Digestion 19: 328-334 (1979)
Hepatic Adenoma Associated with Portasystemic Shunting in a Young Woman Marshall W. Webster, David H. Van Thiel, Klaus M. Bron and E. Leon Barnes Departments of Surgery, Medicine, Radiology and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
Key Words. Hyperestrogenemia • Portal hypertension • Hepatic adenoma
Introduction
Hepatic adenomas were well described but rarely encountered prior to the past decade. Henson et al (10) documented only four hepat ic cell adenomas in a review of the Mayo Clinic experience from 1907 to 1954. At the Los Angeles County Hospital between 1918 and 1974 only two liver cell adenomas were di agnosed out of a total of 418 liver tumors discovered in 50,000 autopsies (7). Hepatic adenomas have been seen more fre quently in clinical medicine coincident with the recent increased use of sex steroids. Bernstein et al. (4) in 1971 first reported the development of hepatocellular carcinoma in a patient with Fanconi’s syndrome receiving oxymethalone. In 1972, Johnson et al. (12) reported an addition al 4 patients who had developed hepatocellular
carcinoma while on androgenic steroid therapy. More recently Baum et al. (3) have reported 7 cases of benign hepatic adenomas in women using oral contraceptives. Since these original observations, many individual case reports and several substantial series of hepatic adenomas and hepatocellular carcinoma in patients using either estrogenic or androgenic hormones have been published (1 ,2 , 14, 15). Thus, the statisti cal association between the use of hormones and the development of hepatic neoplasia, though still questioned by some (9, 13), ap pears convincing (8). In addition to adenomas in individuals re ceiving sex steroids for medicinal reasons, spon taneous hepatic adenomas have been noted to occur in women during pregnancy, particularly in the last trimester (11) or in the early postpar tum period (5, 17). In addition to these preg
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Abstract. The development of a hepatic adenoma is described in a young female of reproductive age who had documented portasystemic shunting and hyperestrogenemia. The intrinsic hyperestro genemia and the increased hepatic arterial blood flow, both of which occurred as a result of the portasystemic shunting secondary to portal venous obstruction, may have been important factors in the development of her hepatic tumor. We would postulate that prolonged endogenous hyperestrogenemia, like exogenous sex steroids, may predispose to hepatic adenoma formation.
Hepatic Adenoma and Portasystemic Shunting
329
nancy-related hepatic adenomas, there is a re port of a hepatic adenoma developing in the presence of a functioning ovarian tumor (16). Thus, the presence of increased levels of sex steroids would seem to be associated with the development of adenoma formation in tire liver. Here we report tire spontaneous develop ment of a hepatic adenoma in a young female with prehepatic portal hypertension and docu mented endogenous hyperestrogenemia. We postulate that either the endogenous hyper estrogenemia or the increased hepatic arterial blood flow secondary to portasystemic shunt ing (or both acting together) may have been
risk factors in the development of hepatic neoplasia in this woman.
Flg. 1. The arterial phase of the selective celiac arteriogram obtained on May 17, 1968 demonstrated a
normal left hepatic artery branch (arrow) and left lobe.
Case Report
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A 21-year-old Caucasian female, bom in 1954, was first hospitalized at age 5 with acute upper gastrointes tinal bleeding from esophageal varices. Splenoportog raphy demonstrated ‘cavernous transformation’ of the portal vein. A splenectomy was performed in an attempt to control bleeding. A liver biopsy obtained at that operation was reported as normal. At age 7 she underwent transthoracic ligation of esophageal varices for recurrent bleeding. At age 14 another major gastrointestinal hemorrhage occurred and arteriography again demonstrated esophageal vari-
330
Webster/Van Thiel/Bron/Barncs
Fig. 2. Celiac arteriogram obtained on Decem ber 27, 1971 for recurrent gastrointestinal bleeding indicated a hypervascular mass in the left hepatic lobe. Two dilated left hepatic artery branches encompass the mass (arrows) which measures 11 X 13 cm. The
mass contained multiple, fine, tortuous vessels, with normal attenuation, and no tumor stain or A/V shunt ing. The artériographie findings suggested a benign hepatic adenoma.
Bilirubin SCOT SGPT Alkaline phosphatase Prothrombin time Gamma-GTP
Nov 60 age 6
Apr 68 age 14
Nov 70 age 16
Dec 72 age 18
Mar 74 age 20
Sep 75 age 21
NL 1.5 1.5 NL
NL NL NL NL
NL NL NL 2.7
NL 2.0 2.5
-
-
—
100%
NL NL NL 6.5 X NL 74%
—
—
—
—
—
3.9 mg% 34.8 X NL 26.1 X NL 10.9 X NL 100% 4.2 X NL
X X
NL NL
X
NL
X X
-
NL NL
Liver function studies at indicated times during patient's disease. NL = Within normal limits; upper limit of normal.
