A liver secretome gene signature-based approach for determining circulating biomarkers of NAFLD severity.

Non-invasive biomarkers of non-alcoholic fatty liver disease (NAFLD) supporting diagnosis and monitoring disease progression are urgently needed. The present study aimed to establish a bioinformatics pipeline capable of defining and validating NAFLD biomarker candidates based on paired hepatic global gene expression and plasma bioanalysis from individuals representing different stages of histologically confirmed NAFLD (no/mild, moderate, more advanced NAFLD). Liver secretome gene signatures were generated in a patient cohort of 26 severely obese individuals with the majority having no or mild fibrosis. To this end, global gene expression changes were compared between individuals with no/mild NAFLD and moderate/advanced NAFLD with subsequent filtering for candidate gene products with liver-selective expression and secretion. Four candidate genes, including LPA (lipoprotein A), IGFBP-1 (insulin-like growth factor-binding protein 1), SERPINF2 (serpin family F member 2) and MAT1A (methionine adenosyltransferase 1A), were differentially expressed in moderate/advanced NAFLD, which was confirmed in three independent RNA sequencing datasets from large, publicly available NAFLD studies. The corresponding gene products were quantified in plasma samples but could not discriminate among different grades of NAFLD based on NAFLD activity score. Conclusion: We demonstrate a novel approach based on the liver transcriptome allowing for identification of secreted hepatic gene products as potential circulating diagnostic biomarkers of NAFLD. Using this approach in larger NAFLD patient cohorts may yield potential circulating biomarkers for NAFLD severity.

Laparoscopic deroofing of hepatic cysts: The most effective treatment option.

OBJECTIVES: With advances in laparoscopic surgery, laparoscopic deroofing has gained wide acceptance in the surgical community to treat symptomatic non-parasitic hepatic cysts. Published non-surgical data still favour aspiration and sclerotherapy as treatment in these cases, though morbidity is higher and recurrence rates are not acceptable. We reviewed all patients that had been treated by laparoscopic deroofing in our department over a period of 6 years in order to find out if the surgical approach should be considered the standard treatment. MATERIALS AND METHODS: Over a 6 year period, 34 laparoscopic deroofings were performed in 21 patients with symptomatic cysts. Patients underwent laparoscopy followed by radical deroofing using an Ultracision device. RESULTS: All cases were completed laparoscopically, no intraoperative adverse events were recorded. Mean operation time was 101 ± 22.7 min. The mean size of treated cysts was 9.7 ± 2.18 cm. Follow up showed only one symptomatic recurrence (3.3%) two months after surgery. CONCLUSION: Laparoscopic deroofing of hepatic cysts is a safe and effective treatment option. Recurrence rates are unprecedentedly low. Our data suggest that the risk of operation is justified and that the method is superior to sclerotherapy.

Fewer urological complications after laparoscopic inguinal hernia repair without indwelling catheter.

INTRODUCTION: The number of procedures involving transabdominal preperitoneal laparoscopic surgery for inguinal hernia (TAPP) has increased in Denmark. Optimized perioperative regimens are needed. MATERIAL AND METHODS: This retrospective, single-institution study included consecutive patients during an eight-year period from 1 January 2002 to 31 December 2007 (period I) and from 1 January 2008 to 31 December 2009 (period II). In period II, perioperative indwelling catheter (Foley catheter) was not used routinely. Furthermore, the surgical technique was adjusted, a small team of dedicated TAPP surgeons was established, and two of the surgeons attended prearranged surgical training programmes. Additionally, period II patients were enrolled into structured patient protocols. The primary endpoint was complications within the first 30 days after surgery, and we also registered the rate of reoperation due to recurrence. RESULTS: A total of 684 patients underwent TAPP surgery for 946 inguinal hernias. From period I to II, the number of TAPP surgeons was reduced to a third and two surgeons received TAPP training. During period I, minor urological complications were observed in 5% (confidence interval (CI) 3.1-6.9%) compared with 1% in period II (0.0-2.5%). The overall morbidity rate was 13%. Serious complications were observed in 3% (CI 3.1-6.9%) of the cases in period I and in 2% (0.0-2.5%) of the cases in period II. For the entire eight-year study period, the cumulative rate of re-operation due to recurrence was 2%. CONCLUSION: TAPP without routine use of an indwelling catheter may reduce the risk of urological complications.

Presumed cryptogenic liver disease in Germany: High prevalence of autoantibody-negative autoimmune hepatitis, low prevalence of NASH, no evidence for occult viral etiology.

