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1 From the Departments of Gastroenterology (EC and MAG) and Biochemistry (JMH-P, LF, CP, and AC), Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain
2 Supported by grants from the Fondo de Investigación Sanitaria (FIS 96/1368) and Instituto de Salud Carlos III (C03/02) of the Spanish Government. JMH-P received a grant from the Fondo de Investigación Sanitaria of the Spanish Government (BAE 98/5066) and the Fundació per a la Recerca Biomèdica Germans Trias i Pujol. 3 Address reprint requests to MA Gassull, Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, 08916 Badalona, Catalonia, Spain. E-mail: mgassull{at}ns.hugtip.scs.es.
ABSTRACT
Background: In rats, 30–70% of dietary fatty acids (FAs) are absorbed through the portal vein. Whether this occurs in humans is unknown, but it may occur in persons with cirrhosis, who show a blunted chylomicronemic response to dietary fat without significant steatorrhea.
Objective: The objective was to investigate whether portal FA absorption occurs in humans with cirrhosis.
Design: Six control subjects and 10 patients with (n = 5) and without (n = 5) cirrhotic ascites were fed [1-13C]palmitic and oleic acids in a test meal. Samples were drawn before and 30, 60, 90, 120, 240, 360, 480, and 720 min afterward for plasma [1-13C]-labeled FAs and breath 13CO2 assay. Fecal [1-13C]-labeled FAs were also measured.
Results: [1-13C]-Labeled FAs increased in chylomicrons in all groups, but less in ascitic cirrhotic patients, because their median area under the curve from 120 to 720 min was significantly lower than in the control subjects for labeled palmitate [520 (interquartile range: 192–1137) compared with 2862 (2674–4175) µmol · min/L] and oleate [829 (781–1263) compared with 3119 (2939–4986) µmol · min/L]. [1-13C]-Labeled FA enrichment of VLDL was also lower in cirrhotic patients. [1-13C]-Labeled FA in free FAs peaked earlier in ascitic than in nonascitic patients and control subjects, mainly for [1-13C]oleate, and the median area under the curve from 0 to 120 min was significantly higher in ascitic patients than in control subjects [301 (255–400) compared with 48 (34–185) µmol · min/L]. Fecal excretion of [1-13C]-labeled FA was negligible and not significantly different between groups.
Conclusions: The low [1-13C]-labeled FA concentrations in chylomicrons and VLDL, without increased fecal losses, confirm previous data in cirrhotic patients with the use of an unlabeled fat load. The earlier [1-13C]-labeled FA appearance in free FAs supports the portal absorption of dietary fat in patients with advanced cirrhosis with spontaneous portal-systemic shunting.
Key Words: Cirrhosis • fat absorption • stable isotopes • [1-13C]palmitic acid • [1-13C]oleic acid • lipoproteins • free fatty acids • mass spectrometry
INTRODUCTION
About 40% of the adult energy requirement is supplied by fat, mostly as long-chain triacylglycerols. In the intestinal lumen, long-chain fatty acids (FAs) are hydrolyzed from triacylglycerols by pancreatic lipase, reesterified into mucosal triacylglycerols, and finally discharged as chylomicrons into the lymphatic vessels before reaching the thoracic duct and the systemic circulation (1). In contrast, short- and medium-chain FAs pass unesterified into the portal vein (2).
However, as early as the 1950s, studies in rats with biliary fistulas suggested that long-chain FAs do not always exit from gut in the lymph (3). Subsequently, studies in healthy rodents showed that between 30% and 70% of the intraduodenally infused long-chain FAs bypass the lymph and directly enter the portal vein (4, 5).
Whether portal absorption of long-chain FAs occurs in humans is unknown, but it could conceivably be of relevance in the setting of bile deficiency (6, 7). Intraluminal bile acid deficiency occurs in liver cirrhosis (8) as well as in other abnormalities, such as splanchnic lymphatic hypertension and intestinal lymphangiectasia (9–11), which may lead to impaired micelle formation and long-chain FA absorption through the usual lymphatic route. In fact, a blunted chylomicronemic response after an oral lipid load has been reported in cirrhotic persons (12, 13). However, because this occurred in the absence of significant steatorrhea (12, 13), an alternate route of absorption through the portal vein can be postulated. If the portal absorption of long-chain FAs occurs in cirrhosis, it could be of pathophysiologic importance because substantial amounts of fat could reach the liver in these patients.
