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Liver toxicity of retinoid therapy
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Liver toxicity of retinoid therapy Henry H. Roenigk, Jr., M.D. Chicago, IL Vitamin A metabolism involves storage in the liver. Hypervitaminosis A results in liver abnormalities, including fibrosis and cirrhosis. Ito cells are increased and promote fibrogenesis, which results in cirrhosis. Retinoids (Accutane and Tegison) are used clinically for the treatment of a variety of skin diseases. Since retinoids are analogs of vitamin A, their potential to produce liver disease is reviewed. Animal and human studies of liver function tests suggest some abnormalities in the liver in about 25% of patients treated. Liver biopsy studies have included isolated case reports and two retrospective and one prospective liver biopsy study of retinoids in humans. Although some increase in kistologic liver changes have been noted, most liver biopsy specimens showed no change or improvement. Retinoids do not appear to produce consistent toxic liver abnormalities. (J AM ACAD DERMATOL 1988;19:199-208.)
Vitamin A enters the body as the provitamin /3-carotene or as preformed retinol./3-Carotene is cleared by an intestinal dioxygenase enzyme to yield two molecules of retinal, 1 which is then reduced to retinol. After esterifications, the retinyl esters are associated with chylomicrons in the lymph and are absorbed by the liver as chylomicron remants. Approximately 90% of the total body pool of vitamin A in a normal animal is found in the liver. During vitamin A deficiency, liver retinol and retinyl ester pools decrease rapidly, whereas the supply to plasma and peripheral tissues remains unaltered, only to drop after liver depletion. 2 Vitamin A concentrations in liver biopsy specimens are compared with relative dose response, the percentage increase in plasma retinol level relative to the plasma retinol level 5 hours after oral administration of a standard oral dose (450 m g of retinyl acetate) and have been used to establish criteria of a minimal liver vitamin A concentration to maintain health. 3 The stellate (Ito) cell of the liver is thought to be
From the Department of Dermatology, Northwestern University Medical School. Reprint requests to: Dr. Henry H. Roenlgk, Jr., Department of Dermatology, Northwestern University Medical School, Ward Building 3-191,303 East Chicago Ave,, Chicago, IL 60611,
the major storage cell for retinyl esters, 4 The parenchymal cell, in addition to some storage capacity, appears to have a role in secreting retinol in complex with the retinol-binding protein (RBP). These two liver cells are vital in retinol use, transport, and function.~ The stellate (Ito) cell appears to be important mainly in storage under conditions of either normal or excess vitamin A nutrition.6 In addition to the liver functioning as a depot for vitamin A, recent findings suggest that liver tissue may also need retinol for its normal functioning. HYPERVITAMINOSIS A
Vitamin A is recognized as a nutrient essential for life. It has also been effective in the treatment of various keratinizing disorders in humans, and there is evidence of its antitumor effect in animals and possibly in humans. 7,s Because the public recognized the beneficial effects of vitamin A, they assume that taking large amounts of it may be beneficial, especially in the prevention of cancer. The first report of chronic toxicity of vitamin A was in a child in 19449 and later in an adult in 1952.1~Hypervitaminosis A syndrome may present with skeletal pain, pseudotumor cerebri, headache, pruritus, or desquamafive dermatitis with hair lOSS.tI't3 Since vitamin A is stored in the liver, 199
200 Roenigk
hepatomegaly with or without abnormal liver function is frequently seen with vitamin A intoxication. Bauernfeind14has recently summarized 75 reported adult cases of chronic hypervitaminosis A and reports that clinical symptoms of toxicity can develop between a few weeks to 9 years after the start of long-term daily oral vitamin A. The current recommended dietary allowance of vitamin A is 5000 IU/day for adult males and 4000 IU/day for nonpregnant adult females. Prolonged doses only 10 times the recommended daily dietary allowance (i.e., 50,000 IU/day) may cause toxicity. Vitamin A is normally released from liver stores as retinol bound to its specific protein carrier, RBP, as an equimolar complex. In this form vitamin A is delivered to peripheral tissues where it is released from RBP for cellular use. In hypervitaminosis A,~S.16the capacity of RBP to transport vitamin A is exceeded, and the excess begins to circulate as retinyl esters nonspecifically bound to plasma lipoproteins. When delivered to peripheral tissues in this nonphysiologic manner, vitamin A exhibits surface-active, membranolytic activity that may ultimately result in cellular and tissue damage. In a detailed study of three cases of chronic hypervitaminosis A, Smith and Goodman ~5,16demonstrated that the excess of total vitamin A relative to RBP could be accounted for by elevated levels of lipoprotein-bound retinyl esters. Animal studiesx7 with large doses of vitamin A show lysosomal and mitochondrial damage of the liver. Kupffer cells are markedly enlarged, and the cytoplasm is filled with fat droplets. Liver biopsy specimens from humans with chronic vitamin A introxication show a pattern of perisinusoidal fibrosis, central vein sclerosis, and focal congestion associated with perisinusoidal lipid storage cells. The massive accumulation of lipid storage cells (Ito cells) is found in the network of basement membranes with numerous bundles of collagen, reticilin fibers, and lymphocytes.~8Russel et al. 19suggested that the lesion could result in obstruction of hepatic blood flow, parenchymal cell atrophy, and eventual portal hypertension. Ito cells are considered transformed fibroblasts with lipid-storing capacity. They may be transformed into fibroblasts that can
Journal of the American Academyof Dermatology produce type III collagen. This transformation that promotes fibrogenesis may result in cirrhosis. Forouhar et al.2~ have confirmed the role of the Ito cells in vitamin A toxicity in transforming them into fibroblasts producing collagen. Vitamin A fluoresence and direct assays of liver revealed substantial increases in vitamin A content during the hypervitaminosis state. VITAMIN A AND HEPATOCELLULAR CARCINOMA
The rate of growth of Morris hepatomas and their ability to incorporate radioactive retinol are inversely related,21 thus suggesting a direct relationship between differentiation and retinol content of hepatoma tissue. DeLuca et al. 2~were unable to detect retinyl palmitate in hepatomas, which suggested that hepatomas were vitamin A deficient relative to the host liver. Thus it is established from animal studies and some human hepatomas 2~that hepatic carcinoma is vitamin A deficient. Whether this is a consequence of carcinogenesis or a contributory factor to tumor progression is under investigation. RETINOIDS AND THE LIVER
Oral retinoids represent a significant advance in the therapeutic field of specific dermatologic disorders such as severe acne vulgaris, keratinizing skin diseases, and psoriasis vulgaris. The rationale of the therapeatic use of derivatives of retinoic acid (Accutane and Tegison) was based on the capacity of the liver to absorb and store retinol but its failure to store retinoic acid. Thus retinoic acid derivatives have their effects on extrahepatic target organs. Etretinate (Tegison) is the aromatic derivative that has been studied extensively for possible hepatotoxicity. METABOLISM AND PHARMACOKINETICS
The retinoid etretinate is an analog of vitamin A acid or retinoic acid. It is absorbed through the portal system but does not accumulate in the liver in appreciable amounts. 24 The major biliary metabolite is retinoyl-/~-glucuronide, which is reabsorbed, thereby producing
Volume 19 Number 1, Part 2 July 1988 enterohepatic circulation. Retinoic acid is transported in plasma bound to serum albumin. There is evidence that etretinate is excreted unchanged in feces, but the conjugation with/3-glueuronate in the bile with rapid secretion is thought to protect the fiver. Pharmacokinetic investigations of the aromatic etretinate have revealed discrepancies between single and multiple dosing in humans. Plasma concentration time profiles after a single intravenous dose and oral administrations could fit a linear threecompartment model. However, this model failed to describe a phase of slow elimination after longterm dosing. Both etretinate and its main metabolite have been detected in plasma for several months after cessation of treatmentY Although these concentrations could never be correlated with therapeutic or toxic effects, they are of importance with respect to the teratogenic potential. Efforts have been undertaken to determine possible storage sites that are suggested by this pharmacokinetic behavior. Because the liver is the specific storage organ for vitamin A, it has been postulated that the liver might also be the storage depot for etretinate.
Liver toxicity of retinoid therapy 201
Table I. Classification of liver biopsy findings
Normal; fatty infiltration mild, nuclear variability, mild; portal inflammation, mild Class II: Fatty infiltration, moderate to severe; nuclear variability, moderate to severe, portal tract expansion, portal inflammation, and foczAnecrosis, moderate to severe Class ILia: Fibrosis, mild (portal tirosis denotes formation of septa extending into the lobules; slight enlargement of portal tracts without disruption of limiting or septum does not put the biopsy specimen in class III; this distinction requires a connective tissue stain or reticulum preparation) Class IIIb: Fibrosis, moderate to severe Class IV: Cirrhosis Class I:
noid treatment. However, a more sensitive method of O-dealcylation of 7-ethoxycoumarine activity increased significantly beginning on the eighth day of treatment until the end of the study.
