Association of nonalcoholic fatty liver disease and growth hormone deficiency: a systematic review and meta-analysis

Abstract

An association exists between nonalcoholic fatty liver disease (NAFLD) and growth hormone (GH). Patients with growth hormone deficiency (GHD) may be more susceptible to NAFLD. The prevalence of NAFLD and nonalcoholic steatohepatitis (NASH) in GHD patients is currently unknown. Multiple databases were searched for experiments related to NAFLD (or NASH) and GHD. Screening, quality evaluation and data extraction were carried out independently by two authors. Analyses used random or fixed effects models, including NAFLD prevalence, NASH prevalence, odds ratio (OR) and 95% confidence interval (CI). We included 10 studies with a total of 782 participants. The results showed that the prevalence of NAFLD in GHD patients was 51% (95% CI: 39–63). The risk of NAFLD in GHD patients was significantly higher than that in controls (age-, sex- or body mass index-matched, without GHD) (pooled OR = 4.27, 95% CI: 1.33–13.68%, p = 0.015). The prevalence of NASH in GHD patients was 18% (95% CI: 5–31). The prevalence of NAFLD in GHD patients is significantly higher than that in the general population, especially NASH. There is a need to develop targeted strategies for the early identification, prevention, or control of NAFLD/NASH in patients with GHD.

NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) is defined as steatosis in the absence of excessive alcohol intake with or without mild inflammation of the liver (NAFL) or moderate to severe inflammation (NASH) [1, 2]. NAFLD can lead to an increase in all-cause mortality, cardiovascular-related mortality and cancer-related mortality [3]. In the United States, NASH has developed into one of the leading causes of liver cancer and is a common cause of liver transplantation [4]. The current global prevalence of NAFLD is estimated at 32.4%, with a significant upwards trend based on historical data (25.24% in 2016) [5, 6]. In addition, the prevalence of NAFLD is expected to increase significantly in the future. A recent study projected the global prevalence of NAFLD at 55.7% in 2040 [7]. The widespread prevalence of NAFLD has created an enormous economic and health burden [8].

The pathological mechanism of NAFLD has not been fully elucidated [2]. In the field of endocrinology, NAFLD is believed to be closely related to thyroid hormone, growth hormone and growth factor [4, 9]. Growth hormone has received increasing attention in recent years. Tumours in the saddle area of the pituitary gland, damage to the hypothalamic-pituitary neuroendocrine pathway, head trauma, radiotherapy or chemotherapy can cause pituitary dysfunction and lead to GHD in patients [10]. GH regulates insulin growth factor (IGF-I) and insulin production and function, regulates fat mobilization from white fat and promotes visceral lipolysis, thereby controlling hepatocyte metabolism [10, 11]. Recent studies have analysed the prevalence of NAFLD in GHD patients, but no uniform conclusion has been reached [12, 13]. Some studies showed no significant difference in the prevalence of NAFLD in GHD patients compared to controls [14, 15], but there were opposite views [16, 17]. In summary, the exact relationship between GHD and NAFLD still needs to be confirmed.

Therefore, we conducted this meta-analysis. Our primary aim was to estimate the prevalence of NAFLD and NASH in patients with GHD and to compare it with the prevalence of NAFLD in controls.

Materials and Methods

Search strategy and selection criteria

This study was a systematic review and meta-analysis according to the PRISMA statement [18]. Two authors independently searched the Embase, PubMed, Cochrane Library and Web of Science databases for studies related to NAFLD (or NASH) and GHD, and the search covered the period from database creation to February 1, 2023. The following search terms were used: “nonalcoholic fatty liver disease,” “nonalcoholic steatohepatitis,” “growth hormone,” “growth hormone deficiency,” and synonyms were found through MeSH (search strategy in the Supplementary Document).

We searched for studies that explicitly reported the diagnosis of NAFLD, NASH, and GHD and reported the prevalence of NAFLD in GHD patients (with or without controls). We excluded studies with a history of excessive alcohol consumption, comorbid liver diseases, and medications that cause long-term fat gain. If published studies described the same population, we extracted only the most complete study. Inconsistent results were resolved by discussion between the two authors or by consultation with a third senior researcher.