UNLABELLED: Aim was to investigate possible underlying causes of presumed cryptogenic liver disease. METHODS: A cohort of 126 consecutive patients with presumed cryptogenic hepatitis referred to a university hospital were reanalysed with respect to their clinical, laboratory and histological data. RESULTS: In 19 patients there was evidence for an exogenous-toxic liver damage. Diagnosis of non-alcoholic steatohepatitis could be established in 22 patients. Viral origin was excluded in all patients by serological and PCR-based assays for the known hepatitis viruses and the viruses GBV-C and SENV. Furthermore, transmission studies in non-human primates using acute phase plasma of patients with severe cryptogenic hepatitis revealed no episode of transmissible hepatitis, that could give a hint to so far unknown viruses as etiological agent. In all patients negative autoantibodies were recorded. Nevertheless, in 43 patients the diagnosis of definite or probable seronegative autoimmune hepatitis (AIH) could be assumed by the application of the International Autoimmune Hepatitis (IAH)-Score. Only 42 patients still remained with cryptogenic liver disease (CLD). Compared to patients with seronegative AIH patients with CLD were significantly older, had a longer duration of their disease, lower values of transaminases, more frequently a cholestatic liver enzyme pattern, a lower grade of inflammation in the liver and no response to immunosuppressive therapy. CONCLUSION: Only one third of patients with initially presumed cryptogenic liver disease remained cryptogenic, while another third of patients could be identified as seronegative autoimmune hepatitis by the IAH-Score with obvious benefit from immunosuppressive therapy.

[Congenital absence of the portal vein (CAPV). Two cases of Abernethy malformation type 1 and review of the literature]. / Der kongenitale portosystemische Shunt. Zwei Fallvorstellungen einer Abernethy-Malformation Typ 1 und Uberblick über die Literatur.

The Abernethy malformation is a rare congenital portosystemic shunt in which the blood directly drains into the systemic vein bypassing the liver either through a complete (type 1) or a partial shunt (type 2). The diagnosis is most frequently established primarily with ultrasound. CT and MRI are used for further classification of the shunt and assessment of accompanying liver tumors and malformations. There is a wide spectrum of therapeutic options ranging from noninvasive conservative treatment to liver transplantation. The main prognostic factors are the occurrence of concomitant hepatic neoplasms and hepatic encephalopathy. We report two cases diagnosed with a type 1 shunt, hepatic encephalopathy, and associated liver tumors who underwent successful liver transplantation after having considered all therapeutic options.

[Hormone inactive parathyroid cyst: rare differential diagnosis in the evaluation of cervical cysts]. / Hormoninaktive Nebenschilddrüsenzyste: eine seltene Differenzialdiagnose bei zystischen Veränderungen im Halsbereich.

Parathyroid cysts are a very rare disease entity. Hormone activity is uncommon and they usually present without any clinical symptoms. The differential diagnosis of cystic neck masses should nevertheless include parathyroid cysts as surgical therapy can be very effective. We report the case of a 57-year-old patient presenting to our department with a hormone inactive parathyroid cyst. Final diagnosis was achieved eventually after histological examination of the resected specimen, which is the reason for evaluating the current data for preoperative management of this disease entity in this case report.

Steroid treatment for severe acute cryptogenic hepatitis.

OBJECTIVE: Acute cryptogenic hepatitis may represent both a self-limited disease as well as the onset of chronic hepatitis. The aim of this analysis was to evaluate the effect of steroid treatment in patients with acute cryptogenic hepatitis. METHODS: We retrospectively analyzed four patients with acute cryptogenic hepatitis. Histories were negative for alcohol and hepatotoxic drug intake. Markers of metabolic liver disease, liver-related autoantibodies, and viral markers were negative in all patients. Gamma globulins were in the normal range. ALT rose above 1000 U/L in all patients and bilirubin levels were elevated to more than 400 micromol/L. Histopathological assessment revealed minimal infiltration with plasma cells, eosinophils and bile duct lesions. Using the international scoring system for the diagnosis of autoimmune hepatitis, all patients were classified as 'probable disease' in the absence of specific markers. RESULTS: We started immunosuppressive treatment with prednisolone because of persisting high aminotransferases and impaired liver function. All patients responded to steroids with normalization of liver function and a rapid decrease of aminotransferases. In one patient, additional treatment with azathioprine was necessary due to rebounding aminotransferases during steroid tapering. CONCLUSION: Steroids have to be taken into account in the therapy for severe acute cryptogenic hepatitis. The response to steroid treatment could be indicative for an autoimmune genesis of the disease.

[Hepatocellular adenoma. Malignancy potential and differentiation from hepatocellular carcinoma]. / Leberzelladenom. Entartungspotenzial und Abgrenzung vom hepatozellulären Karzinom.

