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Acetaldehyde, the first product of ethanol in hepatocytes, can react with protein to form acetaldehyde-protein adducts (APAs). Because it has been suggested that these adducts could be involved in the pathogenesis of ethanol-induced hepatic lesions and in fibrogenesis, we performed an ultrastructural immunohistochemical study to precisely define the cellular and subcellular localization of APAs. A preembedding technique of indirect immunoperoxidase was performed in liver biopsy specimens from eight patients with alcoholic liver disease, using a specific antiserum against APAs. In all specimens, APAs were detected in the rough endoplasmic reticulum, in some peroxisomes, and in the cytosol of hepatocytes. In four patients with steatofibrosis or cirrhosis, labeling of Ito cells was also observed. In these cases, the same staining pattern was observed in the cytoplasmic processes of myofibroblasts in areas of fibrogenesis. When isolated rat Ito cells were incubated in the presence of acetaldehyde, APAs were also detected in the cytoplasm. These results show that APA formation occurs in hepatocytes at the sites of acetaldehyde production. Detection of APAs in human and rat Ito cells strongly suggests that acetaldehyde can diffuse into Ito cells and bind to cytoplasmic proteins to form local APAs. Because Ito cells are the main effector cells of liver fibrosis, detection of APAs in these cells points to their possible involvement in liver fibrogenesis.

Brainstem auditory (BAEPs) and somatosensory evoked potentials (SEPs) have been shown to be useful in detecting brainstem or cortical dysfunction in neurological diseases and in combination with other methods to diagnose brain death (37,38). These neurophysiological methods are simple and easy to perform. BAEPs and SEPs can even be easily recorded in intensive care units and guarantee a standardized examination. Moreover, these methods require no extensive patient cooperation and are not heavily influenced by learning effects. The role of BAEPs in the evaluation and diagnosis of hepatic encephalopathy is not clear. BAEPs are obviously strongly influenced by the etiology of liver disease and are normal in viral hepatitis, but prolonged in alcoholic liver disease, Wilson's disease or in hepatic coma (8,12). Unfortunately, BAEPs were not compared to psychometric tests. There was no clear-cut differentiation between various hepatic encephalopathy-gradings. At present, the use of BAEPs in the detection of subclinical hepatic encephalopathy cannot be recommended, whereas in comatose patients BAEPs can be useful as a prognostic marker and for follow-up examinations (12). Recently, Pozessere et al. (12) examined 13 comatose patients with advanced coma stages (Glasgow coma scale 5-10) and recorded unspecific changes in their EEG tracings. In all cases of hepatic coma and in one intoxicated patient they found prolongation of interpeak latencies. In addition, in this small study the interpeak latencies correlated well with the clinical outcome of the patients. Only two studies were performed using SEPs to detect neurophysiological alterations in hepatic encephalopathy (32,33). The design as well as the results of these studies are quite different. Despite the small number of patients (n = 10), the prolongation of late components in 50% of patients with hepatic encephalopathy stage 0 could be a promising result (32). The value of SEPs in detecting subclinical hepatic encephalopathy is rather undefined. The fact that the generation of SEPs is due to an activation of complex structures of the central nervous system justifies the need for further investigations with this modality. The recording of visual evoked potentials requires much more methodological and technical effort than the recording of BAEPs or SEPs. The discrimination between pattern reversal (PVEP) and flashlight (FVEP) stimulation is highly important for the proper interpretation of the published data. Most of the studies were done using FVEPs, which are in particular clinically relevant for comatose patients (31). The conclusions of the authors using FVEPs (22-25) are not supported by the American Electroencephalographic Society (31).(ABSTRACT TRUNCATED AT 400 WORDS)

We have shown that lipid peroxidation stimulates collagen alpha 1(I) gene transcription in cultured cells. Because increased lipid peroxidation and collagen production coexist in many hepatic disorders, including experimental carbon tetrachloride intoxication, we investigated whether lipid peroxidation modulates collagen gene expression in rats treated with carbon tetrachloride. In this animal model, we show colocalization of increased collagen alpha 1(I) mRNA with lipid peroxidation by means of in situ hybridization and immunohistochemical study for malondialdehyde and 4-hydroxynonenal protein adducts, respectively. However, allyl alcohol treatment, which induced a similar degree of hepatocellular injury but without aldehyde-protein adducts, did not increase collagen alpha 1(I) gene expression, suggesting that hepatocyte necrosis is not sufficient to induce the expression of collagen type I. Furthermore, in the absence of an inflammatory response, coculture experiments of hepatocytes and Ito cells treated with carbon tetrachloride indicate that hepatocytes exert a "paracrine" stimulation of both lipid peroxidation and collagen gene expression in Ito cells. These experiments suggest that hepatocyte lipid peroxidation plays a major role in the regulation of collagen alpha 1(I) gene expression by Ito cells and that it may be a link between hepatocyte injury and hepatic fibrosis.