To examine this hypothesis we conducted a study in cirrhotic patients and healthy volunteers to assess the incorporation of orally fed [1-13C]-labeled saturated (ie, palmitic acid, 16:0) and monounsaturated (ie, oleic acid, 18:1n-9) FAs into plasma lipids. Measurements of fecal [1-13C]-labeled FAs and 13CO2 breath excretion were also performed.
SUBJECTS AND METHODS
Subjects
Six healthy volunteers and 10 cirrhotic patients with (n = 5) and without (n = 5) ascites were included in the study. Their demographic, clinical, and laboratory features are summarized in Table 1. Healthy volunteers did not have acute or chronic illness and had not undergone gastrointestinal or hepatobiliary surgery in the past, and their routine laboratory values were within the normal range.
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TABLE 1. Characteristics of the subjects1
All subjects abstained from tobacco and alcohol within the 30 d before the study and were not treated with insulin, glucose- or lipid-lowering drugs, ß-blockers, or glucocorticosteroids during this time. Lactulose, lactitol, cholestyramine, or other bile salt–chelating agents were also not allowed within the 3 d before the study.
Specific exclusion criteria for cirrhotic patients included the biliary etiology of the cirrhosis, the presence of hepatocarcinoma, active infection, acute gastrointestinal bleeding, overt hepatic encephalopathy, portal thrombosis (as assessed by ultrasonography), surgical or intrahepatic portal-systemic anastomosis, acute or chronic pancreatic disease, extrahepatic cholestasis, gastrointestinal surgery, dyslipemia, and fasting glycemia (glucose concentration > 7.7 mmol/L, or 140 mg/dL).
Study design
The study design is depicted in Figure 1. After a 12-h overnight fast, subjects were fed a mixture of [1-13C]-labeled FAs (1 g [1-13C]palmitic acid + 1 g [1-13C]oleic acid per person) (Isomed, Madrid) in 10 g sunflower oil with a standard meal consisting of 20 g margarine, 3 toasted bread slices, and 250 mL of a liquid nutritional supplement (Meritene; Novartis Consumer Health, SA, Barcelona, Spain). Subjects remained awake and in a semirecumbent position for the next 720 min. Venous blood samples for plasma [1-13C]-labeled FA assay were obtained at baseline and 30, 60, 90, 120, 240, 360, 480, and 720 min after tracer administration. The plasma was immediately separated by centrifugation and stored at –80°C until assayed. Also, end-expiratory breath samples for 13CO2 assay were obtained at these same time points and stored in sealed tubes. Fasting venous blood samples for plasma lipoprotein lipase (LPL), hepatic triacylglycerol lipase (HTGL), and lecithin-cholesterol acyltransferase (LCAT) assay were drawn in the morning of the next day. Finally, the total amount of feces yielded for 3 d after tracer administration was collected. Because the subjects were not allowed to eat during the 12-h study period, intravenous glucose (1 mg · kg body wt–1 · min–1) was infused to minimize FA mobilization from adipose tissue. This dose was empirically chosen on the basis of general recommendations for parenteral nutrition. With this regimen, there were no differences in the glycemic response between the 3 groups studied. In all subjects, glycemia peaked 60 min after the test meal. From 120 to 720 min, serum glucose remained between 5.5 and 8.5 mmol/L in all subjects.
FIGURE 1.. Study design. FAs, fatty acids (ie, palmitic and oleic acids).
The study was performed in accordance with the latest revision of the Helsinki Declaration of 1975, as revised in 1983, and was approved by the Ethics Committee of the hospital. Informed consent was obtained from both the patients and the control subjects.
