Journal of Hepatology
Volume 44, Issue 6 , Pages 1196-1207, June 2006

‘Endocrine NAFLD’ a hormonocentric perspective of nonalcoholic fatty liver disease pathogenesis☆

  • Amedeo Lonardo

      Affiliations

    • Corresponding Author InformationCorresponding author. Address: Dipartimento di Medicina Interna, Medicina III, Azienda Ospedaliero-Universitaria, Policlinico, Università degli Studi di Modena e Reggio Emilia, Via del Pozzo, 71, 41100 Modena, Italy. Tel.: +39 059 437 334; fax: +39 059 437 323.
    • ,
  • Cesare Carani
    • ,
  • Nicola Carulli
    • ,
  • Paola Loria

University of Modena and Reggio Emilia, Modena, Italy

published online 05 April 2006.

Article Outline

Abbreviations:: AdipoR, adiponectin receptor, ArKO, aromatase knock out, ASP, acylating system protein, BMI, body mass index, ERKO, estrogen receptor knock out, GLP-1, glucagon-like peptide-1, HOMA-IR, homeostasis model assessment of insulin resistance, HPA, hypothalamo–pituitary–adrenal, IL-6, interleukin-6, IR, insulin resistance, LHRH, luteinizing hormone releasing hormone, MS, metabolic syndrome, NAFLD, nonalcoholic fatty liver disease, NASH, nonalcoholic steatohepatitis, PCOS, polycystic ovary syndrome, RAAS, renin–angiotensin–aldosterone system, SHBG, sex hormone binding globulin, TG, triglycerides, TNF-alpha, tumor necrosis factor-alpha, T2DM, type 2 diabetes mellitus

 

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1. Introduction 

In 1980, Ludwig named nonalcoholic steatohepatitis (NASH) what we now consider to be one of the manifestations of the broader nonalcoholic fatty liver disease (NAFLD) spectrum. He described 20 patients whose liver biopsy specimens were characterized by striking fatty and necroinflammatory changes, Mallory bodies, fibrosis and cirrhosis. The disease was more common in women, most patients were moderately obese, and many had diabetes mellitus, gallstones and thyroid disease [1].

A quarter of a century later, we know that the pathogenesis of NAFLD is complex and multifactorial. Clues to its comprehension, however, were probably suggested by features highlighted in Ludwig's series: insulin resistance (IR) (obesity, diabetes and gallstones), fatty-inflammatory liver changes [now considered components of the metabolic syndrome (MS)] and involvement of the endocrine system (diabetes, thyroid dysfunction and prevalence of the female gender).

The link between IR, sub-clinical inflammation, MS and NAFLD is now widely accepted [2], [3], [4], [5] but a core unifying explanation for the MS is lacking. Starting from the hypothesis that many hormones and cytokines function in metabolic and immune roles and, in doing so, they control inflammation [6], [7], [8] we systematically looked for hormonal derangements associated with NAFLD.

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2. Hormonal derangements associated with NAFLD 

Data suggest an association between specific derangements of a variety of hormones and NAFLD (Fig. 1). However, much research still needs to be done to ascertain the pathogenic significance of this association.

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  • Fig. 1. 

    The ‘Endocrine NAFLD’. The figure illustrates the endocrine organs (left column) involved and respective major derangements (right column) consistently reported in NAFLD. GH, growth hormone; IGF-I, insulin-like growth factor-I; RAAS, renin angiotensin aldosterone system; ASP, acylation stimulating protein; SHBG, sex hormone binding globulin.

2.1. growth hormone (GH) 

The metabolic effects of GH include increased lipolysis, protein retention, hyperglycemia, hyperinsulinemia and stimulated IGF-I activity [9]. Untreated GH-deficiency/insufficiency and low IGF-I plasma concentrations in adults have a phenotype resembling MS [10], [11], [12]. Interestingly, long-term GH replacement in GH deficient men (who are more responsive than women to replacement therapy) reduces levels of inflammatory cardiovascular markers, central fat, and increases glucose levels without affecting lipid levels [13], [14]. These findings suggest a central origin of MS and, conceivably, of NAFLD.

