Disposition of nafcillin in patients with cirrhosis and extrahepatic biliary obstruction

Nafcillin, a semisynthetic penicillin effective against penicillinase-producing staphylococci, is eliminated largely in man via the liver. This study assessed the effect of cirrhosis and extrahepatic biliary obstruction in man on the pharmacokinetics of nafcillin. The plasma clearance of nafcillin controls was 583 +/- 144.2 ml per min (mean +/- SD) and fell strikingly to 291 +/- 147.6 and 163 +/- 56.3 ml per min in patients with cirrhosis and extrahepatic obstruction, respectively (P less than 0.001). In the latter two groups nafcillin excreted in urine increased from about 30 to 50% of administered dose (P less than 0.02), suggesting that renal disease superimposed on hepatic disease would further decrease over-all nafcillin clearance. The depression of nafcillin clearance with hepatobiliary disease did not correlate with any conventional liver laboratory test. The initial volume of distribution of nafcillin (V1) was unaltered but at steady state (Vd()) there was a significant reduction in the distribution volume in the patients with liver disease. Accordingly, the impairment in drug elimination, as assessed by its clearance from plasma, was underestimated by the prolongation of the nafcillin elimination half-life (t1/2(beta)) which was 1.02 +/- 0.20 hr in controls, and 1.23 +/- 0.31 (P greater than 0.05) and 1.73 +/- 0.44 hr (P less than 0.03), respectively, in patients with cirrhosis and extrahepatic obstruction.     

Differential effects on portal and effective hepatic blood flow. A comparison between transjugular intrahepatic portasystemic shunt and small-diameter H-graft portacaval shunt

OBJECTIVE: This study was undertaken to determine the effects of transjugular intrahepatic portasystemic shunt (TIPS) and small-diameter prosthetic H-graft portacaval shunt (HGPCS) on portal and effective hepatic blood flow. SUMMARY BACKGROUND DATA: Mortality after TIPS is higher than after HGPCS for bleeding varices. This higher mortality is because of hepatic failure, possibly a result of excessive diminution of hepatic blood flow. METHODS: Forty patients randomized prospectively to undergo TIPS or HGPCS had effective hepatic blood flow determined 1 day preshunt and 5 days postshunt using low-dose galactose clearance. Portal blood flow was determined using color-flow Doppler ultrasound. RESULTS: Treatment groups were similar in age, gender, and Child's class. Each procedure significantly reduced portal pressures and portasystemic pressure gradients. Portal flow after TIPS increased (21 mL/second +/- 11.9 to 31 mL/second +/- 16.9, p < 0.05), whereas it remained unchanged after HGPCS (26 mL/second +/- 27.7 to 14 mL/second +/- 41.1, p = n.s.). Effective hepatic blood flow was diminished significantly after TIPS (1684 mL/minute +/- 2161 to 676 mL/minute +/- 451, p < 0.05) and was unaffected by HGPCS (1901 mL/ minute +/- 1818 to 1662 mL/minute +/- 1035, p = n.s.). CONCLUSIONS: Both TIPS and HGPCS achieved significant reductions in portal vein pressure gradients. Portal flow increased after TIPS, although most portal flow was diverted through the shunt. Effective hepatic flow is reduced significantly after TIPS but well preserved after HGPCS. Hepatic decompensation and mortality after TIPS may be because, at least in part, of reductions in nutrient hepatic flow.     

Role of the liver and gut in systemic diphenhydramine clearance in adult nonpregnant sheep

We investigated the contribution of the liver and gut to systemic diphenhydramine (DPHM) clearance in adult nonpregnant sheep in two separate studies. In the first study, a simultaneous 50-mg bolus each of DPHM and its deuterium-labeled analog ([2H10]DPHM) was administered to five sheep via the femoral (i.v.) and the portal venous (p.v.) routes in a randomized manner. Arterial plasma concentrations of DPHM, [2H10]DPHM, and their deaminated metabolites, DPMA (diphenylmethoxyacetic acid) and [2H10]DPMA, were measured using gas chromatography-mass spectrometry. The hepatic first-pass extraction of DPHM after p.v. administration was 94.2 +/- 3.7%. However, the area under the plasma concentration versus time profile of the metabolite after i.v. dosing was only 32.5 +/- 14.0% relative to that after p.v. administration. Thus, only approximately 32.5% of the i.v. dose is metabolized in the liver and a significant extrahepatic systemic clearance component is evident. Using the calculated total hepatic blood flow values, it was found that 98.6 +/- 9.2% of the i.v. dose eventually was delivered to the "hepatoportal" system. Because the drug delivered to the hepatoportal system is almost completely eliminated in a single pass (hepatic extraction approximately 94%), this indicates a lack of any significant pulmonary drug uptake. Also, because only approximately 32.5% of the i.v. dose is metabolized in liver, the gut is most likely responsible for the clearance of the remainder. This gut contribution to systemic DPHM clearance was confirmed in a separate direct study in four sheep where the steady-state DPHM gut extraction ratio was 49.0 +/- 3.0%. Thus, gut accounts for a significant proportion (>/=50%) of DPHM systemic clearance in sheep in spite of a very high hepatic drug extraction efficiency.     

