Introduction
Background
Hepatocellular adenomas (HA) are uncommon benign liver tumors that occur mostly in women of childbearing age and are associated primarily with the use of birth control pills.
Since the 1960s, a dramatic increase in the incidence of the disease has occurred; this increase is attributed to the advent of oral contraceptive pills (OCPs). In 1958, Edmonson reported finding only 2 adenomas among 50,000 autopsy specimens. In a case series of 3 patients, Baum (1973) suggested the association between hepatic adenomas and OCPs. Klatskin (1977) and Rooks (1979) later showed that patients taking higher potency hormones, patients of advanced age, or patients with prolonged duration of use have a significantly increased risk of developing hepatocellular adenomas. Currently, decreases in dosages and the types of hormones contained in OCPs have led to a reduction in incidence.
Other risk factors include the use of androgen steroid therapy and the presence of type 1 glycogen storage disease.
Pathophysiology
Hepatocellular adenomas consist of sheets of hepatocytes without bile ducts or portal areas. Kupffer cells, if present, are reduced in number and are nonfunctional. Hepatocellular adenomas are tan in color, smooth, well circumscribed, fleshy in appearance, and vary from 1-30 cm in size. They have large blood vessels on the surface, and the lesions may outgrow their arterial blood supply, causing necrosis within the lesions. A fibrous capsule may be present or absent; if absent, this may predispose to intrahepatic or extrahepatic hemorrhage. Most hepatocellular adenomas present as solitary lesions in the lobe of the liver; however, tumors do occur in both the right lobe and the left lobe, and up to 20% of cases involve multiple lesions.
The pathogenesis is thought to be related to a generalized vascular ectasia that develops due to exposure of the vasculature of the liver to oral contraceptives and related synthetic steroids. Estrogen may exert an influence via estrogen receptors on hepatocytes. However, this remains controversial. Adenomas also have been associated with diabetes mellitus and glycogen storage disease (GSD), leading to speculation as to whether imbalances between insulin and glucagon also play a role.
Patients with GSD are more likely to present with multiple lesions. Lesions associated with GSD often appear in younger patients (early third decade of life) and have a male-to-female ratio of 2:1. In this group, the abnormal amounts of stored glycogen may have some effect, perhaps oncogene stimulation. Insulin and glucagon appear to play a larger role because GSD-related adenomas have been reported to seemingly disappear with dietary manipulation.
A distinct pathologic entity known as hepatic adenomatosis has been identified. Although overlap is possible, adenomatosis is generally defined as the presence of more than 10 adenomas within the liver in the absence of steroid use or by persistence after steroid withdrawal. Adenomatosis affects both men and women and is associated with elevations of alkaline phosphatase.
Frequency
United States
The annual incidence of hepatic adenoma is 1 case per 1 million persons per year. However, 3-4 cases per 100,000 people per year occur among women who have had exposure to estrogen-containing OCPs. A 5-fold increased risk exists with 5-7 years of OCP exposure, and a 25-fold increased risk exists with greater than 9 years of OCP exposure. Associations also exist with diabetes mellitus; pregnancy; the use of anabolic steroids by men; and type 1 or 3 GSD, galactosemia, beta-thalassemia, or tyrosinemia.
Mortality/Morbidity
- From 20-25% of cases involve right upper quadrant pain, and 30-40% involve hemorrhage (one third within mass, two thirds into the abdomen).
- The mortality rate associated with an acute hemorrhage into the peritoneum may be as high as 20%.
- The risk of malignant transformation is not completely known and may be as high as 13% based on small studies.
- Pregnancy has been associated with hepatic adenoma, and rupture of the adenoma during pregnancy has been associated with high rates of maternal and fetal mortality.
Race
No racial predisposition exists.
Sex
Approximately 90% of patients are female.
Age
Most patients are aged 15-45 years.
