Risk and Prognosis of Acute Liver Injury Among Hospitalized Patients with Hemodynamic Instability: A Nationwide Analysis Introduction and aim. Critically ill patients in states of circulatory failure are at risk of acute liver injury, from mild elevations in aminotransferases to substantial rises consistent with hypoxic hepatitis or "shock liver". The present study aims to quantify the national prevalence of acute liver injury in patients with hemodynamic instability, identify risk factors for its development, and determine predictors of mortality.

The 2009-2010 Nationwide Inpatient Sample was interrogated using ICD-9-CM codes for hospital admissions involving states of hemodynamic lability. Multivariable logistic regression was used to evaluate the risks of acute liver injury and death in patients with baseline liver disease, congestive heart failure, malnutrition, and HIV.

Of the 2,865,446 patients identified in shock, 4.60% were found to have acute liver injury. A significantly greater proportion of patients with underlying liver disease experienced acute liver injury (22.03%) and death (28.47%) as compared to those without liver disease (3.18% and 18.82%, respectively). The odds of developing acute liver injury were increased in all baseline liver diseases studied, including all-cause cirrhosis, hepatitis B, hepatitis C, alcoholic liver disease, and non-alcoholic fatty liver disease, as well as in congestive heart failure and malnutrition. All-cause cirrhosis and alcoholic liver disease, however, conferred the greatest risk. Similar trends were seen with mortality. HIV was not a predictor for acute liver injury.

Liver injury is a major concern among patients with protracted circulatory instability, especially those suffering from underlying liver disease, heart failure, or malnutrition.

Hypoxic hepatitis (HH), also known as ischemic hepatitis or shock liver, is characterized by a massive, rapid rise in serum aminotransferases resulting from reduced oxygen delivery to the liver. The most common predisposing condition is cardiac failure, followed by circulatory failure as occurs in septic shock and respiratory failure. HH does, however, occur in the absence of a documented hypotensive event or shock state in 50% of patients. In intensive care units, the incidence of HH is near 2.5%, but has been reported as high as 10% in some studies. The pathophysiology is multifactorial, but often involves hepatic congestion from right heart failure along with reduced hepatic blood flow, total body hypoxemia, reduced oxygen uptake by hepatocytes or reperfusion injury following ischemia. The diagnosis is primarily clinical, and typically does not require liver biopsy. The definitive treatment of HH involves correction of the underlying disease state, but successful management includes monitoring for the potential complications such as hypoglycemia, hyperglycemia, hyperammonemia and hepatopulmonary syndrome. Prognosis of HH remains poor, especially for cases in which there was a delay in diagnosis. The in-hospital mortality rate is >50%, and the most frequent cause of death is the predisposing condition and not the liver injury itself.

Disturbances in hepatic microcirculation are believed to be involved in the mechanisms regulating the progression of acute liver injury (ALI). Evaluation of hepatic hemodynamics in patients with acute liver injury might be helpful in understanding the extent of the intrahepatic microcirculatory disturbances. Therefore, we investigated whether contrast-enhanced ultrasonography (CEUS) is useful to evaluate the changes in hepatic hemodynamics in patients with ALI.

CEUS was performed in 21 patients with ALI and coagulopathy. Participants were injected with 0.0075 mL Sonazoid/kg body weight, and time-intensity curves were simultaneously recorded for the hepatic and portal veins. The data were compared with those of 10 healthy volunteers.

The arrival time of Sonazoid in the hepatic vein was similar to that in the portal vein in the patients, whereas the arrival time in the hepatic vein was delayed relative to that in the portal vain in the controls (interval between the hepatic and portal vein arrival times, control vs patients 6.74 ± 3.07 s vs 1.13 ± 1.07 s, P < 0.001). Repeated examination revealed that the interval between the hepatic and portal vein arrival times was extended by improvements in hepatic function. The early arrival of Sonazoid in the hepatic vein in the patients is likely to reflect the formation of intrahepatic shunts as a result of hepatic microcirculatory disturbances.

