Stable Cirrhotic Patients Research Articles

Oral amino acid load mimicking hemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver.

This study tests the hypothesis that administration of an oral amino acid load mimicking hemoglobin in patients with cirrhosis of the liver causes deterioration in neuropsychological function and a reduction in regional cerebral perfusion. Eight overnight fasted, metabolically stable cirrhotic patients with no evidence of overt hepatic encephalopathy were studied prior to and 4 h after simulating an upper gastrointestinal bleed by oral administration of 75 g of a solution mimicking the amino acid composition of hemoglobin. Neuropsychological function was measured using a test battery. Peripheral venous blood was collected for the measurement of ammonia and amino acid concentrations. Regional cerebral perfusion was measured using a head SPECT scanner following intravenous administration of technetium-99m hexamethyl propylamineoxime. The amino acid solution resulted in significant deterioration in the immediate and delayed story recall tests. Ammonia concentration increased from a median of 87 (range 67-94) micromol/L to 105 (98-112) micromol/L at 4 h after the simulated bleed (p < 0.01). The concentration of almost all amino acids increased; only isoleucine levels decreased following the upper gastrointestinal bleed. SPECT analysis showed a significant reduction in cerebral perfusion after the simulated bleed in both temporal lobes, left superior frontal gyrus, and right parietal and cingulate gyrus. An oral amino acid load mimicking hemoglobin in cirrhotic patients produces hyperammonemia and hypoisoleucinemia and causes a significant deterioration in memory tests, probably due to a reduction in regional cerebral perfusion. The model of simulating the metabolic effects of an upper gastrointestinal bleed in patients with cirrhosis of the liver seems to be useful in studying the metabolism of hepatic encephalopathy.

Helicobacter pylori infection is not associated with subclinical hepatic encephalopathy in stable cirrhotic patients.

The importance of ammonia-producing Helicobacter pylori infection as a cause of subclinical encephalopathy in cirrhosis was investigated. In addition, a single psychometric test that can reliably detect subclinical hepatic encephalopathy was sought. Out-patients with cirrhosis and no overt encephalopathy underwent [14C]urea breath testing once and psychometric testing on two separate occasions, with an intervening course of clarithromycin/omeprazole if they had subclinical encephalopathy (two of four psychometric tests abnormal). Subclinical encephalopathy was present in 27 of 69 patients (39%), and Helicobacter pylori infection in 14 of 69 (20%). There was no association between the two conditions (P = 0.769). Subclinical encephalopathy resolved in 75% of treated Helicobacter pylori-positive patients and 37.5% of treated Helicobacter pylori-negative patients (P = 0.285). Number connection test-B had high reproducibility among untreated patients (R = 0.655) and high correlation (P < or = 0.01) with three surrogate gold standards. In stable cirrhotic patients, subclinical hepatic encephalopathy was found to: (1) have a high prevalence, (2) not be associated with Helicobacter pylori infection, and (3) be readily detected with the number connection test-B alone.

Disseminated intravascular coagulation in liver cirrhosis: fact or fiction?

Cirrhosis is commonly associated with haemostatic dysfunction. The similarities of laboratory tests of disseminated intravascular coagulation (DIC) to those found in cirrhosis has led to the belief that DIC is a feature of the haemostatic failure of cirrhosis. The aim of this study was to determine whether DIC is part of the coagulopathy of cirrhosis by applying quantitative tests for prothrombin fragment 1 + 2, antithrombin III, thrombin-antithrombin complex, and specific fribrinogen degradation products levels (XDP), as well as the thrombelastograph for detecting the Clot Lysis Index. Fifty-two stable cirrhotic patients (33 men, 19 women; mean age, 58.8 yr; range, 24-72 yr) with differing etiologies were studied. On tests of thrombin generation: thrombin-antithrombin complexes, fibrin(ogen) degradation products, and prothrombin fragments 1 + 2 were not found to be significantly different from an age- and gender-matched control group (p = 0.18, 0.3, and 0.67, respectively), whereas albumin, Factor V, fibrinogen, antithrombin III, and alpha2-antiplasmin were all significantly low (p = 0.0004, 0.002, 0.06, 0.004, and 0.004, respectively), reflecting reduced synthetic function and correlation in ascitic and non-ascitic patients. There was no correlation between impaired synthesis (antithrombin III and alpha2-antiplasmin) and indices of DIC (prothrombin fragment 1 + 2, thrombin-antithrombin complexes, and XDP) (p = not significant). The percentage of patients with high prothrombin fragments 1 + 2 and thrombin antithrombin levels in each Child grade group was similar. Thrombin time was significantly elevated in the cirrhotic group (a manifestation of low fibrinogen levels). The Clot Lysis Index as measured by thrombelastography was significantly abnormal, indicating mild hyperfibrinolysis. We conclude that DIC is not part of the coagulopathy in stable liver cirrhosis without recent complications.