Portosystemic shunt in Budd-Chiari syndrome: long-term survival and factors affecting shunt patency in 25 patients in Western countries

BACKGROUND: In Budd-Chiari syndrome (BCS) treated by portosystemic shunt, postoperative shunt thrombosis is associated with high morbidity and mortality rates. The aim of this study was to determine factors associated with shunt thrombosis. METHODS: From 1985 to 1991, 25 patients underwent portosystemic shunt for BCS. According to the patency of the shunt during the postoperative period and follow-up, patients were divided into two groups including 17 patients with patent shunt and 8 (32%) with shunt thrombosis. RESULTS: In patients with patent shunt, actuarial survival rate at 5 years was 87% versus 38% in patients with shunt thrombosis (p < 0.05). Duration of symptoms before operation was higher in patients with shunt thrombosis than in patients with patent shunt (315 +/- 483 vs 109 +/- 168 days, p < 0.05). In patients with patent shunt, extensive fibrosis or cirrhosis was observed in 3 of 17 (18%) versus in 5 of 8 (63%) of patients with shunt thrombosis (p < 0.05). Shunt thrombosis was observed in 3 of 3 patients (100%) with the combination of myeloproliferative disorder, duration of symptoms more than 100 days, and cirrhosis versus 0 of 6 (0%) patients without this combination (p < 0.05). CONCLUSIONS: In acute form of BCS (with short history of the disease and absence of extensive fibrosis or cirrhosis), early portal decompression is mandatory, with low risk of shunt thrombosis and good long-term results. In chronic form of BCS, the risk of shunt thrombosis is high and long-term results are bad; in these patients, orthotopic liver transplantation must be considered.     

Hepatic outflow study after piggyback liver transplantation

BACKGROUND: Hepatic vein outflow is discussed in liver transplantation after preservation of recipient retrohepatic vena cava. The aim of this study was to compare two methods of suparahepatic caval anastomosis. METHODS: From January 1993 to January 1995, 81 patients received 88 liver transplants because of liver cirrhosis (n = 70), acute liver failure (n = 7), elective retransplantation after hepatic artery thrombosis (n = 2), giant hemangioma (n = 1), and combined liver-small bowel transplantation (n = 1). Seven patients underwent urgent retransplantation, 12 had preoperative transjugular intrahepatic portocaval stent, and 11 had portal vein thrombosis. Five patients required extracorporeal venous shunt. A total of 82 liver transplantations had preservation of RHVC, and 70 patients received temporary end-to-side portacaval shunt. Suprahepatic caval anastomosis was carried out in 52 patients (group 1) between the graft suprahepatic vena cava and the ostia of recipient left and median hepatic veins. Thirty patients (group 2) had associated 3 cm vertical cavotomy with partial clamping of RHVC. In the fourth postoperative month 20 patients from each group had pressure and gradient measurement made among the hepatic veins, right atria, and the RHVC. RESULTS: Mean pressure gradient between hepatic veins and right atria was 0.75 +/- 0.49 mm Hg in group 1 and 2.06 +/- 0.85 mm Hg in group 2. Between the RHVC and the right atria it was 0.63 +/- 0.5 mm Hg in group 1 and 2.22 +/- 1.29 mm Hg in group 2. A pressure gradient higher than 3 mm Hg was considered hemodynamically significant. This pressure gradient was found between the hepatic veins and right atria in 10% of patients in group 1 and 40% of patients in group 2 (p = 0.03) and between the RHVC and right atria in 15% of patients in group 1 and 30% of patients in group 2 (p = 0.3). CONCLUSIONS: Preservation of the recipient RHVC with recipient caval anastomosis at the ostia of the median and left hepatic veins is a reliable technique without any hepatic venous outflow alteration. Associated cavotomy is not necessary.     

