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Introduction Numerous conditions may cause liver lesions, solitary or multiple, benign or malignant. It can be crucial to establish the correct diagnosis. Splenosis is a rare condition that may result from the spillage of cells from the splenic pulp following abdominal trauma, accidental lesions to the spleen during operation or elective splenectomy. These splenic ‘implants’, which are often multiple, can be located anywhere in the peritoneal cavity, although they are most often found in the left upper quadrant of the abdomen. They may be confused with neoplasms or endometriosis, and may rarely be the cause of small bowel obstruction. Case presentation A 35-year-old man presented with a hepatic mass, and malignancy was suspected. After extensive investigation, it was diagnosed as splenosis using Tc-99m-labelled heat-denaturated red blood cells scintigraphy, without the need for liver biopsy. We consider this the most effective method for diagnosing splenosis. Conclusion When splenosis is suspected, Tc-99m-labelled heat-denaturated red blood cells scintigraphy can be used to confirm the diagnosis, and may avoid invasive investigation.

Background and aims: Primary sclerosing cholangitis (PSC) is a rare chronic progressive cholestatic disorder. We assessed its characteristics and natural history in Israel and compared its outcome with respect to coexisting inflammatory bowel disease (IBD). Methods: Data on characteristics, course and outcome were retrospectively retrieved on patients diagnosed with PSC from five large Israeli medical centers between 1988 and 2012. Patients with isolated PSC were compared with those with coexisting IBD to identify predictors of outcome. Results: Of 141 patients (56% males) with confirmed PSC, 98 (69.5%) had coexisting IBD. The average age at presentation was 38.8±15.4 years and duration of follow-up was 7.93±6.26 years. The crude estimated point prevalence was 4 cases per 105 persons. Demographics and clinical characteristics were similar among all patients except for symptoms at diagnosis (which were more prevalent among PSC–IBD patients) and utilization of multiple diagnostic modalities (which was more prevalent among isolated-PSC patients). More than one-third of the entire cohort had cirrhosis. A total of 15 patients (10.6%) died and 19 patients (13.5%) developed malignancy during follow-up. Nine patients (6.3%) underwent liver transplantation. Mean survival for the entire cohort was 26.3±1.4 years and mean transplant-free survival was 23.5±1.6 years. Cox proportional-hazard regression for transplantation or death revealed two independent risk factors: cirrhosis and malignancy [hazard ratio 4.25 ( p = 0.004) and 2.58 ( p = 0.046), respectively]. Conclusions: Survival rate of PSC patients in Israel is longer than reported rates worldwide and is independent of coexisting IBD. * Abbreviations: : PSC : primary sclerosing cholangitis; IBD : inflammatory bowel disease; CCA : cholangiocarcinoma; LT : liver transplantation; UC : ulcerative colitis; ERCP : endoscopic retrograde cholangiopancreatography; UDCA, ursodeoxycholic acid; MRCP : magnetic resonance cholangiopancreatography; CD : Crohn’s disease.

Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA

Aim: To evaluate the relationship among alveolar bone loss (ABL), bone status and calcium-regulating hormones in liver transplantees. Patients and Methods: Twenty-one liver transplantees underwent a full oral examination. The correlations among bone densitometry, bone metabolic status and drug treatment were examined. Results: Twelve patients had osteopenia, and six were osteoporotic. ABL was 4.33±2.32 mm (range 0.67–9.92). Parathyroid hormone (PTH) levels ranged from 14 to 106 (mean 55.2±26.4). The mean 25(OH)D3 was 11.68±4.7, range 3.5–21.1 ng/ml. Nine patients were vitamin D deficient (

To prospectively evaluate the accuracy of esophagography with barium in diagnosis of esophageal varices (EV) in patients with compensated cirrhosis, with endoscopic gastroduodenoscopy as the reference standard.In this study, which was approved by the local Helsinki Committee and in which all patients consented to participate, 61 patients with cirrhosis (34 men, 27 women; mean age, 61 years; range, 36-76 years) received a diagnosis clinically or with liver biopsy. In 87% (n = 53) of patients, Child-Pugh classification was A; in 13% (n = 8), Child-Pugh classification was B. They were evaluated with endoscopic gastroduodenoscopy, according to Japanese general criteria. Esophagography was performed within 3 weeks of endoscopic gastroduodenoscopy, and EV were assigned grades as follows: 0, no EV were seen; 1, EV manifested as very mild irregularities of the folds; and 2, the irregularity of the folds (EV) was clearly present. They were also assigned grades for shape and size: grade F0, no EV detected; grade F1, small straight EV; grade F2, slightly enlarged tortuous EV occupying less than one-third of esophageal lumen; and grade F3, large coil-shaped EV that occupied more than one-third of esophageal lumen. The sensitivity and specificity and positive and negative predictive values of esophagography for identification of each grade of EV were calculated separately, as was the 95% confidence interval.All large EV (grades F2 and F3) were diagnosed at esophagography. Sensitivity declined with small EV (grade F1) to 71. The overall sensitivity of esophagography was 89% (95% confidence interval: 75.9%, 96.5%), the overall specificity was 83% (95% confidence interval: 64.5%, 94.7%), the overall positive predictive value was 89%, and the overall negative predictive value was 83% (95% confidence interval: 64.5%, 94.7%). Overall accuracy was 87%.Esophagography is highly accurate in diagnosis of EV and can be considered a viable noninvasive alternative for determination of patients who should be selected for prophylactic treatment.

UNLABELLED: Percutaneous needle liver biopsy is an important procedure for the diagnosis and evaluation of liver disease and is frequently associated with pain. In this prospective study, we investigated the prevalence and characteristics of this pain syndrome. Fifty-four subjects, who underwent liver biopsy under ultrasound guidance, received 5 mg of diazepam orally 1 h before the procedure and local infiltration with 10 mL of 2% lidocaine just before needle insertion. Outcome measures included the visual analog scale for measuring pain intensity over 24 h, pain localization on a body scheme, and the Spielberger questionnaire for measuring anxiety levels. Forty-seven (84%) of the 54 respondents reported pain 30 min after the biopsy (visual analog scale, 4.2 +/- 0.5; mean +/- SEM), and 21 (39%) reported pain at the 24-h time point. Biopsy site pain was reported by 9 subjects, right shoulder pain by 14, and pain at both sites by 24. Higher pain intensities were reported by women and by subjects with higher anxiety levels. This study indicates that liver biopsy is a painful condition in most patients. Mild anxiolytic treatment plus local anesthetic infiltration seem to produce insufficient analgesia, thus indicating that a more profound analgesic treatment is required for better control of this pain. IMPLICATIONS: Percutaneous liver biopsy is a painful procedure in most patients. Mild anxiolytic treatment plus local anesthetic infiltration seem to produce insufficient analgesia. A more profound analgesic treatment is required for better control of this pain.