Disseminated intravascular coagulation in liver cirrhosis: fact or fiction?

OBJECTIVE: Cirrhosis is commonly associated with haemostatic dysfunction. The similarities of laboratory tests of disseminated intravascular coagulation (DIC) to those found in cirrhosis has led to the belief that DIC is a feature of the haemostatic failure of cirrhosis. METHODS: The aim of this study was to determine whether DIC is part of the coagulopathy of cirrhosis by applying quantitative tests for prothrombin fragment 1 + 2, antithrombin III, thrombin-antithrombin complex, and specific fribrinogen degradation products levels (XDP), as well as the thrombelastograph for detecting the Clot Lysis Index. RESULTS: Fifty-two stable cirrhotic patients (33 men, 19 women; mean age, 58.8 yr; range, 24–72 yr) with differing etiologies were studied. On tests of thrombin generation: thrombin-antithrombin complexes, fibrin(ogen) degradation products, and prothrombin fragments 1 + 2 were not found to be significantly different from an age- and gender-matched control group ( p = 0.18, 0.3, and 0.67, respectively), whereas albumin, Factor V, fibrinogen, antithrombin III, and α2-antiplasmin were all significantly low ( p = 0.0004, 0.002, 0.06, 0.004, and 0.004, respectively), reflecting reduced synthetic function and correlation in ascitic and nonascitic patients. There was no correlation between impaired synthesis (antithrombin III and α2-antiplasmin) and indices of DIC (prothrombin fragment 1 + 2, thrombin-antithrombin complexes, and XDP) ( p = not significant). The percentage of patients with high prothrombin fragments 1 + 2 and thrombin antithrombin levels in each Child grade group was similar. Thrombin time was significantly elevated in the cirrhotic group (a manifestation of low fibrinogen levels). The Clot Lysis Index as measured by thrombelastography was significantly abnormal, indicating mild hyperfibrinolysis. CONCLUSION: We conclude that DIC is not part of the coagulopathy in stable liver cirrhosis without recent complications.

Macronutrient preference, dietary intake, and substrate oxidation among stable cirrhotic patients.

Anorexia in liver disease is common; however, its association with aberrant metabolism and the type of cirrhosis has not been considered. Dietary intake, nutritional status, fasting substrate oxidation, and macronutrient preference were examined in controls (n = 18) and 65 patients with hepatocellular (n = 31) or biliary cirrhosis (n = 34). Energy intakes were lowest in hepatocellular patients (controls: 9.0 +/- 0.48 megajoules/day compared with biliary: 7.0 +/- 0.40 MJ/day, P <.05; controls compared with hepatocellular 6.5 +/- 0.39 megajoules/day, P <.01). Triceps skinfold was lower only in hepatocellular patients (controls: 109 +/- 9.2% compared with hepatocellular 79 +/- 5.6%, P <.05). The fasting rate of lipid oxidation was elevated in hepatocellular patients when compared with controls and biliary patients (controls: 40.9 +/- 15.1 mg/min compared with hepatocellular 62.8 +/- 16.8 mg/min, P <.001, and biliary : 45.5 +/- 17.0 mg/min compared with hepatocellular, P <.001). Control subjects exhibited a greater preference for the high fat, moderate carbohydrate food (controls: median 7.0 IQR 2.0 compared with biliary: median 5.0 interquartile range [IQR] 4.7, P <.01) (controls compared with hepatocellular: median 6.0 IQR 4.0, P <.01). Cirrhotic patients' spontaneous dietary intake is lower than that of controls and recommended intakes. Although macronutrient preference ratings were different within cirrhotic patient groups it remains unclear whether associated nutrient deficits are metabolically driven and dictated by primary cause.