The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients

The effect of metformin therapy on glucose metabolism was examined in eight overweight newly presenting untreated type II diabetic patients (five males, three females). Patients were treated for 12 weeks with either metformin (850 mg x 3) or matching placebo using a double-blind crossover study design; patients were studied at presentation and at the end of each treatment period. Insulin action was assessed by measuring activation of skeletal muscle glycogen synthase (GS) before and during a 4-hour hyperinsulinemic euglycemic clamp (100 mU.kg-1 x h-1). Metformin therapy was associated with a significant decrease in fasting blood glucose (6.8 +/- 0.6 v 8.3 +/- 0.9 mmol.L-1, P < .01) and glycosylated hemoglobin ([HbA1] 7.7% +/- 0.4% v 8.5% +/- 0.5%, P < .01) levels. Fasting hepatic glucose production (HGP) was also significantly decreased following metformin therapy (1.98 +/- 0.13 v 2.41 +/- 0.20 mg.kg-1 x min-1, P < .02), whereas fasting insulin and C-peptide concentrations remained unaltered. The decrease in basal HGP correlated closely with the decrease in fasting blood glucose concentration (r = .92, P < .001). Insulin-stimulated glucose uptake was assessed using the hyperinsulinemic euglycemic clamp technique and was increased post-metformin (3.8 +/- 0.6 v 3.1 +/- 0.7 mg.kg-1 x min-1, P < .05). This was primarily the result of increased nonoxidative glucose metabolism (1.1 +/- 0.6 v 0.4 +/- 0.6 mg.kg-1 x min-1, P < .05); oxidative glucose metabolism did not change. Metformin had no measurable effect on insulin activation of skeletal muscle GS, the rate-limiting enzyme controlling muscle glucose storage.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma lipoprotein(a) levels in patients with hyperthyroidism

Thyroid function and regulation were studied in 14 consecutive male outpatients with asymptomatic human immunodeficiency virus (HIV) infection (CDC II/III, n = 8) or AIDS (CDC IV, n = 6) who were free of concomitant infections and hepatic dysfunction, and in eight healthy, age- and weight-matched male controls. Blood was sampled every 10 minutes over 24 hours for measurement of thyrotropin (TSH). Thereafter, thyroid hormones and TSH responsiveness to thyrotropin-releasing hormone (TRH) were measured. Triiodothyronine (T3) and thyroxine (T4) did not differ between HIV-infected patients and controls, but HIV patients had lower thyroid hormone-binding index ([THBI] HIV patients, 1.01 +/- 0.02; controls, 1.11 +/- 0.03; P < .02), free thyroxine (FT4) index (94 +/- 3 v 110 +/- 4, P < .01), FT4 (11.8 +/- 0.4 v 14.3 +/- 0.4 pmol/L, P < .01), and reverse triiodothyronine (rT3) values (0.18 +/- 0.01 v 0.26 +/- 0.02 nmol/L, P < .001) and higher thyroxine-binding globulin ([TBG] 20 +/- 1 v 16 +/- 1 mg/L, P < .02) values. Mean 24-hour TSH levels were increased in HIV patients (2.39 +/- 0.33 v 1.44 +/- 0.16 mU/L, P < .05), associated with increased mean TSH pulse amplitude and TSH responsiveness to TRH. No differences were observed between asymptomatic HIV-seropositive and AIDS patients. In conclusion, there is a hypothyroid-like regulation of the pituitary-thyroid axis in stable HIV infection, which differs distinctly from the euthyroid sick syndrome in non-HIV-nonthyroidal illnesses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective and unselective clamping in cirrhotic liver

