Liver pathology associated with the use of anabolic-androgenic steroids S0e K L, SOe M, Gluud C . Liver pathology associated with the use of anabolic-androgenic steroids. Liver 1992: 12: 73-79. Abstract: This review examines the liver-damaging side effects of anabolicandrogenic steroids (AAS). It seems that AAS can cause development of peliosis hepatis, subcellular changes of hepatocytes, hepatocellular hyperplasia and hepatocellular adenomas. On the other hand, it has not been convincingly proved that AAS can cause development of hepatocellular carcinomas when used in the usual therapeutic doses. Tumours reported as hepatocellular carcinomas caused by AAS seem to be hyperplastic lesions of a benign nature able to regress with withdrawal of the putative agent. The effects of untraditional combinations and high-dose AAS are not yet known, leaving the possibility of a carcinogenic effect in those cases.
Katrine Lydolph See, Marten See and Christian Gluud Medical Department, Division of Gastroenterology, Hvidovre University Hospital, Copenhagen, Denmark
Key words: anabolic-androgenic steroids hepatic adenomas - hepatocellular carcinoma - peliosis hepatis Christian Gluud M. D, Dr. med. Sci. Medical Department, Division of Gastroenterology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark Received 24 May, accepted for publication 27 December 1991
Anabolic-androgenic steroids (AAS) are used in the treatment of male hypogonadism and to treat certain forms of anaemia, retarded growth, hypopituitarism, impotence, eunuchoidism, infertility, cryptorchism, panmyelopathia and paroxysmal nocturnal haemoglobinuria (1). Furthermore, a substantial amount is used among athletes as selfmedication in order to improve strength (2-4). The use of AAS can cause certain side-effects, however, among which the side-effects on the liver are considered common and serious ( 5 ) . The liver plays a central role in the metabolism of AAS, and it is an organ under the influence of sex hormones: There are receptors for AAS in the liver in both humans and animals, and an increasing number of metabolic processes in the liver are being found to be dependent upon AAS (6, 7). This review presents pathological conditions of the liver due to AAS as presented in the literature, mainly considering human data. The nomenclature of A A S has been described in detail by Murad & Haynes (1). Material and methods
To provide the pertinent literature, several sources have been utilized. A MEDLARS and MEDLINE survey was undertaken up to 1990, searching publications dealing with side-effects and effects of AAS on the human and animal liver. Further, a crossbibliographic check was made. Included were articles dealing with liver pathology in humans associ-
ated with AAS and certain selected animal studies of high scientific quality. Double-publications were excluded. Concerning AAS, trivial names have been used. When first mentioned, however, systematic names are given in parentheses. Vascular changes
AAS are connected to a particular vascular phenomenon known as peliosis hepatis (PH), i.e. bloodfilled spaces in the liver (Table 1). PH has been described in patients with tuberculosis (8). AAS connected with PH are testosterone (17-beta-hydroxy-4-androsten-3-on), norethandrolone (17-alpha-ethyl- 17-beta-hydroxy-androsta- 1,4-dien-3on), fluoxymesterone (9-alpha-fluoro- 11-beta-hydroxy- 17-alpha-methyl-testosterone), oxymetholone (17-beta-hydroxy-2-hydroxymethylene17-alpha-methyl-5-alpha-androstan-3-on), methandros( 17-alpha-methyl- 17-beta-hydroxytenolone androsta- 1,4-dien-3-0n)and nandrolone decanoate (19-nortestosterone-decanoate) (9). PH can appear at any time during AAS treatment and does not seem to depend upon the dose used. PH is also found occasionally in patients with liver tumours associated to AAS (10-17). The pathogenesis of PH is considered to be a progressive dilatation of the liver veins and -sinusoids, due to destruction of intercellular bindings among the hepatocytes, as seen in areas near the cysts in patients with PH (18). The cysts are not 73
See et al. Table 1. Benign and malignant liver-pathological changes associated with anabolic-androgenic steroids in the literature in relation to study design Uncontrolled studies Case histories (no. of patients) Peliosis hepatis Hyperplasia Focal nodular hyperplasia Hepatocellular adenoma Hepatocellular carcinoma Haemangiosarcoma Cholangiocarcinoma Dysplasia
Controlled studies
Series (no. of positive ptt./ total number of patients)
Human (no. of series) Association
No association
Animals (no. of series) Association
No association
20 1 3 15 26 5 4 1
-: No reports.
covered with endothelium but communicate with sinusoids covered with endothelium. Accumulations of hepatocytes in liver veins are described in 9 of 60 cases in patients treated with AAS (18). This phenomenon can cause a mechanical obstruction and thereby an accumulation of blood, leading to dilatation of liver veins and -sinusoids and blood clusters between the hepatocytes. Intravenous accumulation of hepatocytes has not been described in 300 Tru-cut-biopsies from patients suffering from PH, but never treated with AAS (18). The phenomenon seems to be related to the use of AAS (6, 18). The same observations have been made in studies using mice (2). Nevertheless, no increasing prevalence of PH was found in placebo-controlled studies of patients with cirrhotic and non-cirrhotic liver disease treated with AAS (6, 19, 20). The clinical manifestations of PH are hepatomegaly and tenderness of the right hypochondrium. PH is seen among all age groups and it ‘Is not related to sex (9). Biochemical liver tests will usually be normal until advanced stages of the disease. It seems that biopsy is the best choice for revealing PH, even in the early stages of the disease (18, 21), but some authors have described the diagnostic value of ultrasonic examination (22), computed tomography, angiography (21) and even isotope scan (22). PH is one of the most serious side-effects of AAS. It can result in rupture of the liver with haemoperitoneum and liver failure, resulting in death of the patient (9). There have been reports of life-saving lobectomies (9) and of regression of the vascular changes after ceasing AAS treatment (9). It is possible that testosterone treatment through a conversion to oestrogens - may induce a hypercoagulable state and lead to Budd-Chiari syndrome (23, 24). We have been unable to find 74
human studies dealing with the possible effect of AAS on the hepatic artery. Subcellular changes
Light- and electronmicroscopic examinations of liver tissue from patients treated with AAS have revealed a number of pathological changes of hepatocytes. The bile canaliculi show dilatation, the microvilli on their borders are fewer and smaller, and a proliferation of the smooth endoplasmatic reticulum is seen (9, 18). These pathological changes are similar to those seen in cholestatic jaundice. Furthermore, a polarisation of organelles at the perisinusoidal border is seen along with the occurrence of giant mitochondria (18). The latter are often seen in livers damaged by excessive alcohol intake (1 8). None of these pathological patterns is specific for liver patients treated with AAS. Cholestatic jaundice due to AAS was described for the first time in 1947, and since then a number of similar cases have been reported (9). Usually it is discovered after 2-5 months of AAS treatment (1, 9). After withdrawal of AAS the prognosis is generally good, but cases with progression to fatal liver cirrhosis have been described (9). The above-mentioned observations in humans have all been uncontrolled studies. The same kind of cholestatic change, however, has also been found in studies on rats treated with high doses of AAS, making the connection likely (2, 25). In patients with pre-existing liver cirrhosis, however, the occurrence of cholestatic jaundice during testosterone treatment did not differ significantly from placebopatients (6, 19, 23, 26). The AAS-induced jaundice is diagnosed by liver biopsy. In the rim of the acinus cholestasis is found. The liver enzymes are often increased, but to a lesser degree than seen in cholestasis caused by other factors (9). Restitution often follows cess-
Liver pathology and AAS
ation of treatment with AAS making that solution the most rational.