ANIMAL STUDIES: LIVER/RETINOIDS
LIVER FUNCTION STUDIES: ABNORMALITIES WITH RETINOIDS
Studies in rats indicated that the liver retained 16% of the oral dose of etretinate whereas all other tissues had accumulated less than 0.3% of the dose? 6 After 8 days, the level of etretinate in the dog liver was 0.3% of the dose, whereas the level in other tissue was only 0.04%. Toxic doses of etretinate given to dogs result in elevation of alkaline phosphatase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Gerber and Erdman 27 found that the all-trans form of retinoic acid induced hypertriglyceridemia in rats. Liver analysis did not reveal fatty liver or alterations in phospholipid, cholesterol, or vitamin A content in any groups. Goerz et al? 8 gave etretinate during a 36-day period to adult female Wistar rats (5 mg/kg/day) with no histochemically demonstrable changes in the investigated liver enzymes. This may indicate intact function of mitochondrial and lysosomal function during reti-
Several investigators have noted changes in the liver function tests of patients with psoriasis treated with etretinate. Fredriksson29 commented on two patients with abnormal liver functions and indicated the need to follow liver function tests and exclude patients with fiver insufficiency from treatment. Guilhou et al.~ noted that a few patients with psoriasis who received etretinate showed a slight increase in transaminase and alkaline phosphatase. Goerz and Offanos) t in reporting a multicenter controlled study of etretinate in psoriasis, observed moderate changes only in the serum levels of AST and ALT. The concentrations of serum alkaline phosphatase showed a slight increase in a few instances. Some of these alterations gradually returned to normal despite continued but presumably lower dosage of the drug. Dahl et al.32found a slight increase in serum alkaline phosphatase or AST in six of 15 patients with psoriasis treated
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Roenigk
Table II. Serial fiver biopsies by histologic classification in patients with all four biopsies* I
Pretreatment
,
6 mo
Third biopsy
[ [
Fourth biopsy
No. of patients
No change
I
I
I
I
Improved
II III
II III
II I
II I
IV
IV
IV
II
1
III II
III II
III I
I I
1 2
III II
IV
Total no change or improved IV IV
II
III
Worse Total worse
III
3 2 1
10 1 1
2
*Reprinted with permission from R.oenigk Jr HH, Gibstine C, Glazer SD, Sparberg M, Yokoo H. Serial liver biopsies in psorlatie patients receiving long-term etretinate. Br J Dermatol 1985;112:77-81.
with etretinate. Orfanos et al. 33 reviewed the laboratory studies of 278 patients with psoriasis in a multicenter study. They found no significant difference in liver function during or after therapy. Only the serum total bilirubin level showed a trend to increase, although AST was increased in 14 patients and ALT in six patients. These elevations in AST and ALT returned to normal when the drug was stopped, which indicated a possible causative relationship. Orfanos et al. indicated that other drugs, alcoholism preexisting liver damage, and muscular activity need to be evaluated in these patients. Cunningham34 reviewed the records of 652 patients treated in the initial clinical trials conducted in the United States. He indicated that about one third of patients receiving therapy will develop some abnormal liver function studies. LIVER BIOPSIES DURING RETINOID THERAPY
Few liver biopsies have been performed on humans during etretinate therapy. Fredriksson 29 performed a liver biopsy on one patient after treatment with etretinate, who showed chronic aggressive hepatitis. Thune and Mork 3s reported on a 54-year- old woman with ichthyosis given etretinate at a dose of 75 rag/day, with the dose reduced to 50 mg/day during a 3-month period. Laboratory studies showed increases in serum transaminase, bilirubin, and alkaline phosphatase levels. No pretreatment liver biopsy specimen was available, but
the liver biopsy specimen taken 1 week after etretinate therapy was stopped revealed centrilobular necrosis and toxic damage with degeneration of parenchymal cells. Results of hepatitis B antigens were negative. They suggested a relationship between etretinate and the toxic necrosis of the liver cells, but this might be an idiosyncratic type of reaction rather than a true toxic reaction. Weiss et al. 36 reported on clinical hepatitis in a 74-year-old woman with palmoplantar psoriasis treated with etretinate. Weiss et al. 37reported on a second patient with hepatitis from etretinate for psoriasis. This time a fiver biopsy specimen confirmed the histologic changes of chronic active hepatitis. Van Voorst et alY reported histologically confirmed but clinically inapparent reversible hepatitis in one patient with psoriasis and one with the basal cell nevus syndrome, both of which developed during the first month of treatment with etretinate. Gavish et al.39 reported on a case of biochemical and morphologic cholestatic hepatitis induced by etretinate therapy. Vahlquist et al. 4~ reported on biopsy-proved hepatitis during treatment of psoriasis with etretinate. When the patient was rechallenged with etretinate 18 months later, hepatic enzyme levels were again elevated. Isotretinoin therapy, although devoid of hepatoxicity, was only marginally effective clinically. A single case report of toxic hepatitis caused by a combination of methotrexate and etretinate41 leads to a word of caution regarding its combined use.42 Cunningham's 34review of the clinical studies in
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Liver toxicity of retinoid therapy 203
Table IlL Serial liver biopsies for histologic classification in patients with only three biopsies* Pretreatment
6 mo
Third biopsy
patients
II III II
II III II
II III I
3 1 1 5
No change Improved Total no change or improved
*Reprinted with permission from Wake K. Perisinusoidal stellate cells (fat storing ceils, intestinal cells, lipoeytes); their related structure, in and around the liver sinusoids, and vitamin A storing .cells in extrahepatie organs. Int Rev Cystol 1980;66:303-53.
the United States detected only 10 of 652 patients with psoriasis on the etretinate protocol with clinical or hisotlogic hepatitis possibly or probably related to etretinate treatment. In one patient, histologic changes resembling chronic active hepatitis were still found 6 months after discontinuation of therapy. In eight patients liver function tests returned to normal after discontinuation, and one patient was lost to follow-up. Four hepatitis-related deaths have been reported worldwide, and in two of these the patients had received etretinate for a month or less before having hepatic symptoms. These are probably idiosyncratic reactions and not true toxic reactions in the liver. LARGE
GROUPS
OF LIVER BIOPSIES IN
PATIENTS WITH PSORIASIS TREATED WITH ETRETINATE Isolated case reports do not give a clear picture of the true incidence of possible liver toxicity from etretinate+ Therefore liver biopsies have been performed in three larger groups of patients. One study was prospective and two were retrospective.
Prospective study of liver biopsies in patients with psoriasis treated with etretinate A protocol was developed to evaluate the safety and effectiveness of etretinate in psoriasis and also to address the question of hepatoxicity.43 Since pretreatment liver biopsies had never been performed on patients receiving etretinate, this study was designed as a prospective evaluation of fiver biopsies during a 3-year treatment period of 20 patients with severe psoriasis given etretinate. Patients with severe psoriasis with or without psoriatic arthritis having at least 20% skin involve-
merit with psoriasis were selected. Most had more than 50% body coverage and had required previous systemic therapy with either photochemotherapy or methotrexate. Men and women older than 21 years old could be entered, but women with reproductive potential were excluded. Patients must have had an increased risk of hepatotoxicity, which was defined as having one or more of the following: (1) a history longer than 1 year of daily alcohol ingestion of 3 or more equivalent units (1 equivalent equals 12 ounces of beer, 4 ounces of wine, or one mixed drink); (2) a lifetime total use of 2.5 gm or greater of methotrexate; (3) currently with two or more persistent abnormalities of liver function tests; (4) currently with clinical findings of a fiver abnormality; and (5) a biopsy, which when last performed had a classification of class I or II liver biopsy without persistent, significant abnormalities in liver function tests. Patients with abnormal renal function studies were excluded. Those with preexisting conditions that might be exacerbated by hypervitaminosis A were excluded. Patients with liver biopsy changes of cirrhosis were not included, although those with fibrosis were allowed. Patients with fasting triglyceride levels more than twice the upper limit of normal or patients taking systemic medication for hyperlipidemia were also excluded. Only bland topical emollient preparations were used except that 1% hydrocortisone cream could be used to limited areas (less than 5% area). The initial treatment period was 24 weeks (6 months), at which time etretinate was discontinued for 3 months. The second course of treatment lasted 9 months and was given after a 3-month period off the drug. The 3-year course of etretinate
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Roenigk
Table IV. Summary of all liver biopsies in prospective study*
No change or improved Worse
15 2
*Reprinted with permission from Roenigk Jr HH, Gibstine C, Glazer SD, Sparberg M, Yokoo H. Serial liver biospies in psoriatic patients receiving long-term etretinate. Br Dermatol 1985;112:77-81.