Data extraction

Two authors independently extracted and reviewed the following data from the included studies: first author, year, study design, country, number of people with NAFLD, NASH and GHD, diagnostic criteria for NAFLD, diagnostic criteria for NASH, diagnostic criteria for GHD, and status of hormone replacement (except GH) in GHD.

Study quality assessment

Two researchers independently evaluated the quality of the included studies, and disagreements were judged by a third researcher. The study was assessed for quality using the Agency for Healthcare Research and Quality (AHRQ) indicators and involved a total of 11 entries. A score of “0” was recorded if the entry was considered “no” or “unclear,” while a score of “1” was recorded if it was considered “yes.” High-quality studies scored 8–11 with a low risk of bias, average-quality studies scored 4–7 with a medium risk of bias, and low-quality studies scored 0–3 with a high risk of bias.

Statistical analysis

Statistical analyses were performed using Stata SE16. The prevalence of NAFLD and NASH was estimated and expressed with 95% confidence intervals (CI). Statistical heterogeneity was tested using the I² statistic, and the effects model used was judged according to I² (I² ≥ 50% random-effect model, otherwise fixed effect model). The correlation between GHD and risk of NAFLD was estimated using either a random-effect model or a fixed effect model, combining odds ratio (OR) and 95% CI. The results were tested using a two-tailed test, with p < 0.05 considered indicative of statistical significance. Sensitivity analysis was used to assess the robustness of the studies and to exclude studies with large heterogeneity. The reliability of the results of the meta-analysis was tested by publishing a bias test (Egger test).

Result

Characteristics of the included studies

We retrieved a total of 1,243 studies. After removal of duplicate studies, 759 records remained. We excluded 694 ineligible studies by screening titles and abstracts and 65 ineligible studies by reading the full text. Finally, 10 studies were included in the analysis [12-14, 16, 17, 19-23]. The flow chart is shown in Fig. 1.

Fig. 1

The flow diagram of preferred reporting items for systematic reviews and meta-analyses for study selection

All studies were cross-sectional, three of which were retrospective cross-sectional studies. The studies were published between 2008 and 2022. Five countries were included in the 10 studies: South Korea (n = 3), China (n = 2), Brazil (n = 2), Japan (n = 2) and the United Kingdom (n = 1). Diagnostic methods for NAFLD included transient elastography (TE, Fibro Scan) and magnetic resonance imaging (MRI) (n = 1), TE, Fibro Scan (n = 1), ultrasonography (n = 6), magnetic resonance spectroscopy (MRS) (n = 1), and hepatic steatosis index (HSI) (n = 1). Diagnostic methods for NASH included TE, Fibro Scan and MRI (n = 1), liver biopsy (n = 2), fibrosis 4 (FIB‐4) and NAFLD fibrosis score (NFS) (n = 1). The characteristics of the included studies are shown in Table 1.