Defective nonoxidative leucine degradation and endogenous leucine flux in cirrhosis during an amino acid infusion.

The metabolic fate of leucine's first and second carbon may be different depending on the tissue in which leucine is metabolized, as well as the prevailing hormonal milieu of that tissue. However, previous studies of leucine kinetics in humans have used only leucine labeled (as tracer) at the first carbon position. Because cirrhosis is associated with factors (such as insulin resistance and altered fuel substrate utilization) that may influence how leucine is degraded, the kinetics of leucine's first and second carbon using a simultaneous infusion of [1-14C] leucine and [2-13C] leucine were studied in the postabsorptive state and during an amino acid infusion in 6 stable cirrhotic patients and 6 matched controls. The data were normalized for different body compartments that were quantified from the dilution of H2 [180] and bromide. The body cell mass, but not body weight or fat-free body mass, was decreased in cirrhosis (P < .001). In response to the amino acid infusion, total leucine appearance from proteolysis and leucine's incorporation into protein increased significantly in both groups, but were higher in cirrhotic patients. Endogenous protein breakdown decreased in normals but remained unchanged in cirrhosis. These alterations in leucine metabolism became more prominent when data were expressed based on the body cell mass rather than on body weight. The oxidation of leucine's first carbon (C1) was decreased in cirrhosis, but the oxidation of leucine's second carbon (C2) did not differ between groups during both the postabsorptive period and the amino acid infusion, while nonoxidative leucine degradation [the difference between the oxidation of leucine's (C1) and (C2)] was also decreased in cirrhosis. In addition, there was a positive correlation between nonoxidative leucine degradation (which represents leucine incorporation into fat), and the respiratory quotient obtained from indirect calorimetry (r = .87; P < .001). These data suggest that the extent of leucine carbon oxidation is dependent on whether fat or carbohydrate is the prevailing fuel substrate. In addition, cirrhotic patients have decreased nonoxidative leucine degradation and are unable to suppress endogenous protein breakdown normally in response to amino acid administration. These abnormalities may contribute to the diminished fat stores and body cell mass commonly observed in cirrhosis.

Effect of moderate exercise on insulin sensitivity and substrate metabolism during post-exercise recovery in cirrhosis.

We examined whether a single bout of moderate exercise has a beneficial effect on insulin sensitivity and fuel homeostasis in cirrhosis. Clinically stable cirrhotic patients and age-, sex-, and weight-matched controls participated in insulin clamp studies (either euglycemic hyperinsulinemic or hyperglycemic hyperinsulinemic) in combination with indirect calorimetry and [6,6-2H2]glucose. Three to seven days later, studies were repeated following a single bout of exercise (30 minutes of treadmill exercise at 60% of maximal aerobic capacity). After an overnight fast, following exercise, both cirrhotic and control individuals showed a shift in fuel utilization to enhanced lipid oxidation, decreased glucose oxidation, and increased nonoxidative glucose disposal rates (i.e., glycogen synthesis in muscle) when compared with pre-exercise rates but differences were statistically significant only in the patient group. During euglycemic hyperinsulinemia, insulin-mediated glucose disposal was significantly reduced in cirrhotic patients (3.43 +/- 0.26 vs. 7.36 +/- 0.48 mg/kg/min, P < .01). Following exercise, glucose uptake increased significantly in cirrhotic patients when compared with pre-exercise levels (P < .05) but remained unchanged in the control group. The increase in total body glucose disposal in cirrhotic patients was entirely accounted for by an increase in nonoxidative glucose disposal (0.81 +/- 0.20 vs. 0.51 +/- 0.15 mg/kg/min, P < .05). During combined hyperglycemia/hyperinsulinemia, however, insulin sensitivity was unaffected by exercise in both patients and control individuals. In summary, in cirrhotic patients, a single bout of moderate exercise 1) causes a shift in substrate utilization with an increase in lipid oxidation in the postexercise period that is significantly more pronounced than in controls, and 2) increases insulin sensitivity only during euglycemia but not during the more physiological condition of hyperglycemia. Single bouts of moderate exercise therefore may not have a beneficial effect on the metabolic status of patients with chronic liver disease.