In contrast to hepatocellular carcinoma (HCC), very few molecular pathological studies have been carried out on hepatocellular adenoma (HCA). Particularly from the surgical point of view, based on views passed on verbally and in the literature of the 1970s and 1980s, a possible degeneration of the HCA provides grounds for operating. Published cases of transitions from HCA into HCC were evaluated on the basis of today's morphological standards. A comparison was made between the patterns of new molecular pathological studies of HCA, above all the work of our own groups, and those of HCC. The results speak against the suggestion that a typical solitary HCA in pre-menopausal women is a precursor lesion of HCC. After a critical review of the literature, only one casuistic case of a transition of HCA to HCC under a hormone therapy, which is no longer practiced today, remained. A limitation of particular HCA in genetic and metabolic diseases, children, adult males, adenomatosis, and HCA-like tumors with known risk factors of HCC would seem pragmatically meaningful. With classic HCA, however, the oncological indication for surgery does not apply. A prerequisite is a histological clarification, if necessary with the support of molecular pathological methods.

[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.

[Malignant transformation of a juvenile papilloma in a 11 year old boy]. / Maligne Entartung einer juvenilen Kehlkopfpapillomatose bei einem 11-jährigen Jungen.

BACKGROUND: The juvenile laryngeal papilloma is the most common benign neoplasm in children. Often the entity shows an elongated recurrent course of disease with an expansion into the tracheo-bronchial system. Sporadic malignant transformation in adults with a papilloma was reported after treatment with radiotherapy alone or in combination with the intake of additional toxins (e. g. nicotine). Similar reports of a malignant transformation of juvenile papillomas without additional risk factors is very rarely reported. CASE REPORT: We report about an 11 year old boy, who suffered from a juvenile laryngeal papilloma. The multiple laser surgical procedures and a therapy with interferon resulted in a short-term remissions. A tracheotomy was inevitable. Seven months after the first diagnosis of the papilloma a regional metastatic squamous cell carcinoma was found. In spite of combined radiotherapy and chemotherapy the boy died 11 months later. CONCLUSIONS: The spontaneous malignant transformation of a juvenile papilloma in a squamous cell carcinoma is extremely rare. The surgical intervention as well the radiotherapy and chemotherapy using interferon was unsuccessful due to the high grade of malignancy. In view of the very short time interval between first diagnosis of juvenile papilloma and the subsequent malignant transformation, one must consider either the potential presence of a very aggressive form of papilloma or alternative two coincident independent diseases.

Generation and analysis of genetically defined liver carcinomas derived from bipotential liver progenitors.

Hepatocellular carcinoma is a chemoresistant cancer and a leading cause of cancer mortality; however, the molecular mechanisms responsible for the aggressive nature of this disease are poorly understood. In this study, we developed a new liver cancer mouse model that is based on the ex vivo genetic manipulation of embryonic liver progenitor cells (hepatoblasts). After retroviral gene transfer of oncogenes or short hairpin RNAs targeting tumor suppressor genes, genetically altered liver progenitor cells are seeded into the liver of otherwise normal recipient mice. We show that histopathology of the engineered liver carcinomas reveals features of the human disease. Furthermore, representational oligonucleotide microarray analysis (ROMA) of murine liver tumors initiated by two defined genetic hits revealed spontaneously acquired genetic alterations that are characteristic for human hepatocellular carcinoma. This model provides a powerful platform for applications like cancer gene discovery or high-throughput preclinical drug testing.

[Prognosis of hepatocellular carcinoma according to new staging classifications]. / Prognose des hepatozellulären Karzinoms nach neuen Stadieneinteilungen.

BACKGROUND AND OBJECTIVE: We investigated prognostic factors and survival of patients with hepatocellular carcinoma (HCC) in North-Germany. Established staging systems (Child-Pugh, Okuda and UICC classification) were compared with new prognostic scores from Italy (CLIP) and Spain (BCLC). PATIENTS AND METHODS: The clinical course of 62 consecutive patients (34-82 years, 48 males, 14 females) with HCC observed in the Medical School of Hannover from October 1996 to September 1998 were retrospectively analyzed. The patients were classified according to the staging systems of Child Pugh, Okuda, UICC, CLIP and BCLC. Follow-up ended on December 31 (st) 2001. RESULTS: Overall median survival was 11,3 (1 - 59,5) months. At univariate analysis (log-rank test) Okuda, UICC, CLIP and BCLC Score were each associated with a shorter survival. In contrast Child Pugh score provided no significant prognostication. By multiple regression analysis (Cox regression analysis), only the CLIP and UICC score and chronic hepatitis B infection were shown to be independent risk factors. CONCLUSION: Our investigations indicate, that the CLIP and UICC classifications identified those patients with the best prognosis and they, as well as chronic hepatitis C, were shown to be independent risk factors.