and in those cases it seems to be predominantly NT (25).
Hyperplasla
Benign neoplasms
Nodular transformation (NT) and focal nodular hyperplasia (FNH) have been connected to the use of AAS (Table 1). NT is a non-cirrhotic nodular transformation of liver tissue. The aetiology often remains undetected, but myeloproliferative diseases and AAS are known factors (9). In NT the liver is changed into a mass of yellow-brownish nodules containing dysplastic elements in 20% of the cases, very much like the premalignant neoplasia known from guinea-pigs treated with known carcinogens (9). Whether NT belongs to the premalignant conditions of the liver is not yet known. Noduli of NT cause atrophy of the surrounding tissue and NT can cause portal hypertension. We have found no reports of NT in humans. FNH is a tumour characterised by a central starshaped scar, a lighter colour than the surrounding tissue and a benign cytologic and histologic pattern. It has been connected to the use of oral contraceptives for a long time (27). Only three cases have been reported in connection with the use of AAS (1 5, 28, 29). All patients received 17-alkylated AAS (Table 2). No conclusions about a connection can be drawn from such data, as FNH has been reported in all ages and in both sexes, unrelated to the use of AAS (9). In a placebo-controlled study of the effect of testosterone in men with alcoholic cirrhosis, no significant effect of testosterone was found on the development of hyperplastic nodules (30). Neither NT nor FNH was found in biopsies from livers of patients with cirrhosis or alcoholic hepatitis after treatment with AAS (6,20). In contrast, hyperplastic elements were found in all the animals of an AAS-treated group, while no such changes were found in the group given placebo (25). In these studies no distinctions are made between NT and FNH, but in a few cases hyperplasia is described
Since the first description of a liver tumour in a patient treated with AAS in 1965, a number of articles have been written concerning a possible causal connection between AAS and primary benign and malignant liver tumours (Table 1). Sixteen cases of hepatocellular adenoma (HCA) have been described in connection with the use of AAS (13, 14, 16, 17, 22, 31-36). Both 17-alkylated and non-17-alkylated AAS have been involved (Table 2). HCA is a benign tumour as it does not grow invasively and it shows a benign cytologic and histologic pattern (9). Nevertheless, HCA can be fatal because of the risk of rupture causing bleeding into the peritoneum. The greatest risk of such a rupture is in patients treated for anaemia, as these patients often have thrombocytopenia and an impaired clotting mechanism. Rupture of HCA is described in two of the cases (17, 36). No HCA were found in placebo-controlled studies on the effect of A A S treatment of males with cirrhosis and non-cirrhotic liver disease (6,20, 26). In controlled studies of mice, however, it has been found that HCA can develop during treatment with AAS (2). Previously the treatment of HCA was hemi-lobectomy, but this is not always necessary as the tumour regresses after withdrawal of AAS (37,38).
Table 2. Relation between benign human liver pathology associated with the use of 17-alkylated and non 17-alkylated anabolic-androgenic steroids. Number of reported cases Anabolic-androgenic steroid 17-alkylated Non 17-alkylated Peliosis hepatis Hyperplasia Focal nodular hyperplasia Hepatocellular adenoma *
14' 1 3 14'
10 0 0 2
Two patients have received both 17-alkylated and non 17-alkylated steroids.
Malignant neoplasms
The malignant neoplasms mentioned in connection with the use of AAS encompass hepatocellular carcinoma (HCC), hepatic angiosarcoma and cholangiocarcinoma (Table 1). The last two tumour types have been described in only a yery few cases (1 1, 3942), and a causal connection between AAS and these two types of tumours is therefore still hypothe tical. HCC is the kind of liver-tumour most often suspected to be induced by AAS. The suspicion arises from a total of 26 cases of histologically verified HCC in patients treated with AAS (10-15, 22, 29, 40,43-53). A few cases have been reported without any histological verification (37, 54, 55). HCC has also been observed in mice and rats treated with AAS (56), but never in dogs or monkeys (9). The indication for treatment with AAS in patients who developed HCC were hypogonadism, hypopituitarism, impotence, eunuchoidism, infertility, cryptorchism, nephrogenous anaemia, Fanconi's anaemia, idiopathic anaemia, panmyelopa75
S0e et al.
