Adenomas In The Liver

Introduction

Hepatic adenoma is a rare and benign liver tumour that has a strong association with levels of oestrogen in the body. Liver adenomas are most common in people assigned female at birth (AFAB) of reproductive age and those taking oral contraceptive pills (OCPs) containing oestrogen.¹ In recent years, the use of anabolic steroids has been associated with liver adenoma in people assigned male at birth (AMAB).² Although they are benign, hepatic adenomas have a risk of malignancy (13%) and haemorrhage. A hepatic adenoma could be one or many in number, with a single adenoma varying from 1cm - 30cm in size.⁴ When more than ten tumours are formed in the liver, they are called hepatic adenomatosis.³

Types of adenomas

There are four types of hepatocellular adenomas, categorised on their genotype and morphology.

1. Inflammatory HCA (IHCA) constitutes 40-50% of hepatocellular carcinomas. It is the most common subtype.¹ Patients with a high body mass index metabolic syndromes, such as glycogen storage disease or alcoholic liver disease, are at a higher risk of developing IHCA.
2.  HNF-1alpha inactivated mutations are the second most common subtype that constitutes 35-40% of liver adenomas. HNF-1alpha is involved in proliferation and liver development. Biallelic mutation in the TCF-1 gene encoding the HNF-1alpha transcription factor causes this type of hepatic adenoma. Patients with maturity-onset diabetes type 3 (MODY3) and patients with adenomatosis have an increased risk of having HNF-1alpha-inactivated HCA.
3. Beta-catenin-activated mutations form 15% to 20% of hepatic adenomas. These types of tumours are single, and it is rare that multiple adenomas are found in a patient. They also have a higher risk of malignant transformation.⁶ Some of the risk factors associated with this subtype are people's AMAB, exogenous intake of steroids, and glycogen storage disease.⁴
4. Unclassified types are 10% of hepatic adenomas that do not belong to any of the subtypes mentioned above. They have an increased risk of bleeding, and their underlying pathophysiology is not known.⁷

Causes of adenomas in the liver

Association with oral contraceptives and anabolic steroids

Diagnosis of liver adenoma has significantly increased with the usage of OCPs in the 1960s. On average, 90% of people AFAB aged 15 to 45 years developed hepatic adenoma due to OCPs. Among them, people AFAB above 30 years old taking OCP for more than 5 years showed a greater risk of developing liver adenoma. However, in 10% of people with AFAB, a shorter time interval of 6 to 12 months also led to hepatic adenoma. The use of these pills also impacts the growth of the tumour and causes complications such as haemorrhage a rise in mortality during pregnancy or surgical procedures.⁸

Another important cause of liver adenoma is levels of steroids in the body through internal or external sources. Anabolic androgenic steroid use is high in athletes and has been the most common cause of hepatic adenoma in people with AMAB, medications to treat paroxysmal nocturnal haemoglobinuria, Fanconi anaemia or aplastic anaemia.  Internal causes of increased anabolic steroids are polycystic ovarian syndrome and genetic disorders like Klinefelter syndrome.  Some other conditions associated with hepatocellular adenoma are:

1.  Familial adenomatous polyposis
2. Mature onset diabetes of the young (MODY)
3. Iron overload in conditions such as beta-thalassemia
4. Primary haemochromatosis

Another important risk factor is glycogen storage disease. Hepatic adenoma risk is greater in patients diagnosed with glycogen storage disease (Type 1 and II). Rarely is malignant transformation of the adenoma into hepatocellular carcinoma seen.⁹ Malignant transformation into hepatocellular carcinoma is seen 10 times more in people AMAB than people AFAB due to a causal relationship with obesity and metabolic syndromes that affect insulin resistance, increased blood pressure and lipid levels. Obesity can be an independent factor in the development of lesions in the liver. These lesions can be single or multiple in number.⁴

Genetic mutations

The genetic mutations in hepatic adenoma are seen in inflammatory hepatic adenoma, HNF-1alpha inactivated mutations and beta-catenin activation.⁶

Symptoms of adenomas in the liver

Hepatic adenomas do not cause symptoms in 50% of patients. Lesions could be found as an incidental finding during imaging for another medical problem. The symptoms may range from mild stomach aches to severe acute pain in the abdomen. Here is a list of symptoms a patient may have with hepatic adenoma.

1. Right upper quadrant or epigastric pain.
2. A mass may be felt in the abdomen.
3. Severe acute abdominal pain, hypotension, excessive sweating (diaphoresis), and increased heart rate could be suggestive of shock.

