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Guest Lee Harris

Some interesting studies about hair loss

2 posts in this topic

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


Fax + 41 61 306 12 34


© 1999 S. Karger AG, Basel

Key Words

Cystic acne W Biotinidase W Isotretinoin W Biotin


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


Effect of Isotretinoin on

Biotinidase Activity

Skin Pharmacol Appl Skin Physiol




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

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


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.


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,

ÃGt, 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.


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, ÃGt)

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.


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


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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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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