thia and paroxysmal nocturnal haemoglobinuria. In one case a young athlete developed HCC using AAS as a means to gain strength (40). The AAS mentioned in connection with the development of HCC is mainly 17-alkylated forms of AAS, mostly methyltestosterone (17-alpha-methyltestosterone) and oxymetholone. In animal studies, however, a tumour-inducing effect of non-alkylated AAS has been found (25), and two cases of patients treated with non-alkylated AAS have been described (1 1). No significant increase in development of HCC has been found in placebo-controlled studies of men with alcohol-induced cirrhotic and non-cirrhotic liver disease (6, 19, 20, 26). AAS associated neoplasms in patients with Fanconi's disease
The first patient claimed to have a liver tumour associated with AAS was a 27-year-old male with Fanconi's disease (FD). Since then, more cases of malignant and benign liver tumours in AAStreated patients with F D have been published (six malignant; one both malignant and benign; four benign; two unspecified) (12, 13, 17, 35, 43, 50-52, 54). We have chosen to mention this group of patients separately because an increased risk of tumour development has been described in patients with F D (13, 51, 54). The frequent chromosome breaks in these patients have been suggested to be the cause (51). This may cause an increased number of mitoses, possibly leading to an increased risk of malignant transformation ( 12). The likelihood of this explanation is supported by the discovery of multiple small liver tumours in some of the Fanconi patients described (12, 13, 17, 54, 57). A case of HCC in a 7-year-old patient with F D never treated with AAS has also been reported (58). Furthermore, most of the patients with F D have been treated with transfusions of blood, causing an increased risk of hepatitis B and C. This again leads to an increased risk of HCC (59, 60). Only five patients in the articles mentioned above have been tested for hepatitis B virus surface antigen (HBsAg), and four of the tests were negative (17, 50, 51). None have been tested for hepatitis C virus. Discussion
As stated above, and as demonstrated in Table 1, certain pathological conditions of the liver have been described in connection with the use of AAS in case histories and smaller uncontrolled studies. It is known that this can never be sufficient evidence to prove a causal connection. The associ76
ations between AAS and peliosis hepatis, subcellular changes, hyperplasia and HCA are supported by controlled animal studies, where the same pathological pattern was found in a significantly increased number in the AAS-treated animals. Even though animal studies support a possible connection between AAS and HCC, it is still uncertain whether such an association exists in man. Tables 2 and 3 show that both 17-alkylated and non 17-alkylated AAS have been implicated in both benign and malignant liver pathology associated with AAS. The fact that the majority of cases have been described in connection with 17-alkylated AAS, which is not metabolized to oestrogens, could be due to both a greater toxicity of these substances and a greater use. Furthermore, the observation that 17-alkylated AAS is mainly involved makes it unlikely that the effects of AAS are all due to secondary metabolism into oestrogens. AAS interferes with the cellular metabolism by binding to intracellular receptors. It is therefore probable that this binding plays a role too in the induction of the above-mentioned pathological conditions of the liver. This makes the lack of significantly increased occurrence of liver pathological changes in patients with pre-existing liver disease in treatment with AAS a vague argument against an association between AAS and liver disease (19). Patients with cirrhosis of the liver are characterised by having a decreased amount of androgen receptors ( 1 9). Furthermore, patients with liver cirrhosis have increased plasma concentrations of oestrogens, lowering the number of androgen receptors even more and interfering with the binding of AAS to the receptor (19). On the other hand, it is possible that the rare side-effects of AAS have been overlooked in the placebo-controlled studies due to too small a material ( < 150 patients in the AAS-treated groups) (19). The association between AAS and human HCC is uncertain for a number of reasons. HCC is a highly malignant tumour with a median survival time of about 4-6 months after the time of diagnosis (61) and 33-50% already have extra-hepatic metastases at the time of diagnosis (61). Only four cases of AAS-associated HCC (AAHCC) have been reported as having metastases (Table 2) (40, 49, 53). One of these patients (40) had HCC as well as cholangiocarcinoma-elements in the liver tumour, and it is not reported whether the metastases were of one or the other kind, even though a pathological examination was performed. In the other 22 patients (6 Fanconi, 16 non-Fanconi), no metastases were found in five cases, and the rest do not comment on the subject. None of these patients had AAHCC as the primary cause of death. Four of the Fanconi- and two non-Fanconi-
Liver pathology and AAS Table 3. Malignant liver tumours associated with androgenic-anabolic steroids Hepatocellular carcinoma Non-Fanconi’s Fanconi’s disease disease No. of cases Sex (malelfemale) Age (median) (span) Taken 17-alkylated AAS (no. of cases) Diagnostic procedure: (no. of cases) Biopsy Operation material Autopsy Metastasis (yeslno) Regression of tumour (no. of cases) Died of liver disease (no. of cases)
19 1514 33 6-68 18
7 611 20 6-38 6
6 10 5 313 3 2
2 0 5 112 0 4
patients died from liver failure. The other 20 either died of other causes or were alive at the time of publication of their case, often years after being diagnosed as having a liver tumour. Patients with AAHCC also differ from patients with HCC regarding alpha-1-fetoprotein. In patients with HCC, alpha-l-fetoprotein is detected in raised concentrations in 50-80% of the cases (62) and even more often in very young patients (18). In patients with AAHCC the alpha-1-fetoprotein concentration is found within normal limits in most cases. Only two AAHCC patients had raised alpha1-fetoprotein. Case one describes a tumour in a 68year-old male who also was HBsAg positive. The tumour had not been examined histologically and the case does not report anything about survival (55). The second case of raised alpha-1-fetoprotein in association with an AAS-associated tumour is that of a 26-year-old male who had used AAS in an excessive dose and in an unorthodox combination. His tumour was examined histologically, and both hepatocellular carcinoma and cholangiocarcinoma were found within the same tumour (40)* Regression of the tumour after withdrawal of AAS treatment has been reported in three cases (15, 46). This has never before been reported in malignant liver tumours. Finally, 7 out of 26 cases of AAHCC were found in patients with Fanconi’s disease and these patients, as already stated, have an increased tendency towards developing tumours due t o the increased number of chromosome breaks and an increased risk of catching hepatitis due to treatment with blood transfusions. The reason why AAS might lead to development of liver tumours is not known, but can be explained in different ways. Assuming AAS is a carcinogenic compound itself, it could work as a tumour inducer. If the compound itself is not carcinogenic, it could be metabolically changed into a dangerous
Haemangiosarcoma
Cholangiocarcinoma
Unspecified tumour
5
4 4/0 57 26-68 2
4 311 14 8-1 5 4
1 1 2 2/0 0
0
312
3
2 1 3 3/0 0 2
2
0 0 3 0
compound or it could work together with other compounds to cause tumour development (co-carcinogenic effect). The most likely explanation is that AAS can act as a tumour promoter, making already existing liver tumours grow faster or changing a benign liver tumour into one looking malignant (1 3,61). Studies on animals (63) support the latter mechanism. AAS could also act indirectly by increasing the change of harmless compounds of various kinds into dangerous ones by induction of the liver enzyme systems or it could prevent the elimination of dangerous compounds possibly through its cholestatic effect (9, 18, 25). Finally, AAS may speed up liver regeneration, increasing the number of mitoses and thereby the possibility of spontaneous tumour development. It does not seem likely though that AAS can cause development of HCC when used in normal doses. The tumours presented as HCC in most case histories might be tumours that look like HCC histologically, but act as relatively benign tumours. Since the completion of this study, one case of AAS-associated hepatocellular carcinoma with an aggressive course has appeared. (64). This patient was, however, also hepatitis C virus antibody positive. Hepatitis C virus is considered a major cause of HCC (65). Therefore, only future studies will be able to answer the important question of the association between AAS and HCC. Among some sportsmen, AAS are used in untraditional combinations and in much higher doses than for medical treatment (3, 4). It is possible that the effect on the liver is different and may be worse when AAS is used under these conditions. Conclusion
Most of the studies published up till now concerning the side-effects of AAS with regard to the liver are case histories. There are a few controlled 77
See et al.
