Edward D. Nissen

Etiologic factors in the pathogenesis of liver tumors associated with oral contraceptives.

Within the last several years, previously rare liver tumors have been seen in young women using oral contraceptive steroids. The Registry for Liver Tumors Associated with Oral Contraceptives at the University of California, Irvine, has clearly identified 27 cases. The recent literature contains 44 case reports. Common to these 71 cases has been a histopathologic diagnosis of focal nodular hyperplasia, adenoma, hamartoma, and hepatoma. Significant statistical etiologic factors include prolonged uninterrupted usage of oral contraceptive steroids. Eight deaths and liver rupture in 18 patients attest to the seriousness of this new potentially lethal adverse phenomenon.

Role of oral contraceptive agents in the pathogenesis of liver tumors.

Since the introduction of oral contraceptive steroids in 1960 there has been a sharp increase in the incidence of benign liver tumors. Epidemiologic and other evidence links focal nodular hyperplasia and hepatic cell adenoma to the use of these agents. The risk increases with long-term exposure. The majority of patients were less than 35 years old. Most patients were exposed to mestranol (ME) alone or alternately with ethinylestradiol, both synthetic steroidal estrogens. Inability to demethylate ME in the smooth endoplasmic reticulum of hepatocytes may allow massive accumulation of oncogenic metabolites. This is probably a pharmacogenetic variable in a small number of women. Cholestasis, hypervascularity, induction of intracellular enzyme systems, thrombogenesis, and thickening of arterial and venous walls are other known effects of synthetic estrogens and progestogens. All may contribute to the pathogenesis of liver tumors. Many patients are asymptomatic until there is rapid expansion of the tumor. Pain occurs when Glissons capsule stretches. Intrahepatic bleeding and liver rupture are common sequelae. Ligation of the hepatic artery may be lifesaving in the face of exsanguinating liver bleeding. Reports of regression with observation alone are encouraging. Instances of progression of unresected adenomas to rupture during subsequent pregnancy dictate avoidance of sex steroids in patients with hepatic neoplasia. Sonography, computerized axial tomography, radionuclide scans, and selective celiohepatic angiography are useful methods for the diagnosis of liver tumor in the symptomatic patient. There is a primary need to develop biochemical methods for detecting patients at risk for developing liver tumors. Epidemiologic research and central reporting of case histories are needed in the search for common factors.

A prospective investigation of the etiology of febrile morbidity following abdominal hysterectomy.

Abstract A prospective study of 100 consecutive cases was undertaken to elucidate more clearly the causes of febrile morbidity following identical pelvic operations performed by the same surgeon in one hospital. Febrile morbidity was defined as temperature exceeding 100.4° F. on two or more occasions during any consecutive 48 hour period exclusive of the first 24 hours following operation. Thirty-four per cent of the patients fulfilled this criterion. The cut edge of the vaginal cuff was routinely swabbed immediately following removal of the uterus during operation and yielded a culture positive for E. coli in 37 instances. Twenty per cent of the patients produced a positive urine culture. Significantly, only 5 per cent of the patients developed a urinary infection as the result of 24 hour drainage through a self-retention catheter. Fifteen per cent had asymptomatic clinically unrecognized bladder infections present before operation. This study demonstrates the importance of routine culture of the vaginal cuff at abdominal hysterectomy.

Liver tumors and oral contraceptives.

Data on 78 cases of benign hepatic neoplasia among women with a history of oral contraceptive (OC) use are analyzed. Data for the study were collected by the Liver Tumor Registry of the University of California Irvine Medical Center. Factors considered in the analyses include the patients age and duration of OC therapy, histopathology of the tumors, and their symptoms, findings, and prognosis. The pathogenesis and treatment of the tumors are also discussed.

LIVER TUMORS AND ORAL CONTRACEPTIVES

Benign hepatocellular neoplasia has been found in 23 patients receiving oral contraceptives of various types. Because primary liver tumors are rare, this marked increase in incidence within 5 years suggests a cause-and-effect relationship. Since progestogens are enzyme inducers it is possible that they accelerate oncogenesis by increasing toxic metabolites which cannot be excreted due to the cholestatic effect of estrogens. Vascular changes and the hypercoagulation state of pill users may act synergistically to produce hemorrhagic necrosis and tumor rupture. Liver scans, celiac arteriography, and standard liver function tests are impractical and ineffective in the identification of the patient at risk. Management of the suspect patient with an intact liver should consist of biopsy at laparotomy so that the entire liver can be inspected. Observation, discontinuance of oral contraceptives, avoidance of similar steroids, and pregnancy should provide adequate prophylaxis against liver rupture. However, if a large blood-filled sinus lake or an area of coagulation necrosis is encountered, resection is imperative to prevent later rupture.