Growth Hormone Deficiency and Nonalcoholic Fatty Liver Disease with Insights from Humans and Animals: Pediatric Implications

Abstract

In addition to its growth promoting role, growth hormone (GH) has a significant effect on intermediary metabolism in the well state. Despite the latter fact, pediatric practitioners are usually focused on the growth promoting aspects of GH as opposed to those metabolic. In recent years various animal and human studies (in adults mainly) and clinical reports in children have repeatedly shown the association of GH deficiency (GHD) and fatty liver disease. Based on this well-identified association, despite a lack of studies involving children, it behooves the pediatric clinician to ensure that not only patients with GHD are appropriately treated but also that adolescents even beyond the period of linear growth should be appropriately transitioned to adult GH therapy should this be appropriate.

Introduction

Growth hormone deficiency (GHD) has an estimated prevalence of close to 1:4000 patients.¹ Since short stature is a fairly common referral to pediatric practitioners, there tends to be a focus on the growth promoting aspects of growth hormone (GH) and little on the metabolic benefits before epiphyseal closure.

From as early as 1936 in the New England Journal of Medicine, Bernardo Houssay, MD theorized that the anterior pituitary gland, after the liver and pancreas, plays a key role in glucose and fat metabolism.² This key role was attributed partly to GH, which has a two phase effect on glucose metabolism. The initial phase is an insulin-like effect, which causes a decrease in glucose, and a second phase involves gluconeogenesis and fat mobilization.³

So the metabolic aspects of GH while forming a vital piece of the hormone's contribution in the well state remain important even beyond period of active linear growth. Hence, in GHD metabolic abnormalities may develop.

Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of insulin resistance, encompasses a spectrum of liver abnormalities, which include steatosis and nonalcoholic steatohepatitis (NASH), based on the presence of inflammation or fibrosis that are preceded by hepatocyte triglyceride accumulation.^4,5 The overall prevalence of NAFLD which is about 10% in children includes a prevalence of up to 17% in teenagers and 40%–70% among obese children.⁶ Although its complete natural history is not well known in pediatrics, fibrosis, cirrhosis, and liver failure may develop in some patients. It has become the most common cause of pediatric liver disease and the third most common indication for liver transplantation in the United States. Some experts believe that it will eventually become the most common indication for liver transplantation.⁷

In this review, the etiology of NAFLD/NASH development is explored along with evidence from animal and human studies showing its association with GHD. The impact of GH on NAFLD/NASH development is also presented. Based on this evidence, the implications for the pediatric clinician are also discussed.

Etiology of NASH Development

NASH is multifactorial condition based on the theory that a variety of influences, of which GH is one (a so called “hit”), results in changes at the level of the hepatocyte in genetically predisposed individuals.⁸ Currently, there are two proposed mechanisms, the so called two-hit hypothesis, which determine the progression from NAFLD to NASH. First, with insulin resistance and the metabolic syndrome, there is triglyceride accumulation that leads to steatosis (NAFL). Second, there is upregulation of cytokine mediators (inflammation) and the addition of mitochondrial reactive species (oxidative stress response), both mechanisms seek to compensate for altered lipid homeostasis. Ultimately, these events contribute to NASH development and later on possible fibrosis, the final hit.^9,10

Overview of Signal Transduction Involving GH

Knowledge of GH's mechanism of action is important to appreciate the animal models, which allow an understanding of NASH's association with GHD. The GH receptor (GHR) coded for by the human GHR gene consists of an extracellular N-terminal ligand-binding domain linked by a single transmembrane domain to a C-terminal intracellular domain. It is a member of the cytokine receptor family involved in signal transduction.^11
–13 The binding of GH to its homodimeric receptor results in a conformational change, which results in signal transduction.^14
–16 After GH binds to the GHR, Janus kinase 2 (JAK2) is recruited, and this promotes its enzymatic activity by a process of phosphorylation.¹⁷ This phosphorylation in turn leads to the phosphorylation of tyrosine residues on the intracellular portion of the GHR. The intracellular portion of the receptor serves as a docking site for several proteins collectively termed signal transducers and activators of transcription (STATs). These proteins are critically involved in the insulin-like growth factor (IGF) gene transcription mediated by GH.¹⁷ After transcription of the IGF-1 gene, IGF-1, IGF-binding protein (IGFBP-3), and the acid-labile subunit (ALS) are produced. IGF-1, IGFBP-3, and ALS exist in the so called ternary complex imparting stability of these molecules.¹⁸ Please refer to Fig. 1 for an illustration of this pathway.

