Genetic and Radiological Screening of First Degree Family Members of Patients with Familial Liver Adenomatosis

Liver adenomatosis (LA) is a rare disease consisting of multiple adenomas in
the liver. Originally, Flejou et al. defined LA as the presence of at least 10
adenomas in the absence of glycogen storage disease and androgen steroid use,
and suggested a normal distribution between men and women. However, recent
studies have shown that this number of adenomas is rather arbitrarily and not
an evidence based parameter for LA diagnosis. Instead, more focus has come on
the genetic abnormalities found in these patients. More specifically, germline
mutations in hepatocyte nuclear factor 1 alpha(HNF-1alpha) and CYP1B1 are
associated with familial liver adenomatosis whereas a mutation in the *-catenin
gene is associated with simple liver adenomas. It has also been found that
liver adenomatosis is associated with the presence of steatosis.

To determine if LA is a familial disease.
To identify germline mutations in HNF-1 alpha, ß-catenin and CYP1B1 genes in LA
patients.
To screen first degree relatives of patients diagnosed with liver adenomatosis
for the presence of liver adenomas and liver adenomatosis related germline
mutations in HNF-1 alpha, ß-catenin and CYP1B1.
To investigate the association between LA and steatosis using MR-spectroscopy

Patients diagnosed with LA, and their first line relatives are asked to
participate in our study. After obtaining informed consent, an ultrasound and
an MRI are performed for the detection of adenomas and an MRS for steatosis
detection. Blood samples are drawn for assessment of liver enzymes, hepatic
synthesis function, hepatic tumor marker for hepatocellular carcinoma
(alpha-foetoprotein) and determination of features of the metabolic syndrome
associated with steatosis (Insulin resistance and lipid spectrum). Genetic
analysis is performed on our 10 index patients (CYP-1B1, HNF-1 alpha, ß
catenin); if germline mutations are present, their first line relatives will
also be screened for these mutations. Furthermore, first line relatives
diagnosed with adenomas on imaging studies will also undergo genetic analysis.

Study subjects will undergo a venous blood sample for gene, liver and metabolic
abnormalities which poses no risk for the patient. An ultrasound, MRI and MRS
will be performed for possible detection of adenomas and assessment of the
steatosis degree. An MRI will be performed using an intravenous contrast agent
(Primovist®). There is a very small risk of an allergic reaction after contrast
administration. Other than that, these are all non-invasive radiological
methods which are not associated with any substantial risk.
Possible detection of adenomas or a genetic defect in designated genes in the
relatives of LA patients could pose a psychological burden. Presumed healthy
subjects could be diagnosed with a possible liver disease, adenomas or possible
other (unlikely) hepatic lesions, by the radiological examinations. This could
eventually even lead to hospitalization and treatment of these lesions. The
department of clinical genetics has a specialized clinical psychologist for
this purpose.
On the other hand, the detection of the adenomas in an early phase could
prevent possible malignant degeneration of the adenomas, or even
life-threatening bleeding from the adenomas, by surgical or radiological
intervention and close follow-up; a substantial benefit of this study. The
department of clinical genetics can offer specialised psychosocial assistance
if healthy subjects are diagnosed with a disease.