Acetaldehyde, the first product of ethanol oxidation, has been shown to stimulate collagen gene expression and to form protein-acetaldehyde adducts. Because little is known about these adducts in human liver tissue, we assessed, with an immunohistochemical procedure, the presence and location of acetaldehyde-protein adducts in liver biopsy specimens of alcoholic patients. In addition, we correlated the presence of adducts with the progression or subsequent occurrence of liver fibrosis. The group included 106 patients with high alcohol consumption (>90 gm ethanol/day for the last 5 yr), 10 nonalcoholic patients with normal livers and 23 patients with other liver diseases. Sixty-four of the 106 alcoholic patients had a second liver biopsy, whose specimen was used to assess the progression of liver fibrosis. Polyclonal antibodies were produced against homologous low-density lipo-protein purified from rabbit serum and modified in vitro in the presence of acetaldehyde. Protein-acetaldehyde adducts could be detected by immunohistochemistry in biopsy specimens of 90 alcoholic patients (85), in none of the 10 nonalcoholic patients with normal livers and in 65 of the patients with nonalcoholic liver disease. Acetaldehyde-modified epitopes were detected in the intracellular and extracellular compartment. Intracellular protein-acetaldehyde adducts were localized in the cytoplasm of hepatocytes with a more intense staining in zone 3. No correlation existed between the intensity of intracellular staining and the histologically assessed severity of liver disease. Extracellular acetaldehyde-modified epitopes were detected in 55 (52) biopsy specimens of alcoholic patients, with 33 of 39 (85) patients with alcoholic hepatitis or alcoholic hepatitis in cirrhosis, in none of the 10 nonalcoholic patients with normal livers and in 3 (13) of 23 patients with other liver diseases. Extracellular protein-acetaldehyde adducts were colocalized within the extracellular matrix. A brighter staining was seen in areas of histologically assessed active fibrogenesis and no or low staining in the well-organized older fibrous tissue. The presence of extracellular acetaldehyde adducts in the first biopsy specimen was significantly correlated to progression of liver fibrosis in the second biopsy specimen (p < 0.05). The results of our study indicate that covalent crosslinks between acetaldehyde and proteins could be involved in the pathogenesis of liver fibrosis. (Hepatology 1994;19:367–374).

In this study, the capacity of hepatocytes to degrade prostaglandins diminished if the partial oxygen pressure dropped below 5%. This decrease was accompanied by an increased lactate/pyruvate ratio, a decrease in fatty acid oxidation and a drop in the ATP level. The degradation of exogenous adenosine increased with decreasing oxygen tension. At a partial oxygen pressure below 10%, the conversion of uric acid to allantoin, the final catabolite of adenosine in the rat, was strongly inhibited, resulting in the accumulation of uric acid in the medium. A good correlation was observed between the partial oxygen pressure, the oxidation of uric acid to allantoin and the degradation of prostaglandins D2 and E2, suggesting a peroxisomal pathway of hepatic prostaglandin oxidation. Subcellular fractionation of liver homogenates revealed peroxisomes as the site of degradation of prostaglandins D2 and E2 augmented by cytosolic components. The similarity of the degradation products found in the cell-free system, in hepatocytes and in the perfused liver further supports a peroxisomal degradation of prostaglandins in vivo. Stimulated liver macrophages (Kupffer cells) produced the same amount and pattern of eicosanoids at 1% and 21% O2. Even the formation of superoxide remained unaffected down to a partial pressure of 1%. At partial O2 pressures below 1%, the production of prostaglandins and superoxide became strongly inhibited. These results indicate that essential oxygenation reactions in activated Kupffer cells, including prostaglandin synthesis, possess high affinities to oxygen, while the peroxisomal pathway of prostaglandin oxidation in hepatocytes is sensitive to an O2 tension as low as 5%.

