European Journal of Endocrinology (2006) 154 213–220 ISSN 0804-4643 CASE REPORT Elevated transaminases during medical treatment of acromegaly: a review of the German pegvisomant surveillance experience and a report of a patient with histologically proven chronic mild active hepatitis H Biering1, B Saller4,*, J Bauditz1, M Pirlich1, B Rudolph2, A Johne3, M Buchfelder5,*, K Mann6,*, M Droste7,*, I Schreiber4, H Lochs1 and C J Strasburger1,* 1Department of Gastroenterology, Hepatology and Endocrinology, 2Institute of Pathology and 3Institute for Clinical Pharmacology, Charite´-Universita¨tsmedizin Berlin, 10117 Berlin, Germany, 4Pfizer Pharma GmbH, Karlsruhe, Germany, 5Department of Neurosurgery, University Hosiptal, Erlangen, Germany, 6Division of Endocrinology, Department of Medicine, University of Duisberg-Essen, Germany and 7Oldenburg, Germany (Correspondence should be addressed to C J Strasburger, Division of Clinical Endocrinology, Department of Medicine, Charite´-Universita¨tsmedizin Berlin, Schumannstr. 20/21, 10117 Berlin, Germany; Email: [email protected]) *On behalf of the German pegvisomant investigators Abstract Objective: The new GH receptor antagonist pegvisomant is the most effective medical therapy to nor- malize IGF-I levels in patients with acromegaly. Based on currently available data pegvisomant is well tolerated; however, treatment-induced elevation of transaminases has been reported and led to the necessity for drug discontinuation in some patients in the pivotal studies. The aim of this study was to evaluate and characterize the prevalence of elevated transaminases and to describe in detail the findings in a single case who required drug discontinuation because of elevation of transaminases which emerged during treatment and who underwent liver biopsy. Design and methods: Retrospective safety analyses were carried out on 142 patients with acromegaly receiving pegvisomant treatment in Germany between March 2003 and the end of 2004. Of these patients, 123 were documented in a post-marketing surveillance study, one case of elevated transam- inases was reported spontaneously and the other patients were treated in a clinical study. Results: Mean treatment duration with pegvisomant in the ongoing observational study at the end of 2004 was 28.3^19.9 (S.D.) weeks. Twelve out of the 142 patients had elevated transaminases above three times the upper limit of normal, likely caused by biliary obstruction in five of the patients. All patients but one affected by elevated transaminases had been previously treated with somatostatin analogues. In six out of 142 (4%) of patients, pegvisomant was permanently withdrawn because of elevated transaminases. The same number of patients showed a transient increase of transaminases with either spontaneous remission without dose modification (n ¼ 4) or no re-increase of transamin- ases after temporary discontinuation and re-exposure (n ¼ 2). The liver biopsy of one patient who was permanently withdrawn showed a chronic mild hepatitis with a mixed portal inflammation including eosinophilic granulocytes. Conclusions: Liver function tests should be regularly followed on pegvisomant treatment. Biliary com- plications, which may arise from restitution of normal gall bladder motility after cessation of somato- statin analogue treatment, need to be differentiated from pegvisomant-induced abnormalities. The histological pattern of the liver biopsy performed in one of the patients showed a mild chronic active hepatitis. The lack of dose dependency and rather low frequency of elevated transaminases in those cases where a biliary disorder was excluded render this reaction an idiosyncratic drug toxicity. European Journal of Endocrinology 154 213–220 Introduction disease is the principal cause of premature death. Treat- ment goals include relieving clinical symptoms, normal- Acromegaly is a debilitating condition, characterized by izations of biochemical markers, control of tumour mass excess of growth hormone (GH) from a pituitary tumour. and preservation/restoration of pituitary function. Average life expectancy in patients with active acro- Adequate control of GH and insulin-like growth factor-I megaly is reduced by approximately 10 years and cardiac (IGF-I) levels results in normalization of life expectancy q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02079 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 09/30/2021 09:21:41PM via free access 214 H Biering and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154 (1). Standard treatment for acromegaly consists of pitu- phosphatase levels were seen in patients no. 2 and itary surgery and, if insufficient, adjuvant medical no. 9 (1.4- and 1.7-fold ULN respectively). therapy and/or pituitary