studies on animals, researching the effect of AAS on rats and mice, and in these studies side-effects on the liver have been found, but corresponding changes have not been found in dogs or monkeys. Controlled studies of liver function and liver morphology in humans treated with AAS only exist for patients already suffering from liver disease. The theoretically ideal study - the doubleblinded, placebo-controlled study of AAS’s effect on persons with a healthy liver - does not exist. In the attempt to draw a conclusion from a material that consists solely of case histories, one must at least ask for a sufficient pathological description, information about tumour markers in the blood and information about pre-dispositions. Most of the studies in the literature lack this important information. Further, case histories are not very hard proof of any association between AAS and liver pathology when one considers that in, for example, Denmark the use of AAS amounted to 200400 defined daily doses per 1000000 inhibitants during the years 1986-90 (66). Under these circumstances we can only conclude that AAS can lead to peliosis hepatis and cholestatic jaundice when used in the normal therapeutic dosage. This seems well documented by high quality papers. Nodular transformation has been found in animal studies, but not in humans. Most important, there does not seem to be any connection between AAS and HCC as we usually describe it. More likely, AAS can cause development of a kind of tumour that looks like HCC histologically, but acts like a relatively benign tumour. References 1. MURAD F, HAYNES JR R C. Androgens. In: Goodman and
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9. ISHAKK G . Hepatic lesions caused by anabolic and contraceptive steroids. Semin Liver Dis 1981: 1 : 116-128. J L, VALDES-DAPENA M. Hepatoma A T, NAIMAN 10. MEADOWS associated with androgen therapy for aplastic anemia. J Pediatr 1974: 84: 109-1 10. 11. TURANIH, LEVIJ, ZEVIND, KESSLER E. Hepatic lesions in patients on anabolic androgenic therapy. Isr J Med Sci 1983: 19: 332-337. M S, HUNTER 12. BERNSTEIN R L, YACHNIN S. Hepatoma and peliosis hepatis developing in a patient with Fanconi’s anemia. N Engl J Med 1971: 284: 1135-1 136. 13. SHAPIRO P, IKEDAR M, RUEBNER B H, CONNERS M H, HALSTED C C, ABILDGAARD C F. Multiple hepatic tumors and peliosis hepatis in Fanconi’s anemia treated with androgens. Am J Dis Child 1977: 131: 11041 106. 14. BOYDP R, MARKG J. Multiple hepatic adenomas and a hepatocellular carcinoma in a man on oral methyl testosterone for eleven years. Cancer 1977: 40: 1765-1770. 15. MCCAUGHAN G W, BILOUSM J, GALLAGHER N D. Longterm survival with tumor regression in androgen-induced liver tumors. Cancer 1985: 56: 2622-2626. 16. BIRDD, VOWLESK, ANTHONY P P. Spontaneous rupture of a liver cell adenoma after long term methyltestosterone: report of a case successfully treated by emergency right hepatic lobectomy. Br J Surg 1979: 66: 212-213. 17. CHANDRA R S, KAPURS P, KELLEHER JR J, LUBANN, PATTERSON K. Benign hepatocellular tumors in the young. Arch Pathol Lab Med 1984: 108: 168-171. F J, BULLT B, WESTABY D, MURRAY-LYON I 18. PARADINAS M. Hyperplasia and prolapse of hepatocytes into hepatic veins during long-term methyltestosterone therapy: possible relationships of these changes to the development of peliosis hepatis and liver tumours. Histopathology 1977: I: 225-246. 19 GLUUDC. Testosterone and alcoholic cirrhosis. Epidemiologic, pathophysiologic and therapeutic studies in men. (Thesis). Dan Med Bull 1988: 35: 564575. C L, ANDERSON S, GARCIA-PONT P et al. 20 MENDENHALL Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N E n d J Med 1984 311: 1464-1470. 21. I S H ~ K G, ZIMMERMAN H J. Hepatotoxic effects of the anabolic/androgenic steroids. Semin Liver Dis 1987: 7 : 230-23 6. 22. WESTABY D, PORTMANN B, WILLIAMS R, Androgen related primary hepatic tumors in non-Fanconi patients. Cancer 1983: 51: 1947-1952. 23. THECOPENHAGEN STUDYGROUPFOR LIVERDISEASES. Testosterone treatment of men with * alcoholic cirrhosis: a double-blind study. Hepatology 1986: 6: 807-81 3. 24. GLUUD C. Steroid hormones and Budd-Chiari syndrome. Vasc Surg 1989: suppl. 107-1 14. W, SNOWBALL S, LESNAM. The effects of long-term 25. TAYLOR administration of methyltestosterone on the development of liver lesions in BALB/c mice. J Path 1984: 143: 211-218. 26. GLUUDC. Anabolic-androgenic steroid treatment of liver diseases. Liver 1984: 4: 159-169. W. Hepatic tumors induced by 27. MAYSE T, CHRISTOPHERSON sex steroids. Semin Liver Dis 1984: 4 147-157. J J, ISKANDARANI M, JEFFERS L, ZEPPAR, 28. ALBERTI-FLOR SCHIFFE R. Focal nodular hyperplasia associated with the use of a synthetic anabolic androgen. Am J Gastroenterol 1984: 79: 150-151. 29. SERKE s, DIENEMANN D, SPECK B, ZIMMERMANN R, BAER U, HUHND. Hepatocellular carcinoma and focal nodular hyperplasia associated with norethandrolone-therapy: a case report. Blut 1986: 52: 1 1 1-1 16. P, ERIKSENJ, WANTZINP, 30. GLUUDC, CHRISTOFFERSEN