BACKGROUND/AIMS: Liver surgery requires a reduction of the operative blood loss especially for patients with cirrhosis. Selective or unselective liver clamping during hepatic resection is performed to minimize the surgical risk for such compromised patients. METHODOLOGY: We carried out elective hepatic resection in 158 patients with the use of total hilar clamping (Pringle's manoeuvre) or selective vascular clamping (Makuuchi's manoeuvre). The clinical outcomes were evaluated according to the clamping method and the condition of background liver. RESULTS: Pringle's manoeuvre was used in 132 patients who underwent all types of hepatectomy, whereas Makuuchi's manoeuvre was applied selectively to 26 patients, most of whom underwent segmentectomy or subsegmentectomy. A modified Makuuchi's manoeuvre was used in eight healthy donors who underwent left-sided hepatectomy for transplantation. The cumulative clamping times and blood losses were 61 +/- 47 min (mean +/- SD) and 831 +/- 716 ml in the Pringle's manoeuvre group, and 95 +/- 47 min and 1.035 +/- 577 ml in the Makuuchi's manoeuvre group. In patients with normal hepatic parenchyma the longest clamping time was 322 min, and in those with cirrhosis it was 202 min. All the patients in this series tolerated vascular clamping well, and their hepatic functional parameters returned, regardless of the presence or absence of cirrhosis, to the baseline levels within a week. As a whole, the operative morbidity and mortality rates were 20.3% and 0%, respectively. CONCLUSIONS: Intermittent total or selective clamping can be an indispensable procedure during hepatic resection for all patients, irrespective of the degree of hepatic dysfunction, to improve safety and resectability.     

Propoxyphene and norpropoxyphene plasma concentrations after oral propoxyphene in cirrhotic patients with and without surgically constructed portacaval shunt

Plasma concentrations of propoxyphene and its major metabolite, norpropoxyphene, were determined over at least 12 hr after oral administration of 130 mg dextropropoxyphene hydrochloride to eight men with hepatic cirrhosis, of whom four had a surgically constructed portacaval shunt, and to seven healthy men. Propoxphene concentrations were appreciably higher and norpropoxyphene concentrations were much lower in the patients than in the normal subjects. The ratio of areas under the plasma concentration-time curve from 0 to 12 hr, norpropoxyphene: propoxyphene, was 0.70 +/- 0.46 (x +/SD) in patients and 3.94 +/ 0.83 in normal subjects. A similar decrease in this ratio was observed previously in otherwise healthy dogs after surgical construction of portacaval shunt when propoxyphene was given orally, but not after intravenous injection of the drug. A woman with portacaval shunt and essentially complete renal failure was also studied; she exhibited the highest propoxyphene peak concentration in this investigation and had no detectable norpropoxyphene in plasma. Most of the patients, unlike the normal subjects, experienced considerable sedation after propoxyphene. These results are probably due to increase systemic availability of orally administered propoxyphene in patients with hepatic cirrhosis and possibly to increased receptor response to the drug by these patients. It is concluded that propoxyphene should be administered cautiously and in reduced doses to patients with hepatic dysfunction.     

A controlled trial of choleretic and hepatoprotective actions of Livzon and dehydrocholic acid in a model of obstructive jaundice in albino rats

Ascites becomes refractory to medical treatment in nearly 10% of cirrhotic patients, who then require repeated large-volume paracentesis. In this prospective study we evaluated the use of transjugular intrahepatic portosystemic shunt (TIPS) in 30 patients with refractory ascites. TIPS was successful in all and resulted in a 54% reduction in portacaval gradient (from 22.8 +/- 0.8 to 10.4 +/- 0.6 mm Hg). Ascites became easily controlled with diuretics in 26 patients following TIPS. Ascites recurrence associated with shunt stenosis was observed during follow-up in eight patients; revision could be undertaken in five of them and resulted in good control of ascites. In responders, a marked decrease in plasma aldosterone and renin activity, a reduction in serum creatinine, and a rise in urinary sodium excretion were observed. Creatinine and inulin clearances improved significantly; PAH clearance remained unchanged. However, new-onset or worsening hepatic encephalopathy was seen in 14 patients. Severe disabling chronic encephalopathy occurred in five patients; it could be reversed successfully by balloon occlusion of the shunt in three. The cumulative survival rate was 41 and 34% at 1 and 2 years, respectively. In summary, TIPS can control refractory ascites in a majority of patients but is associated with a high rate of chronic disabling HE. In addition, the survival rate is poor. Randomized trials are needed to evaluate the exact role of TIPS in the management of refractory ascites. It is unlikely to improve survival but can ameliorate quality of life in nontransplant candidates and be useful as a bridge to transplantation, in particular, to improve denutrition associated with longstanding tense ascites.     

