I. Graziadei

High-dose interferon-α2b treatment prevents chronicity in acute hepatitis C

Acute hepatitis C takes a chronic course in 50–80% of cases. Results with interferon treatment are conflicting. To evaluate the efficacy of high-dose interferon treatment, we initiated a pilot study in 1992 using 10 MU interferon-α2b administered subcutaneously daily until normalization of serum transaminase concentrations. Treatment was begun when a diagnosis of acute hepatitis C was established. HCV-RNA was tested using PCR prior to treatment, three times weekly during the first two weeks of treatment, and then once weekly until the end of therapy. During the 15-month follow-up, HCV-RNA tests were performed monthly up to month 6 and every two to three months thereafter. Twenty-four patients were enrolled at the time of writing; age ranged from 18 to 76 years (mean=32), and nine patients were men. All patients presented with cholestatic hepatitis; 19 were actively abusing intravenous drugs, four had no known parenteral exposure, and one was a medical laboratory technician. All patients were anti-HCV positive, HCV-RNA positive, and HIV negative. Five patients were infected with genotype 3, five with genotype 1a, five with genotype 1b, three with genotypes 3 and 2, and one with genotypes 1 and 2. All patients exhibited normalized serum transaminase concentrations within 18–43 days; HCV-RNA became negative in all patients within 4–12 days. Toxicity did not exceed grade 1 and disappeared within three days of treatment. In the follow-up period, which ranged from six to 29 months (mean=19.5±10.4), serum ALT concentrations remained normal and HCV-RNA remained negative in all patients except two dropouts and two patients who developed relapsing disease after having been HCV-RNA negative for three and eight months, respectively. In both patients, the same HCV genotype 3 reemerged. Serum ALT concentrations ranged from 531 to 1940 IU/liter (mean=1055; normal <22). Concentrations of HCV-RNA (Quantiplex; Chiron, Emeryville, California) were <3.5×105 eq/ml in nine of 14 PCR-positive patients. In the other five patients, concentrations ranged from 10.4×105 eq/ml to 131.6×105 eq/ml (mean=69.6×105). No correlation was observed between HCV-RNA concentrations and serum ALT concentrations at presentation (r=0.331;P=0.67) and total dose of interferon-α2b administered until normalization of ALT (r=−0.088;P=0.74). Twenty-two of 24 patients completed treatment (two were noncompliant). Of these, 20 achieved a complete response (HCV-RNA negative for at least six months). Two of these patients relapsed, and 18 (90%) remained HCV-RNA negative for 18.65 (±9.7) months. These findings suggest that high-dose interferon-α2b is well tolerated and effective in preventing a chronic course of hepatitis C infection.

Treatment of refractory cholestatic pruritus after liver transplantation with albumin dialysis

Albumin dialysis has been shown to improve the outcome in patients with cholestatic liver failure caused by chronic liver disease. This study reports 7 liver transplant recipients who were treated with albumin dialysis for intractable pruritus of different origin (ductopenic graft rejection, non‐anastomotic strictures, and recurrence of hepatitis C). Treatment with histamine (H1) blockers, opioid antagonists, and cholestyramine had not been effective. The Molecular Adsorbent Recirculating System (MARS; Teraklin, Rostock, Germany) was used for albumin dialysis. All patients presented with numerous scratch marks, 6 of whom had a pronounced icterus. Six patients (86%) responded to 3 consecutive treatments with significant reduction of pruritus. The mean pruritus score, which was quantified by a visual analog scale (VAS), decreased from 9.7 ± 0.5 to 3.7 ± 0.8 (SD). The mean duration of 1 treatment was 15.6 hours. The procedure was well tolerated by all patients. The mean total serum bilirubin in patients who responded to therapy declined from 19.11 ± 16.96 mg/dL (SD) before MARS therapy to 9.24 ± 3.52 mg/dL after treatment. The mean serum concentration of 3α‐hydroxy bile acids decreased from 192.67 ± 58.12 μmol/L (SD) to 42.33 ± 31.58 μmol/L (SD). Follow‐up in 3 cases showed sustained improvement of pruritus lasting for more than 3 months. In 3 patients, however, pruritus relapsed. One patient, who showed severe pruritus, without relevant elevation of serum bile acids before treatment, did not respond to albumin dialysis. Our data indicate that MARS is an effective therapeutic option for patients with intractable cholestatic pruritus. (Liver Transpl 2004;10:107–114.)

