Point Shear Wave Elastography by Acoustic Radiation Force Impulse Quantification in Comparison to Transient Elastography for the Noninvasive Assessment of Liver Fibrosis in Chronic Hepatitis C: A Prospective International Multicenter Study.

PURPOSE: The aim of the present prospective European multicenter study was to demonstrate the non-inferiority of point shear wave elastography (pSWE) compared to transient elastography (TE) for the assessment of liver fibrosis in patients with chronic hepatitis C. MATERIALS AND METHODS: 241 patients with chronic hepatitis C were prospectively enrolled at 7 European study sites and received pSWE, TE and blood tests. Liver biopsy was performed with histological staging by a central pathologist. In addition, for inclusion of cirrhotic patients, a maximum of 10 % of patients with overt liver cirrhosis confirmed by imaging methods were allowed by protocol (n = 24). RESULTS: Owing to slower than expected recruitment due to a reduction of liver biopsies, the study was closed after 4 years before the target enrollment of 433 patients with 235 patients in the 'intention to diagnose' analysis and 182 patients in the 'per protocol' analysis. Therefore, the non-inferiority margin was enhanced to 0.075 but non-inferiority of pSWE could not be proven. However, Paired comparison of the diagnostic accuracy of pSWE and TE revealed no significant difference between the two methods in the 'intention to diagnose' and 'per protocol' analysis (0.81 vs. 0.85 for F ≥ 2, p = 0.15; 0.88 vs. 0.92 for F ≥ 3, p = 0.11; 0.89 vs. 0.94 for F = 4, p = 0.19). Measurement failure was significantly higher for TE than for pSWE (p = 0.030). CONCLUSION: Non-inferiority of pSWE compared to TE could not be shown. However, the diagnostic accuracy of pSWE and TE was comparable for the noninvasive staging of liver fibrosis in patients with chronic hepatitis C.

Determination of inner implant's volumes: a pilot study for microleakage quantification by stereomicroscopy and spectrophotometry.

AIM: Microleakage quantification of fluids and microorganisms through the connections of different implant parts seems to be sparse. Moreover, no data exist regarding the determination of the volumes of inner parts of dental implant systems. This study aims to determine the volumes of inner parts of three dental implant systems with the same interface and to evaluate the microleakage phenomenon. MATERIALS AND METHODS: Three implant system sets (Euro-teknika(®), Astra Tech(®) and Implantium(®)) were used in this study. Implants were inoculated with safranin, brain heart infusion and distilled water. After inoculation and assembly of the different parts, different inner volumes (V1, V2, V3, V4, V5 and V6) were measured and, the surfaces of the micro gaps were observed through a stereomicroscope. Implants containing safranin were immersed in vials containing distilled water. Samples then were taken to determine optical density using a spectrophotometer. RESULTS: Regardless the used substance, volumes of the 3-implant systems are different. Although volumes V1, V 2, V 3 and V5 appeared to be constant within the same system regardless the used substance, volumes V4 and V6 were not. CONCLUSION: The determination of the volumes and the evaluation of leaked substance using stereomicroscopic and spectrophotometric methods showed the accuracy of these methods and the importance of their use in the study of microleakage. CLINICAL SIGNIFICANCE: Leakage is an important factor for chronic inflammatory infiltration and marginal bone resorption. Studies have shown fluid and bacterial leakage into abutment- implant (A-I) assemblies of certain implants with 'closely locked' abutments and the creation of a constant bacterial reservoir in the empty space found between the implant and the abutment.

Gender differences in patient receiving liver transplantation for viral hepatitis.

INTRODUCTION: The course of viral hepatitis shows wide interindividual differences, ranging from asymptomatic disease to liver failure. Only limited data on gender differences in patients undergoing liver transplantation (OLT) exist. We studied the gender distribution in patients who underwent liver transplantation for viral hepatitis. METHODS: A retrospective analysis was performed on a cohort of 368 patients who underwent OLT for viral hepatitis-associated acute or chronic liver failure. In 96 of them, additional hepatocellular carcinoma (HCC) was present at transplantation. Gender ratios of the different hepatitis virus infections and in relation to HCC were evaluated. RESULTS: Significantly more males than females underwent OLT for chronic HBV. In contrast, patients after OLT for fulminant HBV were more frequently females. In patients transplanted for chronic HCV or HDV, no significant gender differences were found. However, men presented more frequently with HCC in both groups of chronic liver disease. CONCLUSIONS: There was a gender difference in HBV infection with more women developing fulminant hepatic failure in acute HBV while more men progressed to end-stage liver disease in chronic HBV. The role of gender in chronic HCV and HDV infection was less pronounced, except for a male predominance among patients with HCC.