Effect of moderate exercise on insulin sensitivity and substrate metabolism during post-exercise recovery in cirrhosis

We examined whether a single bout of moderate exercise has a beneficial effect on insulin sensitivity and fuel homeostasis in cirrhosis. Clinically stable cirrhotic patients and age-, sex-, and weight-matched controls participated in insulin clamp studies (either euglycemic hyperinsulinemic or hyperglycemic hyperinsulinemic) in combination with indirect calorimetry and [6,6-2H2]glucose. Three to seven days later, studies were repeated following a single bout of exercise (30 minutes of treadmill exercise at 60% of maximal aerobic capacity). After an overnight fast, following exercise, both cirrhotic and control individuals showed a shift in fuel utilization to enhanced lipid oxidation, decreased glucose oxidation, and increased nonoxidative glucose disposal rates (i.e., glycogen synthesis in muscle) when compared with pre-exercise rates but differences were statistically significant only in the patient group. During euglycemic hyperinsulinemia, insulin-mediated glucose disposal was significantly reduced in cirrhotic patients (3.43 +/- 0.26 vs. 7.36 +/- 0.48 mg/kg/min, P < .01). Following exercise, glucose uptake increased significantly in cirrhotic patients when compared with pre-exercise levels (P < .05) but remained unchanged in the control group. The increase in total body glucose disposal in cirrhotic patients was entirely accounted for by an increase in nonoxidative glucose disposal (0.81 +/- 0.20 vs. 0.51 +/- 0.15 mg/kg/min, P < .05). During combined hyperglycemia/hyperinsulinemia, however, insulin sensitivity was unaffected by exercise in both patients and control individuals. In summary, in cirrhotic patients, a single bout of moderate exercise 1) causes a shift in substrate utilization with an increase in lipid oxidation in the postexercise period that is significantly more pronounced than in controls, and 2) increases insulin sensitivity only during euglycemia but not during the more physiological condition of hyperglycemia. Single bouts of moderate exercise therefore may not have a beneficial effect on the metabolic status of patients with chronic liver disease. (Hepatology 1997 Oct;26(4):972-9)

Skeletal muscle glycogen content in patients with cirrhosis

We investigated stable cirrhotic patients for muscle glycogen content. Muscle biopsy samples were taken of 14 patients after overnight fasting. Electron microscopy showed normal intracellular distribution of glycogen (n = 8). Muscle glycogen concentration was 16.5 +/- 7.1 gm/kg wet muscle weight (normal range, 10 to 20 gm/kg). Basal, early postabsorptive, exercise-induced and insulin-induced respiratory quotients as well as insulin sensitivity (euglycemic clamp technique, 7.2 pmol insulin/kg body weight/min) and glucose tolerance were assessed. The glucose disposal rate was 23.0 +/- 10.1 mumol/kg/min (mean +/- S.D.), indicating moderate insulin resistance in these patients. We found no association between basal muscle glycogen content and basal or postprandial respiratory quotient, insulin sensitivity, nutritional status or glucose tolerance. However, there was a positive correlation between muscle glycogen content and exercise, as well as insulin-induced respiratory quotient (r = 0.651, p < 0.03 and r = 0.587, p < 0.03, respectively). We conclude that postabsorptive muscle glycogen stores, which are effectively maintained in patients with cirrhosis, are one determinant of exercise-induced and insulin-induced whole body fuel metabolism in these patients.

