Paolo Avagnina

Hepatic clearance of D-sorbitol: noninvasive test for evaluating functional liver plasma flow

The hepatic clearance of D-sorbitol, a natural polyol which is metabolized by the liver, was studied in normal and cirrhotic subjects after bolus intravenous injection (2 g) and during constant infusion (54 mg/min) with the aim of providing a noninvasive and simple measure of functional liver plasma flow. The high hepatic extraction of D-sorbitol and the dose-independence of its clearance pointed to a flow-dependent clearance regimen. The renal excretion was taken into account when computing the hepatic clearance. Day-to-day reproducibility of the test was good. No significant difference was found when the hepatic clearance was measured by bolus injection or constant infusion methods. As measured by the bolus injection method, the mean (+/- SD) hepatic clearance in the normal subjects (911 +/- 137 ml/min) was significantly greater (P less than 0.001) than that of the cirrhotics (456 +/- 181 ml/min).The hepatic clearance ofd-sorbitol, a natural polyol which is metabolized by the liver, was studied in normal and cirrhotic subjects after bolus intravenous injection (2 g) and during constant infusion (54 mg/min) with the aim of providing a noninvasive and simple measure of functional liver plasma flow. The high hepatic extraction ofd-sorbitol and the dose-independence of its clearance pointed to a flow-dependent clearance regimen. The renal excretion was taken into account when computing the hepatic clearance. Day-today reproducibility of the test was good. No significant difference was found when the hepatic clearance was measured by bolus injection or constant infusion methods. As measured by the bolus injection method, the mean (±sd) hepatic clearance in the normal subjects (911±137 ml/min) was significantly greater (P<0.001) than that of the cirrhotics (456±181 ml/min).

Combined evaluation of total and functional liver plasma flows and intrahepatic shunting

A diagnostic protocol was studied, designed to evaluate the main parameters of liver circulation in man. A water solution ofd-sorbitol (S) and indocyanine green (ICG) was infused intravenously in six controls and nine cirrhotics. Steady-state renal and hepatic S clearances as well as hepatic ICG clearance were calculated. In controls the values (mean ±sd) of the independent measurements of S and ICG hepatic clearance were 978±107 and 519±142 ml/min, respectively, while in cirrhotic patients they were 554±238 and 231±90 ml/min. Owing to the kinetic properties of S, its hepatic clearance may be regarded as a measure of functional liver plasma flow (FLPF). The total liver plasma flow (TLPF) values (mean±sd), calculated according to Ficks principle, were 1091±157 ml/min (S method) and 1033±153 ml/min (ICG method) in controls, and 1251±554 and 1284±677 ml/min in cirrhotics. In controls, FLPF was found to be very close to TLPF. In cirrhotic patients the difference between TLPF and FLPF (ranging from 169 to 2093 ml/min when measured by S method) was considered as an approximate estimate of intrahepatic shunting. The procedure is safe and simple and may add a new dimension to the investigation of hepatic circulation.

Vegan–vegetarian diets in pregnancy: danger or panacea? A systematic narrative review

Although vegan–vegetarian diets are increasingly popular, no recent systematic reviews on vegan–vegetarian diets in pregnancy exist.

Assessment of the hepatic circulation in humans: new concepts based on evidence derived from a D-sorbitol clearance method.

D-Sorbitol (SOR) is safe, is easy to measure, and has an exceptionally high extraction ratio in the normal liver of 0.93+/-0.05 (mean+/-SD). Together with the general interest in hepatic hemodynamics, these facts motivated us to review the usefulness of this compound for the assessment of liver plasma flow in humans. We concluded that in subjects without liver disease the nonrenal clearance of SOR-measured noninvasively-very closely approximates hepatic plasma flow. Because of its lower and more variable extraction ratio, indocyanine green should no longer be used without hepatic vein catheterization. Even in patients with cirrhosis, SOR exhibits higher hepatic extraction ratios than indocyanine green. To fully explore the potential of SOR in the evaluation of such patients attention needs to be paid to the complex changes in architecture and function occurring in this disease. In cirrhotics the noninvasively measured nonrenal clearance of SOR presumably approximates the flow through intact and capillarized sinusoids (functional flow) and reflects the amount of blood having functional contact with hepatocytes. The theoretic background of the method, its accuracy, further research needs, and potentials of various approaches are discussed in detail.