Background/Aims : Von Willebrand factor (vWf) is found in high levels in plasma of patients with acute and chronic liver disease. The role of vWf in liver injury and repair is unknown. We studied the effect of liver mass and remodeling on plasma and tissue vWf after partial hepatectomy. Methods : Rats were sacrificed postoperatively at intervals ranging from 60 min to 5 days, and vWf plasma levels were measured by enzyme-linked immunosorbent assay, using rabbit anti-human vWf, and by immunoperoxidase on cryosections, using rabbit anti-vWf/factor VIII. Northern blot hybridization was prepared with a complementary DNA specific to human vWf. Results : vWf plasma levels increased early after sham operation and after 70% partial hepatectomy. The highest levels were reached at 24 h, remaining high for 5 days. Immunostaining showed intense staining of sinusoidal lining cells 4 h after partial hepatectomy, remaining so for 5 days. Non-significant changes in overall liver messenger RNA expression of vWf were seen over 5 days in sham operation and partial hepatectomy. Conclusions : After partial hepatectomy, plasma vWf is increased, probably due to both acute-phase reaction and decreased degradation. An increase in sinusoidal vWf immunostaining may suggest a role for this factor in tissue remodeling.

Background: Liver disease and transplantation affect bone turnover. The role of cylosporin A (CsA) in aggravating bone loss is controversial. The aim of the present study was to examine the effect of liver cirrhosis, transplantation, and immunosuppressive therapy with either CsA or tacrolimus on alveolar bone height. Methods: The experimental group consisted of 13 liver cirrhosis (LC) patients. A second experimental group included 24 post-liver transplantation patients (PT) receiving CsA or tacrolimus. Seventeen healthy subjects formed a control group. Panoramic x-rays were taken and digitized using a computerbased measurement software to assess alveolar bone height of all available teeth. Results: Bone loss in the PT group (4.57 ± 0.56 mm) was significantly higher than the control (C) (2.73 ± 0.38 mm); however, it was significantly lower (P = 0.0005) than the LC (6.47 ± 0.75 mm). Likewise, alveolar bone loss showed a trend for negative correlation (R = 0.404, P = 0.06) with the duration of immunosuppressive therapy post-liver transplantation. Conclusions: Liver cirrhosis patients demonstrated greater bone loss compared to healthy controls. Restoration of liver functions following transplantation seems to have the potential to reverse some of these radiographic changes. Further longitudinal studies will be necessary to substantiate these findings. J Periodontol 2002;73:313-316.

Background The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. Methods We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r–ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of

Gaucher's disease (GD) may go undiagnosed for many years, leading to severe complications that are preventable or reversible by enzyme replacement therapy with imiglucerase. GD is associated with cytopenia, bone complications, hepatosplenomegaly, hypermetabolism, and hyperactivity of the immune system manifested by polyclonal hyper gamma-globulinemia and an increased incidence of monoclonal gammopathies. High ferritin and presence of autoimmune antibodies may present and because of these abnormalities, clinical similarities with primary liver diseases may occur. We report on two patients who suffered diagnostic delay that could potentially lead to life-threatening manifestations of GD. Potential complications include: avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure, and liver pathology. Physician awareness will increase the likelihood of prompt detection of GD and improve its management.

OBJECTIVE: Total serum bile acid concentrations are elevated in individuals with liver disease. Ursodeoxycholic acid (UDCA) therapy in such patients results in a further significant rise in plasma levels to the extent that it becomes the major circulating bile acid. In laboratory animals, bile acids, such as taurocholic acid, have also been shown to possess a diuretic-like action, as they can promote diuresis, natriuresis, and kaliuresis by inhibiting tubular sodium reabsorption. The aim of the present study was to assess the effect of 1 month’s UDCA therapy on cardiovascular function in cirrhotic patients. METHODS: Two groups of patients with cirrhosis were studied, six with primary biliary cirrhosis (PBC) and six with postnecrotic liver cirrhosis (PNC). Cardiovascular function was assessed by determination of blood pressure, heart rate, and by two-dimensional and pulsed Doppler echocardiography. RESULTS: In PBC patients, 1 month’s treatment with UDCA significantly reduced diastolic volume without changing systolic, diastolic, and mean blood pressures, heart rate, systolic and stroke volumes, ejection fraction, cardiac output, and systemic vascular resistance. In PNC patients, UDCA significantly reduced cardiac output, with a tendency to reduce left ventricular volumes, without any changes in systolic, diastolic, and mean blood pressures. CONCLUSIONS: UDCA caused reductions in diastolic volume in the PBC patients and cardiac output in the PNC patients. Such reductions are not unlike that seen in individuals treated with diuretics. This diuretic-like action deserves further study, particularly in cirrhotic patients who are also being treated with diuretics or show evidence of cardiac myopathy.

Liver cirrhosis is characterized by high serum growth hormone levels and low serum insulin-like growth factor I and growth hormone-binding protein levels. The present study was designed to characterize the serum profile of growth hormone and growth hormone pharmacokinetics in postnecrotic liver cirrhosis, correlating it with liver function and nutritional states.Fifteen patients were grouped by the Child-Pugh score (group 1, score of 5 to 8; group 2, score of 9 to 12). Five healthy subjects served as controls. Nutritional status was assessed by the creatinine-height index. Baseline growth hormone, insulin-like growth factor, and growth hormone binding protein were measured, and growth hormone pharmacokinetics was followed for 48 h after administration of subcutaneous recombinant human growth hormone (0.06 mg/kg).Trough serum growth hormone (microg/l) was higher in both patient groups (5.3+/-3.6) than in controls (1.0+/-0.3; p0.01). More pulses were recorded in cirrhotic patients, and mean pulse amplitude (microg/l) was higher in cirrhotic patients than in controls (p0.01). After subcutaneous recombinant human growth hormone injection, maximal growth hormone was higher in cirrhotic patients and the area under the curve over 24 h was greater (626+/-120) than in controls (330+/-54; p0.01). Single regression analysis showed a weak correlation of both the Child-Pugh score and the creatinine-height index with the pharmacokinetic parameters.Due to decreased growth hormone clearance, patients with liver cirrhosis have increased trough and peak serum growth hormone levels, as well as lower serum growth hormone binding protein and insulin-like growth factor. Recombinant human growth hormone pharmacokinetics are typical of a high hepatic extraction substance administered to patients with liver disease and portal hypertension, and this may be relevant to the further use of growth hormone therapy.

