Rapidly evolving liver decompensation with some remarkable features 14 years after biliopancreatic derivation: a case report and literature review.

Because of the rising incidence of obesity the use of bariatric surgery is also increasing. For the obese it is the only treatment with a proven long-term benefit on weight, comorbidities including non alcoholic steatohepatitis, and long-term mortality. There are, however, several reports on hepatic complications after bariatric surgery leading to malabsorption. The risk of liver decompensation or cirrhosis is one of the reasons jejunoileal bypass has been abandoned. Hepatic complications following Roux-en-Y gastric bypass and biliopancreatic derivation (BPD) are also reported but never beyond 2 years of follow-up. There is only one confirmed case of development of cirrhosis following BPD which presented 10 months after surgery. We present a case of a 39-year-old patient who developed rapidly evolving, and ultimately fatal, liver decompensation in previously unknown cirrhosis, 14 years after BPD. This is the first report of a severe hepatic complication such a long time after a BPD. Existing literature on hepatic complications after bariatric surgery is discussed as are 2 coincidental findings of pronounced ductular reaction on histology and autoimmune haemolytic anaemia.

Treatment of cirrhotic ascites.

Cirrhosis is the most common cause of ascites and accounts for almost 85% of all cases. It is the most common complication of cirrhosis, after development of ascites only 50% of patients will survive for 2 to 5 years. Successful treatment is dependent on accurate diagnosis of the cause of ascites. Because sodium and water retention is the basic abnormality leading to ascites formation, restriction of sodium intake and enhancing sodium excretion is the mainstay of the treatment of ascites. Patients with cirrhosis and ascites must limit sodium intake to 2 gram per day. Enhancement of sodium excretion can be accomplished by usage of oral diuretics. The recommended initial dose is spironolactone 100-200 mg/d and furosemide 20-40 mg/d. usual maximum doses are 400 mg/d of spironolactone and 160 mg/d of furosemide. The recommended weight loss in patients without peripheral edema is 300 to 500 g/d. There is no limit to the daily weight loss of patients who have edema. About 90% of patients respond well to medical therapy for ascites. Refractory ascites is defined as fluid overload that is unresponsive to sodium restricted diet and high dose diuretic treatment (diuretic resistant) or when there is an inability to reach maximal dose of diuretics because of adverse effects (diuretic-intractable). It has a poor prognosis. Treatment options for patients with refractory ascites are serial therapeutic paracentesis, transjugular intrahepatic stent-shunt (TIPS) or peritoneovenous shunt and liver transplantation. TIPS should be considered in patients who repeatedly fail large-volume paracentesis and have relatively preserved liver functions. Liver transplantation is the only modality that is associated with improved survival.

Biopsy of focal liver lesions: guidelines, comparison of techniques and cost-analysis.

When a focal liver lesion is discovered, differentiation between a benign and malignant nature and further characterization are mandatory to guide further treatment. Histology remains the golden standard. Improving imaging techniques such as contrast enhanced Doppler ultrasonography, spiral CT and new MRI procedures are promising, but not 100% accurate. When there is any doubt, biopsy should be performed. Fine Needle Aspiration Biopsy (FNAB) has a high sensitivity and specificity (90-95%) in experienced hands, but has a high insufficient sampling rate (up to 15%). In a series of 245 Fine Needle Tru-cut Biopsies (FNTCB) of focal solid liver lesions performed at our institution, sensitivity and specificity for the diagnosis of malignancy were 86% and 100% respectively, with an overall accuracy of 88%. Positive predictive value was 100%, but negative predictive value was rather low (56%). Insufficient sampling rate was low (2.5%), and a more accurate histological characterization was possible compared to FNAB. Finally, the cost-analysis of different biopsy techniques is presented for the Belgian situation according to used materials, pathology procedures and hospitalization.

Autoimmune hepatitis, autoimmune gastritis, and gastric carcinoid in a type 1 diabetic patient: a case report.

