**3. Risk factors**

The most important risk factor seems to be the use of oral contraceptives. Hepatic adenoma used to be exceptionally rare before the age of oral contraceptives, but after these became popular as a contraceptive solution, more and more cases of HA were reported. In women who were long-time users of oral contraceptives, the incidence was 1 in 30–40,000, whereas in women who have never used oral contraceptives, the incidence was 1 in 1 million, which proves a strong link between these two. Hepatic adenomas in women with prolonged use of oral contraceptives tend to be more numerous, more voluminous, and with a higher risk of spontaneous rupture and bleeding [9–12].

Another important risk factor that became even more important than other known risk factors, such as glycogen storage diseases and diabetes mellitus type 2 alone, is the metabolic syndrome. Obesity is more and more prevalent in the general population, and thus, it became a more important risk factor in this pathology. Weight loss should be considered as the first therapeutic option in the management of HA in obese patients [13]. A recent study has proved that bariatric-induced weight loss results in significant regression of HA in severely obese women, which emphasizes the role of overweight in HA pathophysiology [14]. Even more so, patients with metabolic syndrome and hepatic adenomas seem to be associated with a higher rate of malignization [8]. The association between oral contraceptive use and metabolic syndrome on one hand and HA on the other tends to prove an important hormonal sensitivity of the tumor (obesity is associated with higher estrogen levels), and this is supported by the fact that adenomas may stop their evolution or even regress as a result of oral contraceptive cessation [15]. In spite of this, immunohistological studies failed to prove the direct effect of these hormones via steroid receptors in normal and adenomatous hepatic tissue, and so the mechanism by which high estrogen levels may cause an adenomatous transformation is still incompletely understood [16]. As a hyperestrogenic state, pregnancy has also been

**121**

**Figure 1.**

*Resected specimen after mesohepatectomy for a large IHA.*

*Challenging Issues in Hepatic Adenoma DOI: http://dx.doi.org/10.5772/intechopen.87993*

(β catenin-1 gene) [20].

**4. Pathology**

be present in HA.

incriminated as a risk factor, and there have been many reports of ruptured HAs in pregnant patients with a very high mortality for both mother and child [16–19]. Apart from estrogen, use of anabolic androgens has also been linked to a higher

Hepatic adenoma has also been linked to glycogen storage disease and hepatocyte nuclear factor 1A maturity onset diabetes of the young (HNF1A MODY). The incidence is 51% in patients with type I glycogen storage disease and 25% in those with type III glycogen storage disease (GSD) [8]. Hepatic adenoma in GSD occurs before the age of 20 years, is more common in males, and is typically multiple. Dietary therapy and correction of insulin, glucose, and glucagon levels have been proved to lead to regression of adenomas [15]. The mechanism by which GSD is

Finally, there seems to be a genetic predisposition, and nowadays, HAs are believed to result from specific genetic mutations involving TCF1 (transcription factor 1 gene), IL6ST (interleukin 6 signal transducer gene), and CTNNB1

HAs present as solitary lesions in most cases (70–80%), although multiple adenomas can exist of variable sizes. HAs usually occur in the right hepatic lobe. Macroscopically, HAs present as a smooth, tan-colored lesion, well demarcated from the normal hepatic tissue in spite of not having a capsule, often with areas of hemorrhage and necrosis (**Figure 1**). Large blood vessels that surround it are the source of hemorrhage in a complicated adenoma. The lack of a fibrous capsule means that the bleeding can extend into the liver parenchyma unrestricted. Microscopically, adenomas are made of adenoma cells, which are typically larger than normal hepatocytes and contain glycogen and lipid inclusions (**Figures 2** and **3**). The nuclei are small and regular and mitoses are infrequent. The normal architecture of hepatic tissue is severely disrupted, with no portal tracts of bile ducts, while adenoma cells are disposed in trabeculae interspersed with arteries and thin-walled blood vessels and sinusoids. The absence of bile ducts is a notable feature that helps in the differential diagnosis of HA with nonneoplastic liver tissue and focal nodular hyperplasia. Kupffer cells may only rarely

incidence in HAs, which is being proved not only in body builders but also in patients treated with steroids for Fanconi syndrome, aplastic anemia, etc. Cessation

of steroid use has also been linked to regression in size of HAs [15].

involved in the development of HA is also unknown.

#### *Challenging Issues in Hepatic Adenoma DOI: http://dx.doi.org/10.5772/intechopen.87993*

incriminated as a risk factor, and there have been many reports of ruptured HAs in pregnant patients with a very high mortality for both mother and child [16–19].

Apart from estrogen, use of anabolic androgens has also been linked to a higher incidence in HAs, which is being proved not only in body builders but also in patients treated with steroids for Fanconi syndrome, aplastic anemia, etc. Cessation of steroid use has also been linked to regression in size of HAs [15].

Hepatic adenoma has also been linked to glycogen storage disease and hepatocyte nuclear factor 1A maturity onset diabetes of the young (HNF1A MODY). The incidence is 51% in patients with type I glycogen storage disease and 25% in those with type III glycogen storage disease (GSD) [8]. Hepatic adenoma in GSD occurs before the age of 20 years, is more common in males, and is typically multiple. Dietary therapy and correction of insulin, glucose, and glucagon levels have been proved to lead to regression of adenomas [15]. The mechanism by which GSD is involved in the development of HA is also unknown.

Finally, there seems to be a genetic predisposition, and nowadays, HAs are believed to result from specific genetic mutations involving TCF1 (transcription factor 1 gene), IL6ST (interleukin 6 signal transducer gene), and CTNNB1 (β catenin-1 gene) [20].