FIG. 1.

GH signal transduction and certain identified pathways in the association between GHD and hepatic steatosis. GHD, growth hormone deficiency. Color images available online at www.liebertpub.com/met

The Association Between GHD and NASH: Evidence from Animal Studies

In recent years, several animal models have provided possible mechanisms for NASH development. Along the pathway of GH's action outlined before, different abnormalities provide insight into the association between GHD and NASH.

Abnormalities involving GH releasing hormone (GHRH) and its receptor GHRH-R, which result in altered GH secretory patterns, may cause glucose and lipid dysregulation by affecting insulin sensitivity.¹⁹ By extension, these abnormalities may be associated with NASH development.²⁰ The effect of GH on glucose and lipid metabolism is seen in the macrophage-specific GH receptor-null (MacGHR-KO) mouse model. In these mice and controls when exposed to a normal diet, glucose profiles and insulin tolerance test results are similar. However, when challenged with a high-fat diet, proinflammatory cytokine (interleukin [IL]-1β, tumor necrosis factor-α, IL-6, and osteopontin) expression increases. Affected mice also develop abnormal glucose tolerance profiles.²¹ This shows that the anti-inflammatory effect of GH is critical in maintaining normal glucose tolerance. So with GHD, since glucose and lipid metabolism will be affected, NASH could develop.

Hepatic steatosis is seen in liver specific, near total deletion of the GHR (GHR-L) mouse model. This causes increased circulating GH levels, insulin resistance, glucose intolerance, and increased free fatty acid levels. In this model, when hepatic GHR signaling is reconstituted via adenoviral expression of the GHR, triglyceride output is restored to normal. This illustrates that GH signaling is an essential regulator of lipid metabolism.²² In another similar mouse model as expected, insulin resistance develops. However, restoration of the liver's IGF-1 expression by a hepatic IGF-1 transgene (to isolate possible IGF-1 effects on lipid metabolism) improves insulin sensitivity and serum lipid profile. In this model, hepatic inflammation induced by steatosis still occurs. This illustrates again that GH and not IGF-1 has a direct action on lipid uptake and lipogenesis.²³

In addition to cytokines originating outside adipose tissue, adipokines are also impacted by GH; hence, both leptin and adiponectin are integral in the mechanism linking GHD with hepatic steatosis. To test the hypothesis that chronic GH administration regulates adipose tissue function in diet-induced obese mice by improving glucose tolerance, 12-week-old obese male mice received GH daily for 6 weeks. In these mice, GH administration counteracts the dietary-induced changes in the gene expression of leptin and adiponectin. Its administration also prevents oxidative stress marker increase, but causes an increase in antioxidant enzyme gene expression. These findings show that GH is important in modifying the effect of obesity-induced dysfunction, based on its effect on glucose intolerance in obese mice. It is likely that GH's effect occurs by a decrease in adipose tissue mass. So, in GHD there is likely to be increased oxidative stress and chronic visceral fat inflammation, which may be associated with insulin resistance, of which NASH is a hepatic manifestation.^24,25

