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Senior Member
Join Date: Mar 2006
Posts: 4,778
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tamoxifen effect on the liver (independent of chemotherapy)
Tamoxifen has been used for breast cancer since the mid 1970s so it is most likely that although some liver tissue is replaced by fat this probably does not cause clinical problems, or they would have discovered them by now. It is just one more thing to think about when choosing your antihormonal. This is hot off the press.
ABSTRACT: Fatty liver and transaminase changes with adjuvant tamoxifen therapy [Anti-Cancer Drugs]
We investigated the time it took to develop fatty liver and changes in serum aspartate aminotransferase and alanine aminotransferase levels in patients with breast cancer treated with adjuvant tamoxifen. Liver sonography to detect fatty liver and measurement of serum aspartate and alanine aminotransferase levels were performed regularly for patients with early breast cancer. The results were compared in groups of patients with and without adjuvant tamoxifen as well as those on chemotherapy. Eighty-two of 156 patients treated with tamoxifen developed fatty liver, compared with eight of 62 patients not taking it. Fatty liver appeared as early as 3 months after beginning tamoxifen and was detected within 2 years in most cases. It persisted for 48 months after discontinuing tamoxifen in 17 of the 82 patients who developed it. The incidence of fatty liver in patients receiving both chemotherapy and tamoxifen was the same as that in patients receiving tamoxifen alone. While 115 patients had elevations of aspartate aminotransferase, alanine aminotransferase or both, the magnitude of the elevation was clinically significant in only 32 patients. Patients on both chemotherapy and tamoxifen had a higher incidence of elevated transaminases than those on tamoxifen alone. Adjuvant tamoxifen increases the incidence of fatty liver, but has only a minimal effect on aspartate aminotransferase and alanine aminotransferase. Fatty liver may appear as early as 3 months after beginning tamoxifen and may persist for more than 4 years after discontinuing it. Therefore, long-term follow-up is warranted. Chemotherapy is not clearly associated with fatty liver, but may cause a greater degree of hepatocellular damage than does tamoxifen.
from the Merck manual:
Fatty liver (hepatic steatosis): Excessive accumulation of lipid in hepatocytes, the most common response of the liver to injury.
The liver occupies a central position in lipid metabolism. A small, rapidly used pool of free fatty acids (FFAs), absorbed from the diet or released into the blood from chylomicrons or fat cells, accommodates almost all of the energy requirements of a fasting animal. FFAs are taken up by the liver to join the hepatic pool of FFA, a portion of which the liver synthesizes. Some FFAs are oxidized to CO2 in the liver for energy, but most are rapidly incorporated into complex lipids (eg, triglycerides, phospholipids, glycolipids, cholesterol esters). Some of these complex lipids enter a slowly used pool that comprises the structural lipids of liver cells and their storage site. Most triglycerides enter an active pool where they combine with specific apoproteins to form lipoproteins (eg, very low density lipoproteins [VLDLs]), which are secreted into plasma. The liver is also responsible for lipid degradation (eg, low density lipoproteins, chylomicron remnants).
Fatty liver occurs when lipid accumulation exceeds the normal 5% of liver weight. In the macrovesicular type, large fat droplets balloon the liver cell, displacing the nucleus to the periphery of the cell, like an adipocyte. Triglyceride accumulates most commonly because it has the highest turnover rate of all hepatic fatty acid esters. Liver uptake of FFA from adipose tissue and the diet is unrestrained, whereas FFA disposition by oxidation, esterification, and VLDL secretion is limited.
In microvesicular fatty liver, small fat droplets accumulate, cells appear foamy, and nuclei are central. Triglycerides collect in subcellular organelles (eg, endoplasmic reticulum), reflecting widespread metabolic disturbance. Mitochondrial injury limits FFA oxidation, while apoprotein synthesis necessary for VLDL secretion is depressed, leading to triglyceride accumulation.
In phospholipidosis, phospholipids accumulate in association with certain drug use (eg, amiodarone). Liver cells are large and foamy.
Etiology
Diffuse fatty change of the liver, often zonal in distribution, is associated with many clinical situations. Alcoholism, obesity, and diabetes are the most common causes of macrovesicular fatty liver in developed countries. Other causes include malnutrition (especially the protein-deficient diet of children with kwashiorkor), inborn metabolic disorders (of glycogen, galactose, tyrosine, or homocysteine), drugs (eg, corticosteroids), or systemic illnesses with fever. Microvesicular fatty liver occurs in acute fatty liver of pregnancy, Reye's syndrome, certain drug toxicities (valproic acid, tetracycline, salicylate), or inborn metabolic defects (of the urea cycle enzymes or involving mitochondria in FFA oxidation).
Focal fatty change is much less common and less well recognized. These nodules of fatty liver cells are subcapsular. They are usually an incidental finding on ultrasound or CT, presenting as multiple space-occupying lesions of the liver. Such focal fat may appear in patients apparently at risk of developing this change (eg, obese or alcoholic patients).
Pathogenesis
Triglycerides accumulate in the liver because of increased input through synthesis from FFA or decreased export as VLDL from the hepatocytes. Increased triglyceride synthesis may result from increased delivery or availability of FFA (from the diet or mobilized from adipose tissue), from acetylcoenzyme A, or from decreased oxidation of FFA in the liver. Reduced elimination of triglyceride involves depressed packaging with apolipoprotein, phospholipid, and cholesterol, resulting in decreased VLDL secretion.