CEUS using Sonazoid is a useful method to estimate the changes in hepatic hemodynamics in patients with ALI.

Plasma clearance of D-sorbitol, a nontoxic polyol, occurs predominantly in the liver and has been used to measure functional liver blood flow after bolus and steady- state intravenous administration. However, it is not known which of these two administration methods is superior. Therefore, plasma D-sorbitol clearance was studied in an animal model both after a bolus dose and under steady-state (SS) conditions and compared directly with liver blood flow, under normal conditions, and after the induction of endotoxin (LPS) sepsis. Adult male Wistar rats (526 +/- 38 g body wt; n = 27) were anesthetized and mechanically ventilated. Hemodynamics, hepatic arterial flow, and portal venous flow were measured. Two groups were studied, namely healthy animals that served as controls and a sepsis group that received 5 mg/kg LPS intravenously (Escherichia coli O127:B8). Each animal received either a SS infusion (0.1 mg/100 g body wt per min) or a bolus (3 mg/100 g body wt) of a 5% D-sorbitol solution intravenously in a randomized order. After the initial measurements and a 60-min pause time in between (T(1/2,sorbitol) = 9 min), a crossover was done. The hepatic clearance of D-sorbitol in the control group showed a good correlation between bolus and SS (Spearman's r = 0.7681, P = 0.0004), and both techniques correlated well with total liver blood flow (TLBF) (r = 0.7239, P = 0.0023 and r = 0.7226, P = 0.0023, respectively). Also in the sepsis group there was a good correlation between bolus and SS sorbitol clearance (r = 0.6655, P = 0.0182). In the sepsis group, only the SS clearance correlated with TLBF (r = 0.6434, P = 0.024). In conclusion, in normal and under septic conditions, hepatic clearance of D-sorbitol either by bolus or a SS infusion is comparable. In healthy animals, this also correlated well with TLBF but not in septic conditions. However, this is expected because of the changes in the liver microcirculation, shunting, and decreased hepatocyte function in sepsis.

Although the study of hepatic circulation is complicated by the dual blood supply and complex anatomy of the liver, many distinct methods are available to facilitate its study. Before embarking on an investigation of hepatic hemodynamics, the investigator must be familiar with the available methods and their applications. All methods have their own attributes and limitations. No one method is superior to the others, but, depending on the aspect of hepatic hemodynamics to be investigated, a particular methodology may yield distinct advantages.

Fractional systemic bioavailability of orally administered drugs was found to be unexpectedly low in liver cirrhosis, even after surgical portal-systemic shunting. Fecal loss or intestinal first-pass elimination were assumed to explain the finding. In this paper we evaluated alternative pathophysiological interpretations relating low bioavailability to adaptive circulatory modifications. D-Sorbitol was used because its hepatic extraction is very high and hepatic removal follows a flow-dependent clearance regimen. D-Sorbitol bioavailability was measured at steady state in pigs submitted to end-to-side portacaval anastomosis, immediately after surgery and four weeks later. Intestinal first-pass elimination dependent on fecal loss and intraluminal degradation was excluded by administering D-sorbitol into the superior mesenteric artery. Almost complete bioavailability was observed immediately after surgery (N = 6, 0.96+/-0.08); four weeks later the bioavailability dropped (-36.8+/-18.7%; P < 0.001) while hepatic clearance significantly increased (+83.6+/-47.9%; P < 0.01). Experimental data support the hypothesis that adaptive circulatory changes spontaneously occur after some time, leading to a lower than expected portal bioavailability.