[1-13C]-Labeled fatty acid assay in plasma samples
Chylomicrons, VLDL, LDL, and HDL were isolated from plasma by sequential ultracentrifugation according to the Havel method (14). Heptadecanoic acid (15 µL of a 1 g/L solution) was added to 400 µL plasma as internal standard for free FA (FFA). On the other hand, known amounts of 10 g/L solutions of glyceryl triheptadecanoate, phosphatidyl cholyl heptadecanoate and cholesteryl heptadecanoate were added to each lipoprotein fraction, as internal standards for triacylglycerols, phospholipids, and cholesteryl esters, respectively. Assay of the [1-13C]-labeled FAs was performed by gas chromatography–mass spectrometry (GC-MS) as described in detail elsewhere (15)
Lipid extraction was performed in chloroform:methanol according to Bligh and Dyer (16). Then, FFAs, phospholipids, triacylglycerols, and cholesteryl esters were separated by thin-layer chromatography in silica gel plates with hexane:diisopropyl ether:acetic acid (80:20:1, by vol) as mobile phase. Lipid fractions were recovered from plates and reextracted with chloroform:methanol (2:1, by vol). The chloroform layer was dried and hydrolyzed to FAs in alcoholic potassium hydroxide at 70°C for 2 h. FAs were derivatized to trimethylsilyl (TMS) esters with bis-N,O-trimethylsilyl trifluoroacetamide + 5% TMS for 30 min at 70°C. TMS esters were then dried and redissolved in 1 mL hexane.
A volume of 1 µL of this extract was injected with the use of an autosampler AS 2000 (Thermo Quest, Milan, Italy) into a quadrupolar mass spectrometer MD 800 (Thermo Quest, Manchester, United Kingdom) operating in positive electronic impact set to100 µA, connected to a gas chromatograph CG 8060 (Thermo Quest, Milan, Italy) equipped with a J&W DB-1 (60m, 0.25 mm, 0.25 µm) column (Cromlab SA, Barcelona, Spain), and with helium as a carrier. Injection was performed on splitless mode at 300°C. TMS esters were separated at constant pressure (175 kPa) with the following temperature program: 165°C for 1 min, increase at a rate of 10°C/min up to 210°C, isotherm at 210°C for 27 min, a further increase at a rate of 40°C/min up to 315°C, and isotherm at 315°C for 5 min.
To assess both the isotopic enrichment and the individual FA concentrations (both natural and [1-13C]-labeled) with the same GC-MS run, a dual-acquisition program was designed in single-ion monitoring mode. This program records 2 signals (m and m + 1) from each FA. The following mass-to-charge ratios were acquired: 313.25 and 314.25 for TMS-palmitate, 327.27 and 328.27 for TMS-heptadecanoate, and 339.27 and 340.27 for TMS-oleate
Standard mixtures of labeled and unlabeled FAs were prepared gravimetrically to obtain different molar percent excesses (MPE) of labeled over unlabeled compounds. Aliquots of these standard mixtures were treated and derivatized as described above, and their MPE measured by GC-MS
Five calibration curves for isotopic enrichment of each FA were made by plotting the GC-MS obtained against the real gravimetrically obtained MPE values. Each curve was obtained by 50% dilution of the preceding one. The best calibration curve for deriving the FA concentration in plasma samples was selected in terms of the internal standard peak area that better fit with that of the sample. The concentration of each [1-13C]-labeled FA was finally calculated by multiplying its MPE by the concentration of its corresponding natural compound.
With this method, the isotopic ratio is not dependent on the amount of the analyte in the sample within a 10-fold range of concentration, with a maximum uncertainty of 0.34% in terms of MPE. In addition, both the within-day and between-day imprecision of the method were <1% (15). With this method, the recovery rates for both [1-13C]palmitic acid and [1-13C]oleic acid were 92% and 99%, respectively (15).
Breath 13CO2 assay
The breath 13CO2 assay was performed in duplicate by means of isotope ratio MS with an Automated Breath Carbon Analyzer Spectrometer (PDZ Europa, Cheshire, United Kingdom). 13C isotopic enrichment is expressed as by comparison with a 13C PDB international standard.