Clinical
History
The clinical presentation of patients with hepatocellular adenoma can vary widely. Salient features of the history and physical examination may include the following:
- Pain in the right upper quadrant or epigastric region is common, occurring in 25-50% of patients with hepatocellular adenomas.
- Lesions may be noticed by patients as a palpable mass. Lesions may also be discovered incidentally during an abdominal imaging study for an unrelated reason.
- History of birth control or anabolic steroid use should be elicited in patients with suspected hepatocellular adenomas.
- Patients may also present with severe, acute abdominal pain with bleeding into the abdomen, which results in signs of shock (eg, hypotension, tachycardia, diaphoresis).
- Hemoperitoneum occurs more frequently if the patient is taking a high-dose OCP, is actively menstruating or pregnant, or is within 6 weeks postpartum. Location of the lesion also is important, with those near the surface of the liver more prone to causing hemoperitoneum.
Physical
The physical examination findings are often nonspecific. Patients may be asymptomatic, or they may appear ill, with pallor and abdominal distress.
- Palpable tender or nontender mass in the right hypochondrium
- Findings consistent with hemorrhage
- Vital signs
- Tachycardia
- Hypotension
- Orthostasis
- Head, ears, eyes, nose, and throat (HEENT) examination
- Anicteric sclera (Jaundice has been reported due to compression of the biliary tree by the tumor.)
- Possible pale conjunctiva, if hemorrhage has occurred
- Cardiovascular findings - Tachycardia if actively bleeding
- Abdominal findings
- Possible right hypochondrial mass with or without tenderness
- Possible hepatomegaly
- Possible fluid wave in cases of hemoperitoneum
- Possible peritoneal signs, including guarding or rebound in cases of tumor rupture
- Skin findings - Possible Grey-Turner sign or Cullen sign in cases of hemoperitoneum
- Examination findings of the neck, chest, and extremities - Unremarkable
- Neurologic examination findings - Unremarkable
Causes
- Oral contraceptive medications containing mestranol
- Anabolic steroids
More on Hepatocellular Adenoma |
 Overview: Hepatocellular Adenoma |
| Differential Diagnoses & Workup: Hepatocellular Adenoma |
| Treatment & Medication: Hepatocellular Adenoma |
| Follow-up: Hepatocellular Adenoma |
| References |
| Next Page » |
References
Baum JK, Bookstein JJ, Holtz F. Possible association between benign hepatomas and oral contraceptives. Lancet. Oct 27 1973;2(7835):926-9. [Medline].
De Carlis L, Pirotta V, Rondinara GF. Hepatic adenoma and focal nodular hyperplasia: diagnosis and criteria for treatment. Liver Transpl Surg. Mar 1997;3(2):160-5. [Medline].
Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology. Aug 1977;DA - 19770825(2):386-94. [Medline].
Lee RG. Neoplasms and other masses: Benign hepatocellular tumors. In: Diagnostic Liver Pathology. St. Louis, Mo:. Mosby-Yearbook;1994:422-430.
Mergo PJ, Ros PR. Benign lesions of the liver. Radiol Clin North Am. Mar 1998;36(2):319-31. [Medline].
Mortele KJ, Ros PR. Benign liver neoplasms. Clin Liver Dis. Feb 2002;6(1):119-45.
Reddy KR, Schiff ER. Approach to a liver mass. Semin Liver Dis. Nov 1993;13(4):423-35. [Medline].
Rooks JB, Ory HW, Ishak KG. Epidemiology of hepatocellular adenoma. The role of oral contraceptive use. JAMA. Aug 17 1979;242(7):644-8. [Medline].
Weimann A, Ringe B, Klempnauer J. Benign liver tumors: differential diagnosis and indications for surgery. World J Surg. Nov-Dec 1997;21(9):983-90; discussion 990-1. [Medline].
Further Reading
Keywords
HA, benign hepatoma, hepatic adenoma, liver cell adenoma, oral contraceptives, oral contraceptive pills, OCP, glycogen storage disease, GSD