Hepatic steatosis may also be caused by downstream changes from normal GHR signaling, and these changes offer insights into the association between GHD and NAFLD. Although liver-specific JAK2 deficient mice are lean, their GH levels, liver triglycerides, and plasma-free fatty acids are elevated. To provide some mechanism for GH's action, GH-deficient little mice can be crossed to JAK2 L (mice with hepatocyte-specific deletion on JAK2). Since GH is lipolytic, in the GH-deficient little mice fatty acid transporter expression increases, and fatty liver is prevented. This provides a mechanism for fatty liver development based on the effect of GH on plasma fatty acid uptake.²⁶ In another study, disruption of JAK2 in adipocytes is associated with GH resistance, reduced lipolysis, and increased body fat. Crossing mice with liver deletion of JAK2 results in JAK2 L/A mice with increased body fat and decreased lipolysis, despite increased GH levels. With the additional disruption of JAK2 in adipocytes, the increased triglyceride content, serum alanine, and aspartate transaminases almost normalizes. This again also provides a possible mechanism for the action of GH by its effect on lipid transport.²⁷

Mice with STAT5 mutations develop fatty liver, insulin resistance, and elevated GH levels.²⁸ In mice with this mutation, possible contributors to steatosis include CD36, PPARγ, and PPARγ coactivator 1α/β expression, increased free fatty acid synthesis, lipoprotein lipase, and very low-density lipoprotein receptor.²⁹

The Association Between GHD and NASH: Evidence from Human Studies

Case reports and case series involving neonates with GHD (existing usually in this age group as a part of a combined pituitary hormone deficiency) have shown that GHD may be associated with hypoglycemia and not NASH development. Despite an absence of NASH development, hepatic abnormalities, usually jaundice, may develop. GHD in the setting induces giant cell hepatitis and this is thought to impact the development of the biliary circulation.^30,31 GH administration has been shown to improve the histology of damaged hepatocytes in the neonatal period.³²

Both in children and adults, the effect of GHD on NASH has been demonstrated by case reports and several clinical epidemiologic studies. For patients with primary GH insensitivity, Laron syndrome (involving a molecular defect in human GH receptor), NAFLD, IR, and T2 DM develop.³³ While causation may not be inferred from the epidemiologic studies based on their cross-sectional design and clinical reports, when taken along with animal studies, these support the association between GHD and NASH.

One of the earliest accounts of GHD being associated with an insulin resistance type picture in pediatrics was a 17-year-old patient with panhypopituitarism who developed fatty liver. This patient was supplemented initially only with L-thyroxine and hydrocortisone. It was, however, not until GH supplementation was initiated that his fatty liver improved and hepatomegaly decreased. There was also improvement in his liver function tests, and on ultrasound, his liver's echogenicity normalized.³⁴

In another pediatric patient, a craniopharyngioma was diagnosed at age 6 years. At 7 years old, he underwent surgical resection and repeat craniotomy after tumor recurrence. He was subsequently treated by stereotactic radiosurgery for tumor recurrences at 3 and 5 years afterward. After another recurrence at 7 years, he was conservatively treated. Based on his previous nonconservative management, he developed panhypopituitarism with diabetes insipidus, thyroid stimulating hormone (TSH), gonadotropin-releasing hormone (GnRH), and adrenocorticotropic hormone (ACTH) deficiencies and was treated for these with the respective replacement therapies. At age 16 years, when he began experiencing fatigue and abdominal distension secondary to hepatomegaly, abdominal ultrasound showed increased liver echogenicity. On abdominal magnetic resonance imaging (MRI), there was hepatic steatosis. He subsequently underwent a liver biopsy that showed moderate to severe nodule formation and ballooning hepatocyte degeneration consistent with the development of nonalcoholic cirrhosis. Living donor liver transplantation (LDLT) was performed 2 years later when his condition worsened and he developed jaundice, muscle wasting, pedal edema, and hepatic encephalopathy. After his LDLT, NASH redeveloped in the setting of panhypopituitarism. Before transplantation, he was started on 1.2 mgs subcutaneous somatropin and his craniopharyngioma was stable in size. However, 2 months after LDLT, he had an increased liver triglyceride content (measured by¹ H magnetic resonance spectroscopy) to 11.5% (normal less than 5%). His IGF-1 and IGFBP-3 levels were also significantly decreased, consistent with GHD. Based on a hesitancy to increase his GH dose due to concern for further growth or residual craniopharyngioma, strict diet and exercise regimen were started. Five months after transplantation, there was fatty infiltration of the liver with an increased triglyceride content to 50%. With the progression of steatosis, the benefits of increased GH dosing were weighed against the risks. After confirmatory brain MRI showed no residual craniopharyngioma, the GH dose was increased to 5 mgs/day. Five months after, hepatic triglyceride levels fell and liver function tests normalized. Plasma triglyceride levels also normalized.³⁵ These events again provide evidence for the association between GHD and NASH.