Assessment of total fat and [1-13C]-labeled fatty acids in feces
Three-day fecal samples were homogenized and diluted in acidified water (1:1, wt:vol); the lipids were hydrolyzed to FAs with potassium hydroxide, neutralized with hydrochloric acid, and extracted with 30 mL ether petroleum. Two aliquots of the extract were used for the total fecal fat (25 mL) and [1-13C]-labeled FA assay (5 mL). Total fecal fat was measured according to the method of van de Kamer et al (17). Fecal [1-13C]-labeled FAs were assayed with the same CG-MS method as described for plasma samples, with the addition of 1 mL of the heptadecanoic acid solution as internal standard.
Measurement of plasma LPL, HTGL, and LCAT activities
LPL and HTGL were measured in plasma obtained 10 min after intravenous sodium heparin (20 IU/kg body wt) stimulation as described previously (18). Plasma LCAT activity was measured with the method described by Stokke and Norum (19).
Statistical analysis
Data are presented as medians and interquartile ranges. For the time course of [1-13C]-labeled FAs and breath 13CO2, the area under the curve (AUC) was calculated by using the trapezoid rule and was split into 2 time periods: the AUC from baseline to 120 min (AUC0–120 min) and that from 120 to 720 min (AUC120–720 min). All AUCs were computed as above the minimum value.
Variations of labeled and unlabeled FAs and 13CO2 with time in either group were assessed by using Friedman’s within-group repeated-measures analysis of variance (ANOVA). Comparisons among groups at each time point were made by means of the Kruskal-Wallis ANOVA. Post hoc Mann-Whitney U tests were performed (and their P values adjusted for multiple comparisons with Bonferroni’s correction) only if significant differences or a significant interaction between time and group effects were found. The same methods were used to compare the AUCs among groups. Baseline comparison of qualitative variables (sex and etiology of cirrhosis) was made with a chi-square test. Statistical analysis was performed by using STATISTICA 5.5 software (StatSoft Inc, Tulsa OK).
RESULTS
Time course of plasma [1-13C]-labeled fatty acid concentrations
In the 3 groups of subjects, both [1-13C]-labeled FAs increased in chylomicron-associated triacylglycerols early after the test meal, reached a plateau, and finally decreased to near baseline values. However, this response was blunted and less sustained in the cirrhotic patients than in the healthy control subjects, mainly in late samples (Figure 2, A and B; upper portions). This was confirmed by a significantly lower AUC120–720 min for [1-13C]palmitic acid (Figure 2A, lower right portion) and for [1-13C]oleic acid (Figure 2B, lower right portion) in chylomicrons in the ascitic cirrhotic patients than in the control subjects.
FIGURE 2.. Time course and early (0–120 min) and late (120–720 min) areas under the curve (AUCs) for [1-13C]palmitic acid (A) and [1-13C]oleic acid (B) concentrations in chylomicron-associated plasma triacylglycerols from healthy control subjects and nonascitic and asctic cirrhotic patients. *Significantly different from the healthy subjects, P < 0.05 (Kruskal-Wallis ANOVA followed by a post hoc Mann-Whitney U test, adjusted for multiple comparisons with Bonferroni’s correction). The change with time was significant (P < 0.004) in every group for both fatty acids (Friedman’s within-group repeated-measures ANOVA). There were no significant time-by-treatment interactions. Data are expressed as medians; bars represent interquartile ranges.
Similarly, a decreased enrichment of VLDL-associated triacylglycerols with [1-13C]-labeled FAs, particularly [1-13C]oleic acid, was observed in cirrhotic patients (Figure 3, A and B, upper portions). This was also more apparent in the late samples, as evidenced by a lower AUC120–720 min for [1-13C]oleic acid in both ascitic and nonascitic patients than in the control subjects (Figure 3B, lower right portion).