[Diagnostic and interventional abdominal ultrasonography]. / Diagnostische und interventionelle Abdomensonographie.

Abdominal ultrasonography is an essential tool for physicians. In contrast to other imaging methods, ultrasound examination is a cost-effective real-time imaging method without radiation effects. As in all other imaging methods, abdominal ultrasound requires an experienced examiner and high quality equipment to maintain a high quality. Abdominal ultrasonography is at least equal to cross-sectional imaging methods in most clinical issues, e.g., in inflammatory bowel disease, vascular liver diseases, or real-time surveillance of interventions. The range of applications for ultrasound has been markedly expanded by using contrast-enhanced ultrasound to detect and characterize space occupying lesions or perfusion aberrations in- and outside the liver.Ultrasound-guided fine needle aspiration biopsy or drainage of space occupying lesions and pathological liquids are minimally invasive standard ultrasound-guided interventions. Ultrasound-based tumor therapy as well as sclerotherapy of symptomatic nonparasitic cysts of the liver, kidneys, or spleen are also performed. By being able to provide quantitatively reproducible measurement of tissue stiffness, ultrasonography has entered a new era. The development of mechanical elastography also promises a new form of tissue characterization.

ARFI elastography of the spleen is inferior to liver elastography for the detection of portal hypertension.

PURPOSE: To date, the use of transient elastography has been limited to the liver. Acoustic radiation force impulse imaging (ARFI) is a new technology offering elastography of different tissues. Here, we present initial spleen elastography data and evaluate its influencing factors, especially portal hypertension. MATERIALS AND METHODS: Elastography of the spleen and liver using the ARFI method was performed in 30 patients with portal hypertension, 70 patients with chronic liver disease without portal hypertension and 25 healthy controls. RESULTS: ARFI elastography of the spleen was feasible in 99% of patients and valid in 78%. The mean propagation velocity inside the spleen was 2.95 ± 0.60 m/sec, thus much higher than in the normal liver (< 1.10 m/sec). Spleen stiffness was higher in the patients with portal hypertension (p < 0.008) but did not correlate to spleen size. Spleen stiffness increased with patient age and liver stiffness (both p < 0.0001) as confirmed by multivariate analysis (R2 = 0.19, p < 0.01). In ROC analysis, spleen elastography was inferior to liver elastography for the detection of portal hypertension (area under the curve 0.68 vs. 0.90). CONCLUSION: The new ARFI method allows accurate elastography of the spleen. The stiffness of the normal spleen is much higher than that of the normal liver and increases with age. However, spleen elastography is inferior to liver elastography for the detection of portal hypertension.

[Alpha1-antitrypsin deficiency]. / Alpha1-Antitrypsinmangel.

Alpha(1)-antitrypsin deficiency is characterized by a pathologic reduction of the serum concentration of alpha(1)-antitrypsin, the most important antiprotease in man. It is one of the most common hereditary diseases in Caucasians. Approximately 2% of obstructive airway diseases are caused by alpha(1)-antitrypsin deficiency. Patients above 35 years may develop lung emphysema, especially in the lower lobes. Symptoms are those of chronic obstructive pulmonary disease such as cough, sputum expectoration, and progressive dyspnoea. Patients with homozygous defect often develop cholestatic hepatitis in the neonatal period. However, only few adult patients develop chronic liver disease up to liver cirrhosis with an elevated risk for malignant liver tumors. The diagnostic hallmark is the reduced serum concentration of alpha(1)-antitrypsin while genetic testing proves the defect. An early recognition of the disease is decisive for prophylactic and therapeutic measures. Smoking should be stopped immediately. Treatment of lung disease includes physiotherapy, antiobstructive and antiinflammatory medication, augmentation with human alpha(1)-antitrypsin and lung surgery including lung transplantation. Liver toxins should be avoided. Besides experimental therapeutic approaches, liver disease can only be treated by liver transplantation.