Infectious mononucleosis due to Epstein-Barr virus (EBV) is almost always a self-limited disease, most commonly seen in young adults. Hepatitis is a well-recognized complication of EBV infection that usually resolves spontaneously. Jaundice occasionally results from the unusual complication of autoimmune haemolytic anaemia rather than hepatitis. We report a 60-year-old man with severe cholestatic jaundice whose history, liver histology and laboratory findings suggested EBV infection. He also developed significant jaundice related to his hepatitis, but not to autoimmune haemolysis, a situation that led to diagnostic delay. Costly diagnostic laboratory tests and invasive procedures were performed to rule out a malignant extrahepatic biliary obstruction. Physicians need to be aware of this complication and EBV infection should be included in the differential diagnosis of cholestatic jaundice in the elderly.

Our aim was to study the prognostic value ofgrowth hormone (GH)-stimulated insulin-like growthfactor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3)generation in patients with compensated [group 1 (N = 8) with a Child-Pugh (CP) score of 5-8] anddecompensated postnecrotic liver cirrhosis [group 2 (N= 7) with a CP score of 9-12]. Serum levels of IGF-I,GH-binding protein (GHBP), and IGFBP-3 were measuredbefore and 24 hr after a single subcutaneous injectionof recombinant human GH (rhGH, 0.14 units/kg). Patients(mean age 56 years) were followed prospectively forthree years. Six patients (40%) died during the follow-up period, of whom half had a CP score 10 nmol/liter had a 100% survival rate at one andtwo years, respectively. Baseline IGF-I (9.98 ± 2.0 vs 6.38 ± 0.8 nmol/liter), GHBP (9.2± 3 vs 5.7 ± 0.8%/50 μl), and IGFBP-3serum levels at baseline (1.7 ± 0.3 vs 0.86± 0.2 mg/liter) and at 24 hr (2.04 ± 0.38vs 0.99 ± 0.3 mg/liter) did not add to the predictive value ofstimulated IGF-I levels at 24 hr and were less accuratein predicting the outcome in comparison to CP score(80%). We conclude that stimulated IGF-1 < 10nmol/liter may be a true predictor of a negative prognosisin patients with liver cirrhosis.

Background & Aims MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis. Methods We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular. Results At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups. Conclusions Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172–based regimens. ClinicalTrials.gov number: NCT01353911.

Liver replacement is necessary for acute and chronic end stage liver failure and for correction of metabolic disorders. Even a temporary liver support is relevant under specific clinical conditions, giving cell based therapy a great potential. The decision on how much liver tissue should be replaced, depends on the degree of liver dysfunction and the chance of the native liver to recover. To minimize complications it is believed that the maximal percentage of engraftment that can be achieved is in the range of 2-5% of the host hepatocytes, whereas 10% are needed for an adequate support in liver failure. Several questions would still rise such as What is the best location for liver cell therapy? What kind of cells should be used? What strategy to increase cell engraftment should be employed? In this review we will discuss the experience gained with intravascular cell transplantation to the liver and future solutions using new technology for biomaterials production. We will expand on our experience with injectable hydrogel scaffold constructs consisting of PEGylated fibrinogen backbone and diacrylate (PEG-DA). The experience with their use for intravascular injection is still limited. Hepatocyte transplantation is a promising alternative method for the treatment of acute liver failure and also for the treatment of end stage liver disease. Hepatic cell transplantation can be used to temporarily gain time for acutely failing liver to recover, and to restore liver function in the chronic stage until a liver transplant becomes available. Transplanted hepatocytes can serve for the correction of congenital metabolic defects and for the transfer of genes by ex vivo gene therapy. The techniques used for cell transplantation may be implemented for other kinds of cells for therapy, including stem cells and immortalizedhepatocytecell lines. Other advantages of cell therapy over whole organ transplantation include the option to perform multiple hepatocyte transplantations in the same patient, and several patients could potentially be treated from one donor at a cost believed to be one tenth that of orthotopic liver transplantation. Studies have been undertaken to improve the methods related to hepatocyte transplantation, which include hepatocyte isolation from donor livers, cell culture propagation of the hepatocytes, hepatocyte preservation, and genetic modification of the hepatocytes to provide liver-specific functions and longevity. In humans, parenchymal hepatocytes isolated from donor livers remain the best cell source for transplantation, and other cell sources, including stem cells, are at the preclinical and early

The present study was undertaken to further explore the comparative dynamics of growth hormone-binding protein (GH-BP) in relation to the turnover of the GH-receptor (GH-R) in vivo in rabbits and rats. The strategy used was to examine the time course of hepatic GH-R turnover over a 3 h period after cycloheximide treatment, with simultaneous measurements of serum GH-BP level. In the rabbit we sampled multiple liver biopsies and serum samples consecutively from each animal. In the rat, experiments on individual animals were conducted for each time point. In the rat, both liver GH-R and serum GH-BP declined after cycloheximide injection following first-order kinetics. The t12 values for GH-R and GH-BP were 29.7–44.5 and 82.7–119.5 min (95% confidence limits), respectively. A significant positive correlation was found between rat liver GH-R and serum GH-BP (r = 0.85; p < 0.001). In contrast, the decline in rabbit liver GH-R, following cycloheximide treatment, was accompanied by simultaneous time-dependent accumulation of serum GH-BP. The t12 for rabbit serum GH-BP accumulation was 30.4–67.6 min. Scatchard analysis of [125I]hGH binding to rabbit GH-BP indicated that the binding capacity increased from 2818 ± 538 fmol/ml, at time zero, to 5236 ± 419 fmol/ml following 60 min cycloheximide treatment (p < 0.05). No significant changes in affinity were observed. Pooling all rabbit data points after cycloheximide injection, a significant negative correlation was found between liver GH-R and serum GH-BP (r = −0.58; p < 0.001). Thus, parallel disappearance of hepatic GH-R and serum GH-BP in the rat following cycloheximide treatment contrasts that in the rabbit, in which the decline in hepatic GH-R was accompanied by simultaneous time-dependent accumulation of serum GH-BP.

