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CASE REPORT |
1 Department of Gastroenterology, Hepatology and Endocrinology, 2 Institute of Pathology and 3 Institute for Clinical Pharmacology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany, 4 Pfizer Pharma GmbH, Karlsruhe, Germany, 5 Department of Neurosurgery, University Hosiptal, Erlangen, Germany, 6 Division of Endocrinology, Department of Medicine, University of Duisberg-Essen, Germany and 7 Oldenburg, Germany
(Correspondence should be addressed to C J Strasburger, Division of Clinical Endocrinology, Department of Medicine, Charité-Universitätsmedizin Berlin, Schumannstr. 20/21, 10117 Berlin, Germany; Email: Christian.Strasburger{at}charite.de)
Abstract
Objective: The new GH receptor antagonist pegvisomant is the most effective medical therapy to normalize 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 transaminases 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 In six out of 142 (4%) of patients, pegvisomant was permanently withdrawn because of elevated transaminases.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 = 4) or no re-increase of transaminases after temporary discontinuation and re-exposure (n = 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 complications, which may arise from restitution of normal gall bladder motility after cessation of somatostatin 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.
Introduction
Acromegaly is a debilitating condition, characterized by excess of growth hormone (GH) from a pituitary tumour. Average life expectancy in patients with active acromegaly is reduced by approximately 10 years and cardiac disease is the principal cause of premature death. Treatment goals include relieving clinical symptoms, normalizations of biochemical markers, control of tumour mass and preservation/restoration of pituitary function. Adequate control of GH and insulin-like growth factor-I (IGF-I) levels results in normalization of life expectancy (1). Standard treatment for acromegaly consists of pituitary surgery and, if insufficient, adjuvant medical therapy and/or pituitary irradiation.
A novel GH receptor antagonist (pegvisomant) has been developed recently which, in clinical studies, is capable of normalizing serum IGF-I in over 90% of patients with active disease. Pegvisomant corrects the metabolic abnormalities of acromegaly, including insulin resistance and lipid metabolism (2–4). Normalization of serum IGF-I with pegvisomant is also associated with normalized bone metabolism (5). Uniquely among treatments for acromegaly, pegvisomant neither acts on the pituitary nor attempts to inhibit GH secretion but rather inhibits GH action. Based on the available data, pegvisomant is well tolerated. Among the possible side-effects, elevation of transaminases seems to be the most relevant. In the first clinical studies with pegvisomant, a tenfold increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in two patients (1.2%). However, since data regarding long-term safety with pegvisomant are limited, the aim of the present report is to summarize the cases with elevated transaminases during pegvisomant treatment seen in Germany so far and to report details of one case who had a liver biopsy and showed histological signs of chronic active hepatitis. In line with the present approved indication, most patients were treated with pegvisomant only after other forms of medical treatment were unable to normalize the disease activity of acromegaly or were not tolerated.
Elevations of transaminases during pegvisomant treatment
Up to the end of 2004, 35 acromegalic patients have been treated in Germany with pegvisomant within clinical trials and 123 acromegalic patients have been included in a non-interventional post-marketing surveillance study (including 17 patients who had already participated in a clinical trial before entering the non-interventional surveillance study). In addition, patients with active acromegaly have been on the commercial drug without being included in clinical trials.
Up to December 2004 there have been reports of elevated transaminases to more than three times the upper limit of normal (ULN) in 12 patients (seven males, five females, age 44 ± 9 years). Four cases were reported as adverse events from clinical trials, six cases from the non-interventional surveillance study and two were reported spontaneously from patients not included in either. Table 1
summarizes the characteristics as well as the clinical and biochemical data of these 12 patients. Alkaline phosphatase and bilirubin levels were available from only a minority of these patients. An increased level of bilirubin to 2.1-fold ULN was seen in patient no. 1. Elevated alkaline phosphatase levels were seen in patients no. 2 and no. 9 (1.4- and 1.7-fold ULN respectively).