Sorbitol and indocyanine green (ICG) have high hepatic extraction fractions (E(sorb) and E(ICG)) in normal subjects. A curved relationship has been observed between E(sorb) and E(ICG) in liver disease. According to one interpretation, the decrease of E(sorb) is a result of intrahepatic shunting and 1 - E(sorb) is the fraction of shunted flow (the shunt hypothesis). Under the further assumption that capillarization of functioning sinusoids prevents hepatic uptake of plasma protein-bound ICG and allows uptake of water-soluble sorbitol, the difference E(sorb) - E(ICG) has been suggested as a measure of capillarization. We propose an alternative hypothesis: that the sinusoidal permeability-surface area products for sorbitol and ICG are reduced in proportion by liver disease (proportional reduction hypothesis). Based on the sinusoidal perfusion model, predictions were produced from both hypotheses for the relation between E(sorb) and E(ICG) and the additional effects of capillarization were described. By use of liver vein catheterization, E(sorb) and E(ICG) were simultaneously measured during continuous infusions in 53 human subjects with varying degrees of liver disease. The data were in better agreement with the predictions of the proportional reduction hypothesis than with the shunt hypothesis. Even though both intrahepatic portosystemic shunts and sinusoidal capillarization are known to occur in cirrhosis and also may have influenced our data, they appeared to be of minor importance from a kinetic point of view. These findings favor the proportional reduction hypothesis and do not support the use of systemic nonrenal clearance of sorbitol as a measure of "functional liver blood flow."

Hepatic arteriovenous shunting in the metastatic liver reduces the advantages of intraarterial infusion of chemotherapeutic agents because of the passage of drugs into the systemic circulation. The aim of this study was to quantitatively assess spontaneous functional hepatic arteriovenous shunting in patients with liver metastases and to determine its implication in the increase in systemic toxic effects of intra-arterial infusion chemotherapy with floxuridine.

Twenty-five patients who underwent implantation of arterial ports for regional chemotherapy of liver metastases were studied. Functional hepatic arterio-venous shunting was evaluated through the bioavailability of intra-arterially administered D-sorbitol, a safe, natural compound whose kinetic features make its hepatic clearance flow dependent. In addition, D-sorbitol hepatic clearance (a parameter reflecting functional liver blood flow) and common liver function tests were evaluated for each studied patient. Patients were then grouped with respect to the percentage of medically-assessed liver occupation by metastases and with respect to systemic toxicity of the chemotherapeutic treatment. Both univariate and multivariate analyses by Student's t-test and stepwise logistic regression, respectively, were performed in both groups for each of the evaluated parameters (age, liver function tests, D-sorbitol hepatic clearance and arterial bioavailability).

Arterial bioavailability of D-sorbitol ranged between 0.05 and 0.72 and was significantly greater in patients with more than 50% liver occupation (0.39+/-0.19) compared with those with minor liver involvement (0.17+/-0.13; p = 0.003); it was also significantly greater in patients experiencing high-grade systemic toxicity (0.40+/-0.19) compared with those with low-grade toxicity (0.16+/-0.11; p<0.001). Multivariate analysis showed that arterial bioavailability of D-sorbitol was the only parameter among those evaluated which was able to predict systemic toxicity of this kind of chemotherapy.

Our results show that, in the metastatic liver, arterial bioavailability of D-sorbitol, an index of functional arteriovenous shunting, varies widely, is significantly greater in patients with massive liver occupation and it is a good predictor of systemic toxicity of intra-arterial regional chemotherapy with floxuridine.

Assessment of hepatic function is based on both liver blood tests and functional tests, the extensive application of which is still controversial. The aim of this study was to evaluate the clinical utility of a few selected tests as discriminatory and prognostic indexes: serum albumin, pseudocholinesterase, prothrombin time, as well as galactose elimination capacity and hepatic sorbitol clearance. Two separate studies were performed: Study I to investigate how well these tests assessed severity, and Study II to evaluate their prognostic value. A total of 128 consecutive cirrhotic patients classified according to the Child-Pugh score were included in Study I; Study II was carried out on 47 of these 128 during a two-year follow-up period. Pairwise correlations between all tests and Child-Pugh score yielded higher significant values for liver blood tests than for the functional ones. In Study I functional tests such as galactose elimination capacity and hepatic sorbitol clearance did not appear to be better than conventional biochemical tests in discriminating clinical severity of cirrhotic patients, as defined by Child-Pugh classification. Results of Study II confirmed that in severe liver cirrhosis Child-Pugh score remains the best method for medium- and long-term prognosis and for planning liver transplantation. Functional tests should be reserved for defining the residual functioning liver mass or for studies about functional liver plasma flow.