therapy consisted of 9 months on the drug and 3 months off drug periods each year. Percutaneous needle liver biopsy specimens were obtained under local anesthesia with a Jamshedi needle before and after 24 weeks of therapy with etretinate and again after each of two subsequent 36-week courses. Each specimen was divided into three portions for light microscopy, electron microscopy, and chemical analysis. Tissue for light microscopy was fixed in 10% buffered neutral formalin and embedded in paraffm; sections were stained with hemotoxylin-eosin, Masson trichrome, Gomori's reticulum, and Perl's iron stain. Liver biopsies were done before treatment, 6 months after etretinate, 2 years after etretinate, and 3 years after etretinate. Table I shows the pathologic classification that was reviewed in a blind fashion by two independent liver pathologists. In one third of the patients, abnormal liver function studies were obtained intermittently over the 3 years. There usually were slight elevations of AST, ALT, or alkaline phosphatase. There was poor correlation between liver function studies and liver biopsy results. Restflts of pretreatment liver biopsy specimens included liver biopsy class I, eight patients; liver biopsy class II, four patients; liver biopsy class IIIa, four patients; and liver biopsy class IIIb, four patients. Twelve patients had abnormal liver biopsy results before starting therapy. Eighteen of 20 patients (90%) showed no change in the classification of the liver biopsy specimens after 6 months of etretinate, and two patients showed progressive liver cell injury and a deterioration of class." One patient went from severe fibrosis to cirrhosis (classes IIIb to IV). The posttreatment liver biopsy specimen revealed the features of alcoholic hepati-
tis with numerous Mallory bodies. This patient admitted to an increase in his normally heavy alcohol intake. One patient's biopsy specimen changed from mild fibrosis to severe fibrosis (classes IIIA to IIIb) and in addition showed necrosis of hepatocytes, collapse of the normal stroma, and an excess of fibers within the lobular parenchyma. Collagen stains revealed an aggregation of the preexisting fibrous tissue without new collagen formation. Three patients at the 6-month biopsy had an increase in fatty metamorphosis but no change in classification. One progressed from mild to moderate and two from moderate fo severe fatty infiltration of the liver. There was no increase in body weight in any of these patients. After the original 3 years, the study was extended to several more courses of etretinate and further yearly liver biopsies. Of our original 20 patients, 12 have had four liver biopsies (Table II). Six patients stopped, although three of these six had three liver biopsies each (and therefore two full 9-month courses of etretinate) before stopping the drugs Table III). Table IV summarizes all the liver biopsy results. Two patients died while receiving the third course of the drug: one died of pancreatic carcinoma and the other of immunoblastic sarcoma. There is no known relationship between these diseases and etretinate therapy. Of the 12 patients who have had all four liver biopsies (Table II), five have shown no change in the biopsy results, five have actually shown an improvement, and two have shown a deterioration of classification. 45 Five patients completed three liver biopsies (Table III), including the two patients who died. Four had no change in their liver biopsy results and one showed improvement. The tissue from 10 patients was processed for electron microscopic examination. The number of Ito cells and hepatocytes was determined by counting all such cells seen in the photographs. Between 300 and 500 hepatocytes were seen per specimen. These numbers were extrapolated to give an Ito cell index, which has been previously defined17 as the number of Ito cells/1000 hepatocytes. In addition, the number of fat lobules per Ito cell was counted and the fine structure of the hepatocytes was examined. The Ito cell index increased in two
Volume 19 N u m b e r 1, Part 2 July 1988
Liver toxicity of retinoid therapy 205
Table V. Clinical and fight microscopic data* Etrefinate duration
Case No.
Age/sex
Prior methotrexate
1-7 (3~, 5t, 4w
Four with prior treatment for up to 5 yr None
Case 3: 1979, severe fatty change Case 5: 1979, minimal fatty change None
5-6
8, 9
Two females, five males, range 24-73 yr 51/M, 28/M
10 11~:
60/F 58/M
3 yr None
61h 589
12, 13, 14
63/F, 34/F, 40/M
5t
Mild lobular hepatitis
15w 16
59/M, 66/F
Two with prior treatment up tolyr None
None 1978--moderate to severe fatty change None None
5
17
48/M
3 mo (1979)
None
51A
18:~
67/F
1 yr (1977)
1978--moderate fatty change
6
Mild periportal fibrosis Piecemeal necrosis, triaditis, moderate to severe fibrosis and moderate fatty change Cirrhosis and severe fatty change
(yr)
Prior biopsy
6, 61A
Biopsy results (1985-1986)t
Minimal or mild fatty change or no pathologic changes Moderate fatty change Severe fatty change Severe fatty change
*Reprinted with permission from Camuto P, Shupack J, Orbuch P, Tobias H, Sidhu G, Feiner H. Long-term effects of etretinate on the liver in psoriasis. Am J Surg Pathol 1987;11:30-7. ~'Patient No. 13 had a biopsy in 1982, 1 year after initiation of therapy and was subsequently followed up for 4 years. :~Prior biopsy available. w of significant alcohol intake.
patients and decreased in eight. When compared with pretreatment, there was no significant change in the number of Ito ceils per lobule. ~ Another portion of the liver tissue was analyzed for etretinate concentration as described by Paravicini et al. 25 The results of liver tissue analysis were available in 18 of 20 patients for retained etretinate. The time elapsed between cessation of drug and liver biopsy, grade of fatty infiltration in the liver (as judged by pathologists reading light microscopic slides), and estimated amount of etretinate in a 1500 g m liver were analyzed. 4~ Etretinate was detected in all samples, including one from a biopsy specimen taken 78 days after discontinuation of the drug. Generally, the highest concentrations were in those livers with moderate or severe fatty infiltration. There was a trend toward higher concentra-
tion of etretinate in those biopsy specimens that had a greater degree of fatty infiltration.