In another patient with pan-hypopituitarism, GH therapy was started at 7 years of age in addition to L-thyroxine and hydrocortisone, but stopped at 18 years with the continuation of the other replacement therapies in addition to gonadotropin replacement treatment. At 31 years old, he was evaluated for liver dysfunction and underwent GH stimulating tests based on the suspicion for existing GHD. These tests showed undetectable GH levels, and he was restarted on GH replacement. Liver function tests improved 6 weeks after restarting GH, and by 6 months, his lipid profile and liver function tests were normal. A liver biopsy specimen at that time showed disappearance of both hepatocyte ballooning and inflammatory infiltrates, which suggests that GH plays a role in improving liver dysfunction secondary to hepatic steatosis occurring with GHD.³⁶

In a case series examining clinical associations between hypopituitarism, hypothalamic dysfunction, and NAFLD, adult patients with a diagnosis of hypopituitarism, hypothalamic obesity or craniopharyngioma, and NAFLD were identified. Under review were clinical, laboratory, and liver biopsy features in 21 patients. After hypopituitary/pituitary dysfunction was diagnosed, before the development of NAFLD, there was a median of 3 years (6.4 ± 7.5 years). By the time NAFLD was diagnosed, the majority of patients developed elevated glucose levels as well as dyslipidemia and two patients had simple steatosis. In long-term follow-up occurring over 66 ± 33 months (range 12–120), of 18 patients, 2 required liver transplantation. Six patients died with two being from liver-related causes. The conclusion was that patients who were at high risk for dyslipidemia were also at high risk for NASH development.³⁷

Low levels of IGF-1 may also have a role in advanced NAFLD development. In a Japanese study involving adults, lower IGF-1 levels were seen in patients with NAFLD when compared to controls. Patient with NASH also had lower IGF-1 standard deviation scores (SDS), when compared to patients with NAFL. The IGF-1 SDS also decreased as the amount of hepatic inflammation and fibrosis increased. This provides support for the possible role of IGF-1 (hence, GH indirectly) in the severity of NAFLD.³⁸

Conversely, serum GH levels have also been shown to be directly associated with NAFLD. In a cross sectional study exploring the association of GH levels with NAFLD, subjects with NAFLD had significantly lower serum GH levels when compared with controls. Subjects with low GH levels also had a higher prevalence of NAFLD and the metabolic syndrome.³⁹

The association of GHD and fatty liver has also been seen, based on a cross-sectional observational study, which compared control subjects and men with hypopituitarism with respect to metabolic parameters and the frequency of fatty liver diagnosed on abdominal ultrasonography. The frequency of fatty liver on abdominal ultrasonography was significantly higher in men with hypopituitarism when compared with control subjects (32.5% vs. 70%, P = 0.001). GH levels were also significantly lower in patients with hypopituitarism having a fatty liver. The presence of fatty liver was also correlated negatively with GH, after adjusting for body mass index (BMI). This shows that severe GHD in hypopituitarism is associated with severe degrees of hepatic steatosis.⁴⁰ One possible criticism of this study is that there was no histological diagnosis confirming the presence of NAFLD. However, the impact of GH replacement on NAFLD diagnosed based on histological evidence has been examined in hypopituitary patients. In patients with hypopituitarism, the prevalence of NAFLD with GHD was significantly greater than in non-GH deficient controls, (77% vs. 12%, and P < 0.001). GH replacement therapy significantly reduced liver enzyme concentrations and also improved the liver's histology. The reduction of fibrotic maker concentrations in patients with NASH not only provides evidence that GH therapy may ameliorate NASH but also that GHD is associated with its development.⁴¹

