Guntram Lock

A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease.

BACKGROUND AND AIMS Factors influencing the progression of chronic hepatitis C virus (HCV) infection are poorly understood. Monocyte chemotactic protein-1 (MCP-1) is a potent chemokine, and its hepatic expression is up-regulated during chronic HCV infection mainly in activated hepatic stellate cells (HSC). In this study, we investigated the correlation of the functional -2518 MCP-1 promoter polymorphism with hepatic MCP-1 expression and the disease outcome in patients with HCV. METHODS MCP-1 genotyping was performed in 206 patients and 139 healthy controls. Hepatic MCP-1 messenger RNA (mRNA) expression was quantified by real-time PCR in 58 HCV patients. Cytokine-induced MCP-1 secretion of activated human HSC (n = 13) was determined by enzyme-linked immunosorbent assay (ELISA). Mobility-shift assays were performed using probes corresponding to the MCP-1 promoter sequence (-2511 to -2528) with or without the A to G mutation at -2518. RESULTS Frequency of MCP-1 genotypes did not differ between HCV patients and controls. However, carriers of the G allele were significantly more frequent in HCV patients with more advanced fibrosis and severe inflammation. In accordance, hepatic MCP-1 mRNA levels were significantly higher in patients with more advanced fibrosis and in patients carrying the G allele. Furthermore, cytokine-induced MCP-1 secretion of HSC isolated from carriers of the G allele was significantly higher, and there was binding activity in nuclear extracts from activated HSC specifically to the G allele, providing a potential mechanism for the differences seen. CONCLUSIONS Inheritance of the -2518 MCP-1 G allele, which appears to affect hepatic MCP-1 expression, may predispose HCV patients to more severe hepatic inflammation and fibrosis.

Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis

Objective To investigate anterior pituitary function (adrenal, somatotropic, thyroid and gonadal axes, and prolactin) in relation to the Child‐Pugh score in male patients with alcoholic and virus‐related liver cirrhosis. Method Anterior pituitary function was evaluated in 52 male cirrhotics (26 Child‐Pugh class A (CPA), 16 Child‐Pugh class B (CPB) and 10 Child‐Pugh class C (CPC)) by a combined pituitary stimulation test, and was compared with 50 age‐matched controls. Results A normal cortisol response to corticotropinreleasing hormone (CRH) stimulation was demonstrated in 57.6% of CPA patients, 31.1% of CPB patients and 20% of CPC patients, while basal levels of adrenocorticotropic hormone (ACTH) and cortisol in cirrhotics were comparable to those in controls. Levels of basal growth hormone (P < 0.001) and stimulated growth hormone (P < 0.01) were significantly higher in cirrhotics compared with controls, while levels of insulin‐like growth factor 1 (IGF‐1) were significantly lower (P < 0.001). Basal prolactin levels were elevated significantly in CPC patients (P < 0.01), while stimulated prolactin as well as basal and stimulated thyroid‐stimulating hormone (TSH) levels were comparable. Basal luteinizing hormone levels were significantly higher in CPA (P < 0.001) and CPB (P < 0.001) patients, and stimulated luteinizing hormone levels were significantly lower in CPC patients than in controls (P < 0.005). Basal and stimulated follicle‐stimulating hormone (FSH) levels were comparable in all groups. Child‐Pugh score was correlated positively to prolactin and was correlated negatively to IGF‐1, stimulated luteinizing hormone and free testosterone. Conclusions In cirrhotics, the hypothalamic‐pituitaryadrenal and ‐gonadal axes and prolactin secretion are impaired. Growth hormone response to growth hormonereleasing hormone (GHRH) is accelerated in cirrhotics. Thus, elevated basal and stimulated levels of growth hormone probably reflect compensation for low levels of IGF‐1, which are associated with deteriorating liver function. The aetiology of cirrhosis was found to have no influence on the degree of alteration of the hypothalamicpituitary‐glandular axes.

HFE C282Y heterozygosity in hepatocellular carcinoma: evidence for an increased prevalence

BACKGROUND & AIMS Iron overload is observed frequently in chronic liver disease, and some studies have suggested that chronic iron overload may contribute to the pathogenesis of hepatocellular carcinoma (HCC). Heterozygosity for hereditary hemochromatosis (HH) is associated with increased body iron stores. The discovery of the HH gene HFE has enabled identification of the heterozygote status. The aim of this study was to evaluate if heterozygosity for HH is a risk factor for HCC. METHODS The C282Y and the H63D mutation of the HFE gene were analyzed in 137 patients with HCC and no history of HH, 107 patients with cirrhosis without HCC and 126 healthy controls. Hepatic iron content was measured by using a semiquantitative histologic score. RESULTS Seventeen of 137 HCC patients (12.4%) were C282Y heterozygote, compared with only 4 of 107 (3.7%) cirrhotic patients without HCC and 6 of 126 (4.8%) healthy controls (P < 0.05). The frequency of the H63D mutation showed no significant differences. C282Y heterozygote HCC patients had significantly higher levels of serum ferritin and transferrin saturation than C282Y wild-type patients (793 +/- 122 vs. 355 +/- 23 ng/mL, and 42.3% +/- 7.3% vs. 29.2% +/- 1.7%, respectively), and significantly higher iron deposition in HCC as well as in nontumorous liver tissue. CONCLUSIONS The C282Y heterozygous genotype is significantly more common in HCC patients and is associated with significantly increased intrahepatic iron deposition and systemic iron stores. These results suggest that C282Y heterozygosity plays a role in liver iron deposition and could contribute to hepatocarcinogenesis via the accumulation of potentially carcinogenic iron. These findings may have implications for HCC screening and prevention strategies.