[CMV-enterocolitis as a cause for repeated intestinal intussusceptions in an adult patient after liver transplantation?]. / CMV-Enterokolitis bei einer erwachsenen lebertransplantierten Patientin als Ursache rezidivierender Invaginationen?

Intestinal intussusception in the adult is often idiopathic but also known to be associated with chronic inflammatory bowel disease, coeliac disease, tumours or previous abdominal operations. A 22-year-old women after liver transplantation due to Crigler Najar Syndrome suffered from repeated episodes of abdominal pain. The diagnosis of repeated self-limited intestinal intussusceptions was made by computed tomography and ultrasonography. A laparoscopy revealed no cause for the intussusceptions. During a new episode of abdominal pain caused again by an intussusception a colonoscopy was performed that showed aspects of a discreet colitis. In the biopsies CMV was detected by qualitative PCR, while blood tests for CMV pp65 antigen were negative. A therapy with gancyclovir was initiated which lead to remission of the patient's symptoms. A colonoscopy six weeks later showed a completely normal colon, while in the biopsies CMV was not detectable. After a follow-up of one year the patient has not suffered from any further episodes. This case demonstrates the role of chronic intestinal CMV infection as a possible causative factor for repeated intussusceptions in immunosuppressed patients. Whenever possible a PCR for CMV in colon biopsies should be carried out to detect an intestinal CMV infection because as shown in our case results for immunohistopathology and CMV pp65 can be negative despite a chronic infection.

Successful treatment of fulminant hepatitis B during pregnancy.

We here report the use of lamivudine 100 mg daily in a young pregnant woman (24th week of gestation) with fulminant hepatic failure due to acute HBV infection. After initiation of oral lamivudine (100 mg/d), ALT levels rapidly decreased from 5046 U/L to normal values within five weeks. HBe seroconversion occured three weeks after treatment start, followed by HBs seroconversion within less than six months. A preterm female baby was delivered at gestational week 29 (weight 1000 gr) (five weeks after start of lamivudine). The infant received simultaneous active and passive HBV immunisation within 12 hours after delivery. The neonatal check-up revealed meconium ileus which was successfully treated by surgery. At last presentation 241 days after initiation of treatment, both mother and infant showed stable HBs-seroconversion (anti-HBs 169 IU/mL and > 1000 IU/L, respectively). Therefore, lamivudine therapy was withdrawn. This case suggests that oral nucleos(t)ides may be safely used in pregnant patients with fulminant hepatitis B potentially preventing liver transplantation and interruption of pregnancy.

Prometheus: from legend to the real liver support therapy.

BACKGROUND: A large number of patients develop liver disease that may evolve into progressive chronic failure. Artificial liver support systems (e.g., MARS and Prometheus) are considered in the framework of the steady increase in the number of patients who could possibly benefit from these blood purification devices. Albumin dialysis and adsorption are now two integrated concepts. The present know-how enabling us to appropriately modify several intrinsic characteristics of the adsorbents--e.g., their chemical nature, the particle and pore size distribution, as well as a larger surface offered to adsorption--has helped in better fine-tuning liver support systems to improve adsorption kinetics and flow characteristics specifically for the intended clinical application. These properties together with an improved biocompatibility have made possible the development of adsorptive techniques for which clearances and total removal rates of target compound would be unthinkable with conventional hemodialysis or hemofiltration. Several adsorptive techniques are already available commercially for the treatment of sepsis and septic shock and of acute liver failure, but controlled studies with clinical end points are still lacking.

[Severe drug hepatitis caused by Chelidonium]. / 58-jähriger Patient mit schwerer cholestatischer Hepatitis.

We report the case of a 58-year-old male patient who was admitted with severe acute cholestatic hepatitis. Liver biopsy showed signs of drug-induced hepatitis. Other causes of acute hepatitis were excluded. Therefore, the ingestion of a Chelidonium-containing preparation (celandine) was thought to be responsible for the hepatitis. Shortly after stopping the administration of Chelidonium, the highly pathological levels of several liver parameters began to normalise. As no autoantibodies were detectable, an idiosyncratic reaction as the cause of drug-induced hepatitis is probable. In cases of unknown hepatitis, herbal medications should be taken into account as a possible cause.