The history of a 45-year-old male type 1 diabetic patient is presented. At the age of 29 years, he was diagnosed to have an autoimmune hepatitis with incipient liver cirrhosis. Five years later, a successful liver/pancreas transplantation was performed. Eighteen months later, however, pancreatic insufficiency occurred due to thrombosis of the pancreatic graft. Besides these conditions, iron deficiency, pernicious anemia, and autoimmune gastritis were also diagnosed. Serum parietal cell antibodies (PCA) and intrinsic factor antibodies (AIF) were positive. At 45, this patient was found to have a gastric carcinoid tumor. The clinical importance of PCA is discussed with regard to chronic atrophic gastritis and pernicious anemia, which both predispose toward gastric carcinoid tumors. Autoimmune type 1 diabetic patients who have a high prevalence of PCA should be screened for gastric autoimmune manifestations and tumors, as the history of this patient illustrates.

Hepatobiliary cystadenoma with mesenchymal stroma mimicking hydatid cyst. Report of a case.

We report on a case of hepatobiliary cystadenoma with mesenchymal stroma in a 44-year-old Caucasian woman who presented with upper abdominal discomfort. Ultrasound (US) and computed tomography (CT) showed a cystic mass resembling hydatid cyst. Endoscopic retrograde cholangiography (ERC) demonstrated communication with the left hepatic duct. At surgery, a cystic mass with communication to the left hepatic duct was found and resected en bloc with a margin of normal liver tissue. Histological examination showed a hepatobiliary cystadenoma with mesenchymal stroma.

HLA association of amoxicillin-clavulanate--induced hepatitis.

BACKGROUND & AIMS: Drug-induced immunoallergic hepatitis typically affects a minority of patients exposed to a particular drug. Its rarity is believed to be due to metabolic or immunologic idiosyncrasy. The presence of an immunologic idiosyncrasy might imply an HLA association. Previous studies reporting an HLA association of drug-induced hepatitis included only small numbers of patients and used serological HLA typing. METHODS: We studied 35 patients with biopsy-documented amoxicillin-clavulanate-induced hepatitis. HLA-A and -B were typed using alloantisera and compared with those of 300 controls (volunteer bone marrow donors). HLA-DRB and -DWB were typed by polymerase chain reaction-line probe assay, with 60 volunteer bone marrow donors serving as controls. RESULTS: The study group was characterized by a higher frequency of DRB1*1501-DRB5*0101-DQB1*0602 haplotype (57.1% vs. 11.7% in controls, P < 0.000005; after correction for the large number of comparisons, P < 0.0002). Patients with DRB1*1501-DRB5*0101-DQB1*0602 haplotype were more likely than patients without it to have a cholestatic (70% vs. 60%) or mixed (30% vs. 13%) than a hepatocellular pattern of hepatitis (0% vs. 27%) (P < 0.05). CONCLUSIONS: Amoxicillin-clavulanate-induced hepatitis is associated with the DRB1*1501-DRB5*0101-DQB1*0602 haplotype. The data support the view that an immunologic idiosyncrasy, mediated through HLA class II antigens, plays a role in the pathogenesis of drug-induced immunoallergic hepatitis. HLA association has a limited impact on the expression of hepatitis.

Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP).