Adams et al. [15] reported that—through excessive weight gain, impaired glucose tolerance, and dyslipidemia—patients with hypothalamic and/or pituitary disease are at risk of developing NAFLD and thus have a high prevalence of cirrhosis. This retrospective study might be biased by strict patient selection, only 2.3% of the 879 patients available having been studied. Furthermore, the degree of IR and levels of adipokines were not measured. However, support to Adams' findings comes from other studies, where a similar clinical course has been observed in pediatric patients submitted to hypophysis surgery [16]. GH-deficiency may link neuro-surgery and NAFLD. Indeed in a young patient with panhypopituitarism, fatty liver improved, not with hydrocortisone or levothyroxine treatment, but with GH administration [17]. Furthermore, adult GH deficiency is associated with higher transaminase levels and hepatic steatosis [18], [19]. Finally, reduced GH concentration is an independent predictor of NAFLD in adult males [20]. These data are of interest given that GH secretion in adults is strongly influenced by nutrition, adiposity, physical fitness and estrogens [21] all of which are accepted/potential therapeutic targets in NAFLD.

Also acromegaly is associated with IR, altered liver enzymes and decreased adiponectin levels, which are reversible following pituitary surgery [22].

2.2. Thyroid hormones 

Thyroid hormones are key-regulators of metabolism through modulation of transcription via nuclear receptors [23]. Human NAFLD has been compared to ‘foie gras’ [24], [25]. Interestingly, overfeeding is associated with both fatty liver and hypothyroidism in geese [26].

Liangpunsakul [27] reported the prevalence of hypothyroidism in 174 patients with NASH to be double that of 442 matched controls (15 vs. 7.2%; OR: 2.3). A major limitation of this study is that those patients who were currently on synthetic T4 replacement were diagnosed as ‘hypothyroid’. Thus, it may be objected that thyroid hormone replacement rather than hypothyroidism ‘per se’ is associated with NASH. However, observation that low circulating free thyroxine levels, albeit normal, are associated with metabolic syndrome in a Chinese population [28] lends support to Liangpunsakul's study. Studies are needed to ascertain whether thyroid hormone receptor β-specific activation can ameliorate aspects of MS in humans through improved cholesterol metabolism and body weight reduction without increasing heart rate [29].

Also hyperthyroidism may be associated with steatosis [30], presumably due to massive overflow to the liver of FFA from adipose tissue.

2.3. Adrenal hormones 

2.3.1. Cortex 

Glucococorticoids act through binding to an intracellular receptor which after nuclear translocation, results in the transcriptional activation of gluconeogenic enzymes [31], [32], [33]. Glucocorticoid excess impairs glucose tolerance primarily by causing IR at the post-receptor level: these hormones increase hepatic glucose production; blunt insulin release and impair glucose uptake by muscle and adipose tissues [34], [35], [36].

Stress-related chronic activation of hypothalamo–pituitary–adrenal (HPA) axis has been implicated in MS [37] and tissue-selective antagonism of glucocorticoid receptors may be a viable therapeutic strategy for MS [38]. Cushing's syndrome is associated with features of MS [39] displaying accumulation of fat in specific sites, omental adipose and also perhaps in the liver, most likely associated with IR. In idiopathic obesity, an excess regeneration of cortisol due to 11beta-hydroxysteroid dehydrogenase (HSD) type 1 (11HSD1) has been proposed as causing visceral fat accumulation; conversely, decreased hepatic 11HSD1 may protect the liver from glucocorticoid excess. Increased inactivation of cortisol by 5alpha- and 5beta-reductases in the liver may drive compensatory activation of the HPA axis, hence increasing adrenal androgens and central obesity. What then, is the relationship between NAFLD and HPA axis?

Altered 11HSD1 and hepatic 5alpha-reductase activity are associated with generalized, rather than central, obesity in humans [40]. Activation of 5beta-reductase in men may contribute to altered bile acid and cholesterol metabolism in NASH. NAFLD is closely correlated with a subtle, chronic activation of the HPA axis in obese, otherwise healthy, individuals [41]. A weaker point of this study, though, is the absence of any histological liver data.

White adipose tissue is an important extra-hepatic production site of angiotensinogen in humans, accounting for increased angiotensinogen in the obese [42], [43], [44]. Angiotensinogen is the precursor of the bioactive peptide angiotensin II via the action of renin and angioconverting enzyme.