Eine 39-jahrige Patientin stellt sich mit uberraschender Erhohung der Leberwerte vor (GOT 1150 U/I; GPT 1662 U/l). Sie klagt uber leichte Ubelkeit, Inappetenz und epigastrische Beschwerden. Die γ-Globuline sind auf das 1,8-Fache der oberen Norm erhoht, die ANA ergeben einen Titer von 1:320.

Giant cell hepatitis is a very rare disease of unknown origin. It has been hypothesized that drugs, viral infections, or autoimmune reactions may play a pathogenetic role. Here, we describe a 33 year old patient with bacterial bronchitis who was treated with doxycycline (100 mg/d) for one week. Furthermore the patient complained of malaise and a distinct jaundice. Liver parameters increased dramatically (AST 4670 U/l, ALT 5350 U/l, bilirubin 226 µmol/l) and liver function was impaired (INR = 1,45). The ultrasound scan showed a hepatomegaly with no signs of cirrhosis, normal spleen size and normal bile ducts; liver perfusion was normal. No evidence of Wilson's disease, hemochromatosis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis A, B, C and E, HIV, CMV, VZV, adenoviral infections, or paracetamol intoxication was found. Subsequently, the patient developed acute liver failure (AST 2134 U/l, ALT 2820 U/l, bilirubin 380 µmol/l, INR 3.0) and a beginning renal failure. Therefore, he was transferred to our transplant center. Due to increasing confusion and somnolence due to cerebral edema mechanical ventilation was needed. Because of an acute renal failure and severe hepatic encephalopathia MARS-hemodialysis was performed. Three weeks after the appearance of the jaundice he underwent liver transplantation (MELD 40). Surprisingly, in the explanted liver the diagnosis of giant cell hepatitis was made. Today--2 years after successful liver transplantation--the patient is in very good condition with normal liver function. In conclusion, giant cell hepatitis is a rare cause of acute liver failure that is often recognized only histologically.

Background and objective If transillumination is not possible, percutaneous endoscopic gastrostomy (PEG) is contraindicated. In these cases the stomach had so far to be punctured directly during radiological monitoring. A new method is described which combines endoscopy and computed tomography (CT) for performing a percutaneous endoscopic gastrostomy. Patients and methods Among 189 patients who were to have the procedure there were eleven (nine men, two women) in whom transillumination was not possible. After endoscopic insufflation of air PEG was done under CT guidance, using the common pull-through technique. Results The combined method was successful in ten of the eleven patients without complication. In one patient with hepatomegaly and interposition of the transverse colon PEG was not possible even with CT guidance. Conclusions The combined endoscopic-radiological method is practicable and safe in cases in which transillumination is not possible. There are several advantages compared with direct puncturing: The common pull-through technique can be used; radiological exposure is low and other clinically relevant findings may be revealed by the endoscopy.

Ultrasonographic determination of gallbladder motility is sparsely performed in clinical practice as the examination is considered to be time consuming and there is uncertainty about a number of parameters possibly influencing the results. The aims of this study were a) to establish normal values for a simple ultrasonographic test and b) to evaluate the influence of different parameters on gallbladder motility.In 62 systematically age- and sex-matched healthy volunteers, ultrasonographic measurements of gallbladder volume (ellipsoid method, planimetry and sum-of-cylinders method) were performed fasting and 5, 10, 20, 30, 40, 50, 60, 70 and up to 75 min after stimulation with a standardized high-caloric liquid meal.Using the ellipsoid method, gallbladder fasting volume (V0) reached a mean value (+/- SD) of 24.6 +/- 10.0 mL with an ejection fraction of 65.9 +/- 19.1%. Age, gender and hair color did not influence parameters of gallbladder contraction. Body mass index showed a weak correlation with V0 but not with ejection fraction. There was a highly significant correlation between the ellipsoid method and longitudinal planimetry and the sum-of-cylinders method, respectively.Ultrasonographic measurement of gallbladder motility in healthy volunteers shows a very wide scattering of normal values. In the interpretation of gallbladder emptying, age, gender and body mass index do not have to be considered. Determination of gallbladder motility may be performed by a rather simple approach with oral stimulation and ellipsoid method or longitudinal planimetry as easily applicable ultrasonographic measurements.