In a retrospective observational study involving hypopituitary patients with adult GHD, patients receiving GH therapy for 24 months were compared with age and sex matched patients not receiving replacement therapy. Using liver biopsy, the long-term effect of GH therapy on patients with NASH was also analyzed. The group receiving GH therapy was divided into responders and nonresponders, and factors associated with the efficacy of treatment were analyzed. Compared with controls, patients receiving GH therapy had a significant reduction in serum liver enzymes and fibrotic markers. GH therapy was also associated with improved liver enzyme concentration in patients diagnosed with NASH. In nonresponders, there was a higher proportion of patients with significant weight gain, and this was the likely factor behind their lack of improvement with GH.⁴²

The Association Between GHD and NASH: The Role of Polymorphisms

Evidence for the genetic contribution in NASH development is seen with differences in NASH progression to cirrhosis based on familial aggregation studies, in which this natural history is increased in some ethnic groups. This points also to the role of polymorphisms in its NASH's occurrence and progression.^43,44

In theory, any biological factor that affects triglyceride accumulation or hepatocyte inflammation may impact NASH initiation and disease progression. Certain polymorphisms and genes (discussed prior) have been identified as being able to impact the natural history of NASH. In addition, certain polymorphisms associated with certain genes may be impacted by GH.^45
–47 So, with GHD, there may be effects on fatty acid transport, oxidation, and hepatic lipid transport, based on the function of these gene products, and as such, NASH development can be impacted.

In the future, as the contribution of these polymorphisms to NASH progression becomes clearer, interventions may be formulated based on knowledge gained through large genome wide association studies. These large population studies may remove some of the biases associated with research involving small ethnic groups, which are currently the main source of genetic information.⁴⁴

Please refer to Table 1 for a description of the certain genes and reported polymorphisms impacting NASH development as well as the function of these gene products in the pathogenesis of NASH.

Table 1.

Certain Gene Associations and Polymorphisms Implicated in Nonalcoholic Steatohepatitis Pathogenesis, Which are Impacted by Growth Hormone

Gene	Gene product function
PPARα^a	Promotes adipocyte differentiation
	Promotes fatty acid uptake
	Impacts LPL
LPL	Partitions fat to adipocytes
LPL	Limits fatty acid flux to liver
VLDL-R	Affects export of cholesterol esters and triglycerides from liver as VLDL
IL-6^a	Proinflammatory cytokine
PPARGC1A^a	Coactivator of PPARα
PPARGC1A^a	Promotes fatty acid oxidation
GH/IGF-1^a	Affects growth, fatty acid oxidation, and LDL clearance
ADIPOQ^a	Anti-inflammatory cytokine that inhibits proinflammatory cytokines such as TNF-α and IL-6
	Insulin sensitizing action
	Induced by PPARγ agonists

Gene with reported polymorphism.

ADIPOQ, adiponectin; GH, growth hormone; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6; LPL, lipoprotein lipase; PPARα, peroxisome proliferator-activated receptor α; PPARGC1A, PPARα coactivator 1-α; TNF-α, tumor necrosis factor-α; VLDL-R, very low-density lipoprotein receptor.

Implications of the Association Between GHD and NAFLD for Pediatric Practitioners

No pediatric discussion on GHD and NASH would be complete without reference to the history of commercially available somatropin. Initially administered GH was derived from cadaveric pituitary extracts. Although GH had been available for over 25 years with a proven efficacy and safety, in 1985, reports surfaced that a 22-year-old former recipient of GH died from the effect of Creutzfeldt-Jakob disease in a “slow virus” encephalopathy. After that report surfaced, there was knowledge of two additional patients who received GH and died of a neurological disease.⁴⁸ However, even before these cases, scientists were prompted to develop new methods for producing GH based on DNA technology. In 1981, clinical trials aimed at determining the safety and efficacy of bioengineered GH began, and in 1985, the results of the trials showed that GH produced by DNA technology was equipotent in raising somatomedin C concentrations.⁴⁹