Interferon alfa (IFN-alpha) is the primary treatment for chronic hepatitis B. The standard duration of IFN-alpha therapy is considered 16 weeks; however, the optimal treatment length is still poorly defined. We evaluated the efficacy and acceptability of prolonged IFN-alpha treatment in patients with chronic hepatitis B. To investigate whether treatment prolongation could enhance the rate of hepatitis B e antigen (HBeAg) seroconversion, we conducted a prospective, controlled, multicenter trial in which all patients were treated with a standard regimen of 10 million units IFN-alpha 3 times per week over 16 weeks. Patients who were still HBeAg-positive after 16 weeks of therapy were randomized to prolongation of the identical regimen up to 32 weeks (prolonged therapy) or discontinuation of treatment (standard therapy). Among the 162 patients who entered the study, 27 (17%) were HBeAg-negative after the first 16 weeks of treatment, and 118 were randomized to standard or prolonged therapy. After randomization, a response (HBeAg seroconversion and sustained hepatitis B virus [HBV]-DNA negativity) was observed in 7 of the 57 (12%) patients assigned to standard therapy versus 17 of the 61 (28%) patients assigned to prolonged therapy (P =.04). A low level of viral replication after 16 weeks of treatment, as indicated by serum HBV-DNA values under 10 pg/mL, was found to be the only independent predictor of response (52% vs. 0%; P <.001) during prolonged therapy. The prolonged IFN-alpha schedule was well tolerated in the large majority of patients. In chronic hepatitis B, prolongation of IFN-alpha therapy up to 32 weeks is superior to a standard course of 16 weeks. Those patients who exhibit a low level of viral replication at the end of the standard regimen benefit most from prolonged treatment.

Interferon-ribavirin for chronic hepatitis C with and without cirrhosis: analysis of individual patient data of six controlled trials. Eurohep Study Group for Viral Hepatitis.

BACKGROUND & AIMS: The aim of this study was to compare interferon (IFN)-ribavirin combination therapy with IFN monotherapy in chronic hepatitis C with particular focus on its efficacy in cirrhosis. METHODS: A multivariate analysis of individual patient data of all randomized controlled trials using an IFN-ribavirin arm, reported between 1991 and March 1998, was performed. Centers included 1 Asian and 5 European university-based referral centers for liver disease. A total of 197 patients with chronic hepatitis C received IFN-alpha (3 MU three times weekly) and ribavirin (1-1.2 g daily) for 6 months, and 147 patients received IFN-alpha (3 MU three times weekly) for 6 months. Patients were characterized according to previous IFN therapy, presence of cirrhosis, and genotype 1. Efficacy of therapy was evaluated by assessing the sustained response rate by logistic regression analysis. RESULTS: Patients without cirrhosis treated with IFN-ribavirin had a significantly higher sustained response rate than those treated with IFN, approximately 3-fold for previously untreated patients (IFN-ribavirin: genotype 1, 33%; genotype 2/3, 65%; IFN: genotype 1, 8%; genotype 2/3, 24%). In cirrhosis, sustained response rates with IFN-ribavirin (previously untreated: genotype 1, 7%; genotype 2/3, 24%) were also significantly higher than those with IFN (previously untreated: genotype 1, 1%; genotype 2/3, 5%). Clinical relevant superiority of combination therapy over IFN monotherapy was also observed for relapse; the same trend was observed for nonresponders. Tolerance for IFN-ribavirin was similar for patients with or without cirrhosis. CONCLUSIONS: Combination with ribavirin significantly enhances the sustained response rate of IFN therapy in major patient types (cirrhosis, genotype 1) with chronic hepatitis C. Thus, IFN-ribavirin combination is likely to become the antiviral therapy of choice for cirrhosis caused by hepatitis C.

Viral hepatitis and pregnancy.