Being involved in the development of both hypertension and IR, angiotensin II mediates interdependency of haemodynamic and metabolic pathways in MS [45], [46]. Essential hypertension is frequently accompanied by IR and the administration of renin–angiotensin–aldosterone system (RAAS) inhibitors is associated with a 14–34% reduction in the development of T2DM [47], [48]. Mechanisms of improved IR through RAAS inhibition include enhanced insulin and glucose delivery to tissues; facilitation of insulin signalling at the cellular level; improved insulin secretion in beta cells; increased lipid utilization in muscles; differentiation of adipocytes; down-regulation of TNF-α and PPARgamma agonism [46], [47], [49]. PPAR-γ is a nuclear receptor that influences the expression of multiple genes involved in glicolipid metabolism and thus an attractive target in the treatment of MS [49].

Losartan treatment in seven patients with both NASH and hypertension [50] resulted in a significant improvement in serum (markers of hepatic fibrosis, plasma TGF-beta1 ferritin concentration and aminotranferase levels) and hepatic histological parameters (improved necroinflammation in five patients, reduced fibrosis in four, disappearance of iron deposits in two).

A remote case-study has related acute fatty liver in late pregnancy to Addison disease [51] but its relevance to predominantly macrovesicular steatosis observed in NAFLD remains unproven.

2.3.2. Medulla—sympathetic neurotransmitters 

Phaeochromocytoma impairs glucose tolerance primarily by inhibiting insulin release [52]. Diehl's group has reported that hepatic fibrogenesis requires sympathetic neurotransmitters [53]. In addition, the sympathetic nervous system regulates liver repair by modulating the phenotypes of hepatic stellate cells and oval cells [54]. Futhermore, norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice [55] and regulates hepatic innate immune system in leptin-deficient mice [56].

Nothing is known, however, about the role, if any, of adrenal medulla hormones in human NAFLD: there is the possibility that such hormones might play a role given that they do as neurotransmitters in experimental animals.

2.4. Sex hormones 

Gender-related differences in the response of the liver to a variety of stressful events depend on the level of circulating sex hormones, hepatic expression of sex hormones receptors and pattern of GH secretion [57]. Although there is no definite evidence for a gender-dimorphism in NAFLD, clues abound. First, factors associated with fatty liver vary according to gender [58]. Recent clinical studies [59], [60], [61], [62], [63] and an impressively large and perhaps neglected collection of epidemiological surveys on NAFLD, which are summarized in Table 1 [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], share the conclusion that male subjects outnumber females. In addition, NAFLD is twice as common in postmenopausal than in premenopausal women; and hormonal replacement therapy of menopause decreases the risk of NAFLD [78]. Finally, male:female ratio declines from 6:1 in teen-agers to 1:1 in octogenarians with NAFLD [68], [79]. As suggested in Ludwig's pioneer report [1], it is possible, though, that female gender is associated with fibrosis in NAFLD [80], [81], [82].

Table 1. Prevalence of male gender in NAFLD
Author [Ref.]No. of. subjectsNAFLD no. (%)Gender (%)M/F ratioComment
Altered LFTs OverallMF
Clark JM [64]15.676a847(5.4)5.74.61.24Male prevalence significant (P<0.01)
Ruhl CE [65]5724b160 (2.8)4.31.62.68Correlation with male gender at univariate analysis (P<0.01)
Liangpunsakul S [66]4376b306 (7)NANANAMale gender independently associated with increased ALT
Ioannou GN [67]6823aNA (12.9)NANANAMale gender independently associated with increased ALT
Schwimmer JB [68]127c29 (22.83)44.46.86.52Male gender independently associated with increased ALT
Pendino GM [69]1605a49 (3.05)4.351.962.22Increased transaminase more often observed in males
Park HS [70]1594d51 (3.19)3.602.801.29Same prevalence of metabolic syndrome in boys and girls
US (bright liver)
Bellentani S [71]67b11 (16.4)NANA1.04Highly selected group from a large population sample
Akahoshi M [72]1212e79 (6.5)7.656.321.21Male prevalence nonsignificant
Omagari K [73]1264c141 (11.2)15.597.272.14Male prevalence significant (P<0.01)
Shen L [74]4009d516 (12.9)15.807.502.11Abnormal ALT male/females ratio 6:0 (P<0.001)
Bedogni G [75]511135 (26.4)NANANAMales accounted for 56% of NAFLD (P<0.01)
Hamaguchi M [76]4401c812 (18.5)25.010.02.50In the follow-up, men had higher incidence of bright liver
NMR (TG>5.5%)
Browning JD [77]2240a708 (31.6)NANA1.10Steatosis ≈two-fold increased in white men vs. women (P<0.03)

