Area Abbonati
doi   10.1700/445.5273

Fulminant liver failure in a patient affected by polycystic liver disease and liver metastases from breast carcinoma

Giovanni Maria Fadda, Davide Adriano Santeufemia, Paolo Cossu-Rocca, Gianfranco Bardino, Salvatore Costantino, Giovanni Sanna, Maria Giuseppa Sarobba, Antonio Farris
1Oncologia Medica, 2Istituto di Anatomia Patologica, and 3Istituto di Scienze Radiologiche,
University of Sassari, Sassari, Italy

Key words:  polycystic liver disease, fulminant liver failure, metastases, breast.


Background. Polycystic liver disease (PLD) is a rare, congenital, benign condition characterized by the presence of multiple bile-duct-derived epithelial cysts in the liver parenchyma. The disease is usually asymptomatic, but cyst growth can result in complications such as ascites, esophageal varices, jaundice and hepatic failure. The exact mechanism leading to cyst growth is unclear, but estrogenic stimulation and paracrine action of vascular endothelial growth factor (VEGF) are thought to play a role in the growth of cyst epithelium.
Case report. We report a case of acute liver failure in a young woman with PLD and liver metastases from breast carcinoma.
Results. No data are available in the literature about metastatic liver involvement in PLD patients affected by breast cancer. The prognosis of patients with liver metastases is generally poor but fulminant liver failure is a very rare occurrence. Estrogen stimulation seems to be a risk factor for breast cancer and severe PLD. In the reported case, the presence of either the cysts or the metastatic lesions may have resulted in more extensive liver damage.
Conclusions. The adoption of drugs selected in relation to their hepatic toxicity together with careful monitoring of liver function is warranted in the management of breast cancer patients affected by PLD, in order to reduce the risk of liver failure.

Cystic lesions of the liver can be classified as developmental, neoplastic, inflammatory or miscellaneous1. Polycystic liver disease (PLD) is included in the group of developmental hepatic cysts. It is a rare, congenital, benign condition characterized by the presence of multiple bile-duct-derived epithelial cysts in the liver parenchyma2. PLD can occur sporadically as an isolated, genetically distinct autosomal dominant entity (ADPLD), or in association with the presence of cysts in other organs3. Bristowe in 1856 first described the association of PLD with autosomal dominant polycystic kidney disease (ADPKD)4. The disease is usually asymptomatic and tends to be underdiagnosed3: ADPLD has a reported prevalence of 0.05-0.13% in autopsy studies5.
Despite the sometimes impressive physical and radiological findings, only a minority of patients will progress to advanced liver disease or develop complications6. Age, female sex and estrogens seem to be risk factors for severe PLD7.
Symptomatic patients complain of vague abdominal distension, early satiety, weight loss, dyspnea, and back pain due to liver enlargement and compression of adjacent structures. Progression of cyst growth may in rare cases result in complications such as ascites, esophageal varices, jaundice and liver failure8-10.
Cases in which subjects affected by PLD develop cancer are rare and the reported data were all related to primary liver tumors11-15. Here we report the case of a 36-year-old woman affected by PLD who developed fulminant liver failure due to metastatic liver involvement from breast cancer.
Although the liver is a common site of metastatic tumor deposits, with evidence of hepatic metastases in 36% of all patients who die of cancer16, to the best of our knowledge no data are available in the literature about metastatic involvement of the liver in patients with PLD. Along with the case description we discuss the issues connected with the diagnosis and management of this occurrence.