This paper reviews data on the mutual relationship between pregnancy and viral hepatitis and the mother-to-infant transmission of the virus. In the western world, hepatitis A, B or C do not seem to influence the course of pregnancy, or to be associated with foetal risks. In contrast, women who contract a hepatitis E infection in their third trimester of pregnancy have a relatively high probability to develop a fulminant hepatitis. Mother-to-infant transmission of hepatitis A seems to be very uncommon. On the contrary, HBsAg and HBeAg positive mothers have a 80-90% risk to transmit the disease to their offspring, more than 85% of these becoming chronic carriers of HBsAg. The risk depends on the level of viral replication. In HBsAg positive and HBeAg negative mothers the rate of transmission is only 2-15%, these babies rarely become carriers. A possible explanation is the transplacental passage of the HBeAg making the infant tolerant to the hepatitis B virus. As most of the infections occur during or directly after delivery, the neonates are suitable for postexposure prophylaxis. It is recommended by the Centers for Disease Control and Prevention and the American Academy of Pediatrics that newborns of HBsAg positive mothers should receive hepatitis B immunoglobulins within 12 hours after birth concurrently with the first paediatric dose of the vaccine. Vaccination should be completed at 1 and 6 months. This regimen confers a protective efficacy of > or = 90%. Vertical transmission of hepatitis C is considered to be relatively rare, around 11% when HCV-RNA is positive. The highest rates of vertical transmission of HCV are noted in women with high HCV-RNA level or concurrent HIV infection. The risk is extremely low when no HCV-RNA is detected. There is currently no treatment to prevent this vertical transmission; routine screening of all mothers is unwarranted, and pregnancies among HCV-positive mothers should not be discouraged, but their infants should be tested for anti-HCV at 1 year and followed for the development of hepatitis. Breast feeding does not seem to play an important role in the transmission of hepatitis B and C.

Tolerance and antiviral effects of high-dose interferon-alpha B/D in patients with chronic hepatitis B.

A novel recombinant interferon-alpha B/D hybrid was applied to assess tolerability, antiviral effect, and biological activity in chronic hepatitis B. The study was designed as an open nonrandomized trial. Treatment comprised a two-week run-in phase with 16 MU three times a week followed by 14 weeks with 64 MU three times a week (or 48 MU if toxicity occurred with 64 MU). Total follow-up was 36 weeks. Nineteen patients were included; three discontinued treatment during the run-in with 16 MU. Fourteen of 16 patients had 14 weeks of treatment with > or = 32 MU three times a week. Fourteen dose reductions were necessary in nine patients. The adverse experience profile was similar to other interferon-alphas. HBV-DNA decreased using all doses studied. HBV-DNA became undetectable in five patients, two of whom had HBeAg seroconversion. No HBsAg seroconversion was observed. It is concluded that interferon-alpha B/D is well tolerated in high doses. The anti-viral effect starts at at least 16 MU three times a week.

Ultrasonically guided fine needle puncture of focal liver lesions. Review and personal experience.

Despite recent advances in diagnostic imaging of the liver, the management of a patient with focal liver lesions often depends on obtaining tissue for histological diagnosis. Ultrasound guided fine needle biopsy is recommended as a safe and reliable method for cyto-histological confirmation of suspected hepatic malignancy. A fine needle is conventionally defined as having an outer diameter < or = 0.9 mm or > or = 19 G. Ultrasound guided fine needle aspiration cytology is found reliable for diagnosing malignancy. Limitations of this method are inadequate sampling and limited value in diagnosis of well-differentiated malignant tumours and benign tumours. Ultrasound guided fine needle cutting biopsy allows to obtain tissue for histological examination according to the Menghini technique. Both methods have high sensitivity, specificity and accuracy in detecting malignancy. In a personal series of 50 fine needle aspiration cytologies, a sensitivity for malignancy of 87% was obtained, with a specificity of 100%. The insufficient sampling rate, however, was 10%. Ultrasound guided fine needle trucut biopsy combines the advantages of a fine needle and a better sampling quality; a lower insufficient sampling rate can be expected without increase in complication rate. Despite the availability of numerous manually operated or (semi-) automated devices, little data have been published up to now on liver lesions. In our hands, it has proven to be a safe and reliable method, with low insufficient sampling rate, allowing correct identification of primary liver malignancies, correct suggestion of the primary source of the majority of metastases and correct identification of most benign liver lesions. Therefore it is considered as the method of choice when focal noncystic liver lesions are to be biopsied.

Efficacy of interferon dose and prediction of response in chronic hepatitis C: Benelux study in 336 patients.