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In five patients (patient nos 1, 2, 9, 11 and 12), sono-graphically proven gallstone disease was present together with elevated levels of 
-GT and/or alkaline phosphatase or bilirubin; in patient no. 6 with sonographically proven gallstones these laboratory data were unavailable. In two of these patients (patients no. 9 and no. 12), bile duct stones could be verified by endoscopic retrograde cholangiography as the most obvious reason for laboratory abnormalities, suggesting biliary complications rather than a drug reaction as the reason for liver enzyme elevations. Additionally, in patient no. 2 the leading enzyme was -GT and gallstones were found.
During follow-up, transaminases returned to normal in all patients after 4–32 weeks (mean 12 weeks). Interestingly, in four patients, transaminases spontaneously normalized despite ongoing treatment with pegvisomant.
Case study
We report here in detail on a 43-year-old man (Table 1
, patient no. 8) who presented in May 1997 in our clinic with typical clinical features of acromegaly and an elevated IGF-I. Magnetic resonance imaging demonstrated a macroadenoma of the pituitary gland with suprasellar extension. Debulking of the tumour by trans-sphenoidal surgery in June 1997 as well as stereotactic radiotherapy of the residual pituitary adenoma in 1999/2000 effectively reduced tumour mass but was not sufficient to control the GH excess. Using several medications (lanreotide, dopamine agonists), only transient and partial suppression of the residual acromegaly disease activity was achieved. Long-acting octreotide (Sandostatin LAR, 30 mg every 28 days) also failed to reduce IGF-I levels to the normal range. The patient was then treated within a clinical trial with Somavert (pegvisomant) in combination with Sandostatin LAR (30 mg). Treatment with Somavert was initiated at a dose of 10 mg/day s.c. and was adjusted to 15 mg/day because of incomplete suppression of IGF-I. Treatment was well tolerated and resulted in significant improvement of clinical symptoms. The patient reported an improved sense of well-being, disappearance of paresthesias and reduced soft tissue swelling of the hands. Biochemical evaluation demonstrated normalization of IGF-I which was reduced to the age-related reference range.
Eight weeks after the start of treatment we noticed a gradual increase of the transaminases. After ALT increased fivefold above the ULN, which persisted over several weeks, we decided to discontinue treatment with Somavert. Treatment with Sandostatin LAR injections at monthly intervals was continued. -GT was only mildly affected. No concurrent increase in serum alkaline phosphatase was observed. Diagnostic work-up for exclusion of other hepatic diseases, including viral hepatitis and haemochromatosis, Wilson’s disease, autoimmune hepatitis and 
-1 anti-trypsin deficiency was performed. Ultrasound examination showed normal echogenicity of the liver parenchyma without signs of steatosis. In addition, there was no evidence of gallstone disease. A liver biopsy was performed for further diagnostic evaluation. Histology demonstrated discrete portal fibrosis without bridging and discrete lobular hepatitis with fatty droplets in 30% of hepatocytes. The majority of the portal tracts showed a mixed inflammatory infiltrate and discrete interface hepatitis. Inflammatory cells were composed of lymphocytes, histiocytes, mast cells and eosinophilic granulocytes consistent with chronic mild active hepatitis (Fig. 1 and 2). Two months after discontinuation of pegvisomant treatment liver transaminases returned to normal values without further specific therapy (Table 2).
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Before commencement of pegvisomant treatment an oral glucose-tolerance test showed completely normal glucose metabolism. During the period of elevation of transaminases we observed an impaired glucose tolerance according to WHO criteria (6) despite normal IGF-I levels (Table 2). Two months after discontinuation of pegvisomant treatment IGF-I levels were again increased twofold above the upper limit and transaminases had returned to normal values. At that time glucose tolerance testing again showed normal results.
Concentrations of haemoglobin A1c, cholesterol, triglyceride, lipid electrophoresis, lipoprotein a, C-reactive protein levels, erythrocyte sedimentation rate, haematocrit, white blood cell count, platelet counts, blood urea nitrogen, creatinine and lactate dehydrogenase were within normal limits at baseline and did not change during treatment.