Two patients who became pregnant after liver transplantation for end-stage liver disease were carefully monitored using pulsed Doppler waveform measurements. One patient with Wilson's disease, on triple immunosuppressive therapy including prednisone, azathioprine and low-dose cyclosporin A, delivered a healthy girl weighing 2650 g after 38 weeks' gestation. The other patient, with HBV-related postnecrotic cirrhosis, became pregnant less than 3 months postoperatively, under triple therapy, after being amenorrheic for 6 years. Episodes of elevation in liver enzymes were noted, and severe osteoporosis with low back pain developed. A healthy boy weighing 2975 g was born at 35 weeks' gestation. Our cases add to previous reports of successful pregnancies under cyclosporin A immunosuppression.

The role of the liver in regulating serum growth hormone-binding protein (GH-BP) was studied. We measured rat serum GH-BP and insulin-like growth factor 1 (IGF-1) 30 min to 96 h after 70% partial hepatectomy (PHP) or sham operation in adult male rats. Serum GH-BP declined sharply from 5.8 +/- 0.1% at baseline to 3.9 +/- 0.5% by 48 h following PHP. By 72 h serum GH-BP at baseline to 3.9 +/- 0.5% by 48 h following PHP. By 72 h serum GH-BP returned to baseline level and remained at that level 96 h postoperatively. In sham-operated female rats, serum GH-BP was about 2-fold higher than in males (10.5 +/- 1.46 versus 5.8 +/- 0.2%), whereas 24 h after hepatectomy a significant drop of about 50% was observed (p0.001). Serum IGF-1 decreased within 2-4 h postoperatively in both sham-operated and PHP groups, but thereafter was lower in the PHP rats, up to 48 h after operation, compared to sham-operated rats (p0.03). The study shows that the liver has an important role in the determination of serum GH-BP levels. The return to normal GH-BP level, even before the liver regained its full size following hepatectomy, suggests an increase in GH-BP production by the regenerating liver.

We studied 67 HBsAg-negative Israeli patients (36 negative for all HBV serological markers as group 1 and 31 positive for antibodies to HBs and HBc as group 2) with chronic liver disease and cirrhosis of unknown origin using a rapid, sensitive and specific assay for the detection of low levels of hepatitis B virus in serum. This technique uses a high-affinity monoclonal antibody to HBs against an a domain epitope of HBsAg to capture the virion, followed by hepatitis B virus DNA amplification with the polymerase chain reaction. In addition, 55 subjects without liver disease served as controls: Group 3 (n = 32) was negative for all hepatitis B virus markers; group 4 (n = 23) was positive for antibodies to HBs and HBc. We found 11 individuals in group 1 (31%) and 10 in group 2 (29%) harboring low levels of hepatitis B virus DNA in serum. In contrast, no one in group 3 or group 4 was positive by this technique (p 30%). We conclude that infection with hepatitis B virus undetectable by conventional assays and with hepatitis C virus may represent important unrecognized causes of idiopathic chronic liver disease in Israel, accounting for the possible origin in more than 90% of patients. (HEPATOLOGY 1991;13:1044–1051.)

We describe a new model of submaximal stimulation of liver regeneration in the rat. Removal of the right lateral lobes in the rat produced a 21% hepatectomy. The measurement accuracy of the incorporation rate of [14C]thymidine into DNA 24 h after 21% hepatectomy (n = 32) was less than that after the standard 34% hepatectomy (n = 32), with S.D./mean being 35% and 130%, respectively (F-test, p less than 0.025). This model was able to detect regeneration-stimulation activity present in liver cytosol extract and serum of 68% hepatectomized rats. Using this model we identified a subfraction of rat serum achieved after treatment of serum with ethanol and ion-exchange column, which had a highly stimulatory effect. Stimulation obtained with serum from hepatectomized pigs showed that these factors are not species specific.

Background and Aims: Acute hepatitis C virus infection in the era of universal screening of blood products has not disappeared, and is thought to be transmitted primarily via injecting drug use. A growing body of evidence supports iatrogenic transmission as an important mode of transmission. The aim of this study was to examine transmission routes and clinical characteristics in a group of patients with acute hepatitis C in Israel. Methods: A retrospective chart review was conducted in three different liver clinics in Israel, of all new hepatitis C patients. Patients identified as possible acute hepatitis C were re-interviewed and all other sources such as blood bank records and pre-employment check-ups reviewed in order to establish the diagnosis of acute hepatitis C infection and to identify the transmission route. Results: Twenty-nine patients were found to have acute hepatitis C, representing 0.75% of all new referrals for hepatitis C. The most frequent (65%) mode of transmission was iatrogenic involving several, often minimal, procedures and clinical settings. The group in which iatrogenic transmission was suspected was older and the patients more often in monogamous relationship compared with other transmission routes groups. Injecting drug use was the second most common route of infection. Spontaneous seroconversion has occurred in approximately one third of the patients. Conclusions: Acute hepatitis C in the post universal blood products screening era was found to be predominantly an iatrogenic disease in the investigated localities. This finding should direct attention and resources towards the development and implementation of preventive measures.