Assessment of functional liver mass and plasma flow in acromegaly before and after long-term treatment with octreotide

Functional liver mass and functional liver plasma flow (FLPF) were assessed in 11 patients with clinical features of acromegaly by determining galactose elimination capacity (GEC) and extrarenal clearance of sorbitol, before and 5 to 7 months after treatment with the long-acting somatostatin analog, octreotide (150 to 600 micrograms/d in three subcutaneous injections). Growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels, as well as liver size by ultrasound, were also recorded. Baseline GEC was increased in every patient but one, for a mean of 0.78 +/- 0.10 g/min (normal, 0.53 +/- 0.07; P < .01). At reevaluation after 5 to 7 months of octreotide treatment, a significant reduction of GEC was observed (0.62 +/- 0.08 g/min, P < .001). Changes of GEC paralleled those of GH (38.6 +/- 34.4 v 11.7 +/- 15.2 micrograms/L, P < .01) and IGF-I (5.0 +/- 1.7 v 2.7 +/- 2.2 U/ml, P < .001). Significant correlations were found between GEC and GH (r = .50, P < .05) and between GEC and IGF-I (r = .55, P < .01). FLPF, assessed by extrarenal clearance of sorbitol, was within the normal limit in all cases (0.98 +/- 0.19 v 0.97 +/- 0.12 L/min, NS) and remained normal after 5 to 7 months of octreotide treatment (0.99 +/- 0.11 L/min). Hepatic structure determined with ultrasonic scanning and conventional liver-function tests were basally normal in all patients, with a slight increase of liver volume in three cases. No change of biochemical and/or morphological features occurred during follow-up evaluation. The results support the hypothesis that GH and especially IGF-I enhance liver metabolic capacity; conversely, functional liver perfusion is largely independent of their actions. Our data also suggest that octreotide is unable to produce well-structured changes of liver circulation when administered long-term.

Non-invasive evaluation of portal-systemic shunting in man by d-sorbitol bioavailability

Portal-systemic shunting is an important circulatory abnormality in patients with cirrhosis. This study explores the potential of the natural polyol D-sorbitol as test compound for non-invasive assessment of shunting. Ten normal subjects, 10 patients with cirrhosis and 12 cirrhotics with surgical portacaval shunts were studied after oral and intravenous administration of a 2 g dose of sorbitol. As measured by the H2 breath test, removal from the intestinal lumen was complete in both groups. Bioavailability of sorbitol, calculated as ratio of the areas under the plasma concentration/time curve after p.o. and i.v. administration, was zero in normal subjects, 0.29 +/- 0.15 in cirrhotic patients, and 0.38 +/- 0.11 in patients with portacaval shunts. Calculation of bioavailability on the basis of urinary outputs of sorbitol gave similar results. It is concluded that the bioavailability of sorbitol reflects portal-systemic shunting, although the relatively low figures suggest some degree of sorbitol metabolism by enterocytes.

Low protein diets in patients with chronic kidney disease: a bridge between mainstream and complementary-alternative medicines?

Dietary therapy represents an important tool in the management of chronic kidney disease (CKD), mainly through a balanced reduction of protein intake aimed at giving the remnant nephrons in damaged kidneys a “functional rest”. While dialysis, transplantation, and pharmacological therapies are usually seen as “high tech” medicine, non pharmacological interventions, including diets, are frequently considered lifestyle-complementary treatments. Diet is one of the oldest CKD treatments, and it is usually considered a part of “mainstream” management. In this narrative review we discuss how the lessons of complementary alternative medicines (CAMs) can be useful for the implementation and study of low-protein diets in CKD. While high tech medicine is mainly prescriptive, prescribing a “good” life-style change is usually not enough and comprehensive counselling is required; the empathic educational approach, on which CAMs are mainly, though not exclusively based, may support a successful personalized nutritional intervention.There is no gold-standard, low-protein diet for all CKD patients: from among a relatively vast choice, the best compliance is probably obtained by personalization. This approach interferes with the traditional RCT-based analyses which are grounded upon an assumption of equal preference of treatments (ideally blinded). Whole system approaches and narrative medicine, that are widely used in the study of CAMs, may offer ways to integrate EBM and personalised medicine in the search for innovative solutions respecting individualization, but gaining sound data, such as with partially-randomised patient preference trials.