Skeletal muscle glycogen content in patients with cirrhosis

We investigated stable cirrhotic patients for muscle glycogen content. Muscle biopsy samples were taken of 14 patients after overnight fasting. Electron microscopy showed normal intracellular distribution of glycogen (n = 8). Muscle glycogen concentration was 16.5 ± 7.1 gm/kg wet muscle weight (normal range, 10 to 20 gm/kg). Basal, early postabsorptive, exercise-induced and insulin-induced respiratory quotients as well as insulin sensitivity (euglycemic clamp technique, 7.2 pmol insulin/kg body weight/min) and glucose tolerance were assessed. The glucose disposal rate was 23.0 ± 10.1 μmol/kg/min (mean ± S.D.), indicating moderate insulin resistance in these patients. We found no association between basal muscle glycogen content and basal or postprandial respiratory quotient, insulin sensitivity, nutritional status or glucose tolerance. However, there was a positive correlation between muscle glycogen content and exercise, as well as insulin-induced respiratory quotient (r = 0.651, p < 0.03 and r = 0.587, p < 0.03, respectively). We conclude that postabsorptive muscle glycogen stores, which are effectively maintained in patients with cirrhosis, are one determinant of exercise-induced and insulin-induced whole body fuel metabolism in these patients.

Hypoxemia In Liver Cirrhosis And Intrapulmonary Shunt Determination Using Tc-99m-MAA Whole Body Scan

Background It is well known that severe hypoxemia is often associated with liver cirrhosis without preexisting cardiac or pulmonary diseases. Pulmonary vascular impairments, more specifically, intrapulmonary shunting have been considered as a major mechanism. Intrapulmonary shunting arises from pulmonary vascular dilatation at the precapillary level or direct arteriovenous communication and has relationship with the characteristic skin findings of spider angioma. However, these results are mainly from Western countries where alcoholic and primary biliary cirrhosis are dominant causes of cirrhosis. It is uncertain that tie same is true in viral hepatitiss associated liver cirrhosis, which is dominant causes of liver cirrhosis in Korea. We investigated the incidences of hypoxemia and orthodeoxia in Korean cirrhotic patients dominantly composed of postnecrotic cirrhosis and the significance of intrapulmonary shunting as the suggested mechanism of hypoxemia. Method We performed the arterial blood gas analysis separately both at the supine and errect position in 48 stable cirrhotic patients without the evidences of severe complications such as ascites, variceal bleeding, and hepatic coma. According to the results of arterial blood gas analysis, all patients were divided into hypoxemic and normoxemic group. In each group, pulmonary function test and Tc-99m-MAA whole body scan were performed. The shunting fraction was calculated based on the fact that the sum of cerebral and bilateral renal blood flow is 32% of the systemic blood flow. Results The hypoxemia of PaO2 less than 80 mmHg was observed in 9 patients(18.8%) and Orthodeoxia more than 10 mmHg was observed in 8 patients(16.7%). Hut there was no patient with significant hypoxemia of PaO2 less than 60 mmHg. PaO2 was significantly decreased in the patients with spider angioma than the patients without spider angioma and showed no correlation with the serologic type and severities of liver function test findings. Any parameters of pulmonary function test did not demonstrate the difference between normoxemic and hypoxemic group. But hypoxemic group showed significantly increased shunt fraction of 11.4±4.1% than normoxemic group of 4.1±2.0% (p<0.05). Conclusions Hypoxemia is not infrequently observed complication in liver cirrhosis and intrapulmonary shunting is suggested to play a major role in the development of hypxemia. But there was no great likelihood of clinically significant hypoxemia in our domestic cirrhotic patients predominantly composed of postnecrotic type.