irradiation. There was one case of elevated transaminases 80.6 A novel GH receptor antagonist (pegvisomant) has weeks after initiation of pegvisomant treatment. In been developed recently which, in clinical studies, is the other 11 patients, the interval between start of peg- capable of normalizing serum IGF-I in over 90% of visomant and onset of elevated transaminases was patients with active disease. Pegvisomant corrects the between 6.4 and 34.7 weeks (15.7^10.7 weeks, metabolic abnormalities of acromegaly, including insu- means^S.D.). The dosage of pegvisomant at the onset lin resistance and lipid metabolism (2–4). Normaliza- of transaminases abnormalities was between 10 and tion of serum IGF-I with pegvisomant is also 25 mg/day (15^5 mg/day).Ten out of the twelve associated with normalized bone metabolism (5). patients had previously received Sandostatin LAR Uniquely among treatments for acromegaly, pegviso- (Novartis Pharma, Basel, Switzerland) as medical mant neither acts on the pituitary nor attempts to inhi- therapy, except for patient no. 6 who received subcu- bit GH secretion but rather inhibits GH action. Based on taneous octreotide and patient no. 10 who was not the available data, pegvisomant is well tolerated. pretreated with somatostatin analogues. At the time Among the possible side-effects, elevation of transamin- of elevated transaminases, two patients were receiving ases seems to be the most relevant. In the first clinical a combination of pegvisomant with 30 mg long- studies with pegvisomant, a tenfold increase of alanine acting octreotide every 4 weeks within a clinical trial aminotransferase (ALT) and aspartate aminotransfer- (patients no. 8 and no. 9). Two patients had discontin- ase (AST) were observed in two patients (1.2%). How- ued Sandostatin LAR for more than 2 years (patients ever, since data regarding long-term safety with no. 11 and no. 12), in six other patients the last dose pegvisomant are limited, the aim of the present report of Sandostatin LAR was given between 7 and 36 is to summarize the cases with elevated transaminases weeks before the elevated transaminases. during pegvisomant treatment seen in Germany so far In five patients (patient nos 1, 2, 9, 11 and 12), sono- and to report details of one case who had a liver biopsy graphically proven gallstone disease was present and showed histological signs of chronic active together with elevated levels of g-GT and/or alkaline hepatitis. In line with the present approved indication, phosphatase or bilirubin; in patient no. 6 with sonogra- most patients were treated with pegvisomant only phically proven gallstones these laboratory data were after other forms of medical treatment were unable to unavailable. In two of these patients (patients no. 9 normalize the disease activity of acromegaly or were and no. 12), bile duct stones could be verified by endo- not tolerated. scopic retrograde cholangiography as the most obvious reason for laboratory abnormalities, suggesting biliary complications rather than a drug reaction as the Elevations of transaminases during reason for liver enzyme elevations. Additionally, in pegvisomant treatment patient no. 2 the leading enzyme was g-GT and gallstones were found. Up to the end of 2004, 35 acromegalic patients have During follow-up, transaminases returned to normal been treated in Germany with pegvisomant within in all patients after 4–32 weeks (mean 12 weeks). clinical trials and 123 acromegalic patients have been Interestingly, in four patients, transaminases spon- included in a non-interventional post-marketing sur- taneously normalized despite ongoing treatment with veillance study (including 17 patients who had already pegvisomant. participated in a clinical trial before entering the non- interventional surveillance study). In addition, patients with active acromegaly have been on the commercial Case study drug without being included in clinical trials. Up to December 2004 there have been reports of We report here in detail on a 43-year-old man (Table 1, elevated transaminases to more than three times the patient no. 8) who presented in May 1997 in our clinic upper limit of normal (ULN) in 12 patients (seven with typical clinical features of acromegaly and an elev- males, five females, age 44^9 years). Four cases were ated IGF-I. Magnetic resonance imaging demonstrated reported as adverse events from clinical trials, six a macroadenoma of the pituitary gland with suprasel- cases from the non-interventional surveillance study lar extension. Debulking of the tumour by trans-sphe- and two were reported spontaneously from patients noidal surgery in June 1997 as well as stereotactic not included in either. Table 1 summarizes the charac- radiotherapy of the residual pituitary