Table 1

Characteristics of included studies in the meta-analysis

Study (year)	Country	Design	GHD		Control		Diagnostic criteria		Status of hormone replacement (except GH) in GHD
			NAFLD (M/F) Total (M/F)	NASH (M/F)	NAFLD Total	NAFLD	NASH	GHD
Fukuda et al. [19] 2008	Japan	Retrospective cross-sectional study	11 (NI) 42 (22/20)	NI	NI	ultrasound	NI	GH stimulation experiment	Sex hormone 38
Hong et al. [17] 2011	South Korea	Cross-sectional observational study	24 (24/0) 34 (34/0)	NI	13 40	ultrasound	NI	Peak GH level of <3 ng/mL	Glucocorticoid 34 Thyroxine 34 Desmopressin 34
Gardner et al. [14] 2012	England	Cross-sectional study	8 (NI) 28 (20/8)	NI	12 24	MRS	NI	Insulin tolerance test	Hydrocortisone 6
Nishizawa et al. [16] 2012	Japan	Cross-sectional study	51 (27/24) 66 (32/34)	14 (6/8)	10 83	ultrasound	liver biopsy	Insulin tolerance test, GH releasing peptide-2 test	Corticosteroid NI L-thyroxine NI Sex steroids NI
Diniz et al. [20] 2014	Brazil	Cross-sectional study	13 (NI) 22 (11/11)	NI	7 25	ultrasound	NI	Short stature, GHRHR mutation	No
Yuan et al. [21] 2019	China	Cross-sectional study	27 (19/8) 50 (36/14)	7 (6/1)	NI	ultrasound	Liver biopsy Clinical diagnostic	Clinical manifestations, Pituitary function test, Provocative tests	No
Carvalho et al. [22] 2019	Brazil	Cross-sectional study	8 (5/3) 22 (1/11)	NI	NI	Fibro Scan	NI	Insulin tolerance test, IGF-I concentration <–2SD	Steroid replacement 21
Kang et al. [23] 2021	South Korea	Cross-sectional study	54 (32/22) 76 (45/31)	26 (17/9)	23 74	Fibro Scan MRI	Fibro Scan MRI	Pituitary function test	No
Huang et al. [13] 2022	China	Retrospective cross-sectional study	47 (39/8) 93 (77/16)	4 (NI)	NI	ultrasound	FIB-4 NFS	Insulin tolerance test	Testosterone 14 Gonadotropins 33 Pulsatile GnRH 4 Estrogen and progesterone 15
Hwang et al. [12] 2022	South Korea	Retrospective cross-sectional study	38 (22/16) 103 (57/46)	NI	NI	HSI	NI	Peak GH level was below 3 ng/mL	No

GHD, Growth hormone deficiency; NAFLD, Nonalcoholic fatty liver disease; NASH, Nonalcoholic steatohepatitis; NI, Not mentioned; M, male; F, female; MRS, Magnetic resonance spectroscopy; TE, Fibro Scan, Transient elastography; MRI, Magnetic resonance imaging; HSI, Hepatic steatosis index; FIB-4, Fibrosis 4; NFS, NAFLD fibrosis score; GH, Growth hormone; No, No hormone replacement therapy or unclear

Quality assessment

The research quality evaluation results are shown in Supplementary Table 1. Evaluation results showed that 2 trials did not include a description of the period used to identify patients, 7 trials did not include a description of the assessment for quality assurance, and 4 trials did not include a statement regarding the manner in which confounding was assessed and/or controlled.

Meta-analysis

Prevalence of NAFLD in patients with GHD

Ten studies [12-14, 16, 17, 19-23] were included in the meta-analysis. After meta-analysis, the prevalence of NAFLD in GHD patients was 51% (95% CI: 39–63), and the results showed a high level of heterogeneity (I² = 88.4%, p = 0.000 for heterogeneity); the random-effects model was adopted (Fig. 2). No studies were found to have a substantial effect on the results after sensitivity analysis (Supplementary Fig. 1.1). This analysis was tested using the Egger test, and the results indicated a very low likelihood of publication bias (p = 0.555) (Supplementary Fig. 1.2).

Fig. 2

Prevalence of NAFLD in GHD patients

In addition, we performed a subgroup analysis based on sex. In seven studies [12, 13, 16, 17, 21-23], the prevalence of NAFLD was analysed in males with GHD and was found to be 60% (95% CI: 47–73). The results showed significant heterogeneity (I² = 82.5%, p = 0.000) (Fig. 3). No studies were found to have a substantial effect on the results after sensitivity analysis (Supplementary Fig. 2.1). In six studies [12, 13, 16, 21-23], female GHD patients were analysed, and the prevalence of NAFLD was 51% (95% CI: 35–67). The results showed significant heterogeneity (I² = 76.6%, p = 0.001) (Fig. 3). No studies were found to have a substantial effect on the results after sensitivity analysis (Supplementary Fig. 2.2). The results of publication bias showed that the analysis results were robust (p = 0.503) (Supplementary Fig. 2.3).