Case report
In June 1999 a 36-year-old white woman came under our observation because she had noted the presence of a fixed, painless nodule of about 1.5 × 1 cm in the upper external quadrant of the right breast. Her history included clinically asymptomatic PLD, incidentally diagnosed in 1996 during routine abdominal ultrasonography. General examination confirmed the presence of the breast mass and showed no other specific features except marked hepatomegaly. Laboratory findings were normal. Biopsy of the breast mass under mammographic guidance resulted in a diagnosis of breast carcinoma. Since staging with total-body CT scan, abdominal ultrasonography, and bone scintigraphy revealed no metastases, the patient underwent an upper external right quadrantectomy with lymphadenectomy in July. At surgery the diameter of the primary tumor was 1.5 cm, and metastasis was present in 1 of 22 axillary lymph nodes. Histological examination showed a poorly differentiated infiltrating ductal carcinoma (Figure 1). Estrogen and progesterone receptors were slightly positive (15% and 10%, respectively), Mib1 was 28% and C-erbB2 was undetermined. Pathological UICC stage was pT1cN1M0. Followig surgery the patient was treated with 6 cycles of adjuvant chemotherapy according to the CMF regimen (cyclophosphamide 600 mg/m 2 day 1 and 8, methotrexate 40 mg/m2 day 1 and 8, and 5-fluorouracil 600 mg/m2 day 1 and 8, every 28 days) and with radiotherapy, for a total dose of 50 Gy to the right breast.

During chemotherapy, periodic liver function tests were performed and no significant changes were observed, so that it was not necessary to delay the chemotherapy courses or reduce the drug doses. After the completion of chemotherapy, hormonal therapy with tamoxifen (20 mg/day) was started.
The patient underwent periodic clinical and instrumental checkups, which were always negative for breast cancer recurrence, and the last tumor marker measurement (CA 15-3, CEA, TPA) of June 26 2000 was normal. In this period liver function did not show any signs of drug-induced toxicity.
She had no symptoms until September 2000, when she started complaining of the progressive onset of fatigue, abdominal distension, early satiety, nausea, pain in the right hypochondrium, and slight weight loss. Because of the worsening of these symptoms she consulted her physician, who suggested repeating the abdominal ultrasonography and laboratory tests. The laboratory findings showed mild liver impairment (GOT 70 IU/L, GPT 66 IU/L, ?GT 48 IU/L, alkaline phosphatase 146 IU/L) and abdominal ultrasonography confirmed the presence of hepatomegaly and multiple cysts in the liver parenchyma.
Considering the presence of PLD and the patient’s history of breast cancer treated with chemotherapy and tamoxifen, we decided to discontinue the hormonal therapy and to admit the patient for further examination in October 2000.
At admission, clinical examination revealed scleral jaundice and abdominal pain on palpation of the upper abdominal region, and confirmed the known presence of marked hepatomegaly. Laboratory findings showed slight anemia (hemoglobin 11.9 g/dL), liver impairment (GOT 586 IU/L, GPT 314 IU/L, ?GT 784 IU/L, total bilirubin 1.91 mg/dL, alkaline phosphatase 591 IU/L, LDH 2250 IU/L) and a noticeable increase in the levels of CA 15-3 (1023 IU/mL) and TPA (5570 IU/L). Other findings were normal. A CT scan of the liver showed marked hepatomegaly due to the presence of hypodense lesions in most hepatic segments ranging in size from 4 mm to 8 cm. Most of the larger lesions showed no enhancement changes after contrast administration, while the smaller lesions showed central enhancement; the former were cysts, the latter metastatic lesions (Figure 2A and B). The presence of ascites in the perihepatic space, paracolic gutters and pouch of Douglas was also evident.
A liver biopsy performed under ultrasound guidance confirmed the suspicion of liver metastases from breast carcinoma (Figure 3A and B). The following days we observed an unexpectedly rapid decline of the patient’s condition with the appearance of acute liver failure (Table 1). The woman died 18 days later, on October 22, despite best supportive care.

Table 1 - Liver tests




Tot Bil

Dir Bil


























































































































GOT, glutamate oxaloacetate transaminase; GPT, glutamate pyruvate transaminase; Tot Bil, total bilirubin; Dir Bil, direct bilirubin; LDH, lactic dehydrogenase; CHE, cholinesterase; ALP, alkaline phosphatase; ?GT, gamma-glutamyltransferase.

