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BACKGROUND: Breast cancer metastasizing to the liver with presence of a parenchymatous icterus presents a therapeutic dilemma. Treatment-related toxicity can be unpredictable due to altered drug clearance, and bilirubin exceeding 5,0 mg/dl is generally considered an absolute contraindication for the administration of cytotoxic agents. The pharmacokinetics of capecitabine--an active oral 5-fluorouracil prodrug for the treatment of advanced breast cancer--are not affected in patients with mild to moderate hepatic dysfunction, but there are no data available for patients with severe hyperbilirubinemia. PATIENT AND METHODS: We herein report the case of a female patient with advanced breast cancer with predominant liver metastases and severe hyperbilirubinemia (12 mg/dl). The patient received oral capecitabine at a dose of 2,500 mg/m2/day in 2 divided doses for 2 weeks, followed by 1 week rest. RESULTS: Several assessments of liver function parameters including serum bilirubin showed a decrease to normal values within 2.5 months. After 7 courses of treatment, a partial remission was confirmed by CT scan. Treatment with capecitabine was well tolerated with grade 2 hand-and-foot syndrome and mild nausea being the only side effects. CONCLUSION: This case report suggests that capecitabine can be safely administered without dose adjustment in patients with extensive liver metastases and hepatic dysfunction.
A retrospective review was made of results of conventional liver function tests in adult patients who received fat-free total parenteral nutrition (TPN) for two weeks or longer and who did not have other obvious causes for liver function abnormalities. A "meaningful" increase (greater than or equal 50% increase above baseline pre-TPN value) in SGOT levels was noted in 68% of patients, in alkaline phosphatase levels in 54%, and in serum bilirubin levels in 21% of patients. The median peak values for SGOT, alkaline phosphatase, and bilirubin were 3-, 1.9-, and 0.25-fold above the upper limit of normal, respectively. The median time interval of peak increase for each of the three tests was between 9 and 12 days after TPN was started. Liver biopsy specimens from four patients, taken when liver function values were abnormal, showed pronounced steatosis in three patients and mild periportal cholestasis in the fourth patient. The cause(s) of the elevated liver values is unknown, but possibilities include cellular damage, such as steatosis, and an "overshoot" of enzymes when starved patients are refed.
Liver function of patients with cancer of the prostate gland was studied while they were receiving oestrogen therapy. When synthetic oestrogens were given, raised values of serum aspartate and alanine amino-transferase (S.G.O.T. and S.G.P.T.) were found in about 30-50% of them. As treatment continued the increased values usually returned to normal levels. No serious liver damage was observed, though the serum bilirubin content rose temporarily in some patients.
Primary organ non-function occurs in 2-17% of patients after liver transplantation (LTX). Liver function tests focus on hepatocytes, underestimating the importance of non-parenchymal cells such as endothelium. Liver endothelium metabolises hyaluronan (HA). The function of endothelium can be estimated by measuring the concentration of HA in serum. We evaluated two organ donor groups, the first with HA levels below 200 microg/l and the second with HA levels above 200 microg/l. Both groups degraded more than 60% of HA during the first 6 h after reperfusion. Determination of hyaluronic acid in patients after LTX gives valuable information about the functional state of liver endothelium. It does not necessarily parallel the release of transaminases. In this study, there was no correlation between the levels of HA in the donor and posttransplant liver function. High HA in organ donors are most likely a consequence of different degrees of trauma and a higher release of HA into the circulation rather than impaired endothelial function.
Antipyrine kinetics, after oral administration to patients with changes in liver function were determined from data obtained by measuring drug concentration in saliva and plasma. Antipyrine kinetics calculated from saliva concentrations did not diverge from values obtained from plasma antipyrine measurements. The saliva and plasma clearance rates were reduced in parallel in subjects with liver parenchymal disease, and showed similar increases in subjects with normal liver treated with enzyme inducing drugs as compared to values in subjects with normal liver and no inducing treatment. The clearance values were related to changes in liver histology. The area under the concentration/time curve was increased in subjects with altered liver histology, and reduced in subjects with normal liver and therapy with enzyme inducing drugs. Antipyrine saliva clearance seems to be a useful method for assessing hepatic drug metabolism and liver microsomal function in vivo in subjects with varying degrees of liver function damage.
The diagnostic usefulness of a single determination of serum cholinesterase activity to distinguish between overt liver disease and non-liver disease clinical problems in which a few of the traditional liver function tests are abnormal was assessed. Using three groups of subjects comprising liver disease, non-liver disease, and healthy controls, we have shown that serum cholinesterase activity helped to distinguish between liver disease and non-liver disease in subjects who had abnormality of a few liver function tests. Serum cholinesterase activity helped also to distinguish between the liver disease subjects and healthy controls. There was no statistically significant difference between the mean serum cholinesterase activities of non-liver disease subjects and healthy controls. We suggest that determination of serum cholinesterase activity is a cost-effective diagnostic means of differentiating between overt liver disease and non-liver diseases where there may be aberration of some liver function tests.