FIGURE 3.. Time course and early (0–120 min) and late (120–720 min) areas under the curve (AUCs) for [1-13C]palmitic acid (A) and [1-13C]oleic acid (B) concentrations in VLDL-associated plasma triacylglycerols from healthy control subjects and nonascitic and asctic cirrhotic patients. *Significantly different from the healthy subjects, P < 0.05 (Kruskal-Wallis ANOVA followed by a post hoc Mann-Whitney U test, adjusted for multiple comparisons with Bonferroni’s correction). The change with time was significant (P < 0.03) in every group for both fatty acids (Friedman’s within-group repeated-measures ANOVA). There were no significant time-by-treatment interactions. Data are expressed as medians; bars represent interquartile ranges.
The enrichment of FFAs with [1-13C]-labeled substrates peaked earlier in ascitic (at 120 min) than in nonascitic (at 240 min) cirrhotic patients than in healthy control subjects (at 360 min) (Figure 4, A and B, upper portions). Interestingly, these differences were particularly evident for [1-13C]oleic acid, as evidenced by its significantly higher concentration at 30 and 60 min (Figure 4B, upper portion) and AUC0–120 min in ascitic patients (Figure 4B, lower left portion).
FIGURE 4.. Time course and early (0–120 min) and late (120–720 min) areas under the curve (AUCs) for [1-13C]palmitic acid (A) and [1-13C]oleic acid (B) concentrations in plasma free fatty acids from healthy control subjects and nonascitic and ascitic cirrhotic patients. *Significantly different from healthy subjects, P < 0.05 (Kruskal-Wallis ANOVA followed by a post hoc Mann-Whitney U test, adjusted for multiple comparisons with Bonferroni’s correction). #Significantly different from nonascitic patients, P < 0.05 (Kruskal-Wallis ANOVA followed by a post hoc Mann-Whitney U test, adjusted for multiple comparisons with Bonferroni’s correction). The change with time was significant (P < 0.02) in every group for both fatty acids (Friedman’s within-group repeated-measures ANOVA). There was a significant time-by-treatment interaction (P < 0.05) for [1-13C]oleic acid. Data are expressed as medians; bars represent interquartile ranges.
There were no significant differences in the time course of [1-13C]-labeled FA enrichment in the triacylglycerols of LDL and HDL between the 3 groups studied. Likewise, no detectable amounts of [1-13C]-labeled FA were found in the phospholipids and cholesteryl esters associated with the different plasma lipoproteins, both in the cirrhotic patients and the healthy control subjects (data not shown).
Time course of plasma total fatty acid concentrations
As expected, total (ie, unlabeled + [1-13C]-labeled) concentrations of both FAs increased after the test meal in the chylomicron-associated triacylglycerols of both the cirrhotic patients and the control subjects (Figure 5). However, there were no significant differences in the time course of FAs between groups (Figure 5, upper right and left portions).
FIGURE 5.. Time course of total palmitic acid and oleic acid concentrations in chylomicron (Chm)- and VLDL-associated triacylglycerols (TG) and in plasma free fatty acids (FFAs) from healthy control subjects and nonascitic and ascitic cirrhotic patients. For both fatty acids, the change with time was significant (P < 0.008) in every group for Chm and FFAs, but not for VLDL (Friedman’s within-group repeated-measures ANOVA). There were no significant time-by-treatment interactions. Data are expressed as medians; bars represent interquartile ranges.
Little change in the total concentration of palmitic and oleic acids in the VLDL-associated triacylglycerols was observed in either group. However, total concentrations of both FAs (particularly oleic acid) remained lower in the ascitic patients than in the nonascitic cirrhotic patients and the healthy control subjects (Figure 5, middle panels).
Plasma concentrations of total palmitic and oleic acids in the FFA fraction were somewhat high at baseline, initially decreased after the test meal (reaching a nadir between 60 and 120 min), and recovered afterward. There were no significant differences in their time course between the 3 groups of subjects studied (Figure 5, lower panels).
Plasma total concentration of both FAs in the LDL- and HDL-associated triacylglycerols remained stable over time, and there were no significant differences between groups (data not shown).
Fecal excretion of total fat and [1-13C]-labeled fatty acids
No significant differences in the 3-d fecal excretion of either total fat or [1-13C]FA were found, among the 3 groups studied (Table 2).