Criteria for selection of studies were the following: population studies, samples from large cohorts (>500 subjects) or intracohorts/subgroup studies published in 2000–2005 and availability of data on the prevalence of NAFLD. NA, not addressed.

aUnselected population.

bAlcohol, hepatitis B, C and iron metabolism disorders excluded.

cAlcohol, hepatitis B and C excluded.

dAlcohol and HBV excluded.

eAlcohol excluded.

2.4.1. Estrogens 

Estrogens act through nuclear-dependent/independent activation of estrogen receptors (ER) α and β and also by nonnuclear actions. These hormones control energy homeostasis, regulate mitochondrial structure/function, enhance insulin release, modulate GH secretion/action, are antioxidants, attenuate inflammation, prevent microcirculatory disturbance and apoptosis induced by several toxic agents, promote hepatic regeneration and inhibit the progression of hepatic fibrosis [21], [83], [84], [85], [86], [87], [88], [89].

Interestingly, estrogens play a gender-dimorphic key-role both in rodent models and in human MS/IR/NAFLD. In rodents, microsomal triglyceride transfer protein (which is critical in preventing steatosis given that it promotes the export of lipids from the hepatocyte) mRNA and protein expression is higher in females, and this difference is abolished by gonadectomy [90]. Ovariectomy, in its turn, is associated with increased white adipose tissue deposition, which is reversible upon estrogen administration [91]. ERα (αERKO) and aromatase knock out (ArKO) mice (the latter lacks the P450-aromatase gene and thus cannot synthesize estrogens) display IR, impaired glucose tolerance and age-dependent obesity due to decreased energy expenditure [92], [93]. Steatosis, however, has been observed in ArKO males alone [94].

Earlier literature reported a decreased metabolic rate in women after ovariectomy, reversed by estrogens [95]. Secondly, the menopausal reduction in circulating estrogens is associated with a shift in body fat from the gluteal to the abdominal region along with an increase in pro-inflammatory cytokines [96], [97]. Thirdly, Turner's syndrome, a chromosomal disorder featuring absent-to-low estrogen secretion, is associated with central obesity, often increased LFTs, which are corrected by estrogens, and with histological NAFLD in 40% of cases [98], [99], [100]. Fourthly, in women treated with tamoxifen, a drug with anti-estrogen activity, a higher risk of developing NASH is observed only in those obese/overweight women with features of metabolic syndrome [101]. Genetic determinants of estrogen serum levels might have a role in tamoxifene-associated NASH, but the disease seems to follow an indolent course [101], [102]. Finally (Fig. 2), as in the case of ArKo mice, also men with estrogen deficiency due to homozygous P450-aromatase gene inactivating mutation develop features of MS including IR and steatohepatitis, which are corrected by estrogen treatment [94], [103].

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  • Fig. 2. 

    Estrogen replacement reverses steatosis in male mice and humans with estrogen-deficiency. Liver biopsy in male ArKO (aromatase knockout) mouse (left panels) and in a male patient with congenital aromatase deficiency (right panels) before and after estrogen replacement. Modified from Hewitt KN, et al. [94] and Maffei L, et al. [103], with permission.

2.4.2. Androgens 

Normal androgen levels keep a healthy balance between lean and fat mass and affect glicolipidic metabolism. Hypoandrogenism in males and hyperandrogenism in females might thus potentially lead to NAFLD via obesity and IR.

Orchiectomized rats show marked IR, which is corrected by physiologic doses of testosterone possibly through rebalancing fat and lean mass and reducing circulating nonesterified fatty acids [104], [105]. Similarly, loss of muscle and doubling of fat mass is associated with testosterone decline in the ageing man [106]. In middle-aged men, hypoandrogenism is an early marker for disturbances in insulin and glucose metabolism that may progress to MS or frank T2DM [107]. Testosterone therapy has accordingly been proposed to treat hypogonadism and to slow/halt progression from MS to its complications [108].