Failure of glucagon to stimulate hepatic glycogenolysis in well-nourished patients with mild cirrhosis

The ability of glucagon to stimulate hepatic glucose production (HGP) was studied in clinically stable cirrhotic patients (n = 8) who had, based on long-term follow-up evaluation, relatively good liver function (Child-Pugh A) and whose dietary intake and physical characteristics were comparable to those of healthy control subjects (n = 8). Plasma glucagon concentration was slightly but not significantly increased in cirrhotic patients versus control subjects in the basal state (190 ± 41 v 126 ± 24 pg/mL, P = NS) and during a continuous 180-minute glucagon infusion at 3 ng/kg/min (349 ± 56 v 243 ± 37, P = NS). The increment in plasma glucagon level (+164 ± 57 v +127 ± 35, P = NS) also was slightly greater in the cirrhotic group. HGP (measured with [6- 3H]-glucose) in the basal state was similar in cirrhotic and control subjects (1.79 ± 0.09 v 1.94 ± 0.15 mg/kg/min, P = NS). In cirrhotic patients, stimulation of HGP by glucagon was blunted during the first 15 to 30 minutes of the infusion period (representing glucagon's predominant effect on glycogenolysis; 0.23 ± 0.20 v 1.06 ± 0.19 mg/kg/min, P < .05), but it was not different from that in control subjects during the remaining course of the experiment (30 to 180 minutes). Basal plasma insulin and C-peptide concentrations did not change from baseline during the glucagon infusion in cirrhotics, whereas they increased slightly but not significantly in controls. These data demonstrate that even in the early stages of cirrhosis, the liver is resistant to the stimulatory effect of glucagon on hepatic glycogenolysis. Whether this resistance is the result of impaired sensitivity to glucagon or of decreased hepatic glycogen stores remains to be elucidated.

Sandostatin Therapy of Acute Oesophageal Variceal Bleeding

This communication deals with the emergency control of variceal bleeding rather than the prevention of rebleeding. The current main options of oesophageal tamponade, emergency sclerotherapy and drug therapy are discussed, with particular reference to the use of somatostatin. Sandostatin (Sandoz, Basel), a synthetic long-acting somatostatin analogue, was found to reduce transhepatic venous gradient by 30% with no effect on systemic haemodynamics in a study of 16 stable cirrhotic patients. In a trial comparing intravenous infusion of Sandostatin (SMS) to oesophageal tamponade (OT) in active variceal bleeding, 18 of 20 bleeds in the SMS group and 19 of 20 bleeds in the OT group were controlled at 4 h. Ten in the SMS group and 14 in the OT group had no further bleeding during the 48-hour study period. Thus SMS may be useful in the temporary control of active variceal bleeding.

Pallidal hyperintensity on magnetic resonance imaging in cirrhotic patients: clinical correlations.

Patients with cirrhosis show increased signal intensity in the globus pallidus on T1-weighted magnetic resonance imaging of the brain. This abnormal appearance of the basal ganglia has been related to the severity of liver failure and to the presence of portal-systemic shunting, although its cause and clinical significance remain unknown. We prospectively assessed the metabolic, neurological and neuropsychological statuses of 30 stable cirrhotic patients and correlated these clinical variables with computed measurements of globus pallidus signals. Some metabolic variables denoting disease severity appeared to be significantly related to image changes, although the strongest association was found with plasma ammonia levels. After adjustment for ammonia level, on multiple regression analysis, the other variables were not significant. Furthermore, pallidal changes were associated with specific neurological symptoms and neurological functions, symptoms and functions that also had a significant correlation with ammonia levels. Our findings suggest that globus pallidus signal abnormality could arise as a marker of brain impairment related to hyperammonemia.

Solid phase extraction and simultaneous high performance liquid chromatographic determination of antipyrine and its major metabolites in urine.