Eine gastroosophageale Refluxkrankheit (GERD) liegt vor, wenn ein Risiko fur organische Komplikationen durch einen gesteigerten gastroosophagealen Reflux (GER) und/oder eine signifikante Storung der Lebensqualitat infolge der Refluxbeschwerden besteht (C). Unter GERD werden die verschiedenen Manifestationen NERD („non erosive reflux disease“), erosive Osophagitis (ERD), Barrett-Osophagus und extraosophageale Manifestationen subsumiert (C).

The aim of this study was to investigate the relationship between esophageal dysfunction and pulmonary involvement in patients with systemic sclerosis (SSc).Pulmonary function parameters were compared between groups of patients with and without manometric evidence for SSc-induced esophageal dysmotility.Twenty-six of 43 patients (60.5%) exhibited a marked hypo- or aperistalsis of the smooth muscle portion of the esophagus. Total lung capacity, inspiratory vital capacity, and forced vital capacity were significantly lower in patients with esophageal dysfunction compared with those with normal esophageal peristalsis (p0.001). Patients with the diffuse form of SSc (n = 20) had significantly lower values for total lung capacity and inspiratory vital capacity compared with patients with the limited type of SSc (n = 23; p0.05).There is a significant association of esophageal dysmotility with reduced lung volumes in SSc. Possible explanations for these findings are pulmonary damage due to increased gastroesophageal reflux and, more likely, simultaneous involvement of the lungs and the esophagus in the disease process.

Lipid peroxidation is an autocatalytic mechanism leading to oxidative destruction of cellular membranes. The deleterious consequences of this mechanism are related in part to the formation of reactive aldehydic products that bind to intra- or extracellular molecules to form adducts. Specific antibodies directed against malondialdehyde (MDA) and 4-hydroxynonenal (HNE) adducts, major aldehydic metabolites of lipid peroxidation, allowed us to investigate in situ, with an immunohistochemical procedure, the occurrence of lipid peroxidation in a panel of different chronic liver diseases. Intracellular HNE and MDA adducts were detected respectively in 24 of 39 cases (62%) and in 12 of 34 cases investigated (35%). They were localized mainly in the cytoplasm of hepatocytes, with the strongest staining observed in hemochromatosis, Wilson's disease, and in areas of acute alcoholic hepatitis in cases of alcoholic liver diseases. A peculiar pattern of immunostaining was observed in primary biliary cirrhosis where biliary cells of destroyed but also intact bile ducts strongly expressed HNE adducts. The liver extracellular matrix also displayed MDA adducts (30 of 34 cases, 88%) and HNE adducts (23 of 39 cases, 59%). While HNE adducts were specifically localized on large bundles of collagen fibers, MDA adducts were detected in a thin reticular network and in sinusoidal cells around portal tracts or fibrous septa. In conclusion, lipid peroxidation by-products are detectable in chronic liver diseases. Immunohistochemical results suggest that this mechanism is implicated very early in the pathogenesis of some of these diseases.

AIMS: To assess the occurrence of lipid peroxidation in chronic hepatitis C and to evaluate its relation to pathological features and liver iron concentrations. METHODS: Liver biopsy samples of 43 patients with untreated chronic hepatitis C were studied by immunohistochemistry using specific antibodies directed against two major aldehyde metabolites of lipid peroxidation, malondialdehyde (MDA), and 4-hydroxynonenal (HNE). RESULTS: MDA and HNE adducts (aldehydes covalently linked to another molecule) were detected in the liver samples in 77% and 30% of cases, respectively. MDA adducts were detected both in the extracellular matrix and sinusoidal cells localised in areas of periportal and lobular necrosis. HNE adducts appeared in the cytoplasm of only a few hepatocytes. Comparison of the semiquantitative assessment of adducts (MDA and HNE indexes) with the grading and the staging of chronic hepatitis showed that the MDA index was correlated with fibrosis score (p < 0.001) and the grade of activity (p < 0.01). There was also a tendency to correlation with liver iron concentration (p = 0.09). No correlation was observed between the HNE index and pathological features or liver iron concentration. CONCLUSION: Lipid peroxidation products are detectable in the liver of chronic hepatitis C patients. The presence of MDA adducts in areas of active fibrogenesis and the correlation between the MDA index and fibrosis score suggest a role for lipid peroxidation in liver fibrosis.