The several possible mechanisms involved in the pathogenesis of the fatty liver may operate alone or together. In obesity, delivery of dietary fat or mobilization from adipose tissue is increased. Decreased oxidation of FFA may contribute to the fatty liver induced by carbon tetrachloride, yellow phosphorus, hypoxia, or certain vitamin deficiencies (niacin, riboflavin, pantothenic acid). Blocked production and secretion of lipoproteins is often the main cause of triglyceride accumulation in the liver. Impaired apolipoprotein synthesis is the most important pathogenetic factor in several types of toxic fatty liver and in the fatty liver produced by protein-calorie malnutrition. Toxic inhibition of protein synthesis can lead to a fatty liver through inhibition of mRNA synthesis or translation.
In microvesicular fatty liver, small droplets of triglyceride plus FFA, cholesterol, and phospholipid collect in subcellular organelles. The basic defect is unknown, even though pathologic and clinical features from diverse causes are somewhat similar. The biochemical basis may be a disturbance in the mitochondrial-oxidative pathway, depressing FFA oxidation and impairing apolipoprotein synthesis for VLDL assembly.
Fatty liver may result from the accumulation of other neutral lipids. Fat and cholesterol (seen as rhomboid birefringent crystals under polarizing microscopy) are present in Wolman's disease and cholesterol ester storage disease. The fat vacuolization is small to medium. In Niemann-Pick disease, the phospholipid sphingomyelin accumulates in hepatocytes and Kupffer cells. Cells appear foamy.
Pathology
When lipid deposition is marked, the liver tends to be grossly enlarged, smooth, and pale. Microscopically, the general architecture can be normal. Triglyceride accumulations appear as large droplets that coalesce and displace the cell nucleus to the periphery. In the typical example, alcoholic fatty liver, hepatocytes are filled with fat vacuoles that displace the nuclei to the periphery of the cell, appearing like a large fat cell (see the discussion of fatty liver under Pathology in Ch. 40). In microvesicular fatty liver, small droplets collect in the endoplasmic reticulum and in secondary lysosomes that do not fuse. Hepatocytes exhibit a foamy cytoplasm and a central nucleus.
With hepatotoxins primarily affecting protein synthesis or with protein malnutrition, the lipid tends to collect in zone 1 (periportal). Microvesicular fat tends to collect in zone 3 (central).
Symptoms, Signs, and Diagnosis
Macrovesicular fatty liver most often is discovered on physical examination as nontender, smooth, diffuse hepatomegaly in an alcoholic, obese, or diabetic patient. It can present with right upper quadrant pain, tenderness, and jaundice, or it may be the only physical abnormality found after a sudden, unexpected, and presumably metabolic death.
There is a poor association between fatty liver and abnormal findings on the commonly used biochemical tests for liver disease. A mild increase may occur in alkaline phosphatase or transaminase. Ultrasound and especially CT may reveal excess fat. Fatty liver is diagnosed with certainty only by liver biopsy. Because such accumulation of fat in the liver may indicate the action of a hepatotoxin or the presence of an unrecognized disease or metabolic abnormality, the diagnosis calls for further evaluation of the patient.
Nonalcoholic fatty liver disease (nonalcoholic steatohepatitis) is an increasingly recognized accumulation of fat in the liver of females who tend to be obese or diabetic. It also occurs after jejunal bypass surgery, with malnutrition, and in association with certain drugs (eg, glucocorticoids, synthetic estrogens, amiodarone, tamoxifen). Hepatomegaly may be present. Histologic diagnosis is based on macrovesicular fatty change and lobular inflammation, sometimes accompanied by fibrosis and Mallory hyaline bodies. The condition is often detected on liver biopsy performed for other reasons, usually in asymptomatic patients who present with a two- to threefold increase in plasma aminotransferase. For diagnosis, negligible alcohol intake must be evident.
Microvesicular fatty liver has a pronounced presentation, with fatigue, nausea, and vomiting soon followed by jaundice, hypoglycemia, coma, and a disseminated intravascular coagulopathy.
Prognosis and Treatment
Potentially reversible, macrovesicular fatty liver usually is not in itself harmful. It is reversible even in potentially fatal instances (eg, in fatty liver of pregnancy, early delivery may be lifesaving). Alcoholic fatty liver may be accompanied by inflammation and necrosis (alcoholic hepatitis) and permanent damage in the form of cirrhosis. Microvesicular fatty liver presents acutely but is reversible if the patient survives.
No specific therapy is available except to eliminate the cause or treat the underlying disorder. Even obesity and diabetes mellitus with fatty liver are thought not to progress to cirrhosis. Although hepatotoxins such as alcohol and carbon tetrachloride (which also produce necrosis) can eventually result in cirrhosis, there is no evidence that a fatty liver per se leads to cirrhosis. Some other event must occur.
Nonalcoholic fatty liver disease generally has a good prognosis, without histologic or clinical progression. Some livers may show increased fibrosis and progression to cirrhosis. Management includes weight loss for obese patients, although this is of unproven benefit. Anecdotal reports indicate a benefit from ursodeoxycholic acid therapy.
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Very helpful info
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