Incomplete improvement of visuo-motor deficits in patients with minimal hepatic encephalopathy after liver transplantation

Previous studies have suggested reversibility of minimal hepatic encephalopathy in patients with liver cirrhosis after liver transplantation (LT), however, this topic is controversially discussed. We investigated this issue in a prospective study on liver cirrhotic patients listed for LT. Patients were investigated before and after liver transplantation (on average 21 months later) using a neuropsychological test battery which measured visuo‐constructive and visuo‐motor ability, verbal fluency, and memory function. To assess visuo‐motor and visuo‐constructive functions, we performed 4 tests: Rey Complex Figure Test copy, trail making tests A and B, and digital symbol test. The average percentile score of the tests, arbitrarily named the visuo‐motor and visuo‐constructive performance score (VMCP), was calculated. After LT, the patients did not demonstrate a significant increase of VMCP (P = .29) and additionally showed significantly lower VMCP score (P = .041) compared to control group. Analysis of individual responses showed that only 7 of 14 patients improved their VMCP values after LT. These data indicate that the cirrhosis‐associated visuo‐motor deficits subside or disappear only in some of the patients after LT, whereas a significant number of patients show no improvement of the visuo‐motor and visuo‐constructive function. We concluded that monitoring of cognitive and visuo‐motor functioning is important for the post‐transplant rehabilitation of patients with liver cirrhosis. (Liver Transpl 2004;10:77–83.)

Percutaneous management of a hepatic artery aneurysm: bleeding after liver transplantation.

In this artical we present an unusual case of hepatic artery aneurysm bleeding due to a hepatic artery thrombosis after liver transplantation. The patient developed a recurrent hepatic artery thrombosis leading to severe graft failure in four consecutive liver transplantations. While being evaluated for a fifth transplant, stabilization of the clinical situation was attempted by interventional therapy. The first intervention was to place a stent into the hepatic artery to prevent further ischemic damage. This failed to improve graft function, but unfortunately led to the development of a pseudoaneurysm at the distal end with a subsequent rupture into the biliary tree. Bleeding was treated successfully by direct puncture and coil embolization of the aneurysm. In addition, the patient demonstrated a hemodynamically relevant portal vein stenosis on the CT scan. Stenting of the portal vein markedly improved graft function. After extensive investigations, a paroxysmal nocturnal hemoglobinuria was found to be the underlying cause of the recurrent hepatic artery thrombosis. Here we suggest that hepatic artery aneurysm bleeding is a rare but potentially fatal complication that can be successfully treated by percutaneous coil embolization. Additionally, we propose that stenting of the portal vein can lead to a significant improvement of the graft perfusion even though the hepatic artery remained occluded.

Unidirectional upregulation of the synthesis of the major iron proteins, transferrin-receptor and ferritin, in HepG2 cells by the acute-phase protein α1-antitrypsin

BACKGROUND/AIMS We have previously shown that the hepatic acute-phase protein alpha1-antitrypsin (alpha1-AT) is an important mediator of changes in iron metabolism in the course of anaemia of chronic disease. Alpha1-AT profoundly reduces growth of erythroid cells by interfering with transferrin-mediated iron uptake. In the present work we investigate the effects of alpha1-AT on hepatic iron metabolism, as the liver plays a central role in body iron metabolism and in metabolic changes during acute-phase response. METHODS The human hepatoma cell line Hep G2 was cultured in RPMI 1640+10% FCS. The effect of alpha1-AT on transferrin-receptor binding was investigated in equilibrium binding assays with 125I-transferrin. Expression of transferrin receptor was determined by saturation experiments and intracellular ferritin was measured in cell lysates after incubating cells either alone or with alpha1-AT. To determine iron regulatory protein binding activity to iron responsive elements we used gel retardation assays and Northern blot analysis was carried out to investigate transferrin receptor and ferritin mRNA expression. RESULTS Alpha1-AT completely prevented transferrin from binding to its receptor and internalization of the transferrin-transferrin receptor complex on HepG2. In addition, alpha1-AT caused a distinct increase in iron regulatory protein binding activity to iron responsive elements, which is characteristic of iron deprivation. Normally, the synthesis of transferrin receptor and ferritin is regulated bidirectionally, but alpha1-AT promoted a unidirectional regulation. Alpha1-AT increased the synthesis of both transferrin receptor and ferritin and, moreover, increased cellular amounts of transferrin receptor mRNA and ferritin H-chain mRNA. CONCLUSIONS The effect of alpha1-AT on transferrin receptor synthesis appears to be mediated via activation of iron responsive element binding affinity of iron regulatory protein leading to an increased stability of transferrin receptor mRNA. Changes in ferritin, however, may be related to a transcriptionally mediated, iron-independent pathway which overrides the influence of activated iron regulatory protein. These specific changes in iron metabolism are the very ones seen in the course of anaemia of chronic disease. Our results emphasize the central role of alpha1-AT as a mediator of altered iron metabolism, characteristic of anaemia of chronic disease, not only with respect to erythroid cells but also with respect to liver cells.