X
NL= times
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:10:05 AM
Table I. Liver function tests obtained in our patient normalized to correct for the variable methods used
331
Fig. 3. Celiac arteriogram obtained on Septem ber 18, 1975, because of acute upper abdominal pain and hematcmesis. The left hepatic mass had dramati
cally changed in appearance since the previous exam ination (fig. 2). The mass had enlarged to 15 X 19 cm and is now relatively hypovascular.
ces with a normal hepatic arterial pattern (fig. 1). In an effort to control the bleeding, transabdominal suturing of gastric and esophageal varices was per formed. 7 months later a 'Tanner- procedure (gastric interruption) was performed for recurrent hemor rhage. Despite these operative procedures another hemorrhage occurred 5 months later but was con trolled with peripheral Pitressin infusion. She did well thereafter, except for symptomatic esophageal reflux and the development of an esophageal stricture. At age 16 she underwent esophagogastrectomy and colon interposition, vagotomy and pyloroplasty for esopha geal stricture at Presbyterian-University Hospital of Pittsburgh. Biochemical liver function studies at that time are shown in table 1. Further gastrointestinal hemorrhage prompted performance of a mesocaval shunt at age 17. A preoperative angiogram demon
strated enlargement of the left lobe of the liver, suggestive of an adenoma (fig. 2). In addition, the abnormal segment of portal vein had changed from multiple vessels to a single narrow irregular branch. The esophageal varices were noted again. A second liver biopsy obtained at that operation showed mild chronic persistent hepatitis. Despite the mesocaval shunt, gastrointestinal bleed ing recurred 1 year later. Liver function studies were only mildly abnormal (table 1). 4 months later the liver function studies had returned to normal except for a persistently elevated alkaline phospha tase. At age 21 she was re-admitted with abdominal pain and hematemesis. On admission she reported that her last menstrual period had been 4 months earlier. Moreover, she described her menstrual periods as
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:10:05 AM
Hepatic Adenoma and Portasystemic Shunting
Wcbster/Van Thiel/Bron/Barnes
Fig. 4. Photomicrograph of the hepatic tumor (without definite margins) composed of cords of hépa tocytes which contained abundant lipochrome pig ment and occasional fat vacuoles. Note the absence of
bile ducts and the presence of well-developed sinu soids. A small vessel is present in the upper right hand corner. HE. X 125.
always having been irregular, occurring at 4- to 6month intervals. She was febrile with a temperature of 39.4 °C. Scleral icterus was noted. Multiple spider angiomata were present over the trunk. Serial blood cultures grew Streptococcus viridans. The white blood cell count was 27,600 mm3, hemoglobin 13.0g%and hematocrit 39.8%. Liver function studies were markedly abnormal (table I). She was treated with intravenous penicillin. An upper gastrointestinal series suggested hepatic en largement, but no varices were seen. A sonogram outlined an 8 X 10 cm cystic mass in the left upper quadrant that appeared completely within the hepatic parenchyma. A celiac arteriogram showed a marked change in the appearance of the hepatic mass (fig. 3) as compared to the previous examination (fig. 2). The
artériographie findings were interpreted as consistent with hemorrhage and/or necrosis within the tumor mass. The patient underwent exploratory laparotomy. The left lobe of the liver was found to be largely replaced by a fluctuant mass from which a large amount of semi-solid material, which cultured Staphy lococcus aureus, was encountered on incision. The left hepatic artery was ligated and the bulk of the mass was excised. The right lobe of the liver was grossly normal. Microscopically, the tumor was composed of cords of uniform well-differentiated hepatocytes con taining glycogen, occasional fat vacuoles, and abun dant granular brown iron-negative pigment presumed to be lipochrome (fig. 4). Bile ducts were absent, lobular architecture was lost and there was no evi dence of cirrhosis or bile stasis. Ischemic changes were
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:10:05 AM
332
Hepatic Adenoma and Portasystemic Shunting
333
Discussion
The patient denied ever using oral contra ceptives. Moreover, she had not used, for ex tended periods, any other drugs that might be implicated in the pathogenesis of liver cell adenoma. The radioimmunoassay methods uti lized to assay the steroids in this patient’s sera included chromatographic separation which virtually eliminates estrogens other than estra diol. In addition, the antisera used are known not to cross-react with the synthetic estrogens 1 Normal postpubertal premenopausal I'SH levels: 6.5-30 mlU/ml; normal postpubertal premenopausal LH levels: 10-25 mlU/ml; normal estradiol levels: follicular 50- 125 pg/ml, luteal 125-200 pg/ml; nor mal progesterone levels: follicular