Liver failure represents a major therapeutic challenge, and yet basic pathophysiological questions about hepatic perfusion and oxygenation in this condition have been poorly investigated. In this study, hepatic blood flow (HBF) and splanchnic oxygen delivery (DO2, sp) and oxygen consumption (VO2,sp) were assessed in patients with liver failure defined as hepatic encephalopathy grade II or more. Measurements were repeated after high-volume plasmapheresis (HVP) with exchange of 8 to 10 L of plasma. HBF was estimated by use of constant infusion of D-sorbitol and calculated according to Fick's principle from peripheral artery and hepatic vein concentrations. In 14 patients with acute liver failure (ALF), HBF (1.78 +/- 0.78 L/min) and VO2,sp (3.9 +/- 0.9 mmol/min) were higher than in 11 patients without liver disease (1.07 +/- 0.19 L/min, P <.01) and (2.3 +/- 0.7 mmol/min, P <.001). In 9 patients with acute on chronic liver disease (AOCLD), HBF (1.96 +/- 1.19 L/min) and VO2,sp (3.9 +/- 2.3 mmol/min) were higher than in 18 patients with stable cirrhosis (1.00 +/- 0.36 L/min, P <.005; and 2.0 +/- 0.6 mmol/min, P <.005). During HVP, HBF increased from 1.67 +/- 0.72 to 2.07 +/- 1.11 L/min (n=11) in ALF, and from 1.89 +/- 1.32 to 2.34 +/- 1.54 L/min (n=7) in AOCLD, P <.05 in both cases. In patients with ALF, cardiac output (thermodilution) was unchanged (6.7 +/- 2.5 vs. 6.6 +/- 2.2 L/min, NS) during HVP. Blood flow was redirected to the liver as the systemic vascular resistance index increased (1,587 +/- 650 vs. 2, 020 +/- 806 Dyne. s. cm-5. m2, P <.01) whereas splanchnic vascular resistance was unchanged. In AOCLD, neither systemic nor splanchnic vascular resistance was affected by HVP, but as cardiac output increased from 9.1 +/- 2.8 to 10.1 +/- 2.9 L/min (P <.01) more blood was directed to the splanchnic region. In all liver failure patients treated with HVP (n=18), DO2,sp increased by 15% (P <.05) whereas VO2,sp was unchanged. Endothelin-1 (ET-1) and ET-3 were determined before and after HVP. Changes of ET-1 were positively correlated with changes in HBF (P <.005) and VO2,sp (P <.05), indicating a role for ET-1 in splanchnic circulation and oxygenation. ET-3 was negatively correlated with systemic vascular resistance index before HVP (P <.05) but changes during HVP did not correlate. Our data suggest that liver failure is associated with increased HBF and VO2, sp. HVP further increased HBF and DO2,sp but VO2,sp was unchanged, indicating that splanchnic hypoxia was not present.

TIPS, an effective procedure applied for the treatment of complications of portal hypertension, is potentially followed by worsening of the hyperdynamic circulation of cirrhosis and the impairment of liver function. The aim of the present study was to evaluate short-term changes of functional liver plasma flow after application of TIPS, using the hepatic (extrarenal) clearance of D-sorbitol (S-HCl).

Twenty-five cirrhotic patients submitted to TIPS for prevention of variceal rebleeding entered the study. At steady-state, during constant infusion of a solution of D-sorbitol (25 mg/min), appropriate blood and urine samples were collected in order to calculate S-HCI before and 120 min after TIPS opening. In addition, the hepatic extraction ratio of D-sorbitol was directly measured at the level of the right (Er), where TIPS was applied, and of the left (El) hepatic veins; meanwhile the portocaval gradient (PCG) was registered, before and after stent dilation. A comparison of values obtained before and after TIPS application was performed by Student's t-test for paired data.