Histologie changes in the liver during etretinate treatment Forgel et al. 47evaluated 32 patients, all of whom were treated with etretinate from 6 to 60 months for Darier's disease, psoriasis, and other keratinizing disorders. The biopsy specimens were compared with a control group of 3 5 biopsy specimens matched with the same age, sex, and year in which the biopsies were done. This was not a prospective study, but six patients had serial fiver biopsies and eight had pretreatment liver biopsies. The results indicated more fatty infiltration in the control group than in the etretinate group, whereas other patients had a tendency to higher
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Roenigk
scores in postetretinate liver biopsies. None of the differences were statistically significant. The eight patients with liver biopsies before and after etretinate treatment showed a tendency to higher scores in the posttreatment liver biopsies, but again this was not significant. No liver biopsy specimens showed the histologic changes of cirrhosis. Long-term effects of etretinate on the liver in psoriasis Camuto et al.48 studied 18 patients with severe psoriasis. There were no pretreatment liver biopsies, and all patients had been treated with etretihate for at least 5 years. Nine patients had previously had methotrexate, and there was a history of significant alcohol intake in at least two patients. Again the liver function studies did not correlate with the histologic changes. A spectrum of liver abnormalities was observed by light microscopy (Table V). Mild periportal fibrosis was seen in two patients, including one patient with heavy alcohol intake. Moderate to severe fatty changes were noted in six patients. One patient had moderate to severe fibrosis and one had cirrhosis. Both of these patients had previously taken methotrexate. Ito cell lipid content but no the Ito cell number was greater in the etretinate group, but it was not statistically significant. There was also no correlation between overall severity of liver pathologic changes and the cumulative dose of etretinate, which is in contrast to the good correlation generally seen with methotrexate hepatotoxicity. DISCUSSION Long-term prospective studies of patients with psoriasis receiving methotrexate have demonstrated that liver function tests are unreliable in assessing structural changes in the liver.49 Vitamin A toxicity has been reported to produce only mild changes in alkaline phosphatase, suIfobromophthalein retention, and prothrombin times. Therefore we felt that a prospective liver biopsy study was important to assure the safety of etretinate. We thought that patients who had potential preexisting liver damage from other hepatotoxins such as methotrexate and alcohol would manifest biopsy changes earlier than would a random group, and the patients were preselected with this in mind. All
Journal of the American Academyof Dermatology patients were encouraged to limit alcohol consumption. Out initial biopsy series 44 concluded that etretihate did not produce a consistent toxic effect on the liver. This conclusion is supported by our subsequent long-term biopsy findings. 45 Our only explanation for the improvement seen in some of our patients is possible sampling error in liver tissue, especially in patients who appear to have reverted from cirrhosis to class II changes. Another explanation is the possible improvement in pathologic liver damage caused by methotrexate when that drug is stopped and etretinate is substituted. Two other large studies, 47'48 both retrospective but with a few pre- and posttreatment liver biopsies, have found some changes on liver biopsy specimens, but none were statistically significant. It appears that long-term administration of etretinate is a safe form of treatment for hepatotoxicity in most patients. The It<)cell has now been evaluated in two of the three large groups studied with etretinate. 4~,48 Camuto et al.4s found no significant changes in the Ito cells. Most of our specimens showed a decrease in the Ito cell index after a 6-month course of etretinate. 46This is in contradistinction to reports in patients with various liver diseases or from other drugs, including methotrexate, in the treatment of psoriasis. 5~s3 Liver diseases may alter the normal metabolism of vitamin A and thereby cause the observed changes in Ito cell counts reported by others. Tissue analysis of the liver biopsy specimen and comparison with fatty infdtration in the liver suggest that etretinate is stored in the liver in the fat. ~ However, it becomes obvious that the liver cannot be the only storage organ for etretinate. This finding suggests that general body fat may be the major storage depot for etretinate. Results from preliminary studies in a few autopsied patients who received long-term courses of etretinate support this conclusion. 4S Rollman and Vahlquist 54 have analyzed the concentration of etretinate in the epidermis, dermis, subcutis, and serum in patients treated with the drug. Serum etretinate and epidermis concentrations correlated, but the drug appeared to concentrate and remain in the fatty tissue in the subcutis for several months after
Volume 19 Number 1, Part 2 July 1988
cessation of therapy. This suggested that adipose tissue was a storage site for etretinate in humans. In summary from extensive evaluation of liver function, histologic examination, and ultrastructure (Ito cells) in a group of patients preselected for potential hepatotoxicity, we found no significant damage to the liver. Etretinate is stored in the fatty tissue of the liver for prolonged periods. The general fatty tissues of the body are probably a more important storage compartment for etretihate. This should be taken into consideration, especially when treating obese patients with etretihate. ProspectiVe studies are underway to evaluate new retinoid derivatives such as Acetretin regarding potential hepatotoxicity. REFERENCES
1. McCollum EV, Davies M. The necessity of certain lipids in the diet during growth. J Biol Chem 1913;15:167-75. 2. Wolf G. Multiple functions of vitamin A. Physiol Rev 1984;6:873-937. 3. Amr.,dee MD, Anderson D, Olson JA. Relation of the relative dose response to liver concentrations of vitamin A in generally well-nourished surgical patients. Am J Clin Nutr 1984;39:898-902. 4. Wake K. Perisinusoidal stellate cells (fat storing cells, intestinal cells, lipocytes), their related structure, in and around the liver sinusoids, and vitamin A storing cells in extrahepatic organs. Int Rev Cystol 1980;66:303-53. 5. DeLuca LM, Creek KE. Vitamin A and the liver. Progress in liver disease. Vol VIII. New York: Grune & Stratton, 1986;81-98. 6. Blom_hoffR, Holte K, Naes L, et al. Newly administered [~H] retinol is transferred from hepatocytes to stellate cells in liver for storage. Exp Cell Res 1984;150:186-93. 7. Shamberger RJ. Inhibitory effect of vitamin A on carcinogenesis. J Natl Cancer Inst 1971;47:667-73. 8. Bollag W. Prophylaxis of chemically induced benign and malignant epithelial tumors by vitamin A acid (retinoic acid). Eur J Cancer Clin Oncol 1972;8:689-93. 9. Josephs HW: Hypervitaminosis A and carotenemia. Am J Dis Child 1944;67:33-43. 10. Sulzberger MB, Lazar MP. Hypervitaminosis A. Report of a case in an adult. JAMA 1951;146:788-93. 11. Oliver TK. Chronic vitamin A intoxication: report of a case in an older child and review of the literature. Am J Dis Child 1959;95:57-67. 12. Muenter MD, Perry HO, Ludwig J. Chronic vitamin A intoxication in adults. Hepatic, neurologic and dermatologic complications. Am J Med 1971;50:129-36. 13. Bobb R, Kieraldo JH. Cirrhosis due to hypervitaminosis A. West J Med 1978;128:244-6. 14. Bauernfeind JC. The safe use of vitamin A: a report of the International Vitamin A Consultative Group. Washington, DC: Nutrition Foundation, 1980. 15. Smith FR, Goodman DS. Vitamin A transport in human vitamin A toxicity. N Engl J Med 1976;294:805-8.
Liver toxicity of retinoid therapy 207
16. Smith JE, Goodman DS. Retinol-binding protein and the regulation of vitamin A transport. Fed Proc 1979; 38:2504-9. 17. Lane BP. Hepatic microanatomy in hypervitaminosis A in man and rat. Am J Pathol 1968;53:591-8. 18. I-Iruban Z, Russel RM, Boyer JL, Glagov S, Bafheri SA. Ultrastructural changes in livers of two patients with hypervitaminosis. Am J Pathol 1974;76:451-61. 19. gussel RM, Boyer JL, Bafheri SA, Hruban Z. Hepatic injury from chronic hypervitaminosis A resulting in protal hypertension and ascites. N Engl J Med 1974;291:43540. 20. Forouhar F, Nadel MS, Gondos B. Hepatic pathology in vitamin A toxicity. Ann Clin Lab Sci 1984;14:304-10. 21. Buchsel R, Reutter W. Plasma membrane change of liver and Morris hepatoma induced by retinol in rats. Cancer Res 1982;42:2450-6. 22. DeLuca LM, Bmgh MD, Silverman-Jones CS. Retinyl palmitate, retinyl phosphate of dolicryl phosphate of post-nuclear membrane fraction from hepatomas, lost liver and regenerating liver: marginal vitamin A status of hepatoma tissue. Cancer Res 1984;44:224-32. 23. Mutt V, Omori M. A novel cellular retinoid-binding protein, F-type, in hepatocellular carcinoma. Ann NY Acad SCI 1981;359:91-103. 24. Goodman PS. Vitamin A and retinoids. Recent advances--introduction, background and general overview. Fed Proc 1979;38:2501-3. 25. Paravicini U, Stockel K, MacNamara P J, Hanni R, Busslinger A. On metabolism and pharmacokinetics of an aromatic retinoid. Ann NY Acad Sci 1981;359:54-67. 26. Hanni R. Pharmacokinetic and metabolic pathways of systemically applied retinoids. Dermatologica 1978; 157(suppl 1):5-10. 27. Gerber LE, Erdrnan JW. Comparative effects of alltrans- and 13-cis-retinoic acid administration on serum and liver lipids in rats. J Nutr 1980;110:343-51. 28. Goerz G, Vizethum W, Kind R, Hornstein M. Influence of a new retinoid (Ro 10-9359) on the cytochrome P-450 system and other enzymes in rats liver. Dermatologica 1978;157(suppt 1):26-31. 29. Frederiksson T. Oral treatment of psoriasis and pustulo~is palmo-plantaris with Ro 10-9359. Dermatologica 1978; 157(suppl 1):13-8. 30. Guilhou J J, Malbos S, Meynadier J. Oral treatment of severe psoriasis with a new aromatic retinoid (Ro 109359). Ann Dermatol Venereol 1978;105:813-8. 31. Goerz F, Orfanos CE. Systemic treatment of psoriasis with a new aromatic retinoid. Dermatologica 1978; 157(suppl 1):38.44. 32. Dahl B, Mollenbach K, Reyman F. Treatment of psoriasis vulgaris with a new retinoid acid derivative Ro 10-9359. Dermatologica 1977;154:261-7. 33. Orfanos CE, Mahrle G, Goerz G, et al. Laboratory investigations in patients with generalized psoriasis under oral retinoid treatment. Dermatologica 1979;159:62-70. 34. Cunningham W. Retinoids and therapy for psoriasis. Video J Dermatol, January 1987. 35. Thune P, Mork NJ. A case of centrolobular toxic necrosis of the liver due to aromatic retinoid--Tigason (Ro 10-9359). Derrnatologiea 1980;160:405-8. 36. Weiss VC, West DP, Ackerman R, Robinson LA.
208
37. 38. 39. 40.
41. 42. 43.
44.
45.