Hepatitis C - contamination of toothbrushes: myth or reality?

Summary.  Chronic hepatitis C patients are advised not to share toothbrushes, razors, nail‐scissors or other personal articles that potentially may have been in contact with blood, with others. This study examines the contamination of toothbrushes in patients with chronic hepatitis C as a model for a possible unconventional way of transmission. In 30 patients with chronic hepatitis C, 2 mL of saliva (before and after toothbrushing) and the toothbrush rinsing water after toothbrushing were tested for HCV‐RNA. Saliva before and after toothbrushing was positive for HCV‐RNA in nine (30%) and 11 patients (36.7%), respectively. Twelve of the toothbrush rinsing water specimens (40%) tested HCV‐RNA‐positive. In six of these 12 patients, the ‘native’ saliva had been negative for HCV‐RNA. Patients with HCV‐RNA‐positive toothbrush rinsing water showed no significant differences from those with negative rinsing water with respect to certain clinical, biochemical and virological parameters. In conclusion, our study demonstrates a contamination with HCV‐RNA of a considerable portion of toothbrushes used by hepatitis C patients, suggesting at least a theoretical risk of infection by sharing these objects and strengthening the recommendations to take care of a clear separation of these personal care objects between patients and their household members.

Comparison of interobserver agreement for different scoring systems for reflux esophagitis: Impact of level of experience.

BACKGROUND The Savary-Miller, the Los Angeles, and the MUSE (metaplasia, ulcer, stricture, erosion) scoring systems have been developed to assess esophageal lesions related to GERD. Interobserver agreement for these systems was compared, with particular reference to the experience of the endoscopist. METHODS By using videoendoscopes, videotapes were made of the gastroesophageal junction of 60 patients who presented with symptoms suggestive of GERD. The Savary-Miller, the Los Angeles, and the MUSE systems were used to score all video clips by 9 endoscopists who were subgrouped by level of experience (3 levels, 3 endoscopists per level). Agreement was assessed by using weighted kappa statistics (kappa). RESULTS The Savary-Miller scoring system revealed moderate agreement for the experienced group (kappa=0.41) but performed poorly when applied by inexperienced raters (kappa=0.16). The Los Angeles system was most reproducible in all subgroups, irrespective of the level of experience (kappa=0.49 to 0.65). The MUSE scoring system was highly similar to the Los Angeles scoring system with respect to erosions and, in addition, allowed assessment of complications of GERD. CONCLUSIONS The Los Angeles and the MUSE scoring systems are most reliable for the assessment of erosions caused by GERD. Because of low reliability, use of the Savary-Miller scoring system is not recommended. For all scoring systems, interobserver agreement varies with the level of experience in the performance of upper endoscopy.

Brain electrical activity mapping of EEG for the diagnosis of (sub)clinical hepatic encephalopathy in chronic liver disease.

We studied the role of brain electrical activity mapping (BEAM) in the assessment of neuropsychiatric disturbances in 48 cirrhotic patients without clinical evidence of hepatic encephalopathy (no HE, n = 19), with subclinical HE (grade 0, denoting pathological psychometric tests, n = 13) and mild-to-moderate HE (grade I, n = 6; grade II, n = 10). Results were compared with 23 healthy controls. BEAM variables quantified were: (i) the peak frequency (PF); (ii) the amplitude of PF; and (iii) the topographic localization of the maximum peak amplitude digitized for quantification by using a co-ordinate system. Mean amplitudes and their topographic localization in the following frequency-bands were analysed: delta (1.0–3.5 Hz), theta (4.0–7.5 Hz), alpha 1 (8.0–9.5 Hz), alpha 2 (10.0–11.5 Hz), beta 1 (12.0–15.5 Hz), beta 2 (16.0–19.5 Hz), and beta 3 (20.0–23.5 Hz). The PF was significantly slower in all HE patients than in healthy controls (8.5 ± 2.0 Hz v. 10.1 ± 1.0 Hz, P < 0.001). Even in no HE, the PF was significantly slower than in controls (8.6 ± 1.5 Hz v. 10.1 ± 1.0 Hz, P < 0.01). No relevant topographic differences of PF were observed. The mean amplitudes of the following bands differed significantly between controls and patients: theta (increased in HE, P < 0.05), alpha 2 (decreased in HE, P < 0.05), and beta 2 and beta 3 (increased in HE, P < 0.05). In HE patients, the topographic localization of all beta bands showed a significant shift from parieto-occipital areas to central areas of the cortex. We conclude that BEAM is a sensitive tool for detecting neuropsychiatric disturbances in cirrhotics with no HE and with subclinical HE. The combination of PF in the theta band, increased mean amplitude in the beta 2 band, and the localization of the latter band in the frontocentral area of the cortex is an objective and sensitive tool for identifying neuropsychiatric disturbances in 85% of cirrhotic patients with no HE. Further studies are required to determine the clinical implications of these abnormal findings in the absence of overt clinical symptoms.