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TABLE 2. Three-day fecal excretion of total fat and [1-13C]-labeled fatty acids1
Time course of breath 13CO2 excretion
Breath 13CO2 excretion showed a progressive increase during the study period in all groups. However, this was somewhat lower in the later samples (and therefore the AUC120–720 min) of ascitic patients (Table 3).
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TABLE 3. Time course and areas under the curve (AUCs) of breath 13CO2 excretion
Plasma activities of LPL, HTGL, and LCAT
As expected the plasma activities of both HTGL and LCAT were significantly lower in the nonascitic and ascitic cirrhotic patients than in the healthy control subjects. LPL activity was lower in the ascitic patients than in the healthy control subjects (Table 4).
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TABLE 4. Plasma activities of lipoprotein lipase (LPL), hepatic-triacylglycerol lipase (HTGL), and lecithin-cholesterol acyltransferase (LCAT)1
DISCUSSION
The present study was designed to assess the absorption pathway and early destiny of dietary long-chain FAs in cirrhosis by tracing orally fed [1-13C]-labeled palmitic and oleic acids—the most abundant dietary FAs—in plasma lipoproteins and feces of cirrhotic patients and healthy control subjects. Because the number of subjects in the study was relatively small, the severity of cirrhosis was defined by the single criterion of the presence of ascites (rather than the widely used Child-Pugh composite index), to render the cirrhotic groups more homogeneous. Also, because of the variable incidence and severity associated with exocrine pancreatic insufficiency in cirrhosis (20), we administered the labeled substrates as unesterified FAs instead of as triacylglycerols.
The incorporation of [1-13C]-labeled FAs in chylomicron- and VLDL-associated plasma triacylglycerols was lower and less sustained in cirrhotic patients than in healthy control subjects, whereas their fecal excretion was similar in both groups. The lower incorporation of labeled FAs in VLDLs is consistent with the well-known impaired export of these lipoproteins from the cirrhotic liver (21, 22), probably because of a decreased synthesis of triacylglycerols (23) and apolipoprotein E (24) in the liver of these patients. Likewise, the decreased enrichment of chylomicrons with labeled substrates confirms the findings of previous studies, which reported a low chylomicronemic response in cirrhotic patients after an oral load of unlabeled fat (12, 13). Indeed, the impaired incorporation of dietary fat (either labeled or unlabeled) in chylomicrons, in the absence of significant fecal losses, strongly supports an alternate absorption route of fat in cirrhosis.
In this sense, the finding that the incorporation of [1-13C]-labeled FAs into plasma FFAs peaked much earlier in the ascitic cirrhotic patients than in the healthy control subjects (with intermediate values for nonascitic cirrhotic patients) is revealing. In fact, an increase in plasma FFAs after an oral fat load in cirrhotic patients was previously reported (25), although it was masked in part by the increased fasting FFA concentrations in these patients (26). Thus, the use of labeled substrates in the present study was particularly useful to confirm that the postprandial increase in plasma FFAs in cirrhosis is, at least in part, of dietary origin. In our view, the best explanation for this phenomenon is that a certain proportion of labeled FAs are absorbed through the portal vein and partly enter the systemic circulation, bypassing the liver, through the portal-systemic collateral vessels present in advanced cirrhotic patients with portal hypertension. An alternative explanation could be that [1-13C]-labeled FAs may have been released by the action of LPL on triacylglycerols of chylomicrons. Indeed, recent studies in healthy subjects fed [1-13C]-labeled FAs indicate that the release of FAs hydrolyzed from triacylglycerols escaping entrapment in adipose tissue mostly account for the enrichment of plasma FFAs with [1-13C]-labeled FAs (27). As in our control group, this does not occur before 120 min and peaks at 360 min (27). Thus, it seems unlikely that the early increase (before 120 min) in [1-13C]-labeled FAs in plasma FFAs occurring in our ascitic cirrhotic patients was due to this mechanism. Moreover, the low plasma LPL activity in these patients strongly argues against this possibility.