After application of TIPS, a substantial reduction was observed in PCG (12.1+/-4.2 vs 24.8+/-4.3 mmHg; p<0.001) and Er values (20.6+/-14.8 vs 57.5+/-22.3 %; p<0.001) but not El values (47.4+/-22.0 vs 53.4+/-21.4 %; p=0.178). S-HCl measured 120 min after TIPS opening was not statistically different from pre-TIPS values (389.2+/-212.1 vs 394.6+/-152.7 ml/min; p=0.892), although S-HCl variations in Child-Pugh class B patients were positively correlated with portal pressure variations (r=0.63, p=0.016).

Our results demonstrate that in patients with advanced cirrhosis, TIPS procedure, while effective in reducing portal hypertension, does not lead to alterations in the functional liver plasma flow within the first 2 h.

The objective of this study was to evaluate whole-body removal kinetics of sorbitol, the use of extrarenal sorbitol clearance to estimate hepatic plasma flow in humans, and to compare measurements of liver flow by Fick's principle using either indocyanine green (ICG) or sorbitol. A sorbitol bolus (5 mmol/kg) was given intravenously to 6 controls for determination of sorbitol elimination capacity (SEC) and distribution volume, V(sorb)d. Sorbitol infusion (287 micromol/ min) was given to 17 liver patients and 11 controls. Extrarenal sorbitol clearance (V(sorb)x was calculated as infusion rate (corrected for renal excretion and accumulation in V(sorb)d) divided by arterial concentration. Liver flow (Q(ICG)) was calculated from the ICG infusion and arterial and hepatic venous ICG concentrations by Fick's principle. Average SEC was 73 micromol/min/kg, V(sorb)d was 0.16 L plasma per kilogram, and in vivo V(sorb)d was 3 mmol/L. Renal sorbitol excretion rate was 0.03 to 0.31 of infusion rate. Extrahepatic extrarenal removal was not significantly different from zero but varied considerably. Hepatic extraction fraction of sorbitol, (E(sorb)), measured by liver vein catheterization, was 0.35 to 1.04 (median, 0.86) in cirrhotic patients and 0.90 to 0.98 (0.86) in controls. The requirements for using Cl(sorb)x as an estimate of Q(ICG) was not violated by the data in controls, Cl(sorb)x/Q(ICG) 0.70 to 1.55 [median, 1.08]), whereas there was a systematic underestimation in cirrhotic patients (0.72-1.08 [0.85]). Liver flow calculated by Fick's principle using either sorbitol or ICG agreed well. E(sorb) > E(ICG) in each individual except one. Curvilinear relationship between E(sorb) and E(ICG) was in agreement with different kinetic parameters for sorbitol and ICG, and did not require additional assumption of intrahepatic shunts.

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.

The magnitude of hepatic plasma flow in patients with liver failure and hepatic encephalopathy (HE) is unknown because a reliable flow estimate has not been available. The purpose of this study was to estimate hepatic plasma flow in patients with HE and to evaluate indocyanine green (ICG) and sorbitol as test compounds. Fourteen patients with acute liver failure (ALF) and nine patients with chronic liver failure (CLF), all with HE grade II or more, were studied. After hepatic vein catheterization, hepatic plasma flow was estimated by use of constant infusion, simultaneous arterial and hepatic vein concentration measurements, and calculated according to Fick's principle. The hepatic extraction fraction of D-sorbitol 0.179+/-0.144 (mean+/-SD) was higher than the hepatic extraction fraction of ICG 0.054+/-0.085 (P < .001). The low hepatic extraction fraction of ICG rendered this compound unfit for estimation of hepatic plasma flow in these patients. In contrast, by using D-sorbitol the hepatic plasma flow could be estimated in 21 of 23 patients with a median SD of 8.4% (range, 2.6% to 29%). The D-sorbitol estimated hepatic plasma flow was 1.2+/-0.5 L/min (n = 12) in patients with ALF and 1.4+/-0.9 L/min (n = 9) in patients with CLF. These values are higher than what has been reported in normal subjects and in patients with cirrhosis without HE. An elevated hepatic flow should increase oxygen delivery and may enhance the failing liver's ability to remove substances from the blood. At the same time, hepatic first pass metabolism is reduced. We conclude that an elevated hepatic flow in these patients is of clinical importance.