Today, although GH manufactured by recombinant DNA technology is in abundant supply, the growth promoting benefits are often highlighted over its actions on intermediary metabolism in pediatrics (mentioned prior). The attention to heightism by pediatric medical practice arguably has been shaped by the burgeoning pharmaceutical industry whose focus has been on this visual parameter.⁵⁰

Studies looking at the metabolic changes in young adults after GH cessation have shown increase in total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B.⁵¹ Also, improvements in cardiovascular risk factors and performance after 12 months of GH replacement in young adults with GHD are shown in some studies.⁵² Many of these studies have been short term, with total study duration being up to 2 years. Based on this relatively short time period for follow-up, the time to developing NAFLD as an outcome when GH therapy has been discontinued has not been evaluated, hence, there's a gap in the literature.

In a study looking at the association between the manifestations and management of GHD during childhood/adolescence and the clinical features in adulthood where the mean duration of interruption was 4.4 years, in nonidiopathic GHD (IGHD) patients, a longer duration of interruption was associated with a worse lipid profile (P < 0.0001). There was no report on NASH development. Based on this, it is recommended that testing for adult GHD should occur soon after the cessation of linear growth and due consideration should be given to GH supplementation if appropriate.⁵³ This point is of importance since adolescence is often a time during which GH therapy may be interrupted secondary to waning patient compliance, and the adverse lipid profile again may worsen the cardiovascular risk as described earlier.

Despite this lack of data on the natural history of NAFLD development after the discontinuation of GH therapy in young adults, based on the information discussed in this review, there are enough data in animals and humans showing the association of NAFLD and GHD.

In conclusion, while the exact duration of time by which pediatric patients with severe GHD will develop NASH in addition to its complications is presently unknown, pediatric practitioners should stress to patients and families the importance of adherence to GH therapy. It is also important for practitioners to transition these patients to adult dosing of GH, should this be indicated after the appropriate testing, since the lack of GH supplementation may not only affect quality of life but also impact morbidity.^54,55

Footnotes

Acknowledgments

The author thanks Naomi Tokar, BS, MT (ASCP) for the illustration used in and Dr. Robert Hoffman for his critical review of this article.

Author Disclosure Statement

No conflicting financial interests exist.

References

Lindsay

, Feldkamp

, Harris

, et al. Utah Growth Study: Growth standards and the prevalence of growth hormone deficiency. J Pediatr, 1994; 125:29–35.

Houssay

. Carbohydrate metabolism. N Engl J Med, 1936; 214:971–986.

Melmed

. Medical progress: Acromegaly. N Engl J Med, 2006; 355:2558–2573.

Huang

, Barlow

, Quiros-Tejeira

, et al. Childhood obesity for pediatric gastroenterologists. J Pediatr Gastr Nutr, 2013; 56:99–109.

Lavine

, Schwimmer

. Non-alcoholic fatty liver disease in the pediatric population. Clin Liver Dis, 2004; 8:549–558, viii-ix.

Clemente

, Mandato

, Poeta

, et al. Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions. World J Gastroenterol, 2016; 22:8078–8093.

Charlton

, Burns

, Pedersen

, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology, 2011; 141:1249–1253.

Takahashi

. The role of growth hormone and insulin-like growth factor-I in the liver. Int J Mol Sci, 2017; 18:E1447.

Day

, James

OFW

. Steatohepatitis: A tale of two “hits”?. Gastroenterology, 1998; 114:842–845.

10.

Jou

, Choi

, Diehl

. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis, 2008; 28:370–379.

11.

Campbell

. Growth-hormone signal transduction. J Pediatr, 1997; 131:S42–S44.

12.

Kelly

, Ali

, Rozakis

, et al. The growth hormone/prolactin receptor family. Recent Prog Horm Res, 1993; 48:123–164.

13.

Leung

, Spencer

, Cachianes

, et al. Growth hormone receptor and serum binding protein: Purification, cloning and expression. Nature, 1987; 330:537–543.

14.