Hepatic encephalopathy is a common problem in cirrhosis. The pathogenesis of this complication of advanced liver disease still remains unclear. Magnetic resonance spectroscopy was used to assess prospectively cerebral metabolism in 51 patients with histologically proven cirrhosis (Child-Pugh classes A, B, and C, 18, 18, and 15, respectively) and 36 healthy volunteers. According to the results of psychometric tests, overt hepatic encephalopathy, subclinical encephalopathy, and no encephalopathy were found in 14, 21, and 16 patients, respectively. Myoinositol/creatine ratios in gray (.36 +/- .17) and white (.35 +/- .22) matter voxel were reduced significantly (P < .0001) in cirrhotic patients compared with healthy volunteers (gray matter, .51 +/- .11; white matter, .64 +/- .16). In addition, patients showed a significant reduction (P = .024) in white matter choline/creatine ratio (.77 +/- .27) compared with controls (.92 +/- .25), and glutamine/glutamate level was elevated in cirrhotic patients compared with controls (gray matter, P < .0001; white matter, P = .036). Changes in cerebral myoinositol and glutamine/glutamate levels correlated significantly with the severity of hepatic encephalopathy (P < .0001). However, these metabolic alterations were also detected in patients without hepatic encephalopathy (normal psychometric test results). N-acetyl aspartate/creatine ratios did not differ between patients and controls. Magnetic resonance imaging detected bright basal ganglia in 37 patients, which correlated significantly with portal-systemic shunting and elevation of glutamine/glutamate, but not with the degree of hepatic encephalopathy. In conclusion, magnetic resonance imaging and spectroscopy showed that alterations of cerebral metabolism are common in patients with cirrhosis, even without evidence of clinical or subclinical hepatic encephalopathy. (Hepatology 1997 Jan;25(1):48-54)

In a 58-year-old woman with erythropoietic protoporphyria, asymptomatic liver involvement had been diagnosed 12 years earlier. For more than 20 years the patient had been known to have symptomatic gallstones. A mild polyneuropathy of the lower limbs had been diagnosed several years ago. In December 1992, she presented with colicky upper abdominal pain, dyspepsia and mild jaundice. Diagnosis of beginning cholestasis in erythrohepatic protoporphyria and coincidental choledocholithiasis was made. A causal relation between choledocholithiasis and deterioration of liver function was assumed. Endoscopic extraction of the bile duct stones, however, could not prevent the development of terminal hepatic failure. Biochemically, an excessive protoporphyrinemia and coproporphyrinuria were found. Five weeks after presentation, the patient underwent orthotopic liver transplantation. Immediately after the operation she developed a severe axonal neuropathy with cranial nerve involvement. One year after transplantation, her general condition has markedly improved, but there is still a disabling polyneuropathy. Recently, there were single reports on patients with very similar neurological symptoms following liver transplantation in erythropoietic protoporphyria. This case supports the assumption of a distinct protoporphyrin-induced neural damage in severe hepatic failure.

In 20 patients with systemic sclerosis (SSc) and 24 healthy controls, gallbladder motility was evaluated by abdominal ultrasonography after stimulation by a standard liquid meal. Results from patients with normal and disturbed oesophageal function were analysed separately in order to investigate the significance of gallbladder motility as a parameter for gastrointestinal involvement in SSc. All patients showed a marked decrease in gallbladder size after stimulation (patients 61 +/- 13%; controls 48 +/- 12%). Patients with oesophageal dysfunction (n = 12) had a slightly lower gallbladder contraction (maximal decrease = 58 +/- 13%) when compared to patients with normal oesophageal function (n = 8; 66 +/- 13%); however, this difference was not statistically significant. Gallbladder motility in patients with SSc was not reduced when compared with healthy controls. SSc-induced oesophageal dysfunction was not associated with impaired gallbladder motility. Thus, measurement of gallbladder emptying is not a helpful tool when looking for gastrointestinal involvement in SSc.

Pharmacological management of acute variceal hemorrhage appears to be effective in patients with liver cirrhosis. Somatostatin and presumably its longer-acting analog, octreotide, are more efficient and safer than other vasoconstrictors like vasopressin, terlipressin or their combination with nitroglycerin. Drug treatment, however, usually represents only a valuable adjunct to other measures to stop bleeding such as endoscopic variceal sclerotherapy. Prophylaxis of first bleeding by beta-blockade appears justified in patients at a high risk of bleeding which still has to be defined more precisely. Prevention of recurrent hemorrhage can be effective in some but not in all of the patients with liver cirrhosis and a first bleeding episode. Treatment of patients with good liver function under direct control of the wedged hepatic vein pressure gradient presumably will reduce the failure rate of prophylaxis with beta-blockade.