PLD is a relatively benign disease and patients rarely have important clinical complications requiring specific treatment6. The disease – although well known – tends to go undiagnosed in the general population3 and is often an incidental finding during a workup for other clinical problems or complaints. In the few cases where PLD becomes symptomatic, its symptoms are the result of cyst growth causing compression of adjacent structures, or they can be related to cyst complications such as rupture, infection, or hemorrhage8-10.
The exact mechanism leading to cyst growth is unclear, but estrogenic stimulation and paracrine action of vascular endothelial growth factor (VEGF) are thought to play a role in the growth of cyst epithelium17,18. Usually the cyst growth is not related to a significant impairment of liver function, although an increase in bilirubin, gamma-glutamyl transpeptidase, alkaline phosphatase and alanine transaminase serum values has been described6.
In the case described here, a patient affected by PLD, previously treated with CMF chemotherapy, who was taking tamoxifen as adjuvant hormonal therapy for breast cancer, presented with clinical and laboratory evidence of liver impairment during follow-up. At that time, liver ultrasonography showed only the presence of the known liver cysts without evidence of tumor relapse. Considering the coexistence of PLD and the possibility of tamoxifen-induced liver damage, we decided to discontinue the hormonal therapy because tamoxifen can cause secondary nonalcoholic steatohepatitis and exacerbation of preexistent hepatic dysfunction 19,20. It is also known that the CMF schedule is associated with a significant incidence of liver dysfunction (up to 40%) during the course of chemotherapy, and such dysfunction can persist after its completion21. Paradoxically, some authors observed a normalization of liver function – instead of the expected worsening – when tamoxifen-based hormonal therapy was given after the completion of CMF22.
However, taking into account the history of our patient, we submitted her to further tests. Liver CT scan showed hypodense lesions of different size in most liver segments. Because a differential diagnosis was necessary for the correct treatment choice, we felt it was reasonable to obtain a histological sample of the lesions. The biopsy result showed recurrence of the breast carcinoma in the liver.
PLD is associated with primary liver tumors, mostly cholangiocarcinomas11-15, which can arise from the transformation of the liver cyst epithelium12. To the best of our knowledge, however, no data are available in the literature about metastatic liver involvement in PLD patients affected by breast cancer, in spite of the fact that most liver tumors are secondary. This makes it difficult to estimate the chances of liver metastases developing in cancer patients affected by PLD. Moreover, the coexistence of PLD in cancer patients may be judged unremarkable by clinicians and is thus likely to remain undescribed.
Metastatic breast cancer involves the liver parenchyma in 60% of cases and in most of these it occurs in the form of multiple intraparenchymal nodular lesions23. The prognosis of patients with liver metastases is generally poor, but fulminant liver failure is very rare. The reported data suggest that only 0.44% of cases of fulminant liver failure are caused by malignancies, mostly hematological16.
In our patient it is unclear whether the presence of the cysts may have facilitated more extensive tumor-induced damage in the liver, or the tumor itself may have disturbed the balance in the function of a liver affected by PLD, both resulting in liver failure. Furthermore, it is unknown whether the administration of tamoxifen might have influenced the cysts of PLD. Estrogenic stimulation has in fact been linked to cyst growth, but due to the rarity of the occurrence we cannot determine the role of either the antiestrogenic effect of the drug or its estrogen-like action on cyst epithelium.
Our experience suggests that PLD may be an important cause of comorbidity in patients affected by liver metastases from breast cancer. The adoption of suitable prophylactic measures such as drugs selected in relation to their toxicity or given in reduced doses, together with careful monitoring of liver function is warranted in the management of these patients in order to try to reduce the risk of liver failure. Although the sequence of CMF chemotherapy followed by tamoxifen is reported to be safe in most women 22, hormonal drugs other than tamoxifen for treating breast cancer, when feasible, should be at least taken into account. Furthermore, when chemotherapy is planned, drugs with lower hepatic toxicity should be privileged.