The possibility that, in certain pathologic conditions, dietary long-chain FAs could be absorbed via pathways not dependent on their incorporation into chylomicrons and subsequent transport through the lymphatic system was already hypothesized by the end of the 1960s. In a study conducted in patients with complete biliary obstruction, in whom the thoracic duct was cannulated, Blomstrand et al (6) showed that feeding [14C]-labeled FAs resulted in low amounts of radioactivity in the lymph from the thoracic duct, together with high radioactivity in feces, but also in the expired air, which suggests the existence of some alternative means of long-chain FA absorption in the absence of bile in the intestinal lumen (6). Similar conclusions were drawn from studies in patients with external biliary drainage in whom the consumption of fat-soluble vitamins increased their plasma concentrations in the absence of both significant steatorrhea and a chylomicronemic response (7).
Indeed, portal absorption of dietary FAs occurs in healthy rats, to an extent ranging from 30% to 70%, depending on the intraduodenally infused FA (4, 5). The portal route of absorption seemed to be particularly efficient for unsaturated rather than for saturated FAs (4), as occurred in our ascitic patients in whom the early incorporation to plasma FFAs was more evident for [1-13C]oleic (ie, unsaturated) acid than for [1-13C]palmitic (ie, saturated) acid.
The fact that significant amounts of dietary fat could be absorbed through the portal route in cirrhosis has both pathophysiologic and therapeutic implications. It is conceivable that the inflow of fat into the liver via the portal vein, combined with the abovementioned impairment in VLDL release by the liver, could facilitate the storage of fat in the liver of cirrhotic patients. In fact, a long-term increase in plasma FAs of dietary origin (namely saturated, monounsaturated, and essential FAs)—but not of those mainly depending on hepatic synthesis (ie, long-chain polyunsaturated FAs)—was reported in cirrhotic patients undergoing portacaval anastomosis compared with unoperated control subjects (28). Because the nutritional status improved similarly in both groups (28), it might well be that the increase in plasma FAs after portacaval anastomosis was due to an increased systemic availability of portally absorbed FAs no longer sequestered in the liver. If this phenomenon is true, fat accumulation could be an additional contributing factor to hepatic inflammation and fibrogenesis in these patients (29), and spontaneous portal-systemic shunting should be viewed as a protective mechanism. Whether the portal absorption of dietary fat has any role in accelerating the progression of chronic liver disease is an issue to be addressed in future investigations.
In the meantime, however, this possibility has to be kept in mind when recommending a diet for cirrhotic patients, particularly in the design of formulas for enteral tube feeding. In rats, the portal absorption of FAs is proportionally greater when low intraduodenal infusion rates are used (30). Accordingly, it may also be particularly efficient in cirrhotic patients receiving continuous low-rate enteral tube feeding. In our experience, cirrhotic patients present a virtually absent chylomicronemic response while receiving lipid-containing continuous enteral nutrition (31). This finding suggests that, under these circumstances, portal lipid absorption is maximal. In this setting, a low-fat diet with a fat source mainly consisting of saturated FAs should, in theory, be preferred. In fact, saturated FAs have been reported to protect against hepatic steatosis in animal models of alcoholic liver disease (32–34).
In summary, cirrhotic patients have a lower incorporation of [1-13C]-labeled FAs in chylomicrons and VLDL, in the absence of increased fecal losses, which confirms the previous data from studies that used an unlabeled fat load. The earlier appearance of [1-13C]-labeled FAs in plasma FFAs favors the portal absorption of (mainly unsaturated) long-chain FAs in advanced cirrhosis with portal hypertension and portal-systemic collaterals. Whether portal FA absorption could be a risk factor for hepatic steatosis in these patients deserves further research.
ACKNOWLEDGMENTS
EC designed the experiment, selected the patients, collected the samples, performed the statistical analysis, and wrote the manuscript. JMH-P analyzed the different samples and contributed to the statistical analysis and the writing of the manuscript. LF helped analyze the samples. CP and AC provided significant advice and consultation regarding the laboratory procedures. MAG contributed to the design of the experiment and the critical review of the manuscript. None of the authors declared a conflict of interest
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