Severe exacerbation of chronic hepatitis B after emergence of lamivudine resistance in a cirrhotic patient: immediate switch to adefovir dipivoxil appears to be indicated.

INTRODUCTION: Lamivudine is a treatment option for the therapy of chronic hepatitis B with an excellent safety profile. Unfortunately, viral resistance to lamivudine is common in the course of therapy. The lamivudine resistant mutants are usually less pathogenic than the wild type, but development of viral resistance can also lead to acute exacerbation of the underlying hepatitis. The recently FDA approved nucleoside analogue adefovir dipivoxil has potent antiviral activity against lamivudine-resistant mutants and can prevent viral replication effectively. CASE REPORT: A 31-year-old man with pre-existing compensated liver cirrhosis developed resistance to lamivudine therapy leading to subacute liver failure. After referral adefovir dipivoxil 10 mg daily was initiated within an early access protocol. Since initiating therapy with adefovir dipivoxil progression of the subacute liver failure was delayed accompanied by a rapid decrease of ALT and decline of HBV viral load. Even so, the clinical course was not reverted but showed slower deterioration. This enabled the patient to undergo living-related liver transplantation. Adefovir dipivoxil was well tolerated in the acute phase of the disease and did not cause nephrotoxicity or favour the development of hepatorenal syndrome. CONCLUSION: Adefovir dipivoxil resulted in a delay of hepatic decompensation and enabled liver transplantation as final treatment option for this patient. Earlier initiation might even have prevented the need of liver transplantation. Thus, in patients with pre-existing liver cirrhosis an early switch to adefovir dipivoxil appears indicated after emergence of lamivudine resistance.

Telomere shortening of epithelial cells characterises the adenoma-carcinoma transition of human colorectal cancer.

BACKGROUND: and aims: Chromosomal instability is one of the most consistent markers of sporadic colorectal cancer in humans. There is growing evidence that telomere shortening is one of the mechanisms leading to chromosomal instability and cancer initiation. METHODS: To test this hypothesis, the telomere length of colorectal epithelial cells and cells from connective tissue was determined at the adenoma-carcinoma transition at the cellular level by quantitative fluorescence in situ hybridisation. RESULTS: Our study showed that the telomere fluorescence intensity of epithelial cells was significantly weaker at the earliest morphologically definable stage of carcinoma-high grade dysplasia with minimal invasive growth-compared with the surrounding adenoma. In contrast, cells from connective tissue had a similar telomere signal intensity at the carcinoma stage compared with the adenoma, and in turn cells from connective tissue had overall significantly stronger telomere fluorescence signals compared with epithelial cells. CONCLUSIONS: These results demonstrate that short telomeres of epithelial cells characterise the adenoma-carcinoma transition during human colorectal carcinogenesis, suggesting that carcinomas arise from cells with critical short telomeres within the adenoma. Since the adenoma-carcinoma transition in colorectal cancer is characterised by an increase in chromosomal instability and anaphase bridges, our data support the hypothesis that short telomeres initiate colorectal cancer by induction of chromosomal instability.

[An older female patient with refractory anemia and hemochromatosis]. / Eine ältere Patientin mit refraktärer Anämie und Hämochromatose.

CASE HISTORY AND CLINICAL FINDINGS: A 69-year-old woman was admitted because of a normocytic anemia. One year before an acute B19 parvovirus infection had been diagnosed, but the anemia was attributed to intestinal bleeding caused by a dysplastic colonic polyp. However, anemia persisted despite polypectomy. There was an excessive elevation of serum ferritin. ADDITIONAL EXAMINATIONS: A bone marrow biopsy and aspirate led to the diagnosis of a myelodysplastic syndrome (pure sideroblastic anemia). Ultrasound demonstrated advanced fibrosis of the liver. Fibrosis in association with severe parenchymatous siderosis was also demonstrated by histology. Analysis of the hemochromatosis gene (B-HFE, nt 845, G/A) was negative. DIAGNOSIS, THERAPY AND CLINICAL COURSE: The patient had secondary hemochromatosis due to a myelodysplastic syndrome. An acute infection with parvovirus B19 had been noted at the time of the first admission, one year before MDS was diagnosed. At that time, hemochromatosis had already caused fibrosis of the liver. However, complete regression of organ siderosis was achieved by deferoxamine administration. The myelodysplastic syndrome itself did not show any progression even 7 years after the diagnosis was established. CONCLUSION: Our case demonstrates the uncommon association between sideroblastic anemia and secondary hemochromatosis. Acute parvovirus infection may induce severe anemia in myelodysplastic syndromes. In acute B19 parvovirus infections an underlying hematologic disease should be excluded.