Ziel: Verbesserung der Gewebecharakterisierung fur die nichtinvasive Diagnose der diffusen Fettanreicherung in der Leber durch die Erstellung quantitativer Parameter fur Ultraschall-Echos (US) in Korrelation mit der Histologie. Methoden und Material: Es wurden Ultraschall-Bilder von Patienten dokumentiert, die wegen anhaltend erhohter Leberenzyme oder einer positiven Virushepatitis-Serologie zur Leberbiopsie (FNP) uberwiesen wurden. Die histopathologischen Berichte wurden uberpruft. Lebersteatose, Entzundung und Ausmas der Fibrose wurden in Schweregrad 0 (normal) bis 3 (schwer) eingeteilt. Patienten mit einem Steatose-Grad von 3 ohne Zeichen der Entzundung oder Fibrose wurden ausgewahlt. Ultraschall-Bilder von 24 Gesunden dienten als Kontrollen. Vier Gewebestruktur-Indices wurden fur einen Zielbereich kalkuliert, der der Biopsie-Region entsprach. Sensitivitat und Spezifitat der Unterschiede zwischen den Gruppen wurden berechnet. Ergebnisse: Fettlebern und gesunde Lebern bildeten zwei klar unterscheidbare Gruppen. In allen Parameter-Unterbereichen gab es jedoch eine leichte Uberschneidung zwischen den Gruppen, wobei einige Falle jenseits der Dichotomie-Linie lagen. Es ergab sich eine hohe Sensitivitat fur alle Indices (90 - 100 %). Schlussfolgerung: Es ist moglich, eine hochst genaue „Ultraschall-Biopsie” der Fettleber zu erhalten. Die beschriebenen Indices konnen als Hilfsmittel fur die computergestutzte Ultraschall-Diagnose der diffusen Leberparenchymerkrankung Anwendung finden, insbesondere fur die schwere Lebersteatose. Aim: To assist in tissue characterisation for the non-invasive diagnosis of diffuse fatty liver infiltration by providing quantitative indices of ultrasonic (US) backscatter with correlation to histology. Methods and Materials: US images from patients referred to US-guided liver needle biopsy (LNB) for persistently elevated liver enzymes or serologically positive markers for viral hepatitis were recorded. The histopathological reports were reviewed. Steatosis, inflammation and degree of fibrosis were scored from 0 (normal) to 3 (severe). Patients with level 3 steatosis without inflammation or fibrosis were selected. US images from twenty-four healthy subjects served as control. Four textural indices were calculated for a selected ROI corresponding to the biopsy site. Sensitivity and specificity of discrimination between the two groups were evaluated. Results: Fatty and healthy livers formed two distinct clusters. However, in all parametric subspaces there was a slight overlap between the groups with a few numbers of cases located across the dichotomy line.The sensitivity for all the indices was high (90 - 100 %). The specificity for each of the indices was moderate. The co-occurrence local homogeneity index yielded the highest specificity (88.5 %), with a sensitivity equivalent to two of the other indices (90 %). Conclusions: Highly accurate “ultrasonic biopsy” may be obtained for severe fatty liver. The described indices can serve as a tool in US computer- aided diagnosis (CAD) of diffuse parenchymal liver disease, in particular for severe steatosis of the liver.

VEGF is a potent angiogenic factor that promotes hepatocyte growth, increases permeability of blood vessels, and induces vasodilatation, and may accelerate engraftment and function of transplanted hepatocytes. The aim was to study the effect of VEGF on early hepatocyte engraftment. Thirty-two Lewis syngeneic female rats underwent 70% partial hepatectomy. Eighteen received 240 ng VEGF165 and 14 received saline for control. Thereafter, intrasplenic transplantation of 107 male hepatocytes was done. Semiquantitative analysis of PCR product of the SRY region of the Y-chromosome was performed. Paraffin-embedded sections were stained for H&E and for PCNA immunostaining. By PCR, male hepatocytes were identified in 8 livers out of 14 VEGF-treated rats at 24 – 48 h, compared with only 1 liver out of 8 controls. Transplanted cells were seen within portal vessels radicles in 7 out of 14 VEGF-treated rats for as long as 48 h posttransplantation, compared with only one control liver at 24 h. There was no histological sign of cell injury to transplanted or adjacent cells. Two weeks after transplantation male transplanted cells were identified in two out of four rats treated with hVEGF165 and in one out of six rats treated with saline. No transplanted cells were detected within portal tracts 14 days after transplantation. hVEGF165 enhances the presence of transplanted hepatocytes within portal vessels after transplantation. We suggest an additional mechanism for cell engraftment, whereby transplanted hepatocytes first stick to each other in the portal radicles. Later they become included in the liver parenchyma as groups of organized cells in a process stimulated by VEGF.

The objective of this study was to compare textural to attenuation/backscatter indices of fatty liver correlated to histology to suggest the better approach for an objective noninvasive ultrasonic "biopsy". Forty-four patients with severe steatosis by histopathology were selected for this study. Ten patients had "pure" fatty liver and 34 had in addition fibrosis and/or inflammation. Ultrasonic images were acquired before needle insertion. The ROI used for biopsy was marked on the ultrasonic image and characterized by three attenuation/backscatter and 18 textural related indices. Statistical analysis was performed using logistic regression. Twenty-one healthy subjects served as control. The attenuation/backscatter indices were superior to textural indices in differentiating between the categories studied. Pure fatty livers could be reliably identified (AUC = 1, SE = 0). Among the 18 textural indices, "co-occurrences sum entropy" and "co-occurrences entropy" presented the best results. Attenuation/backscatter based indices appear to have better potential than the textural based indices.

Background & AimsWe investigated the effects of the fatty acid–bile acid conjugate 3β-arachidyl-amido, 7α-12α-dihydroxy, 5β-cholan-24-oic acid (Aramchol; Trima Israel Pharmaceutical Products Ltd, Maabarot, Israel) in a phase 2 trial of patients with nonalcoholic fatty liver disease (NAFLD).MethodsWe performed a randomized, double-blind, placebo-controlled trial of 60 patients with biopsy-confirmed NAFLD (6 with nonalcoholic steatohepatitis) at 10 centers in Israel. Patients were given Aramchol (100 or 300 mg) or placebo once daily for 3 months (n = 20/group). The main end point was the difference between groups in the change in liver fat content according to magnetic resonance spectroscopy. The secondary end points focused on the differences between groups in alterations of liver enzyme levels, levels of adiponectin, homeostasis model assessment scores, and endothelial function.ResultsNo serious or drug-related adverse events were observed in the 58 patients who completed the study. Over 3 months, liver fat content decreased by 12.57% ± 22.14% in patients given 300 mg/day Aramchol, but increased by 6.39% ± 36.27% in the placebo group (P = .02 for the difference between groups, adjusted for age, sex, and body mass index). Liver fat content decreased in the 100-mg Aramchol group, by 2.89% ± 28.22%, but this change was nonsignificant (P = .35), indicating a dose–response relationship (P for trend = .01). Groups given Aramchol had nonsignificant improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin, but homeostasis model assessment scores did not change. The appropriateness of a single daily dose was confirmed by pharmacokinetic analysis.ConclusionsThree months' administration of the fatty acid–bile acid conjugate Aramchol is safe, tolerable, and significantly reduces liver fat content in patients with NAFLD. The reduction in liver fat content occurred in a dose-dependent manner and was associated with a trend of metabolic improvements, indicating that Aramchol might be used for the treatment of fatty liver disease. ClinicalTrials.gov number: NCT01094158.