Liver pathology and AAS KNUDSEN B B. The Copenhagen Study Group for Liver Diseases. Influence of ethanol on development of hyperplastic nodules in alcoholic men with micronodular cirrhosis. Gastroenterology 1987: 93: 256-260. G B, REISERJ, PARADINAS F J, BURNI. An andro3 1. COOMBES gen-associated hepatic adenoma in a trans-sexual. Br J Surg 1978: 65: 869-870. 32. WESTABY D, OGLES J, PARADINAS F J, RANDELL J B, MURRAY-LYON I M. Liver damage from long-term methyltestosterone. Lancet 1977: ii: 261-263. 33. CARRASCO D, PALLARDO L, PRIETOM, MOLLJ L, CRUZJ M, BERENGUER J. Hepatic adenomata and androgen treatment. Ann Intern Med 1984: 100: 316. 34. SALEG E, LERNERK G. Multiple tumors after androgen therapy. Arch Pathol Lab Med 1977: 101: 600-603. 35. MULVIHILL J J, RIDOLFIR L, SCHULTZF R, BORZYM S, HAUGHTON P B T. Hepatic adenoma in Fanconi anemia treated with oxymetholone. J Pediatr 1975: 87: 122-124. 36. LESNAM, SPENCER I, WALKER W. Liver nodules and androgens. Lancet 1976: i: 1124. 37. MONTGOMERY R R, DUCOREJ M, GITHENSJ H, AUGUST C S, JOHNSON M L. Regression of oxymetholone-induced hepatic tumors after bone marrow transplantation in aplastic anemia. Transplantation 1980: 30: 90-96. 38. LOWDELL C P, MURRAY-LYON I M. Reversal of liver damage due to long-term methyltestosterone and safety of non17-alfa-alkylated androgens. Br Med J 1985: 291: 637. F W, SMITHD H, ISHAKK G. Anabolic steroid 39. STROMEYER therapy and intrahepatic cholangiocarcinoma. Cancer 1979: 43: 440443. 40. OVERLY W L, DANKOFF J A, WANGB K, SINGHU D. Androgens and hepatocellular carcinoma in an athlete. Ann Intern Med 1984: 100: 158-159. 41. FALKH, THOMAS L B, POPPERH, ISHAKK G. Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet 1979: ii: 1120-1123. 42. NORDSTEN M. Haemangiosarcoma hepatis associeret med brug af androgene steroider. Ugeskr Lager 1985: 147: 26 1 5-26 16. 43. JOHNSON F L, FEAGLER J R, LERNER K G et al. Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 1972: ii: 1273-1276. 44. ZIECENFUSS J, CARABASI R. Androgens and hepatocellular carcinoma. Lancer 1973: i: 262. 45. MALTR A, GALDABINI J J, JEPPSSON B W. Abnormal sexsteroid milieu in young adults with hepatocellular carcinoma. World J Surg 1983: 7: 247-252. 46. TREUNER J, NIETHAMMER D, FLACHA, FISCHBACH H, SCHENCK W. Hepatozellulares karzinom nach oxymetholonbehandlung. Med Welt Bd 1980: 31: 952-955. H, COHENA, LEVIJ. Androgen-associated 47. ZEVIND, TIJRANI hepatoma in a hemodialysis patient. Nephron 1981: 29: 274276. 48. COCKSJ R. Methyltestosterone-induced liver-cell tumours. Med J Aust 1981: 2: 617418.
49. FARRELL G C, JOSHUA D E, URENR F, BAIRDP J, PERKINS K W, KRONENBERG H. Androgen-induced hepatoma. Lancet 1975: i: 430-432. 50. GUYJ T, AUSLANDER M 0. Androgenic steroids and hepatocellular carcinoma. Lancet 1973: i: 148. 51. SARNAG, TOMASULO P, LOTZM J, BUBINAK J F, SHULMAN N R. Multiple neoplasms in two siblings with a variant form of Fanconi’s anemia. Cancer 1975: 36: 1029-1033. 52. MOKROHISKY S T, AMBRUSO D R, HATHAWAY W E. Fulminant hepatic neoplasia after androgen therapy. N Engl J Med 1977: 296: 1411-2. 53. ODAK, OGUMA N, KAWANO M, KIMURA A, KURAMOTO A, TOKUMO K. Hepatocellular carcinoma associated with longterm anabolic steroid therapy in two patients with aplastic anemia. Acta Haematol Jpn 1987: 50: 29-36. 54. SCHMIDT E, DEECH J, STORBR. Regression of androgenrelated hepatic tumors in patients with Fanconi’s anemia following marrow transplantation. Transplantation 1984: 37: 452455. 55. HENDERSON J T, RICHMOND J, SUMERLING M D. Androgenic anabolic steroid therapy and hepatocellular carcinoma. Lancet 1973: i: 934. 56. REUBER M D. Effect of age and testosterone on the induction of hyperplastic nodules, carcinomas, and cirrhosis of the liver in rats ingesting N-2-fluorenyldiacetamide. Eur J Cancer 1976: 12: 137-141. 57. RECANTL, LACYP. Fanconi’s anemia and hepatic cirrhosis. Am J Med 1965: 39: 464475. 58. CATTAND, VENN P, WAUTIER J, KALIFAT R, MEIGNAN S. Liver tumours and steroid hormones. Lancet 1974: i: 878. 59. POPPERH. Viral versus chemical hepatocarcinogenesis. J Hepatol 1988: 6: 229-238. 60. KEw M C, HOUGHTON M, CHOOQ L, Kuo G. Hepatitis C virus antibodies in southern African blacks with hepatocelMar carcinoma. Lancet 1990: 335: 873-874. 61. SCHEUERA, GERDESH, LEHMANN F-G. Anabolika und Lebertumoren. Dtsch Med Wochenschr 1979: 104: 779-783. 62. GOODMAN Z D. Pathology of hepatocellular carcinoma: Diagnosis and differential diagnosis. In: Tabor E, Di Bisceglie A M, Purcell R H eds. Etiology, pathology, and treatment of hepatocellular carcinoma in North America. Advances in Applied Biotechnology Series, vol. 13. The Woodlands Texas Portfolio Publishing Co., 1991: 191-208. 63. ERDSTEIN J, WISEBORD S, MISHKINS Y, MISHKINS. The effect of several sex steroid hormones on the growth rate of three Morris hepatoma tumor lines. Hepatology 1989: 9: 62 1-624. 64. GLEESON D, NEWBOULD M J, TAYLOR P, MCMAHON R F, LEAHYB C, WARNEST W. Androgen associated hepatocelMar carcinoma with an aggressive course. Gut 1991: 32: 10841086. S, DUSHEIKO G. Hepatitis C virus updated. Lead65. SHERLOCK ing article. Gut 1991: 32: 965-967. 66. Laegemiddelforbruget i Danmark 1990. Dansk Laegemiddelstatistik 1990: 68.