Fig. 3

Sex subgroup analysis of the prevalence of NAFLD in GHD patients

Risk of NAFLD in GHD patients compared to controls

Five studies [14, 16, 17, 20, 23] involved analysing the risk of NAFLD in patients with GHD compared to controls. The risk of NAFLD was significantly increased in GHD patients compared to controls (pooled OR = 4.27, 95% CI: 1.33–13.68, p = 0.015). The results indicated a high level of heterogeneity, and the random-effects model was adopted (I² = 86.6%, p = 0.000) (Fig. 4). No studies were found to have a substantial effect on the results after sensitivity analysis (Supplementary Fig. 3.1). The results of publication bias showed that the analysis results were robust (p = 0.440) (Supplementary Fig. 3.2).

Fig. 4

NAFLD risk ratio between GHD group and control group

Prevalence of NASH in GHD patients

Four studies [13, 16, 21, 23] involved analysing the prevalence of NASH in patients with GHD, which was 18% (95% CI: 5–31). The results indicated a high level of heterogeneity (I² = 90.8%, p = 0.000), and the random-effects model was adopted (Fig. 5). No studies were found to have a substantial effect on the results after sensitivity analysis (Supplementary Fig. 4.1). The results of publication bias showed that the analysis results were robust (p = 0.086) (Supplementary Fig. 4.2).

Fig. 5

Prevalence of NASH in patients with GHD

In addition, we performed a subgroup analysis by sex. Three studies [16, 21, 23] showed that the prevalence of NASH in male GHD patients was 24% (95% CI: 11–37). The results indicated a high level of heterogeneity (I² = 64.2%, p = 0.061) (Fig. 6). Three studies [16, 21, 23] revealed that the prevalence of NASH in female GHD patients was 19% (95% CI: 6–33). The results indicated a high level of heterogeneity (I² = 58.9%, p = 0.088) (Fig. 6). Due to the small number of included studies, we did not perform sensitivity analyses or tests for publication bias.

Fig. 6

Sex subgroup analysis of the prevalence of NASH in GHD patients

Discussion

To our knowledge, this is the first meta-analysis on the association between GHD and NAFLD. Therefore, we were unable to offer a comparison with other meta-analyses. Our study showed that the prevalence of NAFLD among GHD patients was 51%, which is considerably higher than the global prevalence of NAFLD reported in 2022 (32.4%) [5]. In addition, patients with GHD had a much higher risk of developing NAFLD than the control group (OR = 4.27). The following mechanisms may explain this: First, GH/GH receptors indirectly control hepatocyte metabolism by regulating fat mobilization in white adipose tissue [24] and have a direct effect on lipid uptake and fat formation [25]. In addition, it has been demonstrated that restoring IGF-I levels by transgenesis improves overall insulin sensitivity and reduces obesity but is not sufficient to protect against steatosis-induced liver inflammation and oxidative stress, demonstrating an independent role for GH in hepatocytes [25, 26]. Second, GH promotes IGF-I production in the liver and other target tissues in an autocrine or paracrine manner [27]. IGF-I is a central hormone in metabolic signalling, affecting glucose uptake, lipogenesis, glycogen storage and protein degradation [28]. Based on the above mechanism, GHD patients are more likely to have NAFLD because their GH and IGF-I levels are disturbed.

We analysed the differences in the prevalence of NAFLD in male and female GHD patients. The prevalence of NAFLD was 60% in male GHD patients and 51% in females. According to our meta-analysis, there may not be a significant difference between males and females. According to the global prevalence published in 2022, the prevalence of NAFLD is significantly higher in males than in females (39.7% vs. 25.6%) [5]. Our conclusion can be explained by the following considerations. The causes of GHD are numerous, and most patients have other hormone deficiencies, such as gonadotropin deficiency. Recent studies in mice have demonstrated that oestrogen deficiency can cause changes in intestinal flora, short-chain fatty acids and disturbances in lipid metabolism, leading to the development of NAFLD [29]. In addition, oestrogen can indirectly regulate NAFLD by regulating gene expression in the liver and affecting the production of IGF-I [30]. In contrast, both males and females with GHD are likely to have low levels of sex hormones. According to the literature included in our study, GHD patients in only two studies [13, 22] received replacement therapy with the appropriate sex hormones. Therefore, there may be no significant difference in the prevalence of NAFLD in patients with GHD in terms of gender.