Hansen

, Wang

, Kopchick

, et al. Identification of tyrosine residues in the intracellular domain of the growth hormone receptor required for transcriptional signaling and Stat5 activation. J Biol Chem, 1996; 271:12669–12673.

15.

Meyer

, Campbell

, Cochran

, et al. Growth hormone induces a DNA binding factor related to the interferon-stimulated 91-kDa transcription factor. J Biol Chem, 1994; 269:4701–4704.

16.

Wood

, Sliva

, Lobie

, et al. Mediation of growth hormone-dependent transcriptional activation by mammary gland factor/Stat 5. J Biol Chem, 1995; 270:9448–9453.

17.

Smit

, Meyer

, Billestrup

, et al. The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3, and 5 by GH. Mol Endocrinol, 1996; 10:519–533.

18.

Domene

, Hwa

, Jasper

, et al. Acid-labile subunit (ALS) deficiency. Best Pract Res Clin Endocrinol Metab, 2011; 25:101–113.

19.

Gahete

, Luque

, Castano

. Models of GH deficiency in animal studies. Best Pract Res Clin Endocrinol Metab, 2016; 30:693–704.

20.

Fan

, Fang

, Tajima

, et al. Evolution of hepatic steatosis to fibrosis and adenoma formation in liver-specific growth hormone receptor knockout mice. Front Endocrinol, 2014; 5:218.

21.

, Kumar

, Sun

, et al. Targeted deletion of growth hormone (GH) receptor in macrophage reveals novel osteopontin-mediated effects of GH on glucose homeostasis and insulin sensitivity in diet-induced obesity. J Biol Chem, 2013; 288:15725–15735.

22.

Fan

, Menon

, Cohen

, et al. Liver-specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid metabolism. J Biol Chem, 2009; 284:19937–19944.

23.

Liu

, Cordoba-Chacon

, Kineman

, et al. Growth hormone control of hepatic lipid metabolism. Diabetes, 2016; 65:3598–3609.

24.

Fukushima

, Okamoto

, Katsumata

, et al. Growth hormone ameliorates adipose dysfunction during oxidative stress and inflammation and improves glucose tolerance in obese mice. Horm Metab Res, 2014; 46:656–662.

25.

Furukawa

, Fujita

, Shimabukuro

, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest, 2004; 114:1752–1761.

26.

Sos

, Harris

, Nordstrom

, et al. Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2. J Clin Invest, 2011; 121:1412–1423.

27.

Nordstrom

, Tran

, Sos

, et al. Disruption of JAK2 in adipocytes impairs lipolysis and improves fatty liver in mice with elevated GH. Mol Endocrinol, 2013; 27:1333–1342.

28.

Cui

, Hosui

, Sun

, et al. Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration. Hepatology, 2007; 46:504–513.

29.

Barclay

, Nelson

, Ishikawa

, et al. GH-dependent STAT5 signaling plays an important role in hepatic lipid metabolism. Endocrinology, 2011; 152:181–192.

30.

Drop

SLS

, Colle

, Guyda

. Hyperbilirubinemia and idiopathic hypopituitarism in the newborn period. Acta Paediatr Scand, 1979; 68:277–280.

31.

Copeland

, Franks

, Ramamurthy

. Neonatal hyperbilirubinemia and hypoglycemia in congenital hypopituitarism. Clin Pediatr, 1981; 20:523–526.

32.

Wada

, Kobayashi

, Moriyama

, et al. A case of an infant with congenital combined pituitary hormone deficiency and normalized liver histology of infantile cholestasis after hormone replacement therapy. Clin Pediatr Endocrinol, 2017; 26:251–257.

33.

Laron

. Lessons from 50 years of study of laron syndrome. Endocr Pract, 2015; 21:1395–1402.

34.

Takano

, Kanzaki

, Sato

, et al. Effect of growth hormone on fatty liver in panhypopituitarism. Arch Dis Child, 1997; 76:537–538.

35.

Gilliland

, Dufour

, Shulman

, et al. Resolution of non-alcoholic steatohepatitis after growth hormone replacement in a pediatric liver transplant patient with panhypopituitarism. Pediatr Transplant, 2016; 20:1157–1163.