79
Katrine Lydolph See, Marten See and Christian Gluud Medical Department, Division of Gastroenterology, Hvidovre University Hospital, Copenhagen, Denmark
Key words: anabolic-androgenic steroids hepatic adenomas - hepatocellular carcinoma - peliosis hepatis Christian Gluud M. D, Dr. med. Sci. Medical Department, Division of Gastroenterology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark Received 24 May, accepted for publication 27 December 1991
Anabolic-androgenic steroids (AAS) are used in the treatment of male hypogonadism and to treat certain forms of anaemia, retarded growth, hypopituitarism, impotence, eunuchoidism, infertility, cryptorchism, panmyelopathia and paroxysmal nocturnal haemoglobinuria (1). Furthermore, a substantial amount is used among athletes as selfmedication in order to improve strength (2-4). The use of AAS can cause certain side-effects, however, among which the side-effects on the liver are considered common and serious ( 5 ) . The liver plays a central role in the metabolism of AAS, and it is an organ under the influence of sex hormones: There are receptors for AAS in the liver in both humans and animals, and an increasing number of metabolic processes in the liver are being found to be dependent upon AAS (6, 7). This review presents pathological conditions of the liver due to AAS as presented in the literature, mainly considering human data. The nomenclature of A A S has been described in detail by Murad & Haynes (1). Material and methods
To provide the pertinent literature, several sources have been utilized. A MEDLARS and MEDLINE survey was undertaken up to 1990, searching publications dealing with side-effects and effects of AAS on the human and animal liver. Further, a crossbibliographic check was made. Included were articles dealing with liver pathology in humans associ-
ated with AAS and certain selected animal studies of high scientific quality. Double-publications were excluded. Concerning AAS, trivial names have been used. When first mentioned, however, systematic names are given in parentheses. Vascular changes
AAS are connected to a particular vascular phenomenon known as peliosis hepatis (PH), i.e. bloodfilled spaces in the liver (Table 1). PH has been described in patients with tuberculosis (8). AAS connected with PH are testosterone (17-beta-hydroxy-4-androsten-3-on), norethandrolone (17-alpha-ethyl- 17-beta-hydroxy-androsta- 1,4-dien-3on), fluoxymesterone (9-alpha-fluoro- 11-beta-hydroxy- 17-alpha-methyl-testosterone), oxymetholone (17-beta-hydroxy-2-hydroxymethylene17-alpha-methyl-5-alpha-androstan-3-on), methandros( 17-alpha-methyl- 17-beta-hydroxytenolone androsta- 1,4-dien-3-0n)and nandrolone decanoate (19-nortestosterone-decanoate) (9). PH can appear at any time during AAS treatment and does not seem to depend upon the dose used. PH is also found occasionally in patients with liver tumours associated to AAS (10-17). The pathogenesis of PH is considered to be a progressive dilatation of the liver veins and -sinusoids, due to destruction of intercellular bindings among the hepatocytes, as seen in areas near the cysts in patients with PH (18). The cysts are not 73
See et al. Table 1. Benign and malignant liver-pathological changes associated with anabolic-androgenic steroids in the literature in relation to study design Uncontrolled studies Case histories (no. of patients) Peliosis hepatis Hyperplasia Focal nodular hyperplasia Hepatocellular adenoma Hepatocellular carcinoma Haemangiosarcoma Cholangiocarcinoma Dysplasia
Controlled studies
Series (no. of positive ptt./ total number of patients)
Human (no. of series) Association
No association
Animals (no. of series) Association
No association
20 1 3 15 26 5 4 1
-: No reports.
covered with endothelium but communicate with sinusoids covered with endothelium. Accumulations of hepatocytes in liver veins are described in 9 of 60 cases in patients treated with AAS (18). This phenomenon can cause a mechanical obstruction and thereby an accumulation of blood, leading to dilatation of liver veins and -sinusoids and blood clusters between the hepatocytes. Intravenous accumulation of hepatocytes has not been described in 300 Tru-cut-biopsies from patients suffering from PH, but never treated with AAS (18). The phenomenon seems to be related to the use of AAS (6, 18). The same observations have been made in studies using mice (2). Nevertheless, no increasing prevalence of PH was found in placebo-controlled studies of patients with cirrhotic and non-cirrhotic liver disease treated with AAS (6, 19, 20). The clinical manifestations of PH are hepatomegaly and tenderness of the right hypochondrium. PH is seen among all age groups and it ‘Is not related to sex (9). Biochemical liver tests will usually be normal until advanced stages of the disease. It seems that biopsy is the best choice for revealing PH, even in the early stages of the disease (18, 21), but some authors have described the diagnostic value of ultrasonic examination (22), computed tomography, angiography (21) and even isotope scan (22). PH is one of the most serious side-effects of AAS. It can result in rupture of the liver with haemoperitoneum and liver failure, resulting in death of the patient (9). There have been reports of life-saving lobectomies (9) and of regression of the vascular changes after ceasing AAS treatment (9). It is possible that testosterone treatment through a conversion to oestrogens - may induce a hypercoagulable state and lead to Budd-Chiari syndrome (23, 24). We have been unable to find 74
human studies dealing with the possible effect of AAS on the hepatic artery. Subcellular changes
Light- and electronmicroscopic examinations of liver tissue from patients treated with AAS have revealed a number of pathological changes of hepatocytes. The bile canaliculi show dilatation, the microvilli on their borders are fewer and smaller, and a proliferation of the smooth endoplasmatic reticulum is seen (9, 18). These pathological changes are similar to those seen in cholestatic jaundice. Furthermore, a polarisation of organelles at the perisinusoidal border is seen along with the occurrence of giant mitochondria (18). The latter are often seen in livers damaged by excessive alcohol intake (1 8). None of these pathological patterns is specific for liver patients treated with AAS. Cholestatic jaundice due to AAS was described for the first time in 1947, and since then a number of similar cases have been reported (9). Usually it is discovered after 2-5 months of AAS treatment (1, 9). After withdrawal of AAS the prognosis is generally good, but cases with progression to fatal liver cirrhosis have been described (9). The above-mentioned observations in humans have all been uncontrolled studies. The same kind of cholestatic change, however, has also been found in studies on rats treated with high doses of AAS, making the connection likely (2, 25). In patients with pre-existing liver cirrhosis, however, the occurrence of cholestatic jaundice during testosterone treatment did not differ significantly from placebopatients (6, 19, 23, 26). The AAS-induced jaundice is diagnosed by liver biopsy. In the rim of the acinus cholestasis is found. The liver enzymes are often increased, but to a lesser degree than seen in cholestasis caused by other factors (9). Restitution often follows cess-
Liver pathology and AAS
ation of treatment with AAS making that solution the most rational.
and in those cases it seems to be predominantly NT (25).