Effect of supplemental oxygen on supramaximal exercise performance and recovery in cystic fibrosis

The effects of supplemental O2 on recovery from supramaximal exercise and subsequent performance remain unknown. If recovery from exercise could be enhanced in individuals with chronic lung disease, subsequent supramaximal exercise performance could also be improved. Recovery from supramaximal exercise and subsequent supramaximal exercise performance were assessed after 10 min of breathing 100% O2 or room air (RA) in 17 cystic fibrosis (CF) patients [25 +/- 10 (SD) yr old, 53% men, forced expired volume in 1 s = 62 +/- 21% predicted] and 17 normal subjects (25 +/- 8 yr old, 59% men, forced expired volume in 1 s = 112 +/- 15% predicted). Supramaximal performance was assessed as the work of sustained bicycling at a load of 130% of the maximum load achieved during a graded maximal exercise. Peak minute ventilation (VE) and heart rate (HR) were lower in CF patients at the end of each supramaximal bout than in controls. In CF patients, single-exponential time decay constants indicated faster recovery of HR (tau HR = 86 +/- 8 and 73 +/- 6 s in RA and O2, respectively, P < 0.01). Similarly, fast and slow time constants of two-exponential equations providing the best fit for ventilatory recovery were improved in CF patients during O2 breathing (tau 1VE = 132.1 +/- 10.5 vs. 82.5 +/- 10.4 s; tau 2VE = 880.3 +/- 300.1 vs. 368.6 +/- 107.1 s, P < 0.01). However, no such improvements occurred in controls. Supramaximal performance after O2 improved in CF patients (109 +/- 6% of the 1st bout after O2 vs. 94 +/- 6% in RA, P < 0.01). O2 supplementation had no effect on subsequent performance in controls (97 +/- 3% in O2 vs. 93 +/- 3% in RA). We conclude that supplemental O2 after a short bout of supramaximal exercise accelerates recovery and preserves subsequent supramaximal performance in patients with CF.     

Accuracy of portal and forearm blood flow measurements in the assessment of the portal pressure response to propranolol

BACKGROUND/AIMS: The portal pressure response to propranolol varies significantly in individual patients with cirrhosis. At present, propranolol responders can be identified only by measuring the hepatic venous pressure gradient. The aims of this study were: 1) to investigate whether the noninvasive monitoring of portal blood flow by pulsed Doppler ultrasound and forearm blood flow by strain-gauge plethysmography can predict the hepatic venous pressure gradient response to propranolol in patients with cirrhosis, and 2) to analyze the factors that may influence this response. METHODS: Hemodynamic measurements were undertaken in 80 patients with cirrhosis before and after receiving propranolol (0.15 mg/kg i.v., n = 60) or placebo (n = 20). RESULTS: No changes were observed in the placebo group. Propranolol lowered (p < 0.01) hepatic venous pressure gradient from 17.6 +/- 3.8 to 14.7 +/- 3.8 mmHg, portal blood flow from 1122 +/- 363 to 897 +/- 332 ml/min and forearm blood flow from 7.52 +/- 3.1 to 6.12 +/- 2.3 ml/min%. Changes in hepatic venous pressure gradient were correlated (p < 0.01) with those of portal blood flow (r = 0.82) and forearm blood flow (r = 0.54). The reduction in hepatic venous pressure gradient was > 20% in 23 patients ("responders"). The accuracy of portal Doppler flowmetry in identifying responders was higher than that of forearm plethysmography (88.3 vs. 68.3%, p < 0.05). Multivariate analysis proved that previous variceal bleeding was the only factor independently associated with a lack of response to propranolol (relative risk 3.42, 95% CI 1.5-7.4, p < 0.01). Hepatic venous pressure gradient reduction by propranolol was higher in non-bleeders than in bleeders (-19.9 +/- 9.4 vs. -11.3 +/- 8.6%, p < 0.01). CONCLUSIONS: Portal Doppler ultrasound can be used as a reliable surrogate indicator of the hepatic venous pressure gradient response to acute propranolol administration. In addition, our study indicates that this response is mainly influenced by previous variceal hemorrhage.     

Converting-enzyme inhibitor versus calcium antagonist in cyclosporine-treated renal transplants