Sex hormone binding globulin (SHBG) binds testosterone and prolongs its metabolic clearance. Conditions commonly associated with NAFLD (obesity, hyperinsulinemia and hypothyroidism) decrease the hepatic production of SHBG [109]. Low SHBG predicts the development of T2DM in either sex [110], [111], [112] and MS in middle aged-men [113] suggesting sub-clinical IR [114]. Studies link abnormal control of HPA axis, increased glucocorticoid production/turnover and mild hypoandrogenism in men with abdominal obesity [115], [116].

The polycystic ovary syndrome (PCOS), a leading cause of infertility, is associated with IR which predisposes the development of MS [117], [118]. Even as early as 1921 hyperandrogensim and IR were clinically recognized in the phenotype: ‘diabetes des femmes à barbe’ [119] and are featured in the endocrine profile of PCOS along with other hormonal derangements [118].

Hyperinsulinemia directly and indirectly affects the production, clearance and bioavailability of ovarian androgens and is deemed to be the causal factor of hyperandrogenism of PCOS [114]. Insulin-lowering drugs improve insulin sensitivity, hyperandrogenemia and metabolic abnormalities in many women with PCOS [118].

Hypoadiponectinemia observed in (obese and lean) women with PCOS might be the result of a variable degree of IR [120]. A cross-sectional study reported elevated ALT values in 21/70 of subjects with PCOS [121]. Given that this study failed to perform ultrasonographic, metabolic and histologic evaluations, this represents an underestimated prevalence of NAFLD.

2.5. Pancreatic hormones 

Insulin binds to its cell membrane receptors: the stimulated insulin receptor phosphorylates itself and several substrates, including members of the insulin receptor substrate family, thus initiating downstream signalling events that ultimately lead to the activation of glycogen synthase and to the translocation of glucose transporter GLUT-4 to the cell surface [122], [123], [124]. Insulin also promotes intracellular influx of FFA and apo B synthesis. While insulin's role as a key mediator of the pancreas–liver axis is widely accepted [125], the gastrointestinal hormone glucagon-like peptide 1 (GLP-1) is emerging as an essential regulator of insulin secretion and glucose homeostasis [126].

2.5.1. Insulin 

The T2DM–NAFLD relationship highlights the importance of IR in the pathogenesis and natural history of NAFLD.

T2DM is an acknowledged risk factor for NAFLD [127] and the prevalence of NAFLD in T2DM is 30%–50% [128], [129]. This is due to substrates and molecular machinery for increased hepatic adipogenesis provided by IR [130]. Once established, steatosis-associated hepatic IR further contributes to peripheral IR.

Raised GOT, GPT or GGT—surrogate markers for NAFLD—consistently predict future development of T2DM [131], [132] and increasing glycemic levels predict both NAFLD and T2DM [133], [134]. Among diabetic patients with NAFLD, 50% have steatohepatitis and 19% cirrhosis [135], [136]. Furthermore, T2DM predicts NASH in NAFLD and fibrosis in NAFLD [137], [138], [139] indicating that T2DM has has an impact on hepatic histology [78], [140].

In addition, diabetic patients have an increased mortality rate for chronic liver disease, cirrhosis and liver cancer [141]. The standardized mortality ratio for cirrhosis of diabetics is greater than that for cardiovascular disease and the incidence of HCC is increased four-fold in patients with T2DM [129], [142].

Furthermore, NAFLD increases cardiovascular risk among patients with T2DM independent of classical risk factors and this increase is only partly explained by the occurrence of MS [143] suggesting that sub-clinical hepatic inflammation is detrimental to vessels.

Finally, treatment of NAFLD with insulin-sensitizers approved for use in T2DM results in decreased liver enzymes and volume and improved hepatic histology [144], [145], [146] indicating a close pathogenetic relationship between T2DM and NAFLD, which is further supported by mitochondrial abnormalities [147], [148] and (micro) circulatory changes shared by both conditions [125], [149].

