Liver and Biliary Tract

Source of the Circulating Alkaline Phosphatase in Patients with Hepatobiliary Disorders 

The association between hyperphosphatasemia and hepatobiliary disorders was first reported in 1930 (R24) and until the late 1960s, this association was explained in terms of the excretion theory. According to this theory, skeletal alkaline phosphatase is normally excreted by the liver and failure of this excretory process, as in biliary obstruction, results in serum alkaline phosphatase elevation (G28). 

The excretion theory is now thoroughly discounted and there is considerable evidence to suggest that in hepatobiliary disease, the eirculating alkaline phosphatase comes from the liver and/or the bile passages (H15a, K7, P19, R21, S24). It now appears established that biliary obstruction leads to increased synthesis of alkaline phosphatase in the hepatobiliary system (K6) and that the newly synthesized enzyme then reaches the blood via canalicular-sinusoidal connections (R23). 

The alkaline phosphatase(s) circulating in patients with hepatobiliary disorders can be shown to be distinct from skeletal, intestinal, and placental alkaline phosphatases by a variety of techniques (Mc3). Placental and intestinal alkaline phosphatases are believed to differ from human hepatobiliary alkaline phosphatase because they are synthesized in response to different structural genes (S23), whereas the differences between skeletal and hepatobiliary alkaline phosphatases may be due to post-translational events (S23). 

General Principles in the Use of Serum Alkaline Phosphatase Estimations in the Diagnosis of Hepatobiliary Disorders 

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A large multicentric cohort study of European vinyl chloride workers revealed a nearly threefold increase in liver cancer based on 24 observed deaths vs. 8.4 expected. The excess was clearly related to time since first exposure, duration of employment, and estimated ranked and quantitative exposures. A cohort study of 10,173 US men who had worked at least 1 year in jobs involving exposure to vinyl chloride confirmed a significant mortality excess in angiosarcoma (15 deaths), cancer of the liver and bilary tract [standardized mortality ratio (SMR) = 641], and cancer of central nervous system (SMR = 180). ° A recent follow-up of this cohort found that excess mortality risk from cancer of the liver and biliary tract, largely due to angiosarcoma, continued risk of mortality from brain cancer had attenuated and excess of deaths from cancer of connective and soft tissue appeared for the first time but was based on few cancers of assorted histology."... 

Bond GG, McLaren EA, Sabel FL, et al. 1990. Liver and biliary tract cancer among chemical workers. Am J Ind Med 18 19-24. 

Carey JB (1958) The serum trihydroxy/dihydroxy bile acid ratio in liver and biliary tract disease. J Clin Lab Invest 17 1494-1497... 

Seven cohort studies have examined the risk of cancer among populations exposed to dichloromethane. Two studies observed an excess of pancreatic cancer, but the three others which reported on this tumour did not. One study observed an excess of liver and biliary tract cancers among longer-term employees. One study observed an excess of prostate cancer that appeared to increase with level of exposure. One study observed an excess of breast cancer and gynaecological cancers among women with the highest likelihood of exposure and another study observ ed an excess of cervical cancer. With the exception of the prostate cancer excess observed in one study, all the excesses were based on small numbers. No estimates of exposure levels were available for two of the six studies. 

Brown (1992) conducted a cohort mortality study of workers employed at four pesticide manufacturing plants. The 1158 workers employed at Plant 3 of the study, which produced aldrin and dieldrin, were also potentially exposed to l,2-dibromo-3-chloropropane produced at the plant between 1975 and 1976. The cohort included all white males employed for six or more months before 1964 with follow-up through 1987. Although overall cancer mortality at Plant 3 was not elevated (SMR, 0.9 95% Cl, 0.7-1.1 = 72), an excess of liver and biliary tract cancer was observed (SMR, 3.9 95% Cl, 1.3-9.2 5 observed). All of the deaths occurred at least 15 years after first employment (SMR, 4.9), but no association was observed with duration of employment. The SMR for lung cancer was 0.7 (95% Cl, 0.4-1.0). Levels of exposure were not reported. Amoateng-Adjepong et al. (1995) reported the results of an update of the same cohort with three additional years of follow-up. No new association was reported. 

Four cohort studies and one population-based case-control study have examined the risk of cancer among populations exposed to l,2-dibromo-3-chloropropane, among other chemicals. In two of the cohort studies, an excess of lung cancer was observed based on small numbers of cases. In a third cohort study, an excess of liver and biliary tract cancers was found, while in the fourth an excess of cervical cancer and a non-significant excess of melanoma and leukaemia were observed. How ever, in both of the last two studies, it... 

M. A. Adson, Primary hepatocellular cancers—Western experience, Survey of the Liver and Biliary Tract (L. H. Blumgart, ed.), Churchill Livingstone Publisher, New York, 1988, pp. 1153-1165. 

MacNamara, E., Goldberg, D.M. Serum enzymes and enzyme profiles in the diagnosis of liver and biliary tract disease. Surv. Dig. Dis. 1985 3 165-186... 

Tab. 26.1 Predisposing factors for organ mycosis, including the liver and biliary tract...