Discussion
Safety and tolerability
Based on the available data, pegvisomant is well tolerated. In the first two double-blind, placebo-controlled trials of pegvisomant for treatment of acromegaly of 46 and 112 patients, respectively, were randomized (7, 8). Many of the patients from these studies have subsequently been transferred to a long-term daily dosing regimen, with normalization of serum IGF-I in 97% of patients. In these studies, a tenfold increase of ALT and AST was observed in two patients (1.2%). Both patients experienced mild fatigue and had normal bilirubin concentrations. Liver transaminases returned to normal several months after drug discontinuation. In one patient, a liver biopsy was performed revealing chronic active hepatitis of unknown aetiology. The second patient was rechallenged and transaminases rose again, proving a causative role of pegvisomant. No other significant adverse events were observed during long-term treatment (9).
Presently available data showed that the incidence of slight increases of transaminases was not different between pegvisomant- and placebo-treated patients. The increases in transaminases did not appear to be dose-related, usually occurred within 3 month of initiation of therapy and were not associated with any identifiable biochemical, phenotypic or genetic predictors. Concurrent increases in serum total bilirubin and alkaline phosphatase, which are established as indicators of serious drug-induced hepatic injury, were not observed. In many cases, increases in transaminases were sporadic and returned to normal without discontinuation of pegvisomant therapy (10).
The present report adds data from 12 patients treated in Germany with elevations of transaminases to more than three times ULN during pegvisomant treatment. In five of these patients, the presence of sonographically proven gallstone disease together with elevated levels of -GT, alkaline phosphatase or bilirubin suggest biliary complications rather than a pegvisomant-induced reaction as the reason for liver enzyme elevations. In two of these patients, cholelithiasis was clearly identified as the reason for liver enzyme elevations; these patients underwent an endoscopic retrograde cholangiograpy with a therapeutical papillotomy.
After discontinuation of pegvisomant treatment, transaminases returned to normal in all patients. Interestingly, in four patients, transaminases spontaneously normalized despite ongoing treatment with pegvisomant. Additionally, in patients no. 1 and no. 12 treatment was recommenced, after temporary discontinuation of pegvisomant for 3–5 months, and no further increase of transaminases was observed.
The mechanism of pegvisomant-induced deranged transaminases remains the subject of conjecture. In order to increase the antagonist’s half-life and to reduce antibody formation, a pegylated formula of the substance was developed. Hepatotoxicity has not been reported with other pegylated compounds in clinical use, and no such adverse events have been evident in any of the animal toxicology studies to date (11, 12). Moreover, attachment of polyethyleneglycol polymers to polypeptides is thought to reduce immunogenicity. It seems unlikely therefore that the drug formulation of pegvisomant has contributed to the hepatotoxicity observed in our patient.
Gilbert’s syndrome is a benign disorder caused by insufficient enzymatic conjugation of bilirubin without alteration of liver function. Bilirubin levels normalized during the phase of acute hepatitis in the described case. It is unlikely therefore that Gilbert’s syndrome contributed to the development of hepatitis. As induction of enzymes, e.g. by barbiturates, normalizes bilirubin, normalization of bilirubin levels during hepatitis was possibly secondary to inflammation-induced induction of hepatic enzymes.
Glucose metabolism
Pegvisomant was not found to induce a glycaemic effect in animal studies (13, 14). Furthermore, in a recent study of healthy subjects, pegvisomant was not associated with deterioration in glucose tolerance (15). GH infusion in normal subjects stimulates gluconeogenesis and lipolysis, which are mediated by the GH receptor, resulting in increased blood glucose and fatty acid levels, causing enhanced insulin secretion and sustained hyperglycaemia (16, 17). Similarly, acromegaly is characterized by increased glucose turnover, insulin resistance and hyperinsulinaemia (18, 19). Adequate control of acromegaly disease activity therefore results in improvement in glucose tolerance by normalization of GH excess.