P1299 PEARL-III: 12 WEEKS OF ABT-450/R/267 + ABT-333 ACHIEVED SVR IN >99% OF 419 TREATMENT-NAIVE HCV GENOTYPE 1B-INFECTED ADULTS WITH OR WITHOUT RIBAVIRIN P. Ferenci, A. Nyberg, P. Enayati, D. Bernstein, Y. Baruch, F.A. Caruntu, V. Chulanov, E. Janczewska, Z. Younes, R.T. Marinho, G. Rizzardini, J. Gervain, R. Planas, C. Moreno, W. Xie, D. Cohen, M. King, T. Podsadecki, K.R. Reddy. Universitaetsklinik fuer Innere Medizin III, Vienna, Austria; Kaiser Permanente, San Diego, California Liver Institute, Los Angeles, North Shore University Hospital, Manhasset, CA, United States; Rambam Health Care Campus, Haifa, Israel; Institutul National de Boli Infectioase ’Prof. Dr. Matei Bals’, Bucharest, Romania; Federal Budget Institute of Science Central Research Institute of Epidemiology, Moscow, Russian Federation; ID Clinic, Myslowice, Poland; GastroOne, Germantown, TN, United States; Centro Hospitalar Lisboa Norte, Lisboa, Portugal; Ospedale Luigi Sacco, Milano, Italy; Szent Gyorgy Hospital, Szekesfehervar, Hungary; Hospital Germans Tŕias i Pujol, CIBERehd, Badalona, Spain; CUB Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium; AbbVie Inc., North Chicago, IL, University of Pennsylvania, Philadelphia, PA, United States E-mail: peter.ferenci@meduniwien.ac.at

Cyclosporin A (CsA) is widely used to prevent liver transplantation failure. CsA-induced gingival overgrowth is a common side effect. However, the effect of cirrhotic liver disease, liver transplantation, and immunosuppressive therapy on the periodontium is yet unclear. The aim of the present cross-sectional study was to examine the effect of liver cirrhosis, transplantation, and immunosuppressive therapy on the periodontium.The experimental group (LC) consisted of 13 liver cirrhosis patients. A second experimental group (PT) included 24 patients, post-liver transplantation, receiving immunosuppressive therapy. Seventeen healthy subjects formed a control group. The Ramfjord index teeth were recorded for plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment level (CAL), and gingival overgrowth (GO).Mean PI and mean GI for the LC, PT, and C groups were not statistically different (P0.05). Mean PD for the LC (3.32+/-0.24 mm) and PT group (3.41+/-0.13 mm) was significantly higher (P = 0.0001, ANOVA) compared to the C group (2.45+/-0.16 mm). Likewise, CAL for the LC (4.89+/-0.47 mm) and PT group (4.68+/-0.47 mm) was significantly higher (P = 0.001, ANOVA) than the C group (2.78+/-0.23 mm). Patients in the PT group exhibited the greatest mean GO scores (0.88+/-0.09) compared to the LC group (0.37+/-0.07) and the C group (0.09+/-0.02). All 3 groups were significantly different from each other (P = 0.0001) despite great variability within the groups. GO in the CsA-treated patients (1.1+/-0.09) was significantly higher (P = 0.0001) than in those treated with tacrolimus (0.57+/-0.1).Liver cirrhosis patients demonstrated greater pocketing and attachment loss compared to healthy matched controls. These same differences were observed in patients post-transplantation. Gingival overgrowth occurred as a result of the immunosuppressive therapy with CsA, while to a lesser degree with tacrolimus. Replacement of CsA by tacrolimus in patients manifesting gingival overgrowth might be recommended whenever possible to overcome this problem.

Background Lipoprotein abnormalities are commonly found in chronic liver diseases (CLDs), particularly hypercholesterolemia in primary biliary cirrhosis (PBC). However, affected patients may not be at increased risk of coronary heart disease. Cirrhotic patients display impaired methionine clearance, and an increased level of homocysteine, a methionine metabolite, is an independent risk factor for coronary heart disease. Thus, we hypothesized that the low risk of coronary heart disease in patients with CLD may be related to low serum levels of homocysteine. The aim of this study was to test this hypothesis after methionine load and to describe the serum lipoprotein profile in patients with PBC and in patients with hepatocellular liver disease. Methods Fifteen female patients (mean age, 58.2±11.7 years) with PBC, 15 female patients (mean age, 54.5 ± 9.6 years) with other causes of CLD, and 15 healthy sex- and age-matched controls were given L-methionine (50 mg/kg of ideal body weight). Basal fasting serum homocysteine level and 2, 4, and 6 hours of post-methionine load were determined using high-performance liquid chromatography with a fluorometric detector. Levels of fasting serum cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), lipoprotein (a) (Lp(a)), and apoprotein B were also determined. Results Results showed that mean basal and post-methionine load (6 hours) serum homocysteine levels were statistically significantly higher in the patients with PBC and with CLD than in the control group ( P=0.04) and that levels of serum cholesterol, LDL, HDL, and apoprotein B were significantly higher in the PBC patients than in the other two groups ( P≤0.05). There was no correlation between any of these parameters and the severity of liver disease. Serum HDL was significantly lower in the CLD group ( P≤0.05) and correlated with severity of liver disease. There was no significant difference in serum cholesterol, LDL, or apoprotein B between the CLD group and the controls. Serum triglyceride and Lp(a) levels were similar for all three groups. Conclusions In contrast to previous reports, the site of the methionine metabolic impairment was found to be below the homocysteine synthesis level. For most patients with CLD, factors other than serum homocysteine or Lp(a) are responsible for the reduction in the risk of coronary heart disease. Further studies with larger samples are needed.

A new clinical indication for GnRH agonists treatment seems to exist in addition to the many indications known so far (4, 5). These previously mentioned indications include: uterine fibroids, precocious puberty, endometriosis, polycystic ovarian disease, ovulation induction for assisted fertilization (in vitro or in vivo), treatment of various tumors such as prostatic, breast, pancreatic, ovarian, and pituitary tumors, and various catamenial disorders such as premenstrual syndrome and porphyria. Women after liver transplantation, who are in the reproductive age and who experience menometrorrhagia or dysfunctional bleeding, seem to be a new indication for application of these useful GnRH analogues. This application may prevent the potential hepatotoxicity or cholestasis of E-P combinations usually used for treatment of dysfunctional bleeding. The recommended treatment is of relatively short duration (3 to 6 months), within the first 2 years of the transplantation, after which a more prolonged treatment should be considered. This treatment may also spare the need for contraception during its administration because both oral contraceptives and intrauterine device are relatively contraindicated in these patients (the latter because of the immunocompromised state). We believe this application to become more common because of increasing numbers of liver transplantations and improved survival rate. It may be looked at as a "new application of a relatively new drug for a new and enlarging situation."