The Swedish adverse drug reactions register, SWEDIS, received 149 case reports of 157 adverse reactions associated with disulfiram from 1971 to 1999, of which 63 cited disorders of the liver and biliary tract (26). Of these 63 reports, seven were classified as serious. In three cases of severe liver damage with a fatal outcome, disulfiram was suspected to have caused the reaction. If signs of liver damage appear, it is recommended that disulfiram be withdrawn and liver function tests performed. 

Minocycline and doxycycline are predominantly eliminated by the liver and biliary tract (70-90%). Therefore, no change in dose is needed in patients with impaired renal function. However, it should be considered that hepatic elimination of doxycychne or minocycline might be accelerated by co-administration of agents that induce hepatic enzymes. 

Briones ER, Iber FL. Liver and biliary tract changes and injury associated with total parenteral nutrition Pathogenesis and prevention. J Am Coll Nutr 1995 14 219-228. 

Studies of workers provide evidence that PCBs were associated with certain types of cancer in humans, such as cancer of the liver and biliary tract. Rats that ate commercial PCB mixtures throughout their lives developed liver cancer. Based on the evidence for cancer in animals, the Department of Health and Human Services (DHHS) has stated that PCBs may reasonably be anticipated to be carcinogens. Both EPA and the International Agency for Research on Cancer (lARC) have determined that PCBs are probably carcinogenic to humans. 

Brown 1987b). Additionally, one of the two liver cancers was not a primary carcinoma as it metastasized from another site (unknown). If the metastatic liver cancer is not included in the analysis, the SMR for liver and biliary tract cancer in the whole cohort loses statistical significance (SMR=210, p 0.05) (Nicholson and Landrigan 1994). Other findings included a slight increase in rectal cancer in the first study, but not in the follow-up (see Section 3.2.8.2.3). Limitations of these studies include small number of deaths, relatively short periods of observation, and possible misclassification of the cause of death because it is not clear in every case if death was due to primary cancer of the liver, biliary tract, or gall bladder. 

Deaths from cancers of the digestive system were statistically significantly increased in the Bertazzi et al. (1987) study of capacitor workers summarized in Section 3.2.8.2.1. This category was not specific for the stomach and intestines as it included other parts of the digestive system, including the liver and biliary tract. Of six observed deaths from digestive system cancers, one was due to hepatocellular carcinoma and another from a cancer of the biliary tract. 

Mathematical and Computer-Assisted Procedures in the Diagnosis of Liver and Biliary Tract Disorders... 

Henschler has reviewed the toxicity of organochlorine compounds.32 Many are carcinogens (e.g., vinyl chloride, which is associated with liver and biliary tract cancers and angiosarcomas).33 One of the most toxic is 2,3,7,8-tetra-chlorodibenzo p dioxin (3.3). 

Mowat AP (1984) Metabolic, genetic, and congenital disorders of the liver and biliary tract. In Weath-erall DJ, Ledingham JGG and Warrell DA, eds. Oxford Textbook of Medicine, pp. 12.221-12.229. Oxford University Press, Oxford. 

C25H24O12, Mr 516.46. Powder with a weak sweetish taste, mp. 227-228 °C, [a] -59° (CH3OH). C. occurs in the leaves of artichokes (Cynara scolymus, Astera-ceae), in flowers of Rhus typhina, as well as in Sene-cio nemorensis and Cirsium arvense. It is used for liver and biliary tract diseases. A cholesterol-lowering activity has also been reported. The biosynthesis pro-... 

Sternlieb, I. Present Status of Diagnosis and Prophylaxis of Asymptomatic Patients with Wilson s Disease in "Progress in Liver and Biliary Tract Diseases", Ed. Levey, C.M.,... 

In 1956, Hamre (159) reported a detailed study of the liver and biliary tract changes associated with vitamin A deficiency in rats. The animals were fed the diet for approximately 5 weeks. At autopsy, 86% of the rats showed pathological changes. The proximal two-thirds of the common ducts as dilated, and the bile contained masses of epithelial cells. Calculus-like bodies, either hard and chalky white or fragile and dull, were found in the dilated common ducts and consisted predominantly of masses of compacted epithelial cells. Crystals of inorganic salts, cholesterol, bile salts, and others were identified by microscopic examination of crushed stones. All calculi contained both acid-soluble and ether-soluble material. 

Matsumoto T, Kobayashi S, Shimizu H, et al (2000) The liver in collagen diseases pathologic study of 160 cases with particular reference to hepatic arteritis, primary biliary cirrhosis, autoimmune hepatitis and nodular regenerative hyperplasia of the liver. Liver 20 366-373 Meyers RL, Scaife ER (2000) Benign liver and biliary tract masses in infants and toddlers. Semin Pediatr Surg 9 146-155... 

Smadja C, Blumgart LH (1994) The biliary tract and the anatomy of biliary exposure. In Blumgart LH (ed) Surgery of the liver and biliary tract, 2nd edn. Churchill Livingstone, London... 

Crawford JM, Liu C. Liver and biliary tract. In Kumar V, Abbas AK, Fausto N, Aster JC, Eds. Pathologic Basis of Disease. 8th ed. Philadelphia, PA Saunders Elsevier 2010. p. 833-90. 

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