In this study a mathematical model was applied to predict how changes in hepatic extraction ratio (E), fractional portal inflow (P) and renal elimination ratio (R) may affect fractional D-sorbitol bioavailability in cirrhotic patients. D-sorbitol bioavailability was computed as the ratio between cumulative urinary outputs measured after infusion into the superior mesenteric (Uma) or the hepatic artery (Uha) and a systemic vein (Usv). The present work was aimed at explaining by mathematical simulation the very large difference observed in the regression lines when plotting Uma or Uha against Usv values. The study was performed by considering a pathophysiological model of the hepatic circulation and simulating independent variations of the above considered parameters or assuming particular pathophysiological conditions like hepatic arterialization and hepatofugal flow. Computational results account for the wide dispersion of experimental data obtained in previous studies and provide reasonable explanations of unexpected findings.

Angiographic visualization of the hepatic vascular bed by selective angiography can be profitably complemented with the evaluation of functional portal-systemic shunting by D-sorbitol bioavailability. Seventeen patients requiring diagnostic arterial catheterization were studied: most of them had biopsy-proven liver cirrhosis. Patients were studied at rest and after overnight fasting on two subsequent days, in which a sterile pyrogen-free solution (1.5%) of D-sorbitol was administered by direct infusion (15 mg/min for 20 min) into the superior mesenteric artery and an antecubital vein, respectively. The fractional bioavailability (Fma) of D-sorbitol was calculated as the ratio between the net cumulative urinary outputs obtained after infusion through the catheter into the superior mesenteric artery and the systemic vein, respectively. A good correlation was found between the estimated fractional portal-systemic shunting, which in the present study ranged between 1.4% and 96.7%, and a suitable index scoring the clinical evidence of collateral circulation. Since the hepatic removal of D-sorbitol is not affected by sinusoidal capillarization and its hepatic extraction ratio is quite high and only slightly modified by reduction in the number or functional activity of hepatocytes, the measured Fma can be assumed as a parameter reflecting the entity of portal-systemic shunting. The test is safe and inexpensive, and appears potentially useful in several situations in which portal-systemic shunting is pathophysiologically relevant.

The standard enzymatic assay for quantification of D-sorbitol in plasma was adapted to the automatic analyzer Cobas Mira S. In the assay, NAD (reagent) in the presence of sorbitoldehydrogenase (SDH; start reagent) converts D-sorbitol to fructose with formation of NADH, which was detected automatically as the difference between the first and last readings at 340 nm. The sample blank values for each specimen were subtracted to exclude both endogenous D-sorbitol and sugars, which also react as substrates for SDH. The method is simple, rapid (40 samples/h), precise down to endogenous concentrations (coefficient of variation < 5%; limit of determination: 0.38 mg/L) and linear up to 100 mg/L. Samples with higher D-sorbitol concentrations were estimated after dilution. The method was used to measure disposition curves of sorbitol in volunteers after a single intravenous dose of 0.8 g sorbitol.

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.