A reversed phase gradient high performance liquid chromatographic method utilizing solid phase extraction has been described for the simultaneous determination of antipyrine (AP), 4-hydroxyantipyrine (4-OHAP), norantipyrine (NorAP) and 3-hydroxymethylantipyrine (3-OHMAP) in human urine after hydrolysis with beta-glucuronidase. The C-18 sorbent cartridges were conditioned and urine samples were applied, washed with 1 x 4 mL of phosphate buffer and eluted with 3 x 100 microL of 20% v/v of acetonitrile in methylene chloride. The eluent was evaporated to dryness, reconstituted in 100 microL phosphate buffer and injected. The calibration ranges were 2.0-250 micrograms/mL (AP), 2.5-250 micrograms/mL (NorAP), 2.0-250 micrograms/mL (3-OHMAP) and 5.0-500 micrograms/mL (4-OHAP) with regression coefficients of 0.998 or greater. Specificity was indicated by the absence of interferences in chromatogram of blank urine from normal as well as cirrhotic patients. The average recovery was 86.7% for AP, 90.5% for NorAP, 85.2% for 4-OHAP and 74.2% for 3-OHMAP. The within-assay precision as indicated by the reproducibility of the assayed spiked urine was less than 9% in all cases and the between-assay precision was less than 12%. The method was applied to studies on antipyrine metabolism in stable cirrhotic patients. Following administration of a single oral dose of about 1000 mg to nine stable cirrhotic patients and eight age-matched healthy volunteers, the cumulative account excreted in the urine up to 48 h for AP and the three metabolites was comparable to other literature reports.

Early Postprandial Energy Expenditure and Macronutrient Use After a Mixed Meal in Cirrhotic Patients

The effect of meal ingestion (9 kcal/kg of body weight, 53% carbohydrate, 30% fat, 17% protein, as a liquid formula) on energy expenditure and oxidation rate of carbohydrate, fat, and protein was assessed by indirect calorimetry and urinary nitrogen excretion before and for 3 hours after eating in stable cirrhotic patients and control subjects of comparable age. Postprandial modifications of substrate and hormone levels were also studied. Compared with basal values, the mean +/- SD resting energy expenditure during the first 3 hours after meal ingestion increased similarly in cirrhotic patients (+0.32 +/- 0.12 kcal/min) and control subjects (+0.31 +/- 0.08 kcal/min). Dietary induced thermogenesis was equivalent to 10% of the energy contained in the meal in both groups. Before eating, the carbohydrate oxidation rate was lower and fat oxidation higher in cirrhotic patients than in the control subjects. After eating, glucose oxidation increased whereas fat and protein oxidation rates were reduced in both groups. As a consequence the amount of fat oxidized in the postprandial period remained higher in cirrhotic patients than in the control subjects. After meal ingestion, serum glucose levels increased whereas plasma free fatty acid and glycerol levels decreased in both groups. The substrates, however, remained significantly higher in cirrhotic patients than in control subjects, despite the higher postprandial insulin increment in the patients group, thus suggesting the presence of insulin resistance. Because the postprandial glucose oxidation rate was normal, the low insulin-mediated glucose uptake observed in cirrhotic patients seems to reflect a defect in the nonoxidative disposal of the glucose ingested.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of physiologic hyperinsulinemia on glucose and lipid metabolism in cirrhosis.

Insulin secretion and insulin sensitivity were evaluated in eight clinically stable cirrhotic patients and in 12 controls. OGTT was normal in cirrhotics but plasma insulin response was increased approximately twofold compared with controls. Subjects received a three-step (0.1, 0.5, 1.0 mU/kg.min) euglycemic insulin clamp with indirect calorimetry, [6-3H]-glucose, and [1-14C]-palmitate. During the two highest insulin infusion steps glucose uptake was impaired (3.33 +/- 0.31 vs. 5.06 +/- 0.40 mg/kg.min, P less than 0.01, and 6.09 +/- 0.50 vs. 7.95 +/- 0.52 mg/kg.min, P less than 0.01). Stimulation of glucose oxidation by insulin was normal; in contrast, nonoxidative glucose disposal (i.e., glycogen synthesis) was markedly reduced. Fasting (r = -0.553, P less than 0.01) and glucose-stimulated (r = -0.592, P less than 0.01) plasma insulin concentration correlated inversely with the severity of insulin resistance. Basal hepatic glucose production was normal in cirrhotics and suppressed normally with insulin. In postabsorptive state, plasma FFA conc (933 +/- 42 vs. 711 +/- 44 mumol/liter, P less than 0.01) and FFA turnover (9.08 +/- 1.20 vs. 6.03 +/- 0.53 mumol/kg.min, P less than 0.01) were elevated in cirrhotics despite basal hyperinsulinemia; basal FFA oxidation was similar in cirrhotic and control subjects. With low-dose insulin infusion, plasma FFA oxidation and turnover failed to suppress normally in cirrhotics. During the two higher insulin infusion steps, all parameters of FFA metabolism suppressed normally. In summary, stable cirrhotic patients with normal glucose tolerance exhibit marked insulin resistance secondary to the impaired nonoxidative glucose disposal. Our results suggest that chronic hyperinsulinism may be responsible for the insulin resistance observed in cirrhosis.