To evaluate the clinical utility of a new method with dynamic single photon emission computed tomography (SPECT) and scatter and attenuation compensation to estimate both total and regional liver function quantitatively. Five controls, 20 patients with chronic liver disease, and 2 patients with Budd-Chiari syndrome were studied. Dynamic liver SPECT data were acquired during 20 minutes after injection of Technetium (Tc)-99m diethylenetriaminepentaacetic acid (DTPA) galactosyl human serum albumin (GSA) with scatter and attenuation compensation. The binding rate constant of Tc-99m GSA (Ku) was derived quantitatively from the Patlak plot based on kinetic models for GSA receptor binding. The mean Ku was obtained by dividing the Ku value (total Ku) by the liver volume. Both total and mean Ku were significantly lower in patients with chronic liver disease than in controls (302 +/- 112 vs. 523 +/- 78 ml/min; p < 0.001, 0.26 +/- 0.11 vs. 0.43 +/- 0.03 ml/min/cm3; p < 0.001). In the patient group, both total and mean Ku were significantly correlated with the results of conventional liver function tests and the histological severity of chronic liver disease. In 2 patients with Budd-Chiari syndrome, the mean Ku was lower in the right lobe, where the hepatic veins were occluded, than in the left lobe, where draining veins were patent. In conclusion, this method is a reliable diagnostic technique for estimating total and regional liver function.
Microvascular exchange in the liver is governed by fenestrations in sinusoidal endothelial cells and can be manipulated pharmacologically. Microvascular exchange is affected in alcoholic liver disease and cirrhosis, the former leading to a loss of fenestrae, the latter to sinusoidal capillarization and thereby to loss of liver function in disease.
Five laboratory assays are commonly called liver function tests (LFTs), although these tests are neither specific to the liver nor true measures of liver function. As a result, alanine aminotransferase (ALT or SGPT), aspartate aminotransferase (AST or SGOT), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP) and bilirubin have proven problematic for clinicians and risk selection professionals alike. Further, underwriters and insurance medical directors find these tests difficult to assess because of the lack of data directly relating LFT elevations to mortality outcome. Nonetheless, the tests are frequently encountered, so a strategy for evaluating abnormal results is critical to ensure accurate and fair pricing. This paper reviews basic information on LFTs, available mortality data and the application of this knowledge to the underwriting process.
The systemic availability of total prednisone and unbound prednisolone, and the urinary excretion of 6 beta-hydroxyprednisolone, were measured after an oral dose of prednisone and an i.v. dose of prednisolone in 22 patients covering a wide range of liver function (galactose elimination capacity ranging from 3.3 mg/min X kg body wt to 9.2 mg/min X kg body wt). The area under the plasma concentration versus time curves of prednisolone and of prednisone decreased with increasing galactose elimination capacity. This dependency of the steroid concentrations on liver function was attributed to a decreased metabolic clearance and not to an increased systemic availability of the steroid given p.o. in patients with impaired liver function. The fractional excretion and the fractional clearance of 6 beta-hydroxyprednisolone declined with decreasing metabolic clearance rate of prednisolone or with decreasing galactose elimination capacity. Thus, the enzymes involved in the 6 beta-hydroxylation are not spared as liver function declines, and the exposure to the biologically active unbound prednisolone is increased in patients with impaired liver function in relation to the amount of prednisone or prednisolone administered.
We have already reported that the ratio of portal venous flow 30 min after oral intake of glucose 75 g to that before intake (PVFR30), measured using pulsed-Doppler ultrasonography (US), correlated significantly with other indicators of liver function and that it could be used to estimate hepatic function before surgery, including liver resection. In this study, to assess the disadvantages of pulsed-Doppler ultrasonography, PVFR30 was measured using two-dimensional (2D) phase-shift (PS) magnetic resonance imaging (MRI). PVFR30 was measured in 17 patients and 7 volunteers: 13 with liver cirrhosis (LC) and 11 without LC (non-LC). Portal venous flow could be measured in all patients without any disturbance of intestinal gas or patient fat, or the high degree of technical skill that Doppler US requires. PVFR30 was significantly lower in the LC group than in the non-LC group. In addition, it correlated significantly with other indicators of liver function, including the indocyanine green clearance test, prothrombin time, hepaplastin test, and cholinesterase activity. These results suggest that PVFR30 measured by 2D PS MRI can be used to estimate liver function, and that this MRI method can be performed more easily than pulsed-Doppler US.