2.5.2. GLP-1 

GLP-1 is an incretin linking intestinal absorption of nutrients with substrate assimilation [126]. Its insulinotropic action accounts for the finding that glucose tolerance is more efficient through oral than intravenous route [150]. Not only is GLP-1 necessary for normal glucose tolerance and postprandial insulin release, but it also has a role in pancreatic islet growth and development [151], affects food intake and possibly glucose production/uptake, as well as islet hormone production [150]. GLP-1 is rapidly inactivated by dipeptidyl peptidase IV (DPP-IV), a circulating enzyme produced by endothelial cells.

GLP-1 receptor agonists, inhibitors of DPP-IV that increase circulating levels of endogenous GLP-1, intact and bioactive GLP-1, could all be used for the treatment of T2DM [150]. Interestingly exendin-4, a GLP-1 receptor agonist reverses hepatic steatosis and reduces IR in ob/ob mice [152]. It is unclear, however, whether exendin-4 acts more through its anorexigenic or metabolic effect.

2.6. Adipokines 

Cytokines differ from classical hormones in that they are produced by a number of tissues/cell types (including the adipocyte) and act locally in a paracrine or autocrine manner. Similar to ‘endocrine’ hormones, they are critical in regulating energetic and glico-lipidic homeostasis. Together with TNF-alpha, reviewed elsewhere [153], leptin, acylation stimulating protein (ASP) and adiponectin might be relevant in NAFLD [154], [155] and will be discussed here.

2.6.1. Leptin 

Leptin is an anorexogenic antiobesity peptide hormone that prevents lipotoxicity and regulates fibrosis during wound healing in rodents. Its physiologic effects—hunger, lowered metabolic rate, and weight regain—are more pronounced in the presence of decreased leptin concentrations during weight loss. Leptin deficiency is associated with many neuroendocrine, reproductive and immune system deficiencies [154].

Earlier works suggested that elevated serum leptin levels might promote steatosis and steatohepatitis [156], [157], [158]. However, subsequent studies found that leptin levels are independent predictors of the severity of hepatic steatosis but not of necroinflammatory liver changes [159], ruling out a direct role of leptin in the pathogenesis of human NASH [160], and finally excluding a role of serum leptin in the pathogenesis of NAFLD [161].

Opposite clinical phenotypes such as obesity and lipodystrophy share IR and NAFLD, most likely as a result of leptin deficiency [125], [162], [163]. In patients with severe lipodystrophy, leptin administration reduces liver enzymes, volume [164], [165], [166], fat content [167] and histological features of steatohepatitis but not fibrosis [168]. The finding that also menstrual abnormalities, low estradiol levels and attenuated LH response to LHRH are corrected by leptin replacement in these patients [164] further supports the pathogenic interaction between HPA derangement, estrogen deficiency and NAFLD.

Collectively, these findings suggest that, at variance with primary NAFLD, leptin plays a pathogenetic role in NAFLD secondary to lipodystrophy.

2.6.2. ASP 

ASP is a paracrine signal to increase TG synthesis in adipocytes which is produced from complement factor C3a via an interaction requiring factor B and adipsin (factor D) [154]. The rationale for studying the behaviour of this adipokine in NAFLD is supported by many facts: the stimulatory effects of ASP on TG synthesis are independent of and complementary to those of insulin [169]; insulin increases the production of ASP precursor C3 in adipocytes [170]; all factors needed for ASP production are present in the liver and the production of two of them may be increased by another cytokine, IL-6 [171], which is also increased in patients with NASH [172].

ASP levels in NAFLD are higher than those in patients with chronic hepatitis and controls and are correlated with HOMA-IR values [171]. This finding should be taken with caution given that the study was performed in men only. Nevertheless it suggests the existence of a NAFLD-specific ASP-mediated activation of lipogenic routes. The role, if any, of ASP in the progression from simple steatosis to advanced NASH remains to be ascertained.

2.6.3. Adiponectin 

Adiponectin is an adipocyte-specific, secreted protein consisting of a collagen-like and a globular domain [173]. The latter structurally resembles complement factor C1q and—although evolutionarily linked to the TNF superfamily—has biological effects, which are the opposite of those of TNF-alpha [173]. Adiponectin controls gluco-lipidic homeostasis and is induced during adipocyte differentiation, its secretion being stimulated by insulin [173]. Two receptors for adiponectin have been cloned: muscular AdipoR1, and hepatic AdipoR2 [174]. Adiponectin exerts its insulin-sensitizing effects through decreased muscle triglyceride content, AMP kinase activation and improved insulin signal transduction [175].