Basal Energy Production Rate and Substrate Use in Stable Cirrhotic Patients

The basal energy production rate was measured using indirect calorimetry in 25 stable cirrhotic patients and 10 controls of comparable age. The endogenous substrate oxidation was also calculated by measuring urinary nitrogen excretion. The energy production rate was similar in cirrhotic patients and controls. The origins of liver disease and the degree of liver damage did not seem to influence the energy production rate. On the other hand, in cirrhotic patients, as in controls, a significant correlation was present between the energy production rate and parameters of body size, such as body weight and fat-free mass. As a consequence, cirrhotic patients with poor nutritional status, with a reduced fat-free mass, showed a lower energy production rate. The measured energy production rate was compared with the resting energy expenditure estimated by formulas commonly used in healthy individuals. The good agreement found between the measured energy production rate and calculated energy expenditure suggests that these formulas may be applied to stable cirrhotic patients in clinical practice. In cirrhotic patients, the oxidation of endogenous fat is the main contributor to basal energy production rate. The fat oxidation rate does not appear to be influenced by the hormonal pattern found in the cirrhotic patients. However, a significant correlation was present between fat oxidation and plasma free fatty acid levels. This confirms that the prevalent fat use in cirrhotic patients is supported by the greater availability of fat-derived substrates.

Effects of Branched–Chain Amino Acids on Nitrogen Metabolism in Patients With Cirrhosis

This study was conducted to determine whether an amino acid solution enriched with branched-chain amino acids altered protein catabolic rates and plasma ammonia in patients with cirrhosis. Nine stable subjects were given two peripheral intravenous infusions: a standard amino acid solution (solution A) and a branched-chain-enriched solution containing 97% more leucine (solution B). Each solution was given for separate 9-day (group 1, n = 6) or 3-day (group 2, n = 3) periods. Amino acid solutions delivered 0.7 gm protein.kg-1.day-1. Diets provided an additional 0.3 gm protein plus maintenance calories. Protein turnover was assessed by a primed continuous infusion of [1-14C] leucine in six patients (three patients in group 1 and three patients in group 2). Nitrogen balance and urinary 3-methyl histidine excretion were determined in group 1 patients. Compared with solution A, solution B increased leucine flux and leucine oxidation but had no significant effect on protein synthesis or catabolism based on the plasma specific activity of either leucine or alpha-ketoisocaproic acid. The additional leucine infused with solution B was quantitatively oxidized. Nitrogen balance did not differ with the two solutions and there was also no difference in the urinary excretion of 3-methyl histidine, suggesting that muscle protein catabolism was unchanged. Plasma ammonia concentration decreased significantly during the infusion of solution B and was associated with a slight fall in plasma glucagon concentration. The results indicated that a branched-chain-enriched amino acid solution did not alter protein synthesis or catabolism although it did lower the plasma ammonia when compared with a standard amino acid formula in stable cirrhotic patients.

A Study of Octreotide in Oesophageal Varices

A comparison of octreotide infusion (25 micrograms/h) and placebo in 16 stable cirrhotic patients revealed a 30% reduction in transhepatic venous gradient between 0 and 60 min in the octreotide group without an effect on systemic haemodynamics. In a separate trial, 40 patients with active variceal bleeding were randomized to octreotide infusion (25 micrograms/h for 48 h) or oesophageal tamponade. The 2 treatments gave comparable control of variceal bleeding. Tolerance of treatment was significantly better in the octreotide group. In summary, octreotide infusion is simple to administer, has few side effects, and may be of use in the immediate control of oesophageal bleeding.