“” LIVER IS the central organ in the growth hormone/insulin-like growth factor (GH-IGF) axis, and the acid-labile subunit (ALS) is one important component of that system in humans. The ALS is linked to the far end of the GH-IGF axis and is an integral constituent in the formation of the 150-kDa IGF/insulin-like growth factor binding protein-3 (IGFBP-3) complex that transports most (95%) of the IGF-I in the circulation and determines its bioavailability to tissues (1,2). The ternary complex (IGF-I, IGFBP-3, ALS) has an important function: to prevent the hypoglycemic effect of IGFs, prolong their biological half-life, and prevent cross-endothelial transport of IGFs. The ALS was first identified when the 150-kDa ternary complex was found to dissociate into a 7.5kDa IGF fraction and a 50-kDa IGFBP-3 fraction after acidification (3). The physiology, biology, and pharmacology of ALS and other parameters of the GH axis are very important in health and disease. In their study in this issue of the Journal, Moller et al. (4) report on low ALS levels in adults that correlate with liver dysfunction. By performing hemodynamic studies they show that the liver predominantly secretes ALS, but that some contribution from extrahepatic tissue may exist. Similar observations have been made in in vivo studies in rats (5). mRNA expression of ALS in tissues other than the liver have been shown by an in situ hybridization technique (6). The binding proteins such as ALS, produced in tissues other than the liver, could account for a paracrine effect or local need as compared with the endocrine function of the liver. In liver cirrhosis, ALS serum levels are decreased and participate in the extreme alterations that occur in the GH-IGF axis in this state. Liver cirrhosis is characterized as one of the GHresistant states, whereby GH serum levels are high in the presence of low IGF serum levels (7-9). Other

Background All hepatotropic viruses are known to cause fulminant hepatic failure (FHF). However, in 30% to 40% of patients with FHF, the precise cause remains unknown. We aimed to better define this subgroup. Methods We evaluated the clinical course and outcome of 7 patients admitted during a 22-month period with fulminant viral hepatitis leading to liver transplantation; none had serologic or molecular evidence of hepatitis A, B, C, D, E, or G viral infection, thus the term non–A-G viral hepatitis . All known etiologies of FHF were excluded. Results All patients had prodromal symptoms suggestive of viral causes. Mean age was 30 years. The interval between onset of jaundice and appearance of encephalopathy was 23 days (range, 4-50 days). Five patients had grade III/IV encephalopathy. Serum alanine aminotransferase levels showed a single peak of activity. The duration between first symptoms and liver transplantation was 28 days (range, 12-71 days). Results of histological study of the explanted liver showed submassive (4 patients) or massive (3 patients) hepatocyte necrosis. In all patients, results of polymerase chain reaction analysis did not detect hepatitis B virus DNA, hepatitis C virus RNA, or hepatitis G virus RNA in the explanted liver. After transplantation, 2 patients showed (6 months later) increased liver enzyme levels of undetermined cause, and results of a liver biopsy showed mild lobular hepatitis; 1 patient had lymphoproliferative disorder (Epstein-Barr virus–originated); and 1 patient, aplastic anemia, which is known to be associated with seronegative viral hepatitis. The latter patient died, whereas the other 6 patients are alive (survival rate, 86%). Conclusions Our patients with non–A-G viral hepatitis had a severe acute onset with progressive FHF requiring liver transplantation. There is some suggestion of recurrent viral disease after transplantation implicating other unknown viruses in the etiology.

Vascular endothelial growth factor (VEGF) is an angiogenic factor with a growth-promoting effect that is thought to be restricted to vascular endothelial cells. Its essential role during liver regeneration has yet to be determined. The aim of this study was to document the effect of exogenous VEGF administration on liver regeneration in rats undergoing submaximal hepatic resections.Adult male Sprague-Dawley rats (n = 4/group) undergoing 30% partial hepatectomy were administered 200 ng VEGF165 intravenously and were sacrificed at 24, 36, and 48 h postoperatively. Liver regeneration was monitored by measuring the restituted liver mass, proliferating cell nuclear antigen (PCNA) immunostaining, and hepatic PCNA protein by Western blot.Changes in restituted liver mass 48 h postsurgery were more prominent, but did not differ statistically between VEGF-treated and control rats (47% vs. 29%; p0.06). Nevertheless, PCNA immunostaining showed increased labeling index of hepatocytes, apparent at 36 and 48 h after partial hepatectomy (38% vs. 18% [p0.041 and 42% vs. 11% [p0.021], respectively). Hepatic PCNA proteins measured by Western blot showed a 3-fold increase in VEGF-treated rats 48 h postsurgery compared with controls (p0.01).Exogenous VEGF administration early after partial hepatectomy stimulates liver regeneration in rats. Whether or not VEGF165 is a direct mitogen for hepatocytes remains to be determined.

Budd-Chiari syndrome is characterized by hepatic venous outflow obstruction. Although myeloproliferative disorders are usually responsible for this severe thrombotic disorder, deficiency or dysfunction of the natural anticoagulants can be involved. Resistance to activated protein C caused by factor V Leiden mutation has been recently identified as a major cause of thrombophilia. We report 6 patients with Budd-Chiari syndrome associated with factor V Leiden mutation combined with another acquired thrombophilic state (myeloproliferative disorder and lupus anticoagulant in 3 cases) and without another thrombophilic disorder in the other 3 cases. We conclude that factor V Leiden mutation should be evaluated in any case of hepatic vein occlusion because the prevalence of this mutation in the general population is high.

Objective To compare the effect of budesonide vs prednisone therapy both in combination with azathioprine in pediatric patients with autoimmune hepatitis (AIH). Study design Forty-six patients with AIH (11 males and 35 females) aged 9-17 years were enrolled in a 6-month, prospective, double-blind, randomized, active-controlled, multicenter phase IIb study evaluating budesonide (n = 19; 3 mg twice or 3 times daily) vs prednisone (n = 27; 40 mg/day tapered to 10 mg/day), both with azathioprine (1-2 mg/kg/day), followed by a further 6 months of open-label budesonide therapy. The primary efficacy endpoint was complete biochemical remission (normal serum alanine aminotransferase and aspartate aminotransferase levels) without predefined steroid-specific side effects. Results We observed no statistically significant difference in the percentage of patients who met the primary endpoint between the budesonide (3 of 19; 16%) and prednisone groups (4 of 27; 15%) after 6 months, nor in the percentage of patients who experienced biochemical remission (budesonide, 6 of 19 [32%]; prednisone, 9 of 27 [33%]), lack of steroid-specific side effects (budesonide, 10 of 19 [53%]; prednisone, 10 of 27 [37%]). The mean weight gain was 1.2 ± 3.5 kg in the budesonide group and 5.1 ± 4.9 kg in the prednisone group ( P = .006). A total of 42 patients received open-label budesonide treatment for another 6 months. After 12 months, 46% of these patients achieved complete remission. Conclusion Oral budesonide with azathioprine can induce and maintain remission in pediatric patients with AIH and may be considered an alternative therapy to prednisone. The treatment causes fewer side effects and does not lead to weight gain; however, it may be less effective than prednisone in inducing remission.