The influence of antihypertensive treatment on the long-term evolution of arterial pressure and renal function was studied in a prospective controlled trial conducted in renal transplant recipients treated by cyclosporine. Within six months after transplantation, patients were randomly allocated to treatment by the angiotensin-converting enzyme inhibitor, lisinopril (ACEI, alone or associated with frusemide; N = 14), or the calcium antagonist, nifedipine (CA, alone or associated with atenolol; N = 11). Glomerular filtration rate (TcDTPA clearance) and effective renal plasma flow (hippuran clearance) as well as 24-hour urinary excretion of electrolytes and albumin were estimated at about 1 and 2.5 years of follow-up. Before initiation of antihypertensive therapy, the two groups were similar with regards to mean arterial pressure (119 +/- 2 vs. 120 +/- 4 mm Hg), effective renal plasma flow (285 +/- 26 vs. 248 +/- 33 ml/min/1.73 m2) and glomerular filtration rate (59 +/- 4 vs. 61 +/- 8 ml/min/1.73 m2 in the ACEI and CA groups, respectively). Both ACEI and CA treatments were associated with no change in renal function, a similar change in mean arterial pressure (ACEI -18 +/- 3; CA -13 +/- 5 mm Hg) and identical trough blood levels of cyclosporine. Urinary albumin excretion did not change significantly in any groups. Of interest, only in the ACEI group did filtration fraction significantly decrease (from 0.22 +/- 0.01% to 0.19 +/- 0.01% at final studies). These results indicate that in cyclosporine-treated transplant recipients, a satisfactory control of hypertension is obtained by chronic ACEI, which is as effective on arterial pressure as a combination of CA and atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transvaginal salpingoscopy: an office procedure for infertility investigation

In patients with cystic fibrosis (CF), nasal intermittent positive pressure ventilation (NIPPV) is currently used as a short-term bridge to transplantation but its precise role has yet to be determined. Patients were offered a therapeutic trial of NIPPV when candidates for lung transplantation, with respiratory failure unresponsive to medical treatment. Twelve patients, six male of mean age of 26 +/- 1.4 years, had a trial of NIPPV. At recruitment the mean percentage predicted forced expired volume in one second (FEV1) was 15.1% +/- 1.2%, arterial carbon dioxide (PaCO2) 8.7 +/- 0.6 kPa, arterial oxygen (PaO2) with variable FiO2 7.4 +/- 0.6 kPa and arterial bicarbonate (HCO3-) 40.1 +/- 1.6 mmol l-1. Ten cases tolerated NIPPV for 1-15 months, mean 5.1 +/- 1.4 months, with subjective improvement in headache and quality of sleep. At 3 months, there was significant improvement in forced vital capacity, PaCO2 and arterial HCO3- and there was a reduction in the number of hospital inpatient days (P < 0.05). Subsequently three cases had lung transplantation, four died on the active list and three are awaiting organs. Two patients failed to tolerate NIPPV owing to abdominal bloating and increasing hypercapnia. In conclusion, NIPPV, if tolerated, was a useful adjunct in the treatment of CF patients with hypercapnic respiratory failure awaiting transplantation. Further prospective studies are required to determine the optimum time to commence NIPPV and to clarify its precise role.     

Possible mechanisms by which alcohol may influence the development of oral cancer--a review

Hepatitis C virus (HCV) infection is one of the major causes leading to orthotopic liver transplantation (OLT) worldwide. Although viral infection persists in almost all patients, the pathology of recurrent HCV infection after OLT is not well characterized. To address this issue, we compared the pathological findings of 28 patients who underwent transplantation for HCV-related cirrhosis (group A, aged 47 +/- 15 years; 23 men, 5 women) with those of 21 patients who underwent transplantation for nonviral indications (group B, aged 45 +/- 21 years; 13 men, 8 women) during the first year after transplantation. Patients from group A were assessed for serum HCV RNA by 5' untranslated region nested polymerase chain reaction before and 1 year after OLT. Patients underwent protocol liver biopsies 3 months and 1 year after transplantation. Group A patients more frequently had histological evidence of hepatic steatosis than group B patients, both at 3 months (P = .003) and 1 year (P = .003) after OLT. Fibrosis and portal inflammation were statistically more frequent in group A 1 year after transplantation. The sensitivity of steatosis in detecting histological disease recurrence was 100% at 3 months and 94% at 1 year; the specificity was 40% and 60%, respectively. Conversely, steatosis was 100% specific in detecting viral recurrence, with a sensitivity of 89%. The 1-year actuarial incidence of abnormal transaminase levels was 52% in group A and 13% in group B (P = .05). No biochemical or histological differences between patients infected with genotype 1b and patients with other HCV genotypes were found. Hepatic steatosis is a specific sign of viral recurrence after liver transplantation and a less specific sign of disease recurrence. HCV-infected liver transplant recipients often develop abnormal transaminase levels and liver fibrosis 1 year after OLT; these features are unrelated to HCV genotypes.     