Van der Lely et al. (9) investigated glucose metabolism in 160 patients treated with pegvisomant. The improvement in serum IGF-I was associated with a significant fall in mean fasting insulin and glucose, indicating improved insulin sensitivity. These results were confirmed by Rose & Clemmons (20) who reported a significant progressive increase in insulin sensitivity, which was related to both dose and duration of pegvisomant treatment. Improvement of insulin sensitivity did not appear to be due to changes in body composition or a reduction of lipolysis respectively (20, 21).
Increased insulin resistance in the case described was possibly caused by the toxic hepatitis caused by pegvisomant. Insulin resistance is found in inflammatory liver diseases (22), which are characterized by increased production of tumour necrosis factor- (TNF- ) (23). As TNF- induces insulin resistance by directly inhibiting signalling from the insulin receptor (24), the metabolic changes in this patient are likely to be primarily related to inflammation-mediated effects.
Conclusion
As pegvisomant is the most effective medical therapy for normalizing serum IGF-I levels, the drug represents a major advance in the treatment of acromegaly. Based on currently available data, pegvisomant is well tolerated. However, in a minority of patients increases in transaminases are observed.
The present series summarizes clinical and laboratory data from 12 German patients with elevated transaminases during pegvisomant treatment. It illustrates that in any individual case pegvisomant-induced abnormalities have to be differentiated from biliary complications seen in these patients. These may occur as a consequence of cholecystolithiasis which, after resumption of normal gall bladder contractility following discontinuation of long-acting somatostatin analogue treatment, may be moved into the biliary duct. The mechanism of pegvisomant-induced deranged transaminases remains the subject of conjecture. Because of the low frequency and the dose independence of the untoward reaction, idiosyncratic drug toxicity has to be assumed. Drug surveillance as well as basic research is needed to clearly define the association between the use of pegvisomant and hepatitis. Monitoring of liver transaminases is required during pegvisomant therapy and, beyond assessment of ALT and AST, monitoring should include -GT, alkaline phosphatase and potentially bilirubin levels to facilitate differentiation between hepatotoxicity and cholestatic causes of transaminase elevations.
Acknowledgements
The German Pegvisomant Observational Study is supported by a grant from Pfizer Pharma GmbH Karlsruhe, Germany.
Footnotes
* On behalf of the German pegvisomant investigators 
References
This article has been cited by other articles:
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  I. Bernabeu, J. Cameselle-Teijeiro, F. F Casanueva, and M. Marazuela Pegvisomant-induced cholestatic hepatitis with jaundice in a patient with Gilbert's syndrome Eur. J. Endocrinol., May 1, 2009; 160(5): 869 - 872. [Abstract] [Full Text] [PDF]
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 V. S. Bonert, L. Kennedy, S. Petersenn, A. Barkan, J. Carmichael, and S. Melmed Lipodystrophy in Patients with Acromegaly Receiving Pegvisomant J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3515 - 3518. [Abstract] [Full Text] [PDF]
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S. J. C. M. M. Neggers, M. O. van Aken, J. A. M. J. L. Janssen, R. A. Feelders, W. W. de Herder, and A.-J. van der Lely Long-Term Efficacy and Safety of Combined Treatment of Somatostatin Analogs and Pegvisomant in Acromegaly J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4598 - 4601. [Abstract] [Full Text] [PDF]
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I Schreiber, M Buchfelder, M Droste, K Forssmann, K Mann, B Saller, and C J Strasburger Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: Safety and efficacy evaluation from the German Pegvisomant Observational Study Eur. J. Endocrinol., January 1, 2007; 156(1): 75 - 82. [Abstract] [Full Text] [PDF]
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 S. Melmed Acromegaly N. Engl. J. Med., December 14, 2006; 355(24): 2558 - 2573. [Full Text] [PDF]
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J Feenstra, M O van Aken, W W de Herder, R A Feelders, and A J van der Lely Drug-induced hepatitis in an acromegalic patient during combined treatment with pegvisomant and octreotide long-acting repeatable attributed to the use of pegvisomant. Eur. J. Endocrinol., June 1, 2006; 154(6): 805 - 806. [Abstract] [Full Text] [PDF]
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