Hepatic Adenoma Associated with Portasystemic Shunting in a Young Woman Marshall W. Webster, David H. Van Thiel, Klaus M. Bron and E. Leon Barnes Departments of Surgery, Medicine, Radiology and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
Key Words. Hyperestrogenemia • Portal hypertension • Hepatic adenoma
Introduction
Hepatic adenomas were well described but rarely encountered prior to the past decade. Henson et al (10) documented only four hepat ic cell adenomas in a review of the Mayo Clinic experience from 1907 to 1954. At the Los Angeles County Hospital between 1918 and 1974 only two liver cell adenomas were di agnosed out of a total of 418 liver tumors discovered in 50,000 autopsies (7). Hepatic adenomas have been seen more fre quently in clinical medicine coincident with the recent increased use of sex steroids. Bernstein et al. (4) in 1971 first reported the development of hepatocellular carcinoma in a patient with Fanconi’s syndrome receiving oxymethalone. In 1972, Johnson et al. (12) reported an addition al 4 patients who had developed hepatocellular
carcinoma while on androgenic steroid therapy. More recently Baum et al. (3) have reported 7 cases of benign hepatic adenomas in women using oral contraceptives. Since these original observations, many individual case reports and several substantial series of hepatic adenomas and hepatocellular carcinoma in patients using either estrogenic or androgenic hormones have been published (1 ,2 , 14, 15). Thus, the statisti cal association between the use of hormones and the development of hepatic neoplasia, though still questioned by some (9, 13), ap pears convincing (8). In addition to adenomas in individuals re ceiving sex steroids for medicinal reasons, spon taneous hepatic adenomas have been noted to occur in women during pregnancy, particularly in the last trimester (11) or in the early postpar tum period (5, 17). In addition to these preg
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:10:05 AM
Abstract. The development of a hepatic adenoma is described in a young female of reproductive age who had documented portasystemic shunting and hyperestrogenemia. The intrinsic hyperestro genemia and the increased hepatic arterial blood flow, both of which occurred as a result of the portasystemic shunting secondary to portal venous obstruction, may have been important factors in the development of her hepatic tumor. We would postulate that prolonged endogenous hyperestrogenemia, like exogenous sex steroids, may predispose to hepatic adenoma formation.
Hepatic Adenoma and Portasystemic Shunting
329
nancy-related hepatic adenomas, there is a re port of a hepatic adenoma developing in the presence of a functioning ovarian tumor (16). Thus, the presence of increased levels of sex steroids would seem to be associated with the development of adenoma formation in tire liver. Here we report tire spontaneous develop ment of a hepatic adenoma in a young female with prehepatic portal hypertension and docu mented endogenous hyperestrogenemia. We postulate that either the endogenous hyper estrogenemia or the increased hepatic arterial blood flow secondary to portasystemic shunt ing (or both acting together) may have been
risk factors in the development of hepatic neoplasia in this woman.
Flg. 1. The arterial phase of the selective celiac arteriogram obtained on May 17, 1968 demonstrated a
normal left hepatic artery branch (arrow) and left lobe.
Case Report
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:10:05 AM
A 21-year-old Caucasian female, bom in 1954, was first hospitalized at age 5 with acute upper gastrointes tinal bleeding from esophageal varices. Splenoportog raphy demonstrated ‘cavernous transformation’ of the portal vein. A splenectomy was performed in an attempt to control bleeding. A liver biopsy obtained at that operation was reported as normal. At age 7 she underwent transthoracic ligation of esophageal varices for recurrent bleeding. At age 14 another major gastrointestinal hemorrhage occurred and arteriography again demonstrated esophageal vari-
330
Webster/Van Thiel/Bron/Barncs
Fig. 2. Celiac arteriogram obtained on Decem ber 27, 1971 for recurrent gastrointestinal bleeding indicated a hypervascular mass in the left hepatic lobe. Two dilated left hepatic artery branches encompass the mass (arrows) which measures 11 X 13 cm. The
mass contained multiple, fine, tortuous vessels, with normal attenuation, and no tumor stain or A/V shunt ing. The artériographie findings suggested a benign hepatic adenoma.
Bilirubin SCOT SGPT Alkaline phosphatase Prothrombin time Gamma-GTP
Nov 60 age 6
Apr 68 age 14
Nov 70 age 16
Dec 72 age 18
Mar 74 age 20
Sep 75 age 21
NL 1.5 1.5 NL
NL NL NL NL
NL NL NL 2.7
NL 2.0 2.5
-
-
—
100%
NL NL NL 6.5 X NL 74%
—
—
—
—
—
3.9 mg% 34.8 X NL 26.1 X NL 10.9 X NL 100% 4.2 X NL
X X
NL NL
X
NL
X X
-
NL NL
Liver function studies at indicated times during patient's disease. NL = Within normal limits; upper limit of normal.