Roenigk Hepatotoxic reaction in a patient treated with etretinate (Ro ~0-9359). Arch Dermatol 1984;120:104-6. Weiss VC, Layden T, Spinowitz A, et al. Chronic active hepatitis associated with etretinate therapy. Br J Dermatol 1985;112:591-7. Van Voorst, Voder PC, Houthoff HF, et al. Etretinate (Tigason) hepatitis in two patients. Dermatologica 1984; 168:41-6. Garish D, Katz M, Gotteherr N, Israeli A, Lifovestzky G, Holubar K. Cholestatic jaundice, an unusual side effect of etretinate. J AM ACAO DERMATOL1985;13:669-70. Vahlquist A, Loof L, Nordlinder A, RoUman O, Vahlquist C. Differential hepatotoxicity of two oral retinoids (etretinate and isotretinoin) in a patient with palmoplantar psoriasis. Acta Dermatol Venerol 1985;65:659-62. Beck HI, Fosed EK. Toxic hepatitis due to combination therapy with methotrexate and etretinate in psoriasis. Dermatologica 1983;167:94-6. Zachariae H. Methotrexate and etretinate as concurrent therapies in the treatment of psoriasis [Letter]. Arch Dermatol 1984;120:155. Roenigk Jr HH, Sparberg M, Yokoo H, Glazer SD. Ro 10-9359 in psoriasis: prospective liver biopsy study of potential hepatotoxicity. In: Orfanos C. Braun-Falce O, Farber E, Grupper C H , Polano 1", Schuppli E, eds. Retinoids, advances in basic research and therapy. Berlin: Springer-Verlag, 1981:375-82. Glazer SD, Roenigk Jr HH, Yokoo H, S.parberg M. A study of potential hepatotoxicity of etretinate used in the treatment of psoriasis. J AM ACAD DERMArOL 1982; 6:683-7. Roenigk Jr HH, Gibstine C, Glazer SD, Sparberg M, Yokoo H. Serial liver biopzies in psoriatic patients receiving long-term etretinate. Br J Dermatol 1985; 112:77-8 !.
Journal of the American Academy of Dermatology
46. Glazer SD, Roenigk Jr HH, Yokoo H, Sparberg M, Paravicini U. Ro 10-9359 for psoriasis: ultrastructural survey and tissue analysis of liver biopsies after a 6-month course of etretinate. J AM ACAD DERMATOL 1984;10: 632-8. 47. Fogel B, Bjerring P, Kragballe K, Sogaarad H, Zachariae H. Histologic changes in the liver during etretinate treatment. J AM ACAO DERMATOL1984;1 1:580-3. 48. Camuto P, Shupack J, Orbuch P, Tobias H, Sidhu G, Feiner H. Long term effects of etretinate on the liver in psoriasis. Am J Surg Pathol 1987;11:30-7. 49. Weinstein GD, Roenigk HH, Maibach H, Cosmides J, Halprin K, Millard M. Psoriasis liver--methotrexate interactions. Arch Dermatol 1973;108:36-42. 50. Nyfors A, Poulsen H. Liver biopsies from psoriatics related to methotrexate therapy. 1. Findings in 123 consecutive non-methotrexate treated patients. Acta Pathol Microbiol Seand [A,] 1976;84:253-61. 51. Nyfors A, Poulsen H. Liver biopsies from psoriatics related to methotrexate therapy. 2. Findings before and after methotrexate therapy in 88 patients. A blind study. Acta Pathol Microbiol Scand [A] 1976;84:262-70. 52. Nyfors A. Liver biopsies from psoriatics related to methotrexate therapy. 3. Findings in post-methotrexate liver biopsies from 160 psoriaties. Acta Pathol Microbiol Scand [A] 1977;85:511-8. 53. Zachariae H, Kragballe K, Sogard H. Methotrexate induced liver cirrhosis. Studies including serial liver biopsies during continued treatment. Br J Dermatol 1980; 102:407-12. 54. Rollman O, Vahlquist A. Retinoid concentrations in skin, serum and adipose tissue of patients treated with etretinate. Br J Dermatol 1983;109:439-47.
IIIIII
IIII
IIIII
I II
II IIII
Liver toxicity of retinoid therapy Henry H. Roenigk, Jr., M.D. Chicago, IL Vitamin A metabolism involves storage in the liver. Hypervitaminosis A results in liver abnormalities, including fibrosis and cirrhosis. Ito cells are increased and promote fibrogenesis, which results in cirrhosis. Retinoids (Accutane and Tegison) are used clinically for the treatment of a variety of skin diseases. Since retinoids are analogs of vitamin A, their potential to produce liver disease is reviewed. Animal and human studies of liver function tests suggest some abnormalities in the liver in about 25% of patients treated. Liver biopsy studies have included isolated case reports and two retrospective and one prospective liver biopsy study of retinoids in humans. Although some increase in kistologic liver changes have been noted, most liver biopsy specimens showed no change or improvement. Retinoids do not appear to produce consistent toxic liver abnormalities. (J AM ACAD DERMATOL 1988;19:199-208.)
Vitamin A enters the body as the provitamin /3-carotene or as preformed retinol./3-Carotene is cleared by an intestinal dioxygenase enzyme to yield two molecules of retinal, 1 which is then reduced to retinol. After esterifications, the retinyl esters are associated with chylomicrons in the lymph and are absorbed by the liver as chylomicron remants. Approximately 90% of the total body pool of vitamin A in a normal animal is found in the liver. During vitamin A deficiency, liver retinol and retinyl ester pools decrease rapidly, whereas the supply to plasma and peripheral tissues remains unaltered, only to drop after liver depletion. 2 Vitamin A concentrations in liver biopsy specimens are compared with relative dose response, the percentage increase in plasma retinol level relative to the plasma retinol level 5 hours after oral administration of a standard oral dose (450 m g of retinyl acetate) and have been used to establish criteria of a minimal liver vitamin A concentration to maintain health. 3 The stellate (Ito) cell of the liver is thought to be
From the Department of Dermatology, Northwestern University Medical School. Reprint requests to: Dr. Henry H. Roenlgk, Jr., Department of Dermatology, Northwestern University Medical School, Ward Building 3-191,303 East Chicago Ave,, Chicago, IL 60611,
the major storage cell for retinyl esters, 4 The parenchymal cell, in addition to some storage capacity, appears to have a role in secreting retinol in complex with the retinol-binding protein (RBP). These two liver cells are vital in retinol use, transport, and function.~ The stellate (Ito) cell appears to be important mainly in storage under conditions of either normal or excess vitamin A nutrition.6 In addition to the liver functioning as a depot for vitamin A, recent findings suggest that liver tissue may also need retinol for its normal functioning. HYPERVITAMINOSIS A
Vitamin A is recognized as a nutrient essential for life. It has also been effective in the treatment of various keratinizing disorders in humans, and there is evidence of its antitumor effect in animals and possibly in humans. 7,s Because the public recognized the beneficial effects of vitamin A, they assume that taking large amounts of it may be beneficial, especially in the prevention of cancer. The first report of chronic toxicity of vitamin A was in a child in 19449 and later in an adult in 1952.1~Hypervitaminosis A syndrome may present with skeletal pain, pseudotumor cerebri, headache, pruritus, or desquamafive dermatitis with hair lOSS.tI't3 Since vitamin A is stored in the liver, 199
200 Roenigk
hepatomegaly with or without abnormal liver function is frequently seen with vitamin A intoxication. Bauernfeind14has recently summarized 75 reported adult cases of chronic hypervitaminosis A and reports that clinical symptoms of toxicity can develop between a few weeks to 9 years after the start of long-term daily oral vitamin A. The current recommended dietary allowance of vitamin A is 5000 IU/day for adult males and 4000 IU/day for nonpregnant adult females. Prolonged doses only 10 times the recommended daily dietary allowance (i.e., 50,000 IU/day) may cause toxicity. Vitamin A is normally released from liver stores as retinol bound to its specific protein carrier, RBP, as an equimolar complex. In this form vitamin A is delivered to peripheral tissues where it is released from RBP for cellular use. In hypervitaminosis A,~S.16the capacity of RBP to transport vitamin A is exceeded, and the excess begins to circulate as retinyl esters nonspecifically bound to plasma lipoproteins. When delivered to peripheral tissues in this nonphysiologic manner, vitamin A exhibits surface-active, membranolytic activity that may ultimately result in cellular and tissue damage. In a detailed study of three cases of chronic hypervitaminosis A, Smith and Goodman ~5,16demonstrated that the excess of total vitamin A relative to RBP could be accounted for by elevated levels of lipoprotein-bound retinyl esters. Animal studiesx7 with large doses of vitamin A show lysosomal and mitochondrial damage of the liver. Kupffer cells are markedly enlarged, and the cytoplasm is filled with fat droplets. Liver biopsy specimens from humans with chronic vitamin A introxication show a pattern of perisinusoidal fibrosis, central vein sclerosis, and focal congestion associated with perisinusoidal lipid storage cells. The massive accumulation of lipid storage cells (Ito cells) is found in the network of basement membranes with numerous bundles of collagen, reticilin fibers, and lymphocytes.~8Russel et al. 19suggested that the lesion could result in obstruction of hepatic blood flow, parenchymal cell atrophy, and eventual portal hypertension. Ito cells are considered transformed fibroblasts with lipid-storing capacity. They may be transformed into fibroblasts that can
Journal of the American Academyof Dermatology produce type III collagen. This transformation that promotes fibrogenesis may result in cirrhosis. Forouhar et al.2~ have confirmed the role of the Ito cells in vitamin A toxicity in transforming them into fibroblasts producing collagen. Vitamin A fluoresence and direct assays of liver revealed substantial increases in vitamin A content during the hypervitaminosis state. VITAMIN A AND HEPATOCELLULAR CARCINOMA