Functional hepatic flow and total hepatic flow were determined by non-invasive techniques in 32 patients with cirrhosis and in 32 paired control subjects. Functional hepatic flow was measured by the hepatic clearance of D-sorbitol, while total hepatic flow was determined by pulsed echo-Doppler, as the sum of portal and hepatic arterial blood flow. Functional hepatic flow was significantly reduced in patients with cirrhosis (927 +/- 314 vs. 1287 +/- 315; p < 0.0001), while total hepatic flow was slightly increased (1511 +/- 540 vs. 1261 +/- 321 in controls; p = 0.028). In control subjects functional hepatic flow significantly correlated with total hepatic flow (r = 0.823; p < 0.001), while no correlation was observed in cirrhosis. Functional hepatic flow and the difference between total hepatic flow and functional hepatic flow significantly correlated with the Child-Pugh score in patients with cirrhosis. The data obtained in control subjects support the measurement of functional hepatic flow and total hepatic flow by non-invasive techniques. The finding that in cirrhosis functional hepatic flow is significantly decreased, while Doppler-assessed total hepatic flow is preserved or even increased, confirms that a relevant part of blood flowing through the liver is diverted by intrahepatic shunts. The simultaneous assessment of these two parameters by non-invasive techniques may be proposed as a reliable tool for the study of functional shunting of cirrhosis.

Preoperative assessment of orthotopic liver transplantation candidates requires definition of both the anatomy and metabolic function of the native liver. Current evaluation techniques combine computed tomographic scanning, duplex ultrasonography with blood chemistry analysis, and physical stigmata of end-stage liver disease. Recently, magnetic resonance imaging (MRI) has emerged as an alternative method for delineation of hepatic and portal venous anatomy. In addition, MRI accurately measures hepatic volume and portal venous blood flow.

To examine the role of MRI-derived indexes of hepatic hemodynamics in the preoperative assessment of liver function, 39 consecutive liver transplantation candidates were studied in a prospective manner. Liver function (aspartate aminotransferase), alanine aminotransferase, alkaline phosphatase, total bilirubin, and albumin levels), hematologic indexes (complete blood cell count, prothrombin time), and Child's classification were determined at the time of evaluation. Axial breath-held multiplanar spoiled-gradient echo MRI measured hepatic volume, whereas a cine phase-contrast sequence perpendicular to the portal vein measured flow.

Hepatic index, defined as hepatic mass corrected for body surface area, was found to correlate with prothrombin time (p < 0.04) and platelet count (p < 0.03) by multivariate regression analysis. Portal flow index (PFI), defined as portal flow corrected for hepatic mass), was associated with aspartate aminotransferase (p < 0.02), alanine aminotransferase (p < 0.04), and albumin (p < 0.03) by multivariate regression analysis. In addition, PFI was closely correlated with the patients' functional status as determined by Child's classification system. Increasing values of PFI were associated with declining hepatic functional reserve. Child's class A patients had a mean PFI that was two times less than that of Child's class B patients (0.26 +/- 0.04 versus 0.04 +/- 0.06 ml/min/gm; p < 0.02) and five times less than that of Child's class C patients (0.26 +/- 0.04 versus 1.05 +/- 0.14 ml/min/gm; p < 0.001). Similarly, the mean PFI associated with Child's class B was two times less than that of Child's class C (0.46 +/- 0.06 versus 1.05 +/- 0.14 ml/min/gm; p < 0.01). These data show that MRI-derived indexes of portal hemodynamics and hepatic mass (1) correlate well with biochemical indexes of hepatic dysfunction and (2) serve as anatomic and hemodynamic correlates to Child's functional classification.

We conclude that MRI may serve to noninvasively delineate preoperative hepatic vascular anatomy and metabolic dysfunction in candidates undergoing examination for liver transplantation.

The liver function results from the interaction of anatomical, histological and biochemical aspects. Thus the concept of functioning liver mass must be related to the many biological aspects involved in the process under evaluation, and its measure can be viewed as a virtual parameter averaging the liver function. In the present review the functioning liver mass has been categorized with respect to the many aspects involved (biochemical transformations, membrane transports and passive intraluminal transports) and their interactions (intracellular, transcellular, transacinar and flow-dependent). Parameters reflecting the functioning liver mass (whether static or dynamic) have been considered with respect to the experimental conditions and characterized according to the type of estimate they provide (capacity or activity). Methods for evaluating the functioning liver mass have been presented and discussed, and a protocol has been proposed for clinical applications, based on the association of the galactose elimination capacity measuring the metabolic mass with the hepatic clearance of D-sorbitol evaluating the functional hepatic plasma flow.