A CASE OF NONALCOHOLIC STEATOHEPATITIS IN A CURED ACROMEGALIC PATIENT WITH SEVERE GROWTH HORMONE DEFICIENCY

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1 Case Report A CASE OF NONALCOHOLIC STEATOHEPATITIS IN A CURED ACROMEGALIC PATIENT WITH SEVERE GROWTH HORMONE DEFICIENCY Satoshi Yamagata, MD, PhD 1,2 ; Kazunori Kageyama, MD, PhD 2 ; Shingo Murasawa, MD, PhD 1,2 ; Ken Tomotsune, MD, PhD 1 ; Shoko Kawashima, MD, PhD 1 ; Koshi Makita, MD 2 ; Yoichi Yamamoto, MD 3 ; Koji Shimaya, MD, PhD 3 ; Hiroshi Numao, MD, PhD 3 ; Yasuaki Tazawa, MD, PhD 1 ; Yoshiji Ogawa, MD, PhD 1 ABSTRACT Objective: Acromegaly is associated with metabolic and neoplastic complications, but successful treatment of acromegaly can sometimes result in growth hormone deficiency (GHD). Nonalcoholic fatty liver disease may develop in GHD, although there are few reports of such cases after cured acromegaly. Methods: We report the case of a 41-year-old woman with nonalcoholic steatohepatitis associated with GHD after surgical cure of acromegaly. Results: Growth hormone (GH) replacement therapy improved serum triglyceride, hyaluronic acid, and type IV collagen levels as well as liver function and quality of life. Computed tomography (CT) showed reduced volumes of both visceral and subcutaneous fat and an increased liver/ spleen CT attenuation value. Conclusion: Cured acromegalic patients should be carefully examined if GHD and associated metabolic disorders arise. Appropriate diagnosis of GHD and prompt treatment with GH replacement should ameliorate liver dysfunction and the metabolic changes associated with GHD. (AACE Clinical Case Rep. 2016;2:e194-e198) Submitted for publication April 5, 2015 Accepted for publication July 16, 2015 From the 1 Diabetes Center, Department of Endocrinology, Aomori Prefectural Central Hospital, Aomori, Japan, 2 Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Aomori, Japan, and 3 Department of Gastroenterology, Aomori Prefectural Central Hospital, Aomori, Japan. Address correspondence to Dr. Satoshi Yamagata, Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori , Japan. barracan@hotmail.com. DOI: /EP15763.CR To purchase reprints of this article, please visit: Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; CT = computed tomography; GH = growth hormone; GHD = growth hormone deficiency; HbA1c = glycated hemoglobin; IGF-1 = insulin-like growth factor 1; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis; OGTT = oral glucose tolerance test; rhgh = recombinant human GH INTRODUCTION Acromegaly is primarily caused by a pituitary growth hormone (GH)-secreting tumor, resulting in GH excess and characteristic clinical signs and symptoms (1). The disease is associated with reduced life expectancy and cardiovascular, respiratory, metabolic, and neoplastic complications (2,3). However, successful treatment of acromegaly by surgery and/or radiation can sometimes result in GH deficiency (GHD) (4). GHD in adulthood is characterized by increased fat mass, dyslipidemia, elevated risk of cardiovascular disease, and decreased quality of life (5). Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and includes both nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) (6). NASH is characterized by mixed inflammatory cell infiltration, hepatocyte ballooning, and fibrosis, in addition to the steatosis that is seen in NAFLD (6). NAFLD is caused by multiple factors, such as obesity, diabetes mellitus, and metabolic syndrome (6), and recently it was reported in patients with hypothalamic and pituitary dysfunction (7). In particular, the development of NAFLD may be associated with GHD (8). We report here a case of NASH associated with severe GHD in a surgically cured acromegalic patient. GH e194 AACE CLINICAL CASE REPORTS Vol 2 No. 3 Summer 2016

2 NASH With Severe GHD, AACE Clinical Case Rep. 2016;2(No. 3) e195 replacement therapy improved liver function, volumes of both visceral and subcutaneous fat, and quality of life. CASE REPORT A woman with a 3-year history of type 2 diabetes mellitus (T2DM) was diagnosed with acromegaly at the age of 38 years at our hospital. For 3 years following the diagnosis of diabetes, she had not gone to the hospital regularly. At diagnosis of acromegaly, her height was 163 cm, body weight 66.9 kg, and body mass index (BMI) 25.2 kg/m 2. Her glycated hemoglobin (HbA1c) was 12.3% (111 mmol/ mol). Basal GH and insulin-like growth factor 1 (IGF-1) levels were 2.4 ng/ml and 312 ng/ml (normal range for age: ng/ml), respectively. The nadir GH level following a 75 g oral glucose tolerance test (OGTT) was 2.3 ng/ml. Pituitary magnetic resonance imaging demonstrated a micro-adenoma (6 mm) in the inferior right quadrant of the pituitary gland. Knosp score was grade 0, as indicated by the absence of parasellar adenoma extension. She also had dyslipidemia, but fatty liver was not detected on abdominal ultrasonography or computed tomography (CT). Her biochemical data showed normal ranges of alanine aminotransferase (ALT, 14 IU/L) and aspartate aminotransferase (AST, 21 IU/L). Transsphenoidal surgery was performed at the age of 39 years. Her body weight was 61.0 kg (BMI, 23.0 kg/m 2 ), and her HbA1c was 7.5% (58 mmol/mol). Pathologically, the tumor was diagnosed as a pituitary adenoma with positive immunohistochemical staining for GH. After the operation, random GH and nadir GH levels following a 75-g OGTT were 0.16 and 0.09 ng/ml, respectively. The IGF-1 level decreased to 131 ng/ml, which indicated endocrinologic remission based on recent stringent criteria of random GH level <1.0 ng/ml, GH level after 75-g OGTT A B <0.4 ng/ml, and normal age-related IGF-1 level (9). Ten months after the operation, her biochemical data showed only a slight elevation of ALT (36 IU/L) but not of AST (28 IU/L) or gamma-glutamyl transpeptidase (36 IU/L). Her body weight increased to 68.5 kg (BMI, 25.8 kg/m 2 ), and her HbA1c worsened to 8.8% (73 mmol/mol). Diabetes was then treated with 2,000 mg/day of metformin and 150 mg/day of miglitol. Twenty-six months after surgery, both AST and ALT levels increased to 87 and 100 IU/L, respectively. While her body weight and HbA1c did not change, abdominal CT revealed severe fatty changes in the liver (Fig. 1). She was then referred to us for a liver biopsy. Histologic examination of a hematoxylin and eosin stained section of liver tissue showed significant steatosis (>66%) with hepatocyte ballooning, lobular inflammation, and fibrosis (Fig. 2 A), and a silver-stained section showed pericellular and bridging fibrosis (Fig. 2 B). She had neither a drinking habit nor was taking pharmacologic agents such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Hepatitis B virus surface antigen, hepatitis C virus antibody, antinuclear antibody, and antimitochondrial antibody tests were all negative. Type IV collagen levels and surrogate markers for liver fibrosis were elevated (Table 1). Based on these findings, the patient was diagnosed with NASH. Pituitary hormone levels were all within the normal range (Table 1), and the serum IGF-1 level (155 ng/ml) was also normal. However, both GH-releasing peptide (GHRP-2) test and insulin tolerance test (ITT) demonstrated a weak response of serum GH levels (peak GH level, 5.1 and 2.57 ng/ml, respectively), which was consistent with the diagnosis of GHD (10). She was treated with recombinant human GH (rhgh) injection at 0.2 mg/day and 5 units/day of insulin glargine at the same time to improve Fig. 1. Abdominal computed tomography (CT). (A) Severe fatty changes in the liver 26 months after transsphenoidal surgery. Visceral and subcutaneous fat areas were calculated to be 120 and 168 cm 2, respectively. The liver/spleen CT attenuation value was 0.57 IU. (B) Marked improvement of the liver after 4 months of GH replacement therapy. Visceral and subcutaneous fat areas were calculated to be 93 and 145 cm 2, respectively. The liver/spleen CT attenuation value was 1.1 IU.

3 e196 NASH With Severe GHD, AACE Clinical Case Rep. 2016;2(No. 3) Table 1 Laboratory Data Before and After 3 Months of GH Replacement Blood biochemistry Before After (Normal values) Hormones Before After (Normal values) Fasting glucose (mg/dl) (70-109) GH (ng/ml) ( ) HbA1c (%) ( ) IGF-1 (ng/ml) (95-240) HbA1c (mmol/mol) (27-40) ACTH (pg/ml) ( ) Fasting C-peptide (ng/ml) ( ) Cortisol (μg/dl) ( ) AST (IU/L) (13-33) LH (miu/ml) ( ) ALT (IU/L) (6-27) FSH (miu/ml) ( ) γ-gtp (IU/L) (10-47) Estradiol (ng/ml) ( ) Alkaline phosphatase (IU/L) (6-27) Prolactin (ng/ml) ( ) LDL cholesterol (mg/dl) ( ) TSH (μu/ml) ( ) HDL cholesterol (mg/dl) (40-96) Free T3 (pg/ml) ( ) Triglyceride (mg/dl) (30-149) Free T4 (ng/dl) ( ) Hyaluronic acid (ng/ml) (<50) Urinary free Type IV collagen (ng/ml) (<5) cortisol (μg/day) ( ) Abbreviations: ACTH = adrenocorticotropic hormone; ALT = alanine aminotransferase; AST = aspartate aminotransferase; FSH = follicle-stimulating hormone; GH = growth hormone; γ-gtp = gamma-glutamyl transpeptidase; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; IGF-1 = insulin-like growth factor 1; LDL = low-density lipoprotein; LH = luteinizing hormone; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone. poor glucose control. Both metformin and miglitol were discontinued because of acute enterogastritis and elevation of lactic acid. Three months after rhgh replacement, serum levels of AST and ALT dramatically improved, and her HbA1c level decreased to 7.3% (56.3 mmol/mol) (Table 1). Her body weight and HbA1c were 66.8 kg (BMI, 25.1 kg/m 2 ) and 7.3% (56 mmol/mol), respectively. IGF-1 level increased from 155 to 180 ng/ml. Serum triglyceride level decreased from 746 to 248 mg/dl without any lipid-lowering agents. Hyaluronic acid and type IV collagen levels also declined to 35 and 5.6 ng/ml, respectively (Table 1). Abdominal CT after 4 months of GH replacement therapy revealed an increase in the liver/spleen CT attenuation value from 0.57 to 1.1 IU (Fig. 1 B). Additionally, visceral A B Fig. 2. Liver biopsy samples. (A) Hematoxylin and eosin stained section showing significant steatosis (>66%) with hepatocyte ballooning, lobular inflammation, and fibrosis, which are compatible with the diagnosis of nonalcoholic steatohepatitis (original magnification, 100 ). (B) Silver-stained section showing pericellular and bridging fibrosis (original magnification, 100 ).

