical Analysis
Student’s t test as well as Wilcoxon paired test were
utilized for the statistical analysis of the results.

Results
Obvious remission of their acne was observed
in all (42/42), thinning as well as xerosis
of the skin were found in 33/42 of our
patients. Additional symptoms such as cheilitis
(2/42), increased skin fragility and exfoliation
particularly of the palms (3/42) were
observed, whereas 4 subjects (4/42) experienced
patchy erythema of the forearms after
30 days of treatment (table 1). As is shown in table 2, there was a statistically
significant elevation of liver enzymes
(SGOT, SGPT, alkaline phosphatase, ÁGt)
and lipids (cholesterol, triglycerides, LDL,
VLDL); HDL was slightly reduced on the
30th day on therapy. On the contrary, biotinidase
activity (table 1) was greatly lowered but
not related to the observed skin lesions,
whereas biotin serum levels showed no alteration
at the same time (table 3). In addition,
as presented in table 4, isotretinoin demonstrated
no inhibitory effect on biotinidase activity
even when incubated with high concentrations
of the drug.

Discussion
Isotretinoin is associated with a high incidence
of a number of minor annoying side
effects. The most common of these, occurring
in most patients, is a characteristic cheilitis as
found in our patients; the lips become dry,
scaly and cracked and may be the cause of
considerable discomfort. Other mucosal areas
may also become dry and uncomfortable.
Slight soreness and peeling of the palms and
soles, also found in the patients, are seen but
these are not usually the cause of serious complaint.
Of more significance, as far as the
patients are concerned, is the thinning of their
hair. This rarely results in a significant cosmetic
disability [1–4]. Apart from these rela-
tively minor side effects isotretinoin is capable
of causing serious toxic effects. Transient
abnormalities of liver function have been reported.
Increases of liver function tests are
said to occur in patients on this drug [6–9].
These findings were in agreement with those
of our patients. Additionally up to 25% of
patients on isotretinoin have been reported to
exhibit an elevation of serum triglycerides,
total cholesterol, LDL and decreased HDL [1,
2, 8, 9]. These findings were also found in our
patients. Furthermore, the decreased biotinidase
activities (table 1, value 2), which were
found in our patients, were not related to the
severity of their presented skin side effects of
isotretinoin even though the number of patients who exhibited additional skin problems
other than thinning of hair and xerosis was
small.
According to the literature, neurological
and ocular manifestations were mainly reported
in patients with profound (total) biotinidase
deficiency. The absence of such
symptoms in our patients could be due to
their acquired ‘partial’ biotinidase deficiency
which was presented only with dermatological
symptoms [13]. Additionally, the highest specific
activity of biotinidase was found in liver
and serum [10, 11], kidney and adrenal
glands, but relatively low in the brain [15, 16].
Pispa [17] noted a 50% decrease in the biotinidase
activity in liver, and a 30% decrease in
serum activity of partially hepatectomized
rats. It was concluded that the liver was the
likely source of serum biotinidase. Furthermore,
the serum biotinidase activities in patients
with chronic hepatic diseases were detected
below the lower limit of activity found
in healthy adults [16–18]. Thus, it could be
suggested that isotretinoin impairs the liver
function [8], resulting in low biotinidase activity
as it was previously reported [19]. On
the other hand, the unaltered biotin serum
levels that were evaluated for the first time
in patients with cystic acne before and after
1-month treatment as well as the results of the
in vitro experiments, which showed no direct
isotretinoin effect on biotinidase activity,
could lead to the following preliminary suggestions.
The absence of an in vitro effect of
the drug on biotinidase could possibly be due
to physicochemical factors such as polarity
since isotretinoin was pretty insoluble in water.
At this point it should be noted that there
was also no indication that any spectral isotretinoin
properties have interfered in the in
vitro assay. As regards the in vivo effect of isotretinoin
therapy, it seemed that isotretinoin
isomers-metabolites, such as tretinoin, oxotretinoin
or 4-oxo-isotretinoin, might play a pivotal role towards biotinidase activity [16].
The latter hypothesis deserves to be investigated
through future experiments. However it
could be concluded that the dermatological
lesions (xerosis and thinning of the skin, cheilitis,
erythema etc.), which were found in almost
all the patients on treatment, could be
related to initial symptoms of their low biotinidase
activities. These findings are clinically
important since patients on isotretinoin treatment
may develop symptoms similar to those
observed in patients with partial enzyme deficiency.
Biotinidase deficiency is a potentially
treatable disorder, and empirical evidence
suggests that a supplement of biotin (10 mg/
day) in patients prevents its clinical manifestations
[10]. Therefore, adequate biotin
should be prescribed as a supplement during
isotretinoin treatment in order to restore biotinidase
function and offer more free metabolically
available biotin.

To follow up, I further researched a claim in this article that referenced a 1985 study on the genetic form of biotinidase deficiency.

An infant began experiencing rabid symptoms from his biotinidase deficiency and the physician in this case prescribed daily megadoses of Biotin-Lysine (10 mg). Supposedly all symptoms were relieved from this.

Other posters have commented on taking a Biotin supplement. Any suggestions on your experience?


All I can say is that I hope I caught this side effect while it is still mild and hopefully it will end before it gets noticeably bad. (knocks on wood). The accutane was really doing great things for my acne too, even in such a short amount of time.

I am going to see my dermatologist on Monday and see what he thinks about all of this.



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#2 Guest_Lee Harris_*

Guest_Lee Harris_*
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Posted 16 October 2008 - 09:31 PM

Just to mention... I have heard many people throwing out figures of Alopecia occurring at levels of 10% and so on.

According to UK government statistics, Alopecia occurs at < 1/1000 patients.


That would mean actual baldness, noticeable shedding happens to less than 1/10th of 1 percent of those who take accutane.




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