Introduction Metformin is a first-line drug choice for the treatment of type 2 diabetes mellitus (DM-2). Metformin-induced hepatotoxicity has rarely been reported. We report on a case of metformin-induced mixed hepatocellular and cholestatic liver injury in an elderly patient with DM-2 as well as review and summarize case reports of metformin hepatotoxicity available in English on the PubMed database. Case After receiving metformin 850 mg/day for 2 weeks, a 78-year-old male presented with a 10-day history of abdominal pain, vomiting, diarrhea, and jaundice. Laboratory analysis showed severe hepatocellular and cholestatic hepatic injury. Other causes for acute liver injury were ruled out. Discontinuation of metformin treatment led to significant subjective improvement after 1 week, and all hepatic abnormalities resolved by 2 months. Conclusion Metformin is an important drug for the treatment of DM-2, which is also used for treatment of patients with fatty liver. It can, however, induce hepatocellular and cholestatic hepatic injury; both physicians and patients should be aware of this potential side effect.

A role for fibroblast growth factor in liver regeneration has recently been suggested. In this study we followed the intravenous delivery of recombinant human [125I]basic fibroblast growth factor to the liver of rats following 68% partial hepatectomy. The concentration of [125I]basic fibroblast growth factor was higher in the liver (mean +/- SD, 6.8 +/- 0.89% of injected dose) and the kidney (6.7 +/- 0.2%) of sham-operated rats than in the spleen (2.8 +/- 0.45%). It increased threefold in the liver only, soon after 68% partial hepatectomy (20.3 +/- 5.3%, p < 0.001), and remained high for the first 24 h. We also studied the effect of basic fibroblast growth factor injection on the rate of [3H]thymidine incorporation into liver DNA in rats subjected to either 21% or 68% partial hepatectomy. A significant increase was seen after intramesenteric injection of 500 ng basic fibroblast growth factor into rats subjected to 21% partial hepatectomy (23.5 +/- 7.3 cpm/micrograms DNA) compared to saline-injected rats (14.5 +/- 6.4 cpm/micrograms DNA, p = 0.034). A dose of 5000-25,000 ng injected into a peripheral vein resulted in higher thymidine incorporation than in saline-injected control rats (36.9 +/- 12.7 and 9.7 +/- 6.1 cpm/micrograms DNA, respectively; p < 0.0001). No significant effect was seen after 68% partial hepatectomy. Autoradiography showed that the hepatocytes were the predominant labelled cells early after hepatectomy and basic fibroblast growth factor injection. We conclude that basic fibroblast growth factor uptake by the liver is increased after 68% partial hepatectomy and that basic fibroblast growth factor is mitogenic to liver parenchymal cells early after 21% partial hepatectomy.

The recently characterized GH-binding protein (GH-BP) has an amino acid sequence identical to the extracellular domain of the GH receptor. Serum GH-BP reflects the amount of GH receptors, and the liver seems to be their main source. To evaluate the effect of liver disease on GH-BP, 52 patients with liver cirrhosis were studied. Serum GH-BP was measured by a binding assay with dextran-coated charcoal separation. Levels of GH-BP were correlated against the clinical state, assessed by Pugh's score. The GH-BP of 31 Pugh's class A patients was 9.7 +/- 0.5%/50 microL serum, and that of 21 Pugh's class B and C patients was 7.2 +/- 0.5%/50 microL serum compared to 11.3 +/- 0.5%/50 microL serum in age-matched controls. GH-BP correlated negatively with Pugh's score and serum bilirubin, and positively with serum albumin. It did not correlate with serum liver enzymes or serum insulin-like growth factor-I. Scatchard analysis of GH binding to the GH-BP revealed similar binding affinities in Pugh's A, B, and C patients and controls. The binding capacity in cirrhosis was significantly lower than that in controls. We conclude that serum GH-BP is controlled mainly by the liver and can provide an additional measure of disease severity in liver cirrhosis.

AIM:To determine whether serum vascular endothelial growth factor (VEGF) levels correlates with the severity of liver cirrhosis and whether portal hypertension impacts on the expression of serum VEGF protein.METHODS:Fifty-three patients (mean age 56 ± 2 years) with HCV (n = 26), HBV (n = 13), and cryptogenic liver cirrhosis (n = 14) (Child-Pugh's class A: 24, B: 19 and C: 12) and normal renal function constitute the patient population, who were all diagnosed by clinical, histological and radiological findings. Six healthy people and six patients with acute hepatitis served as controls. Severity of liver disease was evaluated by the CP score. Serum levels of IGF-1 and VEGF were measured by radioimmunoassay and ELISA,respectively.Portal hypertension was assessed using pulsed Doppler ultrasound. RESULTS:The mean serum VEGF levels in all cirrhotic patients (73 ± 58) were significantly lower than those of healthy controls (360 ± 217, P0.01) and acute hepatitis (1123 ± 1261, P0.01) respectively. No significant difference in median serum VEGF levels were noted among the different Child-Pugh's classes (class A: median, 49.4ng/L, range, 21ng/L-260ng/L, Class B: median 59.9ng/L; range 21-92, and Class C: median 69; range 20ng/L-247ng/L). A significant correlation was noted between serum VEGF and two accurate parameters of portal hypertension: portal blood flow velocity (r = 0.6) and spleen size (r = 0.55). No correlation was found between VEGF serum levels and serum albumin, IGF-1, platelets count and aminotrasnferases (r = 0.2, r = 0.1, r = 0.2 and r = 0.2, respectively).CONCLUSION:Circulating VEGF level in patients with liver cirrhosis could not serve as an indicator of the progression of chronic liver disease but rather, they may reflect increased portal hypertension or decreased hepatic regenerative activity or the combination of both.