Diagnosis of adenomas in the liver

Imaging tests¹²

Hepatic adenomas are diagnosed based on the exclusion of other causes of lesions in the liver. Although there is no specific blood test to show a hepatic adenoma, it can be diagnosed with imaging so that patients do not have to undergo invasive techniques such as a biopsy. Imaging techniques that diagnose HCA are:

1. Contrast-enhanced magnetic resonance imaging - The most reliable technique to diagnose hepatic adenoma and helps to differentiate from focal nodular hyperplasia.
2. Ultrasound – Hepatic adenoma will show increased density and will be differentiated in the presence of steatosis. Low density in case of bleeding or rupture. A contrast-enhanced ultrasonography can also help in differentiation from focal nodular hyperplasia, where a spoked-wheel appearance is shown in the latter, and a washout phenomenon is shown in the former.
3. CT scan- When a hepatocellular carcinoma is suspected, a CT scan is done to provide a rapid assessment.¹²

Biopsy

A core biopsy in combination with immunohistochemistry is considered when liver adenoma is inconclusive through imaging or malignancy needs to be confirmed. A fine needle biopsy is nondiagnostic due to normal liver cells or hepatocytes in the mass.

Treatment of adenomas in the Liver

Observation and monitoring

Hepatocellular adenomas (HCAs) are managed depending on sex, age, and coexisting conditions.¹⁰  These factors determine whether a ‘wait and observe’ policy should be considered or the liver adenoma should be treated.

In people with AFAB, cessation of OCPs will cause regression of the tumour. Observation of the adenoma is advised using imaging for 6 months along with lifestyle changes. People with AFAB should be advised regarding weight loss and pregnancy. Pregnancy increases the risk of rupture and bleeding of the liver adenoma due to an increase in levels of hormones during pregnancy.12 It is advisable that people with AFAB should not get pregnant until a hepatic adenoma is resected. For adenomas found during pregnancy, resections have been successfully performed during the second trimester, given the risk of complications.¹¹ Observation and monitoring should also be considered for hepatic lesions due to anabolic steroids.⁵ Hepatocellular adenoma has also been shown to reduce in menopausal people AFAB, and they may not require resection or a routine follow-up if HCA is less than 5 cm.

Whereas, for people with AMAB with liver adenoma, it is recommended that resection of the adenoma should be done irrespective of the size of the tumour, as it has a higher risk of malignancy.¹² Resection is also recommended for tumours that are beta-catenin mutated HCA.

Hepatic adenomas that are less than 5 cm in size and not associated with beta-catenin activation, such as HNF-1alpha and inflammatory HCA, can be considered for conservative management.¹⁰ Lesions that have been stable for 12 months can be annually monitored.¹² Annual imaging with an ultrasound and serum alpha-fetoprotein (AFP) levels are monitored in patients considered for the ‘wait and watch’ method of management.

Surgery (partial hepatectomy or liver transplant)

Resection is recommended as the first line of treatment when hepatic adenoma measures above 5 cm or lesions are increasing in size to avoid the risk of malignancy and complications.

Elective surgical removal of adenoma is the gold standard procedure when treatment of patients with liver cell adenoma is considered. This can be performed as an open surgery or laparoscopically.  Another method of resection is trans arterial embolisation (TEA) or ablation from radiofrequency or microwave ablation. TEA has shown better results when treating haemodynamically unstable patients and those with an acute risk of bleeding. It is considered safe and helps reduce tumour size. Ablation of adenoma may not remove all of the tumours despite multiple sessions. These two procedures could benefit in the resection of smaller lesions in patients for whom surgery is not recommended.

Liver transplant is reserved for patients with non-well-demarcated HCA that can’t be respected, patients with metabolic syndrome such as glycogen storage disease and patients with multiple liver cells growing into malignant liver cells. Patients with multiple HCAs are considered for liver transplantation only in the presence of underlying liver diseases.¹²

Hormonal therapy

A liver adenoma is a hormone-driven adenoma. Cessation of OCPs in people with AFAB can help to regress the tumour. 

Complications of adenomas in the liver

Rupture and bleeding

Rupture and bleeding of liver lesions, also known as haemorrhage of the liver adenoma, is the most common complication. 25% of cases have reported bleeding of liver adenoma. Patients with bleeding may present with acute abdomen or right upper quadrant pain. However, patients with an intramural haemorrhage may not experience any symptoms.

In patients with liver adenomatosis, resection of every lesion is not possible; therefore, adenoma with a higher risk of bleeding should be resected.

Malignant transformation into hepatocellular carcinoma

The risk of hepatic adenoma into hepatocellular carcinoma is shown to be as high as 13%. The risk of malignancy has been greater in people with AMAB compared to people with AFAB with liver adenomatosis. However, there is no clear evidence to suggest that liver cell adenomatosis has a higher risk of malignant transformation compared to a single adenoma. 

Summary

Hepatic adenomas are rare, benign liver cell tumours that are also known as hormone-induced tumours. They are common in people AFAB of childbearing age due to the consumption of oral contraceptive pills. Anabolic steroids, glycogen storage disease, polycystic ovarian syndrome and diabetes have been strongly associated with hepatic adenoma formation. Management of liver adenoma depends on the size of the tumour, risk of malignant transformation and sex of the patient. People with AFAB are advised to avoid pregnancy due to the risk of complications. The most significant complications are haemorrhage and malignant transformation. Cessation of OCPs has been shown to reduce hepatic adenomas; however, complete resolution is achieved by surgical resection. Liver transplantation is only considered when a patient has underlying liver diseases.