Hyperplasla
Benign neoplasms
Nodular transformation (NT) and focal nodular hyperplasia (FNH) have been connected to the use of AAS (Table 1). NT is a non-cirrhotic nodular transformation of liver tissue. The aetiology often remains undetected, but myeloproliferative diseases and AAS are known factors (9). In NT the liver is changed into a mass of yellow-brownish nodules containing dysplastic elements in 20% of the cases, very much like the premalignant neoplasia known from guinea-pigs treated with known carcinogens (9). Whether NT belongs to the premalignant conditions of the liver is not yet known. Noduli of NT cause atrophy of the surrounding tissue and NT can cause portal hypertension. We have found no reports of NT in humans. FNH is a tumour characterised by a central starshaped scar, a lighter colour than the surrounding tissue and a benign cytologic and histologic pattern. It has been connected to the use of oral contraceptives for a long time (27). Only three cases have been reported in connection with the use of AAS (1 5, 28, 29). All patients received 17-alkylated AAS (Table 2). No conclusions about a connection can be drawn from such data, as FNH has been reported in all ages and in both sexes, unrelated to the use of AAS (9). In a placebo-controlled study of the effect of testosterone in men with alcoholic cirrhosis, no significant effect of testosterone was found on the development of hyperplastic nodules (30). Neither NT nor FNH was found in biopsies from livers of patients with cirrhosis or alcoholic hepatitis after treatment with AAS (6,20). In contrast, hyperplastic elements were found in all the animals of an AAS-treated group, while no such changes were found in the group given placebo (25). In these studies no distinctions are made between NT and FNH, but in a few cases hyperplasia is described
Since the first description of a liver tumour in a patient treated with AAS in 1965, a number of articles have been written concerning a possible causal connection between AAS and primary benign and malignant liver tumours (Table 1). Sixteen cases of hepatocellular adenoma (HCA) have been described in connection with the use of AAS (13, 14, 16, 17, 22, 31-36). Both 17-alkylated and non-17-alkylated AAS have been involved (Table 2). HCA is a benign tumour as it does not grow invasively and it shows a benign cytologic and histologic pattern (9). Nevertheless, HCA can be fatal because of the risk of rupture causing bleeding into the peritoneum. The greatest risk of such a rupture is in patients treated for anaemia, as these patients often have thrombocytopenia and an impaired clotting mechanism. Rupture of HCA is described in two of the cases (17, 36). No HCA were found in placebo-controlled studies on the effect of A A S treatment of males with cirrhosis and non-cirrhotic liver disease (6,20, 26). In controlled studies of mice, however, it has been found that HCA can develop during treatment with AAS (2). Previously the treatment of HCA was hemi-lobectomy, but this is not always necessary as the tumour regresses after withdrawal of AAS (37,38).
Table 2. Relation between benign human liver pathology associated with the use of 17-alkylated and non 17-alkylated anabolic-androgenic steroids. Number of reported cases Anabolic-androgenic steroid 17-alkylated Non 17-alkylated Peliosis hepatis Hyperplasia Focal nodular hyperplasia Hepatocellular adenoma *
14' 1 3 14'
10 0 0 2
Two patients have received both 17-alkylated and non 17-alkylated steroids.
Malignant neoplasms
The malignant neoplasms mentioned in connection with the use of AAS encompass hepatocellular carcinoma (HCC), hepatic angiosarcoma and cholangiocarcinoma (Table 1). The last two tumour types have been described in only a yery few cases (1 1, 3942), and a causal connection between AAS and these two types of tumours is therefore still hypothe tical. HCC is the kind of liver-tumour most often suspected to be induced by AAS. The suspicion arises from a total of 26 cases of histologically verified HCC in patients treated with AAS (10-15, 22, 29, 40,43-53). A few cases have been reported without any histological verification (37, 54, 55). HCC has also been observed in mice and rats treated with AAS (56), but never in dogs or monkeys (9). The indication for treatment with AAS in patients who developed HCC were hypogonadism, hypopituitarism, impotence, eunuchoidism, infertility, cryptorchism, nephrogenous anaemia, Fanconi's anaemia, idiopathic anaemia, panmyelopa75
S0e et al.
thia and paroxysmal nocturnal haemoglobinuria. In one case a young athlete developed HCC using AAS as a means to gain strength (40). The AAS mentioned in connection with the development of HCC is mainly 17-alkylated forms of AAS, mostly methyltestosterone (17-alpha-methyltestosterone) and oxymetholone. In animal studies, however, a tumour-inducing effect of non-alkylated AAS has been found (25), and two cases of patients treated with non-alkylated AAS have been described (1 1). No significant increase in development of HCC has been found in placebo-controlled studies of men with alcohol-induced cirrhotic and non-cirrhotic liver disease (6, 19, 20, 26). AAS associated neoplasms in patients with Fanconi's disease
The first patient claimed to have a liver tumour associated with AAS was a 27-year-old male with Fanconi's disease (FD). Since then, more cases of malignant and benign liver tumours in AAStreated patients with F D have been published (six malignant; one both malignant and benign; four benign; two unspecified) (12, 13, 17, 35, 43, 50-52, 54). We have chosen to mention this group of patients separately because an increased risk of tumour development has been described in patients with F D (13, 51, 54). The frequent chromosome breaks in these patients have been suggested to be the cause (51). This may cause an increased number of mitoses, possibly leading to an increased risk of malignant transformation ( 12). The likelihood of this explanation is supported by the discovery of multiple small liver tumours in some of the Fanconi patients described (12, 13, 17, 54, 57). A case of HCC in a 7-year-old patient with F D never treated with AAS has also been reported (58). Furthermore, most of the patients with F D have been treated with transfusions of blood, causing an increased risk of hepatitis B and C. This again leads to an increased risk of HCC (59, 60). Only five patients in the articles mentioned above have been tested for hepatitis B virus surface antigen (HBsAg), and four of the tests were negative (17, 50, 51). None have been tested for hepatitis C virus. Discussion
As stated above, and as demonstrated in Table 1, certain pathological conditions of the liver have been described in connection with the use of AAS in case histories and smaller uncontrolled studies. It is known that this can never be sufficient evidence to prove a causal connection. The associ76