In mammalian cells, nucleoside transport usually is mediated by facilitated diffusion. In addition, a Na(+)-dependent, concentrative nucleoside transport system has been detected in several tissues but not the liver. To further clarify hepatic nucleoside transport mechanisms, we measured the uptake of [2-14C]uridine (2 to 100 mumol/L) and of [8-14C]adenosine (10 to 75 mumol/L) by the isolated perfused rat liver in the presence or absence of extracellular sodium or specific inhibitors of facilitated nucleoside diffusion. Uridine transport and metabolism were monitored by the release of labeled catabolites including 14CO2, which indicated complete degradation of the pyrimidine. Adenosine, uridine and uridine catabolites were measured in the effluent perfusate by reversed-phase high-performance liquid chromatography and a radioactivity flow monitor. The existence of a Na(+)-dependent nucleoside transport system could be inferred from the following observations: (a) Sodium depletion caused a strong inhibition of nucleoside transport reflected by an up to threefold and 15-fold increase in extracellular uridine and adenosine, respectively. The sodium-dependent transport of uridine was saturated when the influent uridine concentration was raised beyond 20 mumol/L. No such saturation was observed for much higher concentrations of adenosine used (10 to 75 mumol/L). (b) Na(+)-free perfusion resulted in a strong suppression of the release of uridine catabolites by the liver. Complete uridine breakdown was depressed to 7% of the amount of 14CO2 released in the presence of sodium and at influent uridine concentrations below 20 mumol/L. (c) Inhibition of uridine (10 mumol/L) transport and degradation was observed after coperfusion with adenosine, deoxyadenosine, guanosine and deoxyguanosine.(ABSTRACT TRUNCATED AT 250 WORDS)

To the Editor: In his letter, Dr. Yarze points out that according to literature there appears to be no difference in the frequency and severity of esophageal dysfunction in patients with the diffuse and the limited subset of systemic sclerosis (SSc). He criticizes that in our study (1) patients with the diffuse variant of SSc were significantly overrepresented in the group with esophageal dysfunction.

Adenosine-degrading enzymes within the liver lobule can modulate both vascular and metabolic effects of circulating adenosine in the liver. Since it has not been fully established whether nonparenchymal cells participate in the elimination of sinusoidal purines, isolated Kupffer cells and endothelial cells were tested for their capacity to degrade extracellular purines. After perfusion and digestion of rat livers by collagenase, the resulting mixed cell population was separated by centrifugal elutriation. The isolated parenchymal and nonparenchymal cells were incubated for up to 2 hr in the presence of [8-14C]adenosine, [8-14C]guanosine and [8-14C]hypoxanthine (50 μmoles per liter). In the deproteinized medium, adenosine, guanosine, inosine, adenine, guanine, xanthine, hypoxanthine, uric acid and allantoin were separated by reversed-phase high-performance liquid chromatography. Radioactive peaks were collected and counted. Nonparenchymal cells catalyzed the degradation of adenosine into inosine and hypoxanthine. However, the formation of xanthine, uric acid or allantoin from adenosine could only be detected in hepatocyte suspensions. Within 15 min, adenosine was completely eliminated from the medium by Kupffer cells, whereas endothelial cells catabolized only less than half of the initial amount of the adenine nucleoside during this time period. Accordingly, incubation of nonparenchymal cells in the presence of hypoxanthine did not result in the formation of further breakdown products of the purine, whereas its catabolites slowly accumulated in the medium of hepatocytes. Guanosine conversion into guanine and xanthine was much slower in endothelial cells as compared to Kupffer cells and hepatocytes. Further degradation of xanthine occurred only in the presence of hepatocytes. The results of our study indicate a rapid breakdown of extracellular purine nucleosides by Kupffer cells and a much slower catabolism by endothelial cells. Further degradation of hypoxanthine or xanthine was exclusively catalyzed by hepatocytes, indicating metabolic cooperation between parenchymal and nonparenchymal liver cells.