Orofacial granulomatosis as initial manifestation of Crohn's disease: a report of two cases.

Patients with Crohns disease generally present with chronic diarrhoea and/or abdominal pain. However, it may be the extraintestinal manifestations as orofacial granulomatosis (OFG)--a rare syndrome with chronic swelling of the lips and the lower half of the face combined with oral ulcerations and hyperplastic gingivitis--that urge patients to seek medical advice. We report two rare cases in which swelling of the lips and cheeks were the initial symptoms that finally led to the diagnosis of Crohns disease.

Hepatocellular Carcinoma in Southern Germany: Epidemiological and Clinicopathological Characteristics and Risk Factors

The aetiology of chronic liver disease leading to hepatocellular carcinoma (HCC) and the clinical characteristics of patients with HCC vary considerably internationally and intranationally. This study analyses the characteristics of HCC patients in southern Germany, a low endemic area of HCC. Methods: The files of 118 consecutive patients with HCC observed in a single tertiary care hospital between 1994 and 2000 have been reviewed. Epidemiological and clinicopathological characteristics such as age at presentation, ethanol consumption, serological hepatitis virus markers, and fibrosis were studied. Additionally, serum levels of α-fetoprotein (AFP) were analysed at the time of diagnosis in 77 patients. Results: The male:female ratio was 4:1 and the mean age at presentation was 61.8 years. Alcohol abuse (49.2%) and chronic hepatitis C infection (17.8%) were the most frequent risk factors. Histologically proven liver cirrhosis in the surrounding non-tumorous tissue was present in only 59.0% of cases. AFP levels were elevated in 78% of cases, but only 34% reached >500 ng/ml, a value considered to be significant for the diagnosis of HCC. AFP levels correlated with the stage of fibrosis. Summary and Conclusions: The sensitivity of AFP serum levels as a tumour marker is poor but might help to detect at least a minority of cases. As in other populations within Europe, chronic alcohol abuse is frequently associated with HCC in southern Germany, confirming that alcohol is still the most important risk factor for hepatocarcinogenesis in areas with low hepatitis virus prevalence. Considering the poor prognosis of HCC, prevention is of pivotal importance, particularly for patients with chronic liver disease and other risk factors for the development of HCC.

Post-traumatic pseudocyst of the spleen: Sclerotherapy with ethanol

We report a case of successful percutaneous treatment of a chronic post-traumatic splenic pseudocyst using alcohol as the sclerosing agent. A 26-year-old man presented with a symptomatic cystic mass located in the spleen. Aspiration of 300 ml of fluid was only temporarily effective, and therefore a drainage catheter was placed 3 days later. After histopathologic and microbiologic exclusion of a malignant or infectious origin, local sclerotherapy with alcohol was performed because of recurrence after percutaneous drainage. This therapy was repeated six times within 2 weeks. Two weeks later, the remaining volume was determined to be 16 ml. Six months after treatment the cyst was no longer visible. To our knowledge this is the first case of a chronic post-traumatic splenic cyst treated with alcohol. Percutaneous sclerotherapy of a symptomatic post-traumatic splenic pseudocyst may be an alternative to surgical treatment.

Anorectal function in systemic sclerosis: Correlation with esophageal dysfunction?

PURPOSE: This study was designed to compare esophageal and anorectal function parameters in patients with systemic sclerosis and to define the role of anorectal manometry in the diagnosis of gastrointestinal involvement of systemic sclerosis. PATIENTS AND METHODS: Twenty-six consecutive patients (22 females) with systemic sclerosis originally referred for assessment of esophageal function were evaluated by esophageal and anorectal manometry. Anorectal function parameters were compared between patients with normal and those with disturbed esophageal function. RESULTS: A total of 17 of 26 patients (65 percent) had severe esophageal dysfunction with aperistalsis of the lower two-thirds of the esophagus, whereas 9 patients (35 percent) had normal esophageal manometry. Only three patients (11.5 percent) suffered from occasional fecal incontinence. Anorectal function parameters (resting pressure, maximum squeeze pressure, perception threshold) were not significantly different between patients with normal and those with disturbed esophageal motility. Rectoanal inhibitory reflex was excitable in nearly 90 percent of patients. CONCLUSION: In an unselected group of patients with systemic sclerosis, fecal incontinence and abnormal anorectal function are rather rare findings. Anorectal manometry cannot differentiate between patients with and without gastrointestinal involvement of systemic sclerosis.