4 NASH With Severe GHD, AACE Clinical Case Rep. 2016;2(No. 3) e197 and subcutaneous fat areas calculated by CT decreased from 120 to 93 cm 2 and from 168 to 145 cm 2, respectively. Six months after rhgh replacement, serum levels of AST and ALT normalized (21 and 31 IU/L, respectively), while both body weight and HbA1c increased to 69.9 kg (BMI, 26.3 kg/m 2 ) and 9.1% (76 mmol/mol), respectively. Quality of life as assessed by the Adult Hypopituitarism Questionnaire was markedly improved: the psychosocial domain score decreased from 119 to 10, and the physical domain score decreased from 153 to 39 (11). DISCUSSION We have described a case of NASH in a cured acromegalic patient with severe GHD. In fact, although the prevalence of NAFLD is 6.4-fold higher in patients with adult GHD than in age-, sex-, and body mass index matched control subjects (8), to our knowledge, the present case is the first report of NASH in a patient with GHD after cured acromegaly. Increased insulin resistance with fat accumulation in the setting of hepatitis may be involved in the development of NASH with GHD, as might mitochondrial reactive oxygen species (7,8), because insulin resistance and excess adiposity are both associated with increased lipid influx into the liver and increased de novo hepatic lipogenesis. Nonutilization of lipids via mitochondrial oxidation and lipid export also may contribute to retention of lipids in the liver. Other factors, including diabetes and obesity, may have an effect on development of NASH. In fact, the prevalence of NASH also increases further to 21 to 40% in obese patients with T2DM (12). Metformin is reported to reduce hepatocellular ballooning (13). Miglitol reduced serum levels of low-density-lipoprotein cholesterol, triglyceride linked to liver lipogenesis, and subcutaneous fat (14). In this case, her body weight and HbA1c levels increased after the operation. However, her body weight and HbA1c levels did not change after treatment of diabetes, while her liver function worsened. On the other hand, after the GH replacement, serum levels of AST and ALT normalized, and the liver/spleen CT attenuation value increased. Together, GH replacement therapy improved liver function and fatty changes in the liver. In addition to possible effects of glycemic control and body weight, this fact would suggest that GHD was a major cause for NASH in this case. Severe GHD was diagnosed in the present case on the basis of GHRP-2 test and ITT results, even though serum GH and IGF-1 levels remained normal. Severe GHD is rare in surgically cured acromegalic patients (15), and Yamada et al (16) suggested that neither basal serum GH nor nadir GH levels in the OGTT are clinically useful in predicting severe GHD after surgery. Additionally, the discrepancy between GH and IGF-1 levels is sometimes found among patients with poorly controlled type 2 diabetes (17). Therefore, GHD-associated NASH might be overlooked because of normal levels of IGF-1 in such patients. Although the incidence of GHD after surgery in patients with macro-adenomas (>10 mm) is higher than that of micro-adenomas (<10 mm), isolated GHD is caused even after surgery of a GH-secreting pituitary micro-adenoma. In fact, the size of the tumor has no relation to the development of anterior pituitary hormone deficiency (16). Cured acromegalic patients even in micro-adenomas should be examined closely when they develop GHD and associated metabolic disorders. The benefits of GH replacement therapy in GHD are well recognized (18). The therapy also improves fatty changes and liver function. Takahashi et al (19) reported that GH replacement drastically ameliorated NASH and abnormal lipid profiles in a patient with GHD (20). In our case, the liver/spleen CT attenuation value increased after 4 months of GH replacement therapy, suggesting fatty liver was improved. Reduction of both visceral and subcutaneous fat areas may indicate decreases in adipocytokines derived from adipose tissue. Moreover, decreases in hyaluronic acid and type IV collagen levels may contribute to the suppression of liver fibrogenesis. GH replacement therapy would therefore ameliorate hepatic steatosis and fibrosis in NASH. CONCLUSION GH replacement therapy improved liver function, volumes of both visceral and subcutaneous fat, and quality of life in our cured acromegalic patient with NASH associated with GHD. Timely diagnosis and treatment of GHD should ameliorate liver dysfunction and the metabolic changes associated with GHD. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Melmed S. Medical progress: acromegaly. N Engl J Med. 2006;355: Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK. Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf). 1994;41: Holdaway IM, Rajasoorya RC, Gamble GD. 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