The rate of growth of Morris hepatomas and their ability to incorporate radioactive retinol are inversely related,21 thus suggesting a direct relationship between differentiation and retinol content of hepatoma tissue. DeLuca et al. 2~were unable to detect retinyl palmitate in hepatomas, which suggested that hepatomas were vitamin A deficient relative to the host liver. Thus it is established from animal studies and some human hepatomas 2~that hepatic carcinoma is vitamin A deficient. Whether this is a consequence of carcinogenesis or a contributory factor to tumor progression is under investigation. RETINOIDS AND THE LIVER
Oral retinoids represent a significant advance in the therapeutic field of specific dermatologic disorders such as severe acne vulgaris, keratinizing skin diseases, and psoriasis vulgaris. The rationale of the therapeatic use of derivatives of retinoic acid (Accutane and Tegison) was based on the capacity of the liver to absorb and store retinol but its failure to store retinoic acid. Thus retinoic acid derivatives have their effects on extrahepatic target organs. Etretinate (Tegison) is the aromatic derivative that has been studied extensively for possible hepatotoxicity. METABOLISM AND PHARMACOKINETICS
The retinoid etretinate is an analog of vitamin A acid or retinoic acid. It is absorbed through the portal system but does not accumulate in the liver in appreciable amounts. 24 The major biliary metabolite is retinoyl-/~-glucuronide, which is reabsorbed, thereby producing
Volume 19 Number 1, Part 2 July 1988 enterohepatic circulation. Retinoic acid is transported in plasma bound to serum albumin. There is evidence that etretinate is excreted unchanged in feces, but the conjugation with/3-glueuronate in the bile with rapid secretion is thought to protect the fiver. Pharmacokinetic investigations of the aromatic etretinate have revealed discrepancies between single and multiple dosing in humans. Plasma concentration time profiles after a single intravenous dose and oral administrations could fit a linear threecompartment model. However, this model failed to describe a phase of slow elimination after longterm dosing. Both etretinate and its main metabolite have been detected in plasma for several months after cessation of treatmentY Although these concentrations could never be correlated with therapeutic or toxic effects, they are of importance with respect to the teratogenic potential. Efforts have been undertaken to determine possible storage sites that are suggested by this pharmacokinetic behavior. Because the liver is the specific storage organ for vitamin A, it has been postulated that the liver might also be the storage depot for etretinate.
Liver toxicity of retinoid therapy 201
Table I. Classification of liver biopsy findings
Normal; fatty infiltration mild, nuclear variability, mild; portal inflammation, mild Class II: Fatty infiltration, moderate to severe; nuclear variability, moderate to severe, portal tract expansion, portal inflammation, and foczAnecrosis, moderate to severe Class ILia: Fibrosis, mild (portal tirosis denotes formation of septa extending into the lobules; slight enlargement of portal tracts without disruption of limiting or septum does not put the biopsy specimen in class III; this distinction requires a connective tissue stain or reticulum preparation) Class IIIb: Fibrosis, moderate to severe Class IV: Cirrhosis Class I:
noid treatment. However, a more sensitive method of O-dealcylation of 7-ethoxycoumarine activity increased significantly beginning on the eighth day of treatment until the end of the study.
ANIMAL STUDIES: LIVER/RETINOIDS
LIVER FUNCTION STUDIES: ABNORMALITIES WITH RETINOIDS
Studies in rats indicated that the liver retained 16% of the oral dose of etretinate whereas all other tissues had accumulated less than 0.3% of the dose? 6 After 8 days, the level of etretinate in the dog liver was 0.3% of the dose, whereas the level in other tissue was only 0.04%. Toxic doses of etretinate given to dogs result in elevation of alkaline phosphatase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Gerber and Erdman 27 found that the all-trans form of retinoic acid induced hypertriglyceridemia in rats. Liver analysis did not reveal fatty liver or alterations in phospholipid, cholesterol, or vitamin A content in any groups. Goerz et al? 8 gave etretinate during a 36-day period to adult female Wistar rats (5 mg/kg/day) with no histochemically demonstrable changes in the investigated liver enzymes. This may indicate intact function of mitochondrial and lysosomal function during reti-
Several investigators have noted changes in the liver function tests of patients with psoriasis treated with etretinate. Fredriksson29 commented on two patients with abnormal liver functions and indicated the need to follow liver function tests and exclude patients with fiver insufficiency from treatment. Guilhou et al.~ noted that a few patients with psoriasis who received etretinate showed a slight increase in transaminase and alkaline phosphatase. Goerz and Offanos) t in reporting a multicenter controlled study of etretinate in psoriasis, observed moderate changes only in the serum levels of AST and ALT. The concentrations of serum alkaline phosphatase showed a slight increase in a few instances. Some of these alterations gradually returned to normal despite continued but presumably lower dosage of the drug. Dahl et al.32found a slight increase in serum alkaline phosphatase or AST in six of 15 patients with psoriasis treated
202
Journal of the American Academy of Dermatology
Roenigk
Table II. Serial fiver biopsies by histologic classification in patients with all four biopsies* I
Pretreatment
,
6 mo
Third biopsy
[ [
Fourth biopsy
No. of patients
No change
I
I
I
I
Improved
II III
II III
II I
II I
IV
IV
IV
II
1
III II
III II
III I
I I
1 2
III II
IV
Total no change or improved IV IV
II
III
Worse Total worse
III
3 2 1
10 1 1
2
*Reprinted with permission from R.oenigk Jr HH, Gibstine C, Glazer SD, Sparberg M, Yokoo H. Serial liver biopsies in psorlatie patients receiving long-term etretinate. Br J Dermatol 1985;112:77-81.
with etretinate. Orfanos et al. 33 reviewed the laboratory studies of 278 patients with psoriasis in a multicenter study. They found no significant difference in liver function during or after therapy. Only the serum total bilirubin level showed a trend to increase, although AST was increased in 14 patients and ALT in six patients. These elevations in AST and ALT returned to normal when the drug was stopped, which indicated a possible causative relationship. Orfanos et al. indicated that other drugs, alcoholism preexisting liver damage, and muscular activity need to be evaluated in these patients. Cunningham34 reviewed the records of 652 patients treated in the initial clinical trials conducted in the United States. He indicated that about one third of patients receiving therapy will develop some abnormal liver function studies. LIVER BIOPSIES DURING RETINOID THERAPY
Few liver biopsies have been performed on humans during etretinate therapy. Fredriksson 29 performed a liver biopsy on one patient after treatment with etretinate, who showed chronic aggressive hepatitis. Thune and Mork 3s reported on a 54-year- old woman with ichthyosis given etretinate at a dose of 75 rag/day, with the dose reduced to 50 mg/day during a 3-month period. Laboratory studies showed increases in serum transaminase, bilirubin, and alkaline phosphatase levels. No pretreatment liver biopsy specimen was available, but
the liver biopsy specimen taken 1 week after etretinate therapy was stopped revealed centrilobular necrosis and toxic damage with degeneration of parenchymal cells. Results of hepatitis B antigens were negative. They suggested a relationship between etretinate and the toxic necrosis of the liver cells, but this might be an idiosyncratic type of reaction rather than a true toxic reaction. Weiss et al. 36 reported on clinical hepatitis in a 74-year-old woman with palmoplantar psoriasis treated with etretinate. Weiss et al. 37reported on a second patient with hepatitis from etretinate for psoriasis. This time a fiver biopsy specimen confirmed the histologic changes of chronic active hepatitis. Van Voorst et alY reported histologically confirmed but clinically inapparent reversible hepatitis in one patient with psoriasis and one with the basal cell nevus syndrome, both of which developed during the first month of treatment with etretinate. Gavish et al.39 reported on a case of biochemical and morphologic cholestatic hepatitis induced by etretinate therapy. Vahlquist et al. 4~ reported on biopsy-proved hepatitis during treatment of psoriasis with etretinate. When the patient was rechallenged with etretinate 18 months later, hepatic enzyme levels were again elevated. Isotretinoin therapy, although devoid of hepatoxicity, was only marginally effective clinically. A single case report of toxic hepatitis caused by a combination of methotrexate and etretinate41 leads to a word of caution regarding its combined use.42 Cunningham's 34review of the clinical studies in
Volume 19 Number 1, Part 2 July 1988
Liver toxicity of retinoid therapy 203
Table IlL Serial liver biopsies for histologic classification in patients with only three biopsies* Pretreatment
6 mo
Third biopsy
patients
II III II
II III II
II III I
3 1 1 5
No change Improved Total no change or improved
*Reprinted with permission from Wake K. Perisinusoidal stellate cells (fat storing ceils, intestinal cells, lipoeytes); their related structure, in and around the liver sinusoids, and vitamin A storing .cells in extrahepatie organs. Int Rev Cystol 1980;66:303-53.