ations between AAS and peliosis hepatis, subcellular changes, hyperplasia and HCA are supported by controlled animal studies, where the same pathological pattern was found in a significantly increased number in the AAS-treated animals. Even though animal studies support a possible connection between AAS and HCC, it is still uncertain whether such an association exists in man. Tables 2 and 3 show that both 17-alkylated and non 17-alkylated AAS have been implicated in both benign and malignant liver pathology associated with AAS. The fact that the majority of cases have been described in connection with 17-alkylated AAS, which is not metabolized to oestrogens, could be due to both a greater toxicity of these substances and a greater use. Furthermore, the observation that 17-alkylated AAS is mainly involved makes it unlikely that the effects of AAS are all due to secondary metabolism into oestrogens. AAS interferes with the cellular metabolism by binding to intracellular receptors. It is therefore probable that this binding plays a role too in the induction of the above-mentioned pathological conditions of the liver. This makes the lack of significantly increased occurrence of liver pathological changes in patients with pre-existing liver disease in treatment with AAS a vague argument against an association between AAS and liver disease (19). Patients with cirrhosis of the liver are characterised by having a decreased amount of androgen receptors ( 1 9). Furthermore, patients with liver cirrhosis have increased plasma concentrations of oestrogens, lowering the number of androgen receptors even more and interfering with the binding of AAS to the receptor (19). On the other hand, it is possible that the rare side-effects of AAS have been overlooked in the placebo-controlled studies due to too small a material ( < 150 patients in the AAS-treated groups) (19). The association between AAS and human HCC is uncertain for a number of reasons. HCC is a highly malignant tumour with a median survival time of about 4-6 months after the time of diagnosis (61) and 33-50% already have extra-hepatic metastases at the time of diagnosis (61). Only four cases of AAS-associated HCC (AAHCC) have been reported as having metastases (Table 2) (40, 49, 53). One of these patients (40) had HCC as well as cholangiocarcinoma-elements in the liver tumour, and it is not reported whether the metastases were of one or the other kind, even though a pathological examination was performed. In the other 22 patients (6 Fanconi, 16 non-Fanconi), no metastases were found in five cases, and the rest do not comment on the subject. None of these patients had AAHCC as the primary cause of death. Four of the Fanconi- and two non-Fanconi-
Liver pathology and AAS Table 3. Malignant liver tumours associated with androgenic-anabolic steroids Hepatocellular carcinoma Non-Fanconi’s Fanconi’s disease disease No. of cases Sex (malelfemale) Age (median) (span) Taken 17-alkylated AAS (no. of cases) Diagnostic procedure: (no. of cases) Biopsy Operation material Autopsy Metastasis (yeslno) Regression of tumour (no. of cases) Died of liver disease (no. of cases)
19 1514 33 6-68 18
7 611 20 6-38 6
6 10 5 313 3 2
2 0 5 112 0 4
patients died from liver failure. The other 20 either died of other causes or were alive at the time of publication of their case, often years after being diagnosed as having a liver tumour. Patients with AAHCC also differ from patients with HCC regarding alpha-1-fetoprotein. In patients with HCC, alpha-l-fetoprotein is detected in raised concentrations in 50-80% of the cases (62) and even more often in very young patients (18). In patients with AAHCC the alpha-1-fetoprotein concentration is found within normal limits in most cases. Only two AAHCC patients had raised alpha1-fetoprotein. Case one describes a tumour in a 68year-old male who also was HBsAg positive. The tumour had not been examined histologically and the case does not report anything about survival (55). The second case of raised alpha-1-fetoprotein in association with an AAS-associated tumour is that of a 26-year-old male who had used AAS in an excessive dose and in an unorthodox combination. His tumour was examined histologically, and both hepatocellular carcinoma and cholangiocarcinoma were found within the same tumour (40)* Regression of the tumour after withdrawal of AAS treatment has been reported in three cases (15, 46). This has never before been reported in malignant liver tumours. Finally, 7 out of 26 cases of AAHCC were found in patients with Fanconi’s disease and these patients, as already stated, have an increased tendency towards developing tumours due t o the increased number of chromosome breaks and an increased risk of catching hepatitis due to treatment with blood transfusions. The reason why AAS might lead to development of liver tumours is not known, but can be explained in different ways. Assuming AAS is a carcinogenic compound itself, it could work as a tumour inducer. If the compound itself is not carcinogenic, it could be metabolically changed into a dangerous
Haemangiosarcoma
Cholangiocarcinoma
Unspecified tumour
5
4 4/0 57 26-68 2
4 311 14 8-1 5 4
1 1 2 2/0 0
0
312
3
2 1 3 3/0 0 2
2
0 0 3 0
compound or it could work together with other compounds to cause tumour development (co-carcinogenic effect). The most likely explanation is that AAS can act as a tumour promoter, making already existing liver tumours grow faster or changing a benign liver tumour into one looking malignant (1 3,61). Studies on animals (63) support the latter mechanism. AAS could also act indirectly by increasing the change of harmless compounds of various kinds into dangerous ones by induction of the liver enzyme systems or it could prevent the elimination of dangerous compounds possibly through its cholestatic effect (9, 18, 25). Finally, AAS may speed up liver regeneration, increasing the number of mitoses and thereby the possibility of spontaneous tumour development. It does not seem likely though that AAS can cause development of HCC when used in normal doses. The tumours presented as HCC in most case histories might be tumours that look like HCC histologically, but act as relatively benign tumours. Since the completion of this study, one case of AAS-associated hepatocellular carcinoma with an aggressive course has appeared. (64). This patient was, however, also hepatitis C virus antibody positive. Hepatitis C virus is considered a major cause of HCC (65). Therefore, only future studies will be able to answer the important question of the association between AAS and HCC. Among some sportsmen, AAS are used in untraditional combinations and in much higher doses than for medical treatment (3, 4). It is possible that the effect on the liver is different and may be worse when AAS is used under these conditions. Conclusion
Most of the studies published up till now concerning the side-effects of AAS with regard to the liver are case histories. There are a few controlled 77
See et al.
studies on animals, researching the effect of AAS on rats and mice, and in these studies side-effects on the liver have been found, but corresponding changes have not been found in dogs or monkeys. Controlled studies of liver function and liver morphology in humans treated with AAS only exist for patients already suffering from liver disease. The theoretically ideal study - the doubleblinded, placebo-controlled study of AAS’s effect on persons with a healthy liver - does not exist. In the attempt to draw a conclusion from a material that consists solely of case histories, one must at least ask for a sufficient pathological description, information about tumour markers in the blood and information about pre-dispositions. Most of the studies in the literature lack this important information. Further, case histories are not very hard proof of any association between AAS and liver pathology when one considers that in, for example, Denmark the use of AAS amounted to 200400 defined daily doses per 1000000 inhibitants during the years 1986-90 (66). Under these circumstances we can only conclude that AAS can lead to peliosis hepatis and cholestatic jaundice when used in the normal therapeutic dosage. This seems well documented by high quality papers. Nodular transformation has been found in animal studies, but not in humans. Most important, there does not seem to be any connection between AAS and HCC as we usually describe it. More likely, AAS can cause development of a kind of tumour that looks like HCC histologically, but acts like a relatively benign tumour. References 1. MURAD F, HAYNES JR R C. Androgens. In: Goodman and
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