Scintillation splenoportography: hemodynamic and morphological study of the portal circulation

The intrasplenic injection of 99mTc-labeled albumin microspheres, followed 30 sec later by an injection of 99mTc-labeled red blood cells with recording of the progression of the two tracers, were performed in 110 patients. This also enabled the plotting of activity versus time curves on splenic, hepatic, cardiac, and pulmonary areas of interest, there by giving access to several hemodynamic variables. Scintillation image demonstrated splenoportal obstruction in 8 cases. Intrahepatic obstruction with reflux via collaterals were observed in 53 cases, 14 with umbilical reflux. In 13 cases, the patency of surgical portacaval anastomoses were verified. The splenoportal blood flow velocity was not significantly different in patients with cirrhosis (V = 10.1 cm per sec +/- 3.0 SD) and in normal subjects (V = 13.2 cm per sec +/- 5.8 SD). The fraction of shunted splenic flow in the case of cirrhosis varied from 0 to 100%; there was no relationship between this percentage and the seriousness of the clinical status. In 3 cases, the presence of intrahepatic shunts was detected. There was a very significant difference between mean transit time (MTT) of red blood cells in patients with cirrhosis (t = 12.2 sec +/- 4.4 SD) and those without cirrhosis (t = 19.9 sec +/- 3.7 SD). Among patients with cirrhosis, those with a history of jaundice had a shorter MTT than those without such a history. On the other hand, the MTT was not significantly different whether the patients with cirrhosis had or did not have hemorrhage, ascites or encephalopathy. There was a positive correlation (P less than 0.01) between MTT and plasma albumin concentration,and between MTT and prothrombin (P less than 0.01). Finally, there was a high negative correlation (P less than 0.001) between MTT and total serum bilirubin. Scintillation splenoportography is a useful technique for assessing hepatic hemodynamics and for demonstrating abnormalities of the intrahepatic circulation.     

Clinical evaluation of hepatic blood flow and liver function with 99mTc-DTPA-HSA

Clinical evaluation of hepatic blood flow and liver function of 30 patients with 99mTc-human serum albumin scintigraphy (99mTc-HSA) was done. In this study we evaluated the ratio of portal venous to total hepatic blood flow as the hepatic perfusion index (HPI), and 99mTc-HSA uptake ratio of the liver to the heart at 2 hrs after bolus injection as the hepatic uptake score (HUS). In clinical study, we estimated both HPI and HUS in patients with liver cirrhosis (LC) and non-liver-cirrhosis (non-LC), and in the same way estimated these two factors in the patients before and after distal splenorenal shunt operations (DSRS). We also estimated the correlation of both HPI and HUS with other liver functions. Finally we made 3 dimensional liver imagings using 99mTc-HSA. The mean HPI was 0.42 +/- 0.24 in the LC group and 0.66 +/- 0.19 in the non-LC group (p < 0.02). The mean HUS was 0.50 +/- 0.17 in the LC group and 0.67 +/- 0.13 in the non-LC group (p < 0.02). The mean HPI decreased to 32-54% after the DSRS operation, but there was no such change with HUS. Correlation between HPI and KICG was significant (r = 0.51, p < 0.02), and there was also a correlation between HUS and PT, HPT (p < 0.02), and ICGR15 (p < 0.02). We concluded that HPI and HUS were both useful factors in estimating hepatic blood flow and liver function.     

Utilization of tyrosine-containing dipeptides and N-acetyl-tyrosine in hepatic failure