Tailoring dialysis and resuming low-protein diets may favor chronic dialysis discontinuation: report on three cases.

Renal function recovery (RFR), defined as the discontinuation of dialysis after 3 months of replacement therapy, is reported in about 1% of chronic dialysis patients. The role of personalized, intensive dialysis schedules and of resuming low‐protein diets has not been studied to date. This report describes three patients with RFR who were recently treated at a new dialysis unit set up to offer intensive hemodialysis. All three patients were females, aged 73, 75, and 78 years. Kidney disease included vascular‐cholesterol emboli, diabetic nephropathy and vascular and dysmetabolic disease. At time of RFR, the patients had been dialysis‐dependent from 3 months to 1 year. Dialysis was started with different schedules and was progressively discontinued with a “decremental” policy, progressively decreasing number and duration of the sessions. A moderately restricted low‐protein diet (proteins 0.6 g/kg/day) was started immediately after dialysis discontinuation. The most recent update showed that two patients are well off dialysis for 5 and 6 months; the diabetic patient died (sudden death) 3 months after dialysis discontinuation. Within the limits of small numbers, our case series may suggest a role for personalized dialysis treatments and for including low‐protein diets in the therapy, in enhancing long‐term RFR in elderly dialysis patients.

Effects of nifedipine on functional liver plasma flow in normal subjects and in patients with cirrhosis.

The short‐term effects of nifedipine (10 mg administered sublingually) on functional liver plasma flow, measured by calculating the extrarenal clearance of sorbitol, were investigated in 12 normal volunteers and 40 patients with cirrhosis scored according to Child‐Pugh classification. Nifedipine significantly increased functional liver plasma flow in healthy subjects (23%, p < 0.0001) and in patients with cirrhosis in the Child‐Pugh class A group (19%, p < 0.001); in patients in the Child‐Pugh class B group functional liver plasma flow was not modified, whereas in the patients in the Child‐Pugh class C group it was significantly reduced (− 7%, p < 0.02). The mean arterial pressure showed a significant reduction in all groups studied. According to the pathophysiologic meaning of functional liver plasma flow, it is suggested that nifedipine meets criteria for an ideal test substance to evaluate the functional reserve of the liver. Furthermore, when used with the Child‐Pugh classification, its effect on functional liver plasma flow may be useful to improve the efficiency of the Child‐Pugh classification, in establishing the prognosis of patients with cirrhosis.

D-Sorbitol plasma disappearance rate: An index to evaluate changes in liver circulation

SummaryThe hepatic clearance of D-sorbitol was proven to be a reliable parameter for evaluating the functional liver plasma flow. Twenty-five normal subjects and 50 cirrhotic patients were studied in order to assess if the measure of the plasma disappearance rate of sorbitol can be used as a simpler procedure to evaluate changes in liver perfusion and to predict modifications of drug bioavailability due to circulatory events. The plasma disappearance rate was calculated between 10 and 20 min after intravenous administration of a 2-g dose because in this time interval plasma levels were in the optimum range for the chemical assay, and the plasma concentration/time curve fitted a decreasing exponential function. Plasma disappearance rate values were found to correlate significantly (r = 0.666, p<0.001) with sorbitol hepatic clearance, as calculated after the 2-h test. The test had a good day-to-day reproducibility both in normal subjects and cirrhotic patients. In 5 patients submitted to surgical side-to-side portacaval shunt, decreases of plasma disappearance rate and sorbitol hepatic clearance showed no significant difference. Mean values (± SD) of D-sorbitol plasma disappearance rate were 0.048 ± 0.014 min-1 in cirrhotic patients, and 0.081 ± 0.014 min-1 in normal subjects (p<0.001).