eMedicine Specialties > Gastroenterology > Liver

Hepatocellular Adenoma

Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Coauthor(s): Kenneth Ingram, PAC, Assistant Professor, Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health Sciences University; Brian S Berk, MD, Assistant Professor, Department of Medicine, Dartmouth Medical School; Director of End Stage Liver Disease, Section of Gastroenterology, Dartmouth Hitchcock Medical Center
Contributor Information and Disclosures

Updated: Jan 3, 2010

Introduction

Background

Hepatocellular adenomas (HAs) are also known as hepatic adenomas or liver cell adenomas. They are rare, benign tumors of presumable epithelial origin and occur in less than 0.004% of the population at risk.

Hepatocellular adenomas occur mostly in women of childbearing age and are strongly associated with the use of oral contraceptive pills (OCPs) and other estrogens. This is reflected by a dramatic increase in the incidence of this disease since OCPs were introduced in the 1960s. For example, before the use of OCPs, no hepatic adenomas were reported at surgery at the Mayo Clinic between 1907 and 1954. Edmonson reported finding only 2 adenomas among 50,000 autopsy specimens at Los Angeles County Hospital between 1907 and 1958.1 However, in women using OCPs, adenomas were more common in patients taking OCPs containing higher doses of estrogen and with prolonged use (73.4 mo) when compared with matched controls (36.2 mo) (P <0.001), as reported by Edmonson et al.2

In a case series of 3 patients, Baum et al suggested the association between hepatic adenomas and OCPs.3 Klatskin4 and Rooks et al5 reported that the greatest risk occurs in women older than age 30 years taking OCPs for longer than 5 years, but in 10% of patients, exposure may be as short as 6-12 months. Cherqui et al also reported that adenomas are occasionally diagnosed after discontinuation of OCPs.6

Decreases in dosages and the types of hormones contained in OCPs have led to a reduction in adenoma incidence, as reported by another study by Edmonson et al.7 Rooks et al reported that in women who have never used OCPs, the annual incidence of hepatic adenoma is 1 to 1.3 per million but increases to 3.4 per 100,000 in long-term users.5

Hepatic adenomas may be single or multiple, and they may occasionally reach a size larger than 20 cm. In addition to OCPs, other conditions associated with adenomas are anabolic steroids, androgenic steroids, beta-thalassemia, tyrosinemia, type 1 diabetes mellitus, and glycogen storage diseases (types 1 and 3). However, multiple hepatic adenomas are more common in glycogen storage disease,8 with an incidence between 22% and 75% in type 1 and 25% in type 3 disease.

In addition to multiplicity of adenomas, hepatic adenomas associated with glycogen storage diseases (GSD) tend to be multiple, occur more commonly in men than women (ratio 2:1) and often develop before the age of 20 years.9,10 This should not be confused with hepatic adenomatosis, which is an equally uncommon condition in which at least 10 lesions develop at equal frequency in either sex in the absence of classic risk factors such as OCP or GSD.11

Pathophysiology

Hepatic adenomas consist of sheets of hepatocytes without bile ducts or portal areas. Kupffer cells, if present, are reduced in number and are nonfunctional. Hepatic adenomas are tan in color, smooth, well circumscribed, fleshy in appearance, and vary from 1 to 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 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 in the cytoplasm or nucleus of hepatocytes. However, this remains controversial as adenomas can occur in males and children without predisposing risk factors, and these receptors have not been identified even with the use of monoclonal antibodies.12 Rebouissou et al13 and Bioulac-Sage et al14,15 also reported that hepatic adenomas are monoclonal tumors and probably develop from an interaction between gene defects and environmental changes such as OCPs and steatosis.

Adenomas have also been associated with diabetes mellitus and 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 germline mutation of the hepatocyte nuclear factor (HNF-1 alpha) was described by Reznik et al in 2 families that had both diabetes mellitus and liver adenomatosis.16 Tumor cell analysis showed biallelic inactivation of HNF-1 alpha.

Frequency

United States

Hepatocellular adenomas are extremely rare. The annual incidence is 1 to 1.3 cases 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 longer than 9 years of OCP exposure.

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 25-30% in patients with large tumors.
  • 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 varies 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
Further Reading
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References

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Keywords

hepatocellular adenoma, HA, benign hepatoma, hepatic adenoma, liver cell adenoma, oral contraceptives, oral contraceptive pills, OCP, glycogen storage disease, GSD

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Contributor Information and Disclosures

Author

Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Coauthor(s)

Kenneth Ingram, PAC, Assistant Professor, Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health Sciences University
Disclosure: Nothing to disclose.

Brian S Berk, MD, Assistant Professor, Department of Medicine, Dartmouth Medical School; Director of End Stage Liver Disease, Section of Gastroenterology, Dartmouth Hitchcock Medical Center
Brian S Berk, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, and American Gastroenterological Association
Disclosure: Nothing to disclose.

Medical Editor

Tushar Patel, MB, ChB, Professor of Medicine, Director of Hepatology, Ohio State University Medical Center
Tushar Patel, MB, ChB is a member of the following medical societies: American Association for the Study of Liver Diseases and American Gastroenterological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

James L Achord, MD, Professor Emeritus, Department of Medicine, Division of Digestive Diseases, University of Mississippi School of Medicine
James L Achord, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Medical Association, American Society for Gastrointestinal Endoscopy, Mississippi State Medical Association, New York Academy of Sciences, Sigma Xi, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

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