36.

Takahashi

, Iida

, Takahashi

, et al. Growth hormone reverses nonalcoholic steatohepatitis in a patient with adult growth hormone deficiency. Gastroenterology, 2007; 132:938–943.

37.

Adams

, Feldstein

, Lindor

, et al. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology, 2004; 39:909–914.

38.

Sumida

, Yonei

, Tanaka

, et al. Lower levels of insulin-like growth factor-1 standard deviation score are associated with histological severity of non-alcoholic fatty liver disease. Hepatol Res, 2015; 45:771–781.

39.

, Xu

, Yu

, et al. Association between serum growth hormone levels and nonalcoholic fatty liver disease: A cross-sectional study. PLoS One, 2012; 7:e44136.

40.

Hong

, Kim

, et al. Metabolic parameters and nonalcoholic fatty liver disease in hypopituitary men. Horm Metab Res, 2011; 43:48–54.

41.

Nishizawa

, Iguchi

, Murawaki

, et al. Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy. Eur J Endocrinol, 2012; 167:67–74.

42.

Matsumoto

, Fukuoka

, Iguchi

, et al. Long-term effects of growth hormone replacement therapy on liver function in adult patients with growth hormone deficiency. Growth Horm IGF Res, 2014; 24:174–179.

43.

Nahon

, Zucman-Rossi

. Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis. J Hepatol, 2012; 57:663–674.

44.

Oliveira

, Stefano

. Genetic polymorphisms and oxidative stress in non-alcoholic steatohepatitis (NASH): A mini review. Clin Res Hepatol Gastroenterol, 2015; 39 Suppl 1:S35–S40.

45.

Kallwitz

, McLachlan

, Cotler

. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease. World J Gastroenterol, 2008; 14:22–28.

46.

Marra

, Bertolani

. Adipokines in liver diseases. Hepatology, 2009; 50:957–969.

47.

Naik

, Kosir

, Rozman

. Genomic aspects of NAFLD pathogenesis. Genomics, 2013; 102:84–95.

48.

Degenerative neurologic disease in patients formerly treated with human growth hormone. Report of the Committee on Growth Hormone Use of the Lawson Wilkins Pediatric Endocrine Society, May 1985. J Pediatr, 1985; 107:10–12.

49.

Kaplan

, Underwood

, August

, et al. Clinical studies with recombinant-DNA-derived methionyl human growth hormone in growth hormone deficient children. Lancet, 1986; 1:697–700.

50.

Meideros

. Heightened Expectations: The Rise of the Human Growth Hormone Industry in America. 2nd ed. Tuscaloosa: University of Alabama Press. 2016.

51.

Johannsson

, Albertsson-Wikland

, Bengtsson

. Discontinuation of growth hormone (GH) treatment: Metabolic effects in GH-deficient and GH-sufficient adolescent patients compared with control subjects. Swedish Study Group for Growth Hormone Treatment in Children. J Clin Endocrinol Metab, 1999; 84:4516–4524.

52.

Colao

, di Somma

, Cuocolo

, et al. Improved cardiovascular risk factors and cardiac performance after 12 months of growth hormone (GH) replacement in young adult patients with GH deficiency. J Clin Endocrinol Metab, 2001; 86:1874–1881.

53.

Koltowska-Haggstrom

, Geffner

, Jonsson

, et al. Discontinuation of growth hormone (GH) treatment during the transition phase is an important factor determining the phenotype of young adults with nonidiopathic childhood-onset GH deficiency. J Clin Endocrinol Metab, 2010; 95:2646–2654.

54.

Herschbach

, Henrich

, Strasburger

, et al. Development and psychometric properties of a disease-specific quality of life questionnaire for adult patients with growth hormone deficiency. Eur J Endocrinol, 2001; 145:255–265.

55.

McKenna

, Doward

, Alonso

, et al. The QoL-AGHDA: An instrument for the assessment of quality of life in adults with growth hormone deficiency. Qual Life Res, 1999; 8:373–383.