the United States detected only 10 of 652 patients with psoriasis on the etretinate protocol with clinical or hisotlogic hepatitis possibly or probably related to etretinate treatment. In one patient, histologic changes resembling chronic active hepatitis were still found 6 months after discontinuation of therapy. In eight patients liver function tests returned to normal after discontinuation, and one patient was lost to follow-up. Four hepatitis-related deaths have been reported worldwide, and in two of these the patients had received etretinate for a month or less before having hepatic symptoms. These are probably idiosyncratic reactions and not true toxic reactions in the liver. LARGE
GROUPS
OF LIVER BIOPSIES IN
PATIENTS WITH PSORIASIS TREATED WITH ETRETINATE Isolated case reports do not give a clear picture of the true incidence of possible liver toxicity from etretinate+ Therefore liver biopsies have been performed in three larger groups of patients. One study was prospective and two were retrospective.
Prospective study of liver biopsies in patients with psoriasis treated with etretinate A protocol was developed to evaluate the safety and effectiveness of etretinate in psoriasis and also to address the question of hepatoxicity.43 Since pretreatment liver biopsies had never been performed on patients receiving etretinate, this study was designed as a prospective evaluation of fiver biopsies during a 3-year treatment period of 20 patients with severe psoriasis given etretinate. Patients with severe psoriasis with or without psoriatic arthritis having at least 20% skin involve-
merit with psoriasis were selected. Most had more than 50% body coverage and had required previous systemic therapy with either photochemotherapy or methotrexate. Men and women older than 21 years old could be entered, but women with reproductive potential were excluded. Patients must have had an increased risk of hepatotoxicity, which was defined as having one or more of the following: (1) a history longer than 1 year of daily alcohol ingestion of 3 or more equivalent units (1 equivalent equals 12 ounces of beer, 4 ounces of wine, or one mixed drink); (2) a lifetime total use of 2.5 gm or greater of methotrexate; (3) currently with two or more persistent abnormalities of liver function tests; (4) currently with clinical findings of a fiver abnormality; and (5) a biopsy, which when last performed had a classification of class I or II liver biopsy without persistent, significant abnormalities in liver function tests. Patients with abnormal renal function studies were excluded. Those with preexisting conditions that might be exacerbated by hypervitaminosis A were excluded. Patients with liver biopsy changes of cirrhosis were not included, although those with fibrosis were allowed. Patients with fasting triglyceride levels more than twice the upper limit of normal or patients taking systemic medication for hyperlipidemia were also excluded. Only bland topical emollient preparations were used except that 1% hydrocortisone cream could be used to limited areas (less than 5% area). The initial treatment period was 24 weeks (6 months), at which time etretinate was discontinued for 3 months. The second course of treatment lasted 9 months and was given after a 3-month period off the drug. The 3-year course of etretinate
204
Journal of the American Academy of Dermatology
Roenigk
Table IV. Summary of all liver biopsies in prospective study*
No change or improved Worse
15 2
*Reprinted with permission from Roenigk Jr HH, Gibstine C, Glazer SD, Sparberg M, Yokoo H. Serial liver biospies in psoriatic patients receiving long-term etretinate. Br Dermatol 1985;112:77-81.
therapy consisted of 9 months on the drug and 3 months off drug periods each year. Percutaneous needle liver biopsy specimens were obtained under local anesthesia with a Jamshedi needle before and after 24 weeks of therapy with etretinate and again after each of two subsequent 36-week courses. Each specimen was divided into three portions for light microscopy, electron microscopy, and chemical analysis. Tissue for light microscopy was fixed in 10% buffered neutral formalin and embedded in paraffm; sections were stained with hemotoxylin-eosin, Masson trichrome, Gomori's reticulum, and Perl's iron stain. Liver biopsies were done before treatment, 6 months after etretinate, 2 years after etretinate, and 3 years after etretinate. Table I shows the pathologic classification that was reviewed in a blind fashion by two independent liver pathologists. In one third of the patients, abnormal liver function studies were obtained intermittently over the 3 years. There usually were slight elevations of AST, ALT, or alkaline phosphatase. There was poor correlation between liver function studies and liver biopsy results. Restflts of pretreatment liver biopsy specimens included liver biopsy class I, eight patients; liver biopsy class II, four patients; liver biopsy class IIIa, four patients; and liver biopsy class IIIb, four patients. Twelve patients had abnormal liver biopsy results before starting therapy. Eighteen of 20 patients (90%) showed no change in the classification of the liver biopsy specimens after 6 months of etretinate, and two patients showed progressive liver cell injury and a deterioration of class." One patient went from severe fibrosis to cirrhosis (classes IIIb to IV). The posttreatment liver biopsy specimen revealed the features of alcoholic hepati-
tis with numerous Mallory bodies. This patient admitted to an increase in his normally heavy alcohol intake. One patient's biopsy specimen changed from mild fibrosis to severe fibrosis (classes IIIA to IIIb) and in addition showed necrosis of hepatocytes, collapse of the normal stroma, and an excess of fibers within the lobular parenchyma. Collagen stains revealed an aggregation of the preexisting fibrous tissue without new collagen formation. Three patients at the 6-month biopsy had an increase in fatty metamorphosis but no change in classification. One progressed from mild to moderate and two from moderate fo severe fatty infiltration of the liver. There was no increase in body weight in any of these patients. After the original 3 years, the study was extended to several more courses of etretinate and further yearly liver biopsies. Of our original 20 patients, 12 have had four liver biopsies (Table II). Six patients stopped, although three of these six had three liver biopsies each (and therefore two full 9-month courses of etretinate) before stopping the drugs Table III). Table IV summarizes all the liver biopsy results. Two patients died while receiving the third course of the drug: one died of pancreatic carcinoma and the other of immunoblastic sarcoma. There is no known relationship between these diseases and etretinate therapy. Of the 12 patients who have had all four liver biopsies (Table II), five have shown no change in the biopsy results, five have actually shown an improvement, and two have shown a deterioration of classification. 45 Five patients completed three liver biopsies (Table III), including the two patients who died. Four had no change in their liver biopsy results and one showed improvement. The tissue from 10 patients was processed for electron microscopic examination. The number of Ito cells and hepatocytes was determined by counting all such cells seen in the photographs. Between 300 and 500 hepatocytes were seen per specimen. These numbers were extrapolated to give an Ito cell index, which has been previously defined17 as the number of Ito cells/1000 hepatocytes. In addition, the number of fat lobules per Ito cell was counted and the fine structure of the hepatocytes was examined. The Ito cell index increased in two
Volume 19 N u m b e r 1, Part 2 July 1988
Liver toxicity of retinoid therapy 205
Table V. Clinical and fight microscopic data* Etrefinate duration
Case No.