The acute-phase protein α1-antitrypsin inhibits transferrin-receptor binding and proliferation of human skin fibroblasts

Abstract Transferrin (Tf) is required for proliferation of most cells, because cellular iron uptake is mainly mediated by binding of Tf to its specific cell surface receptors (TfR). The acute-phase protein α1-antitrypsin (α1-AT) completely inhibits binding of diferric Tf to TfRs on human skin fibroblasts in a dose-dependent fashion. The inhibition is competitive as proved in equilibrium saturation binding and kinetic studies. In saturation binding experiments α1-AT apparently increased the dissociation constant ( K D ), but did not change the maximal density of binding sites ( B max ). As shown in kinetic studies, this reduction of the affinity of Tf to its receptor caused by α1-AT was due to a decrease of the association rate constant ( k +1), whereas the dissociation rate constant ( k −1) remained unchanged. Furthermore, α1-AT almost completely prevented internalization of the Tf–TfR complex. These interactions demonstrated biological implication, as α1-AT reduced the proliferation of human fibroblasts up to maximal 30% of control. The inhibitory potency of α1-AT was already seen in physiologic concentrations; the maximal effect, however, was achieved at concentrations above the normal range, which are attained in the course of inflammation and infection. Therefore, we suppose that α1-AT as an endogenous factor modulates the complex mechanism of fibrogenesis not only by its known antiproteolytic function but also by inhibiting the proliferation of fibroblasts.

Posttraumatic splenic artery aneurysm presenting as occult gastrointestinal bleeding

ZusammenfassungDieser Fallbericht beschreibt den Krankheitsverlauf eines 53-jährigen Patienten, der an einer seit 19 Monaten bestehenden rezidivierenden okkulten gastrointestinalen Blutung leidet. Zahlreiche endoskopische Untersuchungen des oberen und unteren Gastrointestinaltraktes zeigten keine Blutungsquelle. Als der Patient im Rahmen eines Blutungsereignisses synkopierte, wurde an unsere Abteilung transferiert. Eine erneute Gastroskopie zeigte eine große, von der Magen-Hinterwand in das Lumen vorwölbende Raumforderung. Der Tumor imponierte mit weicher Konstistenz sowie einer darüberliegenden intakt wirkenden Magenschleimhaut. Eine endoskopische Ultraschalluntersuchung sowie eine Computertomographie entlarvte den Tumor als teilweise thrombosiertes Milzarterienaneurysma. Mittels Angiographie konnte diese Diagnose bestätigt werden. In weiterer Folge wurde das Milzarterienaneurysma embolisiert. Innerhalb einer nunmehr vier-monatigen Verlaufsperiode sind keine weiteren Blutungsereignisse mehr aufgetreten.Ein Milzarterienaneurysma stellt zwar eine seltene Ursache für eine okkulte gastrointestinale Blutung dar, sollte jedoch bei jeder frustranen Abklärung einer okkulten gastrointestinalen Blutung berücksichtigt werden.SummaryA 53-year-old man presented with a 19-month history of gastrointestinal bleeding. Repeated endoscopic investigation of the upper and lower intestine showed no source of bleeding. When the patient collapsed due to massive gastrointestinal hemorrhage he was referred to our center. Gastroscopy showed a large, bulging tumor protruding from the posterior gastric wall. The consistency of this tumor was soft and the overlying mucosa appeared smooth and intact. Endoscopic ultrasound and contrast-enhanced computerized tomography scan identified a partly thrombosized splenic artery aneurysm (SAA). Arteriography of the celiac trunk confirmed the SAA diagnosis; the SAA was subsequently occluded by coils. So far, four months after discharge, the patient is in excellent health and no further episode of gastrointestinal bleeding has occurred.SAA is a very rare cause of upper gastrointestinal bleeding, but it must be considered when no other common bleeding source can be detected.