Controversial data exists concerning the impact of immunosuppressive therapy on the development of post-transplantation diabetes mellitus (PTDM). Therefore, we investigated glucose metabolism in healthy donors and in recipients of living-donor liver transplants (LD-LTX, n=18) without pre-existing diabetes mellitus before, on day 10, month 6, and month 12 after intervention. The computer-assisted analysis of glucose, insulin, and C-peptide profiles obtained from frequently sampled intravenous glucose tolerance tests allows to achieve an integrated view of factors controlling glucose tolerance, i.e., insulin sensitivity (SI), first and second phase insulin secretion (phi1 and phi2). SI of donors declined by day 10 after operation (SI 2.65 +/- 0.41 vs. 4.90 +/- 0.50 10(-4) minute(-1) microU ml(-1), P < 0.01) but returned to values as before after 6 months. Phi1 did not change. Phi(2), however, significantly increased by day 10 (8.57 +/- 0.82 10(9) minute(-1) to 13.77 +/- 1.53 10(9) minute(-1), P < 0.01) but was in the same range as before after 6 months. In parallel to donors SI of recipients progressively increased after LD-LTX. Phi1 did not alter in recipients. Phi2 continuously decreased and was not different from donors by month 12. The extent of liver injury assessed by liver enzyme concentrations and liver function represented by cholinesterase activity, albumin, and INR were closely related with changes of SI in donors and recipients during the first year after intervention. In conclusion, the extent of liver damage plays a predominant role in regulating glucose tolerance. No impact of immunosuppressive therapy on SI, phi1 and phi2 was detected.
The incidental findings of increased alanine aminotransferase (ALT) and aspartate amino transferase (AST) after uneventful laparoscopic cholecystectomy (LC) prompted us to investigate the incidence and the clinical significance of this phenomenon. Changes in liver function test after LC (n = 55) were compared with those after OC (n = 16). Liver function tests were obtained preoperatively and postoperatively on days 1, 2, and 7. All of the patients fulfilled the selection criteria: normal preoperative liver function test and no endoscopic retrograde cholangiopancreatography, common bile duct exploration, or postoperative biliary complications (injury, infection, or obstruction). Converted cholecystectomies were also excluded. During LC, the intra-abdominal pressure was maintained within the conventional range of 14 to 15 mm Hg. ALT had doubled in the first 48 hours from the preoperative mean in 58.2 per cent in LC patients versus only 6.3 per cent in the OC group. AST doubled from the preoperative mean value in 38.2 per cent in the LC group versus only 6.3 per cent in the OC group. By the 7th postoperative day, the enzymes returned to the preoperative values in both the LC and the OC group. In many instances, a significant increase in ALT and AST blood levels occurred after uneventful LC. The phenomenon is transient as these enzymes returned to normal value within 7 days. These changes are clinically silent in patients with a normal liver function.
Serum cholesterol reflects poorly cholesterol metabolism. From serum noncholesterol sterols cholestanol, campesterol, and sitosterol are surrogate markers of cholesterol absorption, but reflect also cholestasis, while those of lathosterol reflect cholesterol synthesis and hepatic parenchymal function. We investigated these sterols at end-stage of primary biliary cirrhosis (PBC) - prior to liver transplantation and shortly after transplantation in 67 patients to show their role as index of cholestasis and parenchymal liver function. Median preoperative values of cholestanol were increased 7.6 times, those of plant sterols 1.6-3.7 times above and the campesterol/sitosterol ratio was decreased twice below our control values, respective lathosterol levels being mainly subnormal. After transplantation, the proportions to cholesterol of the absorption markers decreased, and those of synthesis markers and the ratios of campesterol/sitosterol increased significantly. Thus, surrogate sterol markers of cholesterol absorption and synthesis in serum are also good clinical markers of chronic cholestasis and degree of hepatic parenchymal cell function in PBC. Postoperative improvement of serum sterol profile indicate clinically good function of the liver graft.
To determine if fasting bile salt concentrations are an accurate indicator of pre-existing and methotrexate-induced liver disease in patients with psoriasis, the plasma concentrations of conjugated cholate, chenodeoxycholate and sulpholithocholate were measured in 18 patients being assessed for methotrexate therapy and 21 receiving long-term therapy. The results were compared with other liver function tests and liver histology. The liver function tests were a poor indicator of occult liver disease and, whilst fasting bile salts appeared more sensitive, they were still unreliable and inadequate for the clinical assessment of the hepatopathy associated with psoriasis. The reasons for these discrepancies are discussed.
1 The effects of methyldopa withdrawal on liver function and drug metabolism were investigated in ten elderly females suffering from the drug-induced orthostatic reaction and resistant hypertension. 2 There was a significant increase in serum albumin level, antipyrine metabolism and urinary excretion of D-glucaric acid 6 months after the methyldopa withdrawal. 3 The results suggest that patients treated with methyldopa might show a reduced metabolizing ability in spite of normal liver function tests.