Age/sex
Prior methotrexate
1-7 (3~, 5t, 4w
Four with prior treatment for up to 5 yr None
Case 3: 1979, severe fatty change Case 5: 1979, minimal fatty change None
5-6
8, 9
Two females, five males, range 24-73 yr 51/M, 28/M
10 11~:
60/F 58/M
3 yr None
61h 589
12, 13, 14
63/F, 34/F, 40/M
5t
Mild lobular hepatitis
15w 16
59/M, 66/F
Two with prior treatment up tolyr None
None 1978--moderate to severe fatty change None None
5
17
48/M
3 mo (1979)
None
51A
18:~
67/F
1 yr (1977)
1978--moderate fatty change
6
Mild periportal fibrosis Piecemeal necrosis, triaditis, moderate to severe fibrosis and moderate fatty change Cirrhosis and severe fatty change
(yr)
Prior biopsy
6, 61A
Biopsy results (1985-1986)t
Minimal or mild fatty change or no pathologic changes Moderate fatty change Severe fatty change Severe fatty change
*Reprinted with permission from Camuto P, Shupack J, Orbuch P, Tobias H, Sidhu G, Feiner H. Long-term effects of etretinate on the liver in psoriasis. Am J Surg Pathol 1987;11:30-7. ~'Patient No. 13 had a biopsy in 1982, 1 year after initiation of therapy and was subsequently followed up for 4 years. :~Prior biopsy available. w of significant alcohol intake.
patients and decreased in eight. When compared with pretreatment, there was no significant change in the number of Ito ceils per lobule. ~ Another portion of the liver tissue was analyzed for etretinate concentration as described by Paravicini et al. 25 The results of liver tissue analysis were available in 18 of 20 patients for retained etretinate. The time elapsed between cessation of drug and liver biopsy, grade of fatty infiltration in the liver (as judged by pathologists reading light microscopic slides), and estimated amount of etretinate in a 1500 g m liver were analyzed. 4~ Etretinate was detected in all samples, including one from a biopsy specimen taken 78 days after discontinuation of the drug. Generally, the highest concentrations were in those livers with moderate or severe fatty infiltration. There was a trend toward higher concentra-
tion of etretinate in those biopsy specimens that had a greater degree of fatty infiltration.
Histologie changes in the liver during etretinate treatment Forgel et al. 47evaluated 32 patients, all of whom were treated with etretinate from 6 to 60 months for Darier's disease, psoriasis, and other keratinizing disorders. The biopsy specimens were compared with a control group of 3 5 biopsy specimens matched with the same age, sex, and year in which the biopsies were done. This was not a prospective study, but six patients had serial fiver biopsies and eight had pretreatment liver biopsies. The results indicated more fatty infiltration in the control group than in the etretinate group, whereas other patients had a tendency to higher
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scores in postetretinate liver biopsies. None of the differences were statistically significant. The eight patients with liver biopsies before and after etretinate treatment showed a tendency to higher scores in the posttreatment liver biopsies, but again this was not significant. No liver biopsy specimens showed the histologic changes of cirrhosis. Long-term effects of etretinate on the liver in psoriasis Camuto et al.48 studied 18 patients with severe psoriasis. There were no pretreatment liver biopsies, and all patients had been treated with etretihate for at least 5 years. Nine patients had previously had methotrexate, and there was a history of significant alcohol intake in at least two patients. Again the liver function studies did not correlate with the histologic changes. A spectrum of liver abnormalities was observed by light microscopy (Table V). Mild periportal fibrosis was seen in two patients, including one patient with heavy alcohol intake. Moderate to severe fatty changes were noted in six patients. One patient had moderate to severe fibrosis and one had cirrhosis. Both of these patients had previously taken methotrexate. Ito cell lipid content but no the Ito cell number was greater in the etretinate group, but it was not statistically significant. There was also no correlation between overall severity of liver pathologic changes and the cumulative dose of etretinate, which is in contrast to the good correlation generally seen with methotrexate hepatotoxicity. DISCUSSION Long-term prospective studies of patients with psoriasis receiving methotrexate have demonstrated that liver function tests are unreliable in assessing structural changes in the liver.49 Vitamin A toxicity has been reported to produce only mild changes in alkaline phosphatase, suIfobromophthalein retention, and prothrombin times. Therefore we felt that a prospective liver biopsy study was important to assure the safety of etretinate. We thought that patients who had potential preexisting liver damage from other hepatotoxins such as methotrexate and alcohol would manifest biopsy changes earlier than would a random group, and the patients were preselected with this in mind. All
Journal of the American Academyof Dermatology patients were encouraged to limit alcohol consumption. Out initial biopsy series 44 concluded that etretihate did not produce a consistent toxic effect on the liver. This conclusion is supported by our subsequent long-term biopsy findings. 45 Our only explanation for the improvement seen in some of our patients is possible sampling error in liver tissue, especially in patients who appear to have reverted from cirrhosis to class II changes. Another explanation is the possible improvement in pathologic liver damage caused by methotrexate when that drug is stopped and etretinate is substituted. Two other large studies, 47'48 both retrospective but with a few pre- and posttreatment liver biopsies, have found some changes on liver biopsy specimens, but none were statistically significant. It appears that long-term administration of etretinate is a safe form of treatment for hepatotoxicity in most patients. The It<)cell has now been evaluated in two of the three large groups studied with etretinate. 4~,48 Camuto et al.4s found no significant changes in the Ito cells. Most of our specimens showed a decrease in the Ito cell index after a 6-month course of etretinate. 46This is in contradistinction to reports in patients with various liver diseases or from other drugs, including methotrexate, in the treatment of psoriasis. 5~s3 Liver diseases may alter the normal metabolism of vitamin A and thereby cause the observed changes in Ito cell counts reported by others. Tissue analysis of the liver biopsy specimen and comparison with fatty infdtration in the liver suggest that etretinate is stored in the liver in the fat. ~ However, it becomes obvious that the liver cannot be the only storage organ for etretinate. This finding suggests that general body fat may be the major storage depot for etretinate. Results from preliminary studies in a few autopsied patients who received long-term courses of etretinate support this conclusion. 4S Rollman and Vahlquist 54 have analyzed the concentration of etretinate in the epidermis, dermis, subcutis, and serum in patients treated with the drug. Serum etretinate and epidermis concentrations correlated, but the drug appeared to concentrate and remain in the fatty tissue in the subcutis for several months after
Volume 19 Number 1, Part 2 July 1988
cessation of therapy. This suggested that adipose tissue was a storage site for etretinate in humans. In summary from extensive evaluation of liver function, histologic examination, and ultrastructure (Ito cells) in a group of patients preselected for potential hepatotoxicity, we found no significant damage to the liver. Etretinate is stored in the fatty tissue of the liver for prolonged periods. The general fatty tissues of the body are probably a more important storage compartment for etretihate. This should be taken into consideration, especially when treating obese patients with etretihate. ProspectiVe studies are underway to evaluate new retinoid derivatives such as Acetretin regarding potential hepatotoxicity. REFERENCES
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46. Glazer SD, Roenigk Jr HH, Yokoo H, Sparberg M, Paravicini U. Ro 10-9359 for psoriasis: ultrastructural survey and tissue analysis of liver biopsies after a 6-month course of etretinate. J AM ACAD DERMATOL 1984;10: 632-8. 47. Fogel B, Bjerring P, Kragballe K, Sogaarad H, Zachariae H. Histologic changes in the liver during etretinate treatment. J AM ACAO DERMATOL1984;1 1:580-3. 48. Camuto P, Shupack J, Orbuch P, Tobias H, Sidhu G, Feiner H. Long term effects of etretinate on the liver in psoriasis. Am J Surg Pathol 1987;11:30-7. 49. Weinstein GD, Roenigk HH, Maibach H, Cosmides J, Halprin K, Millard M. Psoriasis liver--methotrexate interactions. Arch Dermatol 1973;108:36-42. 50. Nyfors A, Poulsen H. Liver biopsies from psoriatics related to methotrexate therapy. 1. Findings in 123 consecutive non-methotrexate treated patients. Acta Pathol Microbiol Seand [A,] 1976;84:253-61. 51. Nyfors A, Poulsen H. Liver biopsies from psoriatics related to methotrexate therapy. 2. Findings before and after methotrexate therapy in 88 patients. A blind study. Acta Pathol Microbiol Scand [A] 1976;84:262-70. 52. Nyfors A. Liver biopsies from psoriatics related to methotrexate therapy. 3. Findings in post-methotrexate liver biopsies from 160 psoriaties. Acta Pathol Microbiol Scand [A] 1977;85:511-8. 53. Zachariae H, Kragballe K, Sogard H. Methotrexate induced liver cirrhosis. Studies including serial liver biopsies during continued treatment. Br J Dermatol 1980; 102:407-12. 54. Rollman O, Vahlquist A. Retinoid concentrations in skin, serum and adipose tissue of patients treated with etretinate. Br J Dermatol 1983;109:439-47.