The impact of hepatic dysfunction on the elimination and hydrolysis of three potential tyrosine sources for total parenteral nutrition, the dipeptides L-alanyl-L-tyrosine (Ala-Tyr) and glycyl-L-tyrosine (Gly-Tyr), and N-acetyl-L-tyrosine (Nac-Tyr) were evaluated in six patients with hepatic failure (five chronic, one acute) and seven healthy subjects. In controls, whole-body clearance (Cltot) of Ala-Tyr was higher than of Gly-Tyr (3,169 +/- 214 vs. 1,780 +/- 199 mL/kg/min, P < .01), and both exceeded clearance of Nac-Tyr (309 +/- 29 mL/kg/min, P > .01). Both dipeptides were hydrolyzed and released tyrosine immediately. In hepatic failure, elimination and hydrolysis of Ala-Tyr and Gly-Tyr were comparable to controls, but Cltot of Nac-Tyr was reduced (236 +/- 26 mL/kg/min). Neither in controls nor in patients an increase in plasma tyrosine concentration was seen after Nac-Tyr, and the major part of Nac-Tyr infused was lost in urine. The Cltot of tyrosine as evaluated after Ala-Tyr infusion (with the immediate release of tyrosine) was severely reduced in hepatic failure (152.7 +/- 38.4 vs. 484.4 +/- 41.4 mL/kg/min, P < .001) and half-life (kle) was retarded from 14.4 +/- 1.4 to 90.2 +/- 32.2 minutes (P < .03). The authors conclude that acute and chronic hepatic dysfunction does not affect elimination and hydrolysis of the dipeptides Ala-Tyr and Gly-Tyr and the constituent amino acids are released immediately. Nac-Tyr elimination was not grossly affected by hepatic failure, but neither in healthy subjects nor in hepatic failure patients was an increase of tyrosine seen. Both dipeptides but not Nac-Tyr may serve as a tyrosine source in parenteral nutrition. Moreover, by its rapid hydrolysis, the use of Ala-Tyr, for the first time, enables a simple rapid nonisotope evaluation of tyrosine kinetics for assessment of liver function.     

Quantification of gluconeogenesis in cirrhosis: response to glucagon

BACKGROUND & AIMS: Accelerated starvation and early recruitment of alternate fuels in cirrhosis have been attributed to reduced availability of hepatic glycogen. The aim of this study was to measure gluconeogenesis (as a marker of protein oxidation) in relation to total glucose production and glucagon-stimulated glycogenolysis. METHODS: Glucose and urea production, gluconeogenesis, and glycogenolysis were calculated using stable isotope methods before and during glucagon infusion (3 ng. kg-1. min-1) in 5 cirrhotic patients and 5 matched controls before and after glycogen repletion. RESULTS: In the basal state, cirrhotic patients had a normal rate of glucose production, but the contribution of gluconeogenesis was increased (74.3% +/- 4.1% vs. 55. 6% +/- 12.1%; P < 0.005). Glycogen repletion normalized the rate of gluconeogenesis. The glycemic response to glucagon (3 ng. kg-1. min-1) was blunted in cirrhotic patients because of a lower rate of glycogenolysis (0.63 +/- 0.23 vs. 1.22 +/- 0.23 mg. kg-1. min-1; P < 0.01) and was not affected by glycogen repletion. Despite increased gluconeogenesis, the simultaneously measured rate of urea synthesis was lower in cirrhotic patients (3.11 +/- 1.02 vs. 5.0 +/- 1.0 mg/kg; P < 0.05). CONCLUSIONS: These data show that in cirrhosis, glucose production is sustained by an increased rate of gluconeogenesis. The hepatic resistance to glucagon action is not caused by reduced glycogen stores.     

A study of laboratory based faecal occult blood testing in Melbourne, Australia. The Faecal Occult Blood Testing Study Group

The effects of chromium (Cr) supplementation on diet-induced insulin resistance produced by feeding a high-fat, low-Cr diet were studied in rats to ascertain the role of Cr in insulin resistance. Wistar male rats were maintained for 16 weeks after weaning on a basal diet containing 40% lard, 30% sucrose, and 25% casein by weight and adequate vitamins and minerals without added Cr (-Cr). Fasting levels of insulin, glucose, and triglycerides and the responses during an intravenous glucose tolerance test (IVGTT) were compared as indices of insulin resistance and the effectiveness of dietary Cr. IVGTTs and blood sampling for data analyses were performed over a 40-minute period after IV glucose injection (1.25 g/kg body weight) in overnight-fasted animals under pentobarbital anesthesia (40 mg/kg body weight). All animals were normoglycemic (-Cr, 109 +/- 3 mg/dL; +Cr, 119 +/- 5), with fasting insulin levels elevated in the -Cr group (65 +/- 10 microU/mL) versus the +Cr group (31 +/- 4 microU/mL). Increases in plasma triglycerides in the -Cr group were not significant. Following glucose injection, the rate of glucose clearance was lower in the -Cr group (1.74 +/- 0.22 v2.39 +/- 0.11%/min), and 40-minute glucose areas in the -Cr group tended to be higher than in the +Cr group. The insulin response to glucose injection was 20% higher in the -Cr group. Forty-minute plasma triglyceride areas were lower in +Cr rats (875 +/- 62 v 1,143 +/- 97 mg/dL.min in -Cr rats). These data demonstrate that the insulin resistance induced by feeding a high-fat, nutrient-stressed diet is improved by Cr.