Repeated administration of a vitamin preparation containing glycocholic acid in patients with hepatobiliary disease.

BACKGROUND: Until now, hydrophilic and lipophilic vitamin preparations had to be administered separately during total parenteral nutrition. By addition of glycocholic acid, a vitamin supplement (Cernevit, Baxter, Heidelberg, Germany) was developed that combines all vitamins into one vial. However, little information exists about possible consequences of bile acid administration such as glycocholic acid, especially if liver disease is pre-existing. AIM: To evaluate the effects of total parenteral nutrition with a vitamin preparation containing high doses of glycocholic acid in patients with and without liver disease. METHODS: In a prospective, randomized-controlled trial, 74 patients, 36 of them with hepatobiliary disease, received total parenteral nutrition for 16 +/- 11 days, either with Cernevit or control vitamin supplements. Patients were closely monitored for clinical and biochemical parameters including serum bile acid profiles measured by high-performance liquid chromatography. RESULTS: Serum glycocholic acid increased in patients with liver disease treated with Cernevit, whereas total bile acids did not significantly change. Other liver function tests remained stable during treatment. No adverse events during Cernevit administration were noted except for a reversible slight increase of transaminases in one patient. CONCLUSIONS: Cernevit was well tolerated after repeated dosing, even in patients with severe liver disease. Apart from standard controls of liver biochemistry, no specific surveillance is necessary during treatment with Cernevit.

Retrospective analysis of the impact of immunosuppression on the course of recurrent hepatitis C after liver transplantation.

INTRODUCTION: In a substantial proportion of patients, recurrent hepatitis C after liver transplantation (OLT) rapidly progresses to graft cirrhosis. The role of different immunosuppressive schemes is not well evaluated. PATIENTS AND METHODS: The clinical course of 130 patients with recurrent hepatitis C after OLT was retrospectively analyzed. Mean trough levels of calcineurin inhibitors and cumulative doses of the remaining immunosuppressants were calculated. The results were compared with liver function tests, histological fibrosis progression, and survival. RESULTS: Survival and fibrosis progression were similar in patients with tacrolimus and cyclosporine and did not correlate with mean trough levels. In contrast, the application of azathioprine (mean dose of more than 25 mg/d during the first 3 months after OLT) was associated with significantly less progression of fibrosis (P = .01). Administration of azathioprine after the early postoperative phase was not related to the long-term outcome. The dose of prednisolone in the long-term course after OLT significantly correlated with the rate of fibrosis progression (P = .008). CONCLUSIONS: The clinical course of recurrent hepatitis C was variable. Survival and fibrosis progression did not correlate with the type or trough level of calcineurin inhibitors. Azathioprine early in the course after OLT and prolonged administration of prednisolone were associated with less fibrosis progression.

Severe hearing loss after liver transplantation.

Little is known about hearing impairment in patients after organ transplantation. Few cases of hearing loss associated with different immunosuppressants have been published. To evaluate severe hearing impairment in patients after liver transplantation (OLT), all living adult patients in need of a hearing aid were analyzed. Out of 521 transplanted patients, 25 (5%) were identified with hearing aids. Nine (36%) of these patients either suffered from hearing loss prior to OLT or experienced risk factors such as ototoxic drugs. Of the remaining 16 patients who developed severe hearing loss after OLT (64%), half were men. Mean age was 42 +/- 18 years at OLT, which took place 8 +/- 4 years ago. Main transplantation indication was virus-induced cirrhosis (44%). In 14/16 (88%) patients, the hearing aid was bilateral. In 50% of patients, the hearing aid was necessary within 2 years post-OLT. Additional tinnitus was present in 9/16 patients (56%), otalgia in three patients (19%). Four patients (25%) reported a history of sudden deafness. In three of them, an association with high levels of calcineurin inhibitors was found. The proportion of patients receiving tacrolimus (50%) was relatively higher than those receiving cyclosporine (50%) compared to control patients (28% respectively 64%, P < .05). In conclusion, a high incidence of severe hearing loss was found in patients after liver transplantation. In most patients, onset of hearing loss is early and bilateral, suggesting a dose-dependent toxicity. The pathogenetic role of different immunosuppressants remains to be evaluated.