X
NL= times
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:10:05 AM
Table I. Liver function tests obtained in our patient normalized to correct for the variable methods used
331
Fig. 3. Celiac arteriogram obtained on Septem ber 18, 1975, because of acute upper abdominal pain and hematcmesis. The left hepatic mass had dramati
cally changed in appearance since the previous exam ination (fig. 2). The mass had enlarged to 15 X 19 cm and is now relatively hypovascular.
ces with a normal hepatic arterial pattern (fig. 1). In an effort to control the bleeding, transabdominal suturing of gastric and esophageal varices was per formed. 7 months later a 'Tanner- procedure (gastric interruption) was performed for recurrent hemor rhage. Despite these operative procedures another hemorrhage occurred 5 months later but was con trolled with peripheral Pitressin infusion. She did well thereafter, except for symptomatic esophageal reflux and the development of an esophageal stricture. At age 16 she underwent esophagogastrectomy and colon interposition, vagotomy and pyloroplasty for esopha geal stricture at Presbyterian-University Hospital of Pittsburgh. Biochemical liver function studies at that time are shown in table 1. Further gastrointestinal hemorrhage prompted performance of a mesocaval shunt at age 17. A preoperative angiogram demon
strated enlargement of the left lobe of the liver, suggestive of an adenoma (fig. 2). In addition, the abnormal segment of portal vein had changed from multiple vessels to a single narrow irregular branch. The esophageal varices were noted again. A second liver biopsy obtained at that operation showed mild chronic persistent hepatitis. Despite the mesocaval shunt, gastrointestinal bleed ing recurred 1 year later. Liver function studies were only mildly abnormal (table 1). 4 months later the liver function studies had returned to normal except for a persistently elevated alkaline phospha tase. At age 21 she was re-admitted with abdominal pain and hematemesis. On admission she reported that her last menstrual period had been 4 months earlier. Moreover, she described her menstrual periods as
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:10:05 AM
Hepatic Adenoma and Portasystemic Shunting
Wcbster/Van Thiel/Bron/Barnes
Fig. 4. Photomicrograph of the hepatic tumor (without definite margins) composed of cords of hépa tocytes which contained abundant lipochrome pig ment and occasional fat vacuoles. Note the absence of
bile ducts and the presence of well-developed sinu soids. A small vessel is present in the upper right hand corner. HE. X 125.
always having been irregular, occurring at 4- to 6month intervals. She was febrile with a temperature of 39.4 °C. Scleral icterus was noted. Multiple spider angiomata were present over the trunk. Serial blood cultures grew Streptococcus viridans. The white blood cell count was 27,600 mm3, hemoglobin 13.0g%and hematocrit 39.8%. Liver function studies were markedly abnormal (table I). She was treated with intravenous penicillin. An upper gastrointestinal series suggested hepatic en largement, but no varices were seen. A sonogram outlined an 8 X 10 cm cystic mass in the left upper quadrant that appeared completely within the hepatic parenchyma. A celiac arteriogram showed a marked change in the appearance of the hepatic mass (fig. 3) as compared to the previous examination (fig. 2). The
artériographie findings were interpreted as consistent with hemorrhage and/or necrosis within the tumor mass. The patient underwent exploratory laparotomy. The left lobe of the liver was found to be largely replaced by a fluctuant mass from which a large amount of semi-solid material, which cultured Staphy lococcus aureus, was encountered on incision. The left hepatic artery was ligated and the bulk of the mass was excised. The right lobe of the liver was grossly normal. Microscopically, the tumor was composed of cords of uniform well-differentiated hepatocytes con taining glycogen, occasional fat vacuoles, and abun dant granular brown iron-negative pigment presumed to be lipochrome (fig. 4). Bile ducts were absent, lobular architecture was lost and there was no evi dence of cirrhosis or bile stasis. Ischemic changes were
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 3:10:05 AM
332
Hepatic Adenoma and Portasystemic Shunting
333
Discussion
The patient denied ever using oral contra ceptives. Moreover, she had not used, for ex tended periods, any other drugs that might be implicated in the pathogenesis of liver cell adenoma. The radioimmunoassay methods uti lized to assay the steroids in this patient’s sera included chromatographic separation which virtually eliminates estrogens other than estra diol. In addition, the antisera used are known not to cross-react with the synthetic estrogens 1 Normal postpubertal premenopausal I'SH levels: 6.5-30 mlU/ml; normal postpubertal premenopausal LH levels: 10-25 mlU/ml; normal estradiol levels: follicular 50- 125 pg/ml, luteal 125-200 pg/ml; nor mal progesterone levels: follicular