We found that the prevalence of NASH in patients with GHD was 18%, and recent studies have shown that the prevalence of NASH in obesity and the general population is 5.4% and 1.33%, respectively [31, 32]. The high prevalence of NASH in GHD patients may suggest a poor liver-related prognosis and a greater likelihood of progression to cirrhosis or even liver cancer [33, 34]. The following mechanisms are currently available to explain the role of GH and IGF-I in NASH. GH may mediate its protective role in the pathogenesis of NASH by regulating the adipogenic pathway [35]. IGF-1 prevents the development of NASH by improving insulin sensitivity in muscle and liver, regulating mitochondrial function, oxidative stress, and inducing senescence in hepatic stellate cells [2, 11, 35]. IGF-I secretion is regulated by GH, and GHD patients have abnormal IGF-I levels and are unable to maintain liver homeostasis through these mechanisms. In conclusion, low levels of GH and IGF-I may be responsible for the higher prevalence of NASH in patients with GHD.

Our study has some clinical implications. First, the onset of GHD preceded NAFLD in the included studies, and the causal relationship is clearer. Second, patients with GHD are at significantly higher risk of NAFLD than the general population, and the significantly increased risk of NASH suggests a more serious prognosis, making early screening and early treatment necessary to control the development of NAFLD. Our study also has some limitations. First, GHD occurs for a variety of reasons, and patients may have concomitant deficiencies in other hormones, such as thyrotropin, adrenocorticotropic hormone and gonadotropins. Although some of the included studies [13, 14, 16, 17, 19, 22] performed hormone replacement therapy in addition to GH, there is still a potential impact of factors such as the effectiveness of replacement therapy and the length of treatment. Therefore, we believe that the available evidence still does not completely avoid the potential impact of other hormones on the prevalence of NAFLD and NASH in patients with GHD. We suggest that future studies should fully consider the potential impact of this factor and conduct more high-quality studies. Second, the individual studies included were focused on patients with GHD who had the disease in childhood and who may have received GH replacement therapy. However, due to the limited number of available studies and the large variation or absence of doses and duration of treatment received, we were unable to analyse the prevalence of NAFLD or NASH in such patients. Third, as not all of the diagnostic criteria for NAFLD and NASH in the included studies used the gold standard, the results of our analysis may underestimate the prevalence of NAFLD and NASH. However, this limitation again supports our conclusion that people with GHD are at much higher risk of developing NAFLD and NASH than the general population, and this must be accounted for by policy makers and healthcare professionals. Finally, the relationship between GHD and NAFLD is currently understudied, and the available studies lack reports from Western countries. The available evidence does not yet allow for a better analysis of the effect of region or ethnicity on the relationship between GHD and NAFLD. More large multicenter studies are recommended for the future, especially in Western countries.

Conclusion

Patients with GHD are at high risk of developing NAFLD, especially NASH. Therefore, there is a need for early diagnosis and intervention in patients with GHD to prevent the development and progression of NAFLD. Future large-scale, high-quality cross-sectional or cohort studies are needed to confirm our results.

Funding

This work was supported by the Zhejiang Provincial Basic Public Welfare Research Project “Study on the correlation between cognitive impairment and intestinal flora dysbiosis in patients with nonalcoholic fatty liver disease” (GF20H030035).

Author Contributions

TTK and LS conceived the study. YPG and TTK designed the search strategy. TTK and YPG performed the literature search. TTK, YPG, LS screened studies for eligibility; RZ and TTK assessed the risk of bias; TTK and RZ performed data extraction. TTK and LS interpreted the data analysis; YPG and RZ assessed the certainty of the evidence; TTK wrote the first draft of the manuscript; and all other authors revised the manuscript. JPS and JL were responsible for the final review and revision of the article. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Acknowledgements

The author would like to thank all colleagues who encouraged the writing of this study.

Disclosure

None of the authors have any potential conflicts of interest associated with this research.

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