[Liver transplantation for metabolic liver disease in adulthood]. / Lebertransplantation bei metabolischen Lebererkrankungen im Erwachsenenalter.

The clinical presentation of metabolic liver disease is highly variable, covering acute liver failure, liver cirrhosis, hepatic cancer and various extrahepatic manifestations. Both natural course and prognosis after liver transplantation are substantially influenced by extrahepatic manifestations. In many types of metabolic liver disease, timely diagnosis allows for successful medical treatment. However, progressive liver failure and severe extrahepatic damage can be the indication for liver transplantation. In general, standard transplantation criteria also apply for metabolic liver disease. They have to be modified by disease-specific criteria, and extrahepatic damage may necessitate multiorgan transplantation. The overall prognosis after liver transplantation for metabolic liver disease is favorable. Furthermore, several metabolic defects are phenotypically cured by liver transplantation. Alternative treatments like hepatocyte transplantation or gene therapy are still in the experimental stage.

[Liver replacement therapy. Reliable indications in acute liver failure]. / Leberersatztherapie. Gesicherte Indikationen bei akutem Leberversagen.

Extracorporeal liver support devices aim at improving the therapeutical options for liver failure. Numerous artificial and bioartificial devices have been tested to reduce the high mortality of this dynamic disease. In particular, the detoxification function of the liver should be upheld, by means of a number of different procedures, either until liver function is restored or until transplantation. Both purely artificial, machine-based procedures including different forms of dialysis and hemoadsorption as well as bioartificial procedures based on hepatocytes are being tested, as are different types of extracorporeal liver perfusion. This paper provides an overview of the different methods and devices and their clinical evidence in order to give a recommendation for the handling of the expensive devices. There is no current indication for the application of liver support devices outside of clinical studies at specialised centres.

[Acute liver failure]. / Akutes Leberversagen.

Acute liver failure is characterized by a dynamic clinical course associated with high mortality. The main prognostic determinant is the development of extrahepatic complications. Close monitoring is mandatory, and prophylactic measures to avoid complications should be initiated. In case of complications, early and aggressive treatment is indicated. To date, artificial liver support devices are still in the experimental phase. Liver transplantation should be considered in patients with predictors of a poor spontaneous prognosis. Therefore, a transplant center should be contacted in every case of acute liver failure.

A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence.

BACKGROUND AND AIM: Autoimmune hepatitis (AIH) has been reported to recur after orthotopic liver transplantation (OLT) in 10-35% of patients in small series with a short follow up. The aim of the present study was to examine the clinical and histological outcome more than 10 years after OLT for AIH. PATIENTS AND METHODS: Seventeen women with a mean age of 30 (12) years at the time of OLT, selected from among 44 patients transplanted for AIH, were followed for more than 10 years. The criteria for definite AIH, as established by the International Autoimmune Hepatitis Group, were met in every case. Liver biopsies were performed 1, 2, 5, and 10 years after OLT, and when indicated by abnormal liver function tests. Specimens were examined for evidence of recurrent AIH, namely interface hepatitis, lobular activity, portal lymphoplasmocytic infiltration, and fibrosis. Other signs of recurrence included hypertransaminasaemia, serum autoantibodies, and the response to steroid reintroduction or significant steroid dose increments. RESULTS: AIH recurred in 7 (41%) of 17 patients. In four patients histological abnormalities were detected by means of protocol biopsies 1-5 years before the onset of biochemical abnormalities. Two patients developed severe recurrences after 10 and 15 years, respectively, and required treatment with steroids and tacrolimus. In the other three patients histological recurrence was detected 0.6-3 years post-OLT, concomitantly with biochemical abnormalities. CONCLUSIONS: AIH recurred in 41% of patients followed for more than 10 years after OLT. As histological signs preceded biochemical abnormalities in four patients (23.5%), regular liver biopsy is warranted after OLT. Detection of isolated histological signs may call for closer follow up and/or a change in immunosuppressive therapy.