Adiponectin levels are controlled by genetics, smoking, dietary factors, and physical exercise [175], [176]. At variance with most adipokines, circulating adiponectin concentrations are reduced in obesity [154] and hypoadiponectinemia is also associated with MS, diabetes, cardiovascular disease [154], [175], ALT and GGT [177], [178]. However, the significance of hypadiponectinemia in NASH is more controversial.

Studies link hypoadiponectinemia with NAFLD in adults and children and, in particular, with necroinflammatory NASH [179], [180], [181], [182]. Additional studies indicate that in NASH (but not in steatosis) local effects of adiponectin are limited through two different mechanisms: decreased adiponectin mRNA and decreased hepatic adipoR2 mRNA expression [183], [184]. Furthermore, hypoadiponectinemia is present before overt diabetes and obesity appear and correlates with the severity of liver histology in NASH [185] thus indicating its pathogenic role in beta-cell dysfunction and hepatic necroinflammation and fibrosis, independent of IR, visceral fat accumulation, TNF-alpha and dietary habits [186]. Other authors though have reported results conflicting with this view [187], [188].

Adiponectin and its receptors are a promising therapeutic target in MS [175] and perhaps atherosclerosis and NAFLD. Indeed adiponectin administration lowers glicemic levels [154], protects hepatocytes from TNF-alpha induced death [189] and reduces steatosis in the ob/ob mouse [190]. Finally, the beneficial effect of rosiglitazone in human NASH may be mediated in part by the induction of adiponectin expression [191], [192].

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3. Conclusions 

Many endocrine derangements are associated with NAFLD through changes in energetic and glicolipidic homeostasis and/or a central shift in body fat distribution (Fig. 3). However, the relationship between endocrine hormones and cytokines and tissue expression of adipokines are unexplored. To this end, the liver in patients with endocrine disease and the (often sub-clinical) endocrine derangements in NAFLD should be evaluated systematically. Finally (Table 2), the endocrine perspective of NAFLD may help to understand the mechanisms through which present treatments work and help to envisage future therapeutic approaches.

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  • Fig. 3. 

    Putative relationship between derangements of hormones/cytokines (visceral) obesity and NAFLD. Hormonal derangements can be primarily responsible for the development of NAFLD via anthropometric changes and/or alterations in the homeostasis of energy and metabolism of glucose and lipids.

Table 2. Endocrine NAFLD
TreatmentMechanism of action
Diet↑ Insulin sensitivity
↑ Adiponectin
Reversal of thyroid hormone deficiency?
Physical exercise↑ GH
↑ Insulin sensitivity
GHReplacement/integration in cases with overt/sub-clinical deficiency
Improved body composition
Thyroid hormonesReplacement/integration in cases with overt/sub-clinical deficiency
↓ Metabolic efficiency
Sex steroidsImproved body composition
EstrogensModulation of GH secretion/action
Improved body composition
↑ Insulin secretion
Correction of metabolic syndrome in aromatase-deficient man
GLP-1 receptor agonists↑ Beta-cell trophism
↑ Insulin secretion
Up-regulation of plasma adiponectin/adiponectin receptors adiponectin receptors agonists↑ Insulin sensitivity
LeptinReplacement/integration in lipodistrophy
Tissue-selective antagonists of glucocorticoid receptors and synthesis↑ Insulin sensitivity
Inhibitors of renin–angiotensin–aldosterone system↑ Insulin sensitivity
↑ Adiponectin
↓ TNF-α

Interpretation of present treatment and a basis for potential future therapy.

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Acknowledgements 

The authors are indebted to Ms Jacqueline Mole for her kind assistance in revising the English language version. We also thank Azienda Ospedaliera Policlinico and AUSL of Modena which supported this study.

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☆ Partly supported by grants from MIUR Ministero Istruzione Università e Ricerca Scientifica -PRIN 2004061213_001.

PII: S0168-8278(06)00170-X

doi:10.1016/j.jhep.2006.03.005

Journal of Hepatology
Volume 44, Issue 6 , Pages 1196-1207, June 2006

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