?1. Mortelé KF, Ros PR: Cystic focal liver lesions in the adult: differential CT and MR imaging features. Radiographics, 21: 895-910, 2001.
?2. Peces R, González P, Venegas JL: Enfermedad poliquística hepática no asociada a poliquistosis renal autosómica dominante. Nefrología, 23: 454-458, 2003.
?3. Qian Q, Li A, King BF, Kamath PS, Lager DJ, Huston J 3rd, Shub C, Davila S, Somlo S, Torres VE: Clinical profile of autosomal dominant polycystic liver disease. Hepatology, 37: 164-171, 2003.
?4. Bristowe F: Cystic disease of the liver associated with a similar disease of the kidneys. Trans Pathol Soc Lond, 7: 229-234, 1856.
?5. Bistritz L, Tamboli C, Bigam D, Bain VG: Polycystic liver disease: Experience at a teaching hospital. Am J Gastroenterol, 100: 2212-2217, 2005.  
?6. Arnold HL, Harrison SA: New advances in evaluation and management of patients with polycystic liver disease. Am J Gastroenterol, 100: 2569-2582, 2005.
?7. Everson GT, Taylor MR: Management of polycystic liver disease. Curr Gastroent Rep, 7: 19-25, 2005.
?8. Ratcliffe PJ, Teeders S, Theaker JM: Bleeding oesophageal varices and hepatic dysfunction in adult polycystic liver disease. Br Med J, 288: 1330-1331, 1984.
?9. Wittig JH, Burns R, Lonmire WP: Jaundice associated with polycystic liver disease. Am J Surg, 138: 383-386, 1978.
10. Washburn WK, Johnson LB, Lewis WD, Jenkins RL: Liver transplantation for adult polycystic liver disease. Liver Transpl Surg, 2: 17-22, 1996.
11. Blustein PA: Association of carcinoma with congenital cystic conditions of the liver and bile ducts. Am J Gastroenterol, 67: 40-46, 1977.
12. Landais P, Grüngeld JP, Droz D, Dreke T, Albouze G, Gogusev J, Chauveau D, Moynot A: Cholangiocellular carcinoma in polycystic kidney and liver disease. Arch Intern Med, 144: 2274-2276, 1984.
13. Imamura M, Miyashita T, Tani T, Naito A, Tobe T, Takahashi K: Cholangiocellular carcinoma associated with multiple liver cysts. Am J Gastroenterol, 79: 790-795, 1984.
14. Azizah N, Paradinas FJ: Cholangiocarcinoma coexisting with developmental liver cysts: a distinct entity different from liver cystoadenocarcinoma. Histopathology, 4: 391-400, 1980.
15. Rehaulova E, Dite P: Multiple carcinomas arising from congenital cysts of the liver and kidneys. Cesk Pathol, 17: 198-203, 1981.
16. Rowbotham D, Wendon J, Williams R: Acute liver failure secondary to hepatic infiltration: a single center experience of 18 cases. Gut, 42: 576-580, 1998.
17. Sherstha R, McKinley C, Russ P, Scherzinger A, Bronner T, Showalter R, Everson GT: Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease. Hepatology, 26: 1282-1286, 1997.
18. Fabris L, Cadamuro M, Fiorotto R, Roskams T, Spirli C, Melero S, Sonzogni A, Joplin RE, Okolicsanyi L, Strazzabosco M: Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases. Hepatology, 43: 1001-1012, 2006.
19. McClain CJ, Mokshagundam SP, Barve SS, Song Z, Hill DB, Chen T, Deaciuc I: Mechanisms of non-alcoholic steatohepatitis. Alcohol, 34: 67-79, 2004.
20. Floren LC, Hebert MF, Venook AP, Jordan VC, Cisneros A, Somberg KA: Tamoxifen in liver disease: potential exacerbation of hepatic dysfunction. Ann Oncol, 9: 1123-1126, 1998.
21. Locateli M, Colleoni M, Noberasco C, Nolé F, Orlando L, Munzone E, Peruzzotti G, Goldhirsch A: Hepatic toxicity from cyclophosphamide, methotrexate, fluorouracil (CMF regimen). Ann Oncol, 10: 1394-1395, 1999.
22. Hirvikoski PP, Kumpulainen EJ, Johansson RT: Hepatic toxicity caused by adjuvant CMF/CNF in breast cancer patients and reversal by tamoxifen. Breast Cancer Res Treat, 44: 269-274, 1997.
23. Martelli O, Coppola L, De Quarto AL, Palma M, Sarmiento R, Foggi CM: Fulminant hepatic failure caused by diffuse intrasinusoidal metastatic liver disease: a case report. Tumori, 86: 424-427, 2000.