BACKGROUND/AIMS: In an attempt to improve the limited efficacy of treatment of chronic hepatitis C with interferon-alpha 3 MU tiw, we studied the effects of double-dose therapy followed by downward titration, and analyzed the pre- and pertreatment factors associated with response or non-response. METHODS: Three hundred and fifty-four consecutive patients in 19 centers were randomized to interferon-alpha 3 MU tiw for 6 months or 6 MU tiw for 8 weeks followed by down-titration (3,1 MU tiw) till alanine aminotransferase remained normal and plasma HCV RNA was repeatedly undetectable. The primary outcome measure was sustained alanine aminotransferase and HCV RNA response 6 months after treatment. RESULTS: Three hundred and thirty-six patients received treatment. The sustained response rate for patients receiving 3 MU tiw for 6 months was 14% (9-21%,) and for patients receiving double dose tiw for 8 weeks and thereafter titrated therapy 15% (10-21%) (p=0.8). Pretreatment factors associated with a sustained alanine aminotransferase plus HCV RNA response were the absence of cirrhosis, presence of genotype 2 or 3, a low viral load and, in addition, a low alanine aminotransferase/aspartate aminotransferase ratio; a model was developed to allow estimation of the chance of response for the individual patient. The most powerful predictor of sustained response, however, was plasma HCV RNA at week 4; a positive test virtually precluded a sustained response (1.7%, 0.4-5.0%). If week 4 HCV RNA was not detectable, the chance of a sustained response was 21% (12-34%) for genotype 1 versus 40% (28-54%) for the others (p=0.02). Six MU tiw led to a significantly higher week 4 HCV RNA response (47% not detectable) than 3 MU (37%) (p=0.02). During down-titration this difference in viral on-treatment response was lost. CONCLUSIONS: In the treatment of hepatitis C, an early HCV RNA response is a prerequisite for long-term efficacy. Doubling the initial interferon dose increases this early response, but subsequent downward titration negates this effect, especially in genotype 1.

Hepatitis C virus genotypes: epidemiological and clinical associations. Benelux Study Group on Treatment of Chronic Hepatitis C.

In a cohort of 292 chronic hepatitis C patients living in the Benelux countries the relationship between viral genotype and geographical origin, route of transmission, clinical characteristics and severity of liver disease was analyzed. HCV-RNA isolates could be classified by the Line Probe Assay (LiPA) as 1a, 1b, 2, 3, 4 or 5 in 286 (98%) cases. Patients of European origin were predominantly infected with HCV subtype 1b (164/254, 65%, CI 58-70%), as were patients of Asian origin (7/13, 54%). Patients originating from Surinam (South America) had predominantly type 2 (9/10, 90%), whereas Africans were mainly infected with type 4 (7/9, 77%). Blood transfusion was the mode of transmission in 142 (50%) patients, intravenous drug abuse (IVDA) in 40 (14%), occupational needle accident or tattoo in 11 (4%); no obvious source of infection was found in 93 (33%). In patients infected by blood transfusion, subtype 1b was predominant (70%, CI 61-77%), whereas subtypes la and 3 were predominant in those infected by IVDA (25% and 45%, respectively, p<0.001). Cirrhosis was observed in 68 (24%) patients; in multivariate analysis, factors independently related to cirrhosis were: the duration of infection, age and prior hepatitis B. No significant relationship was found between the severity of fibrosis or liver inflammation and the HCV (sub)types. In summary, in this large cohort of patients in the Benelux countries the hepatitis C virus (sub)type present was clearly related to the country of origin and the route of transmission, but not to the severity of liver disease.

The role of nitric oxide in portal hypertensive systemic and portal vascular pathology.

Hypotension, low systemic vascular resistance and reduced sensitivity to vasoconstrictor are features of hyperdynamic syndrome in portal hypertension (PH) and are pathogenetic factors triggering most serious clinical complications of liver cirrhosis. Nitric oxide (NO) is a powerful vasodilating agent, released from vascular endothelium cell and effecting relaxation of vascular smooth muscle. An increased release of NO has been proposed to play a role in the pathogenesis of vasodilation and vascular hypocontractility associated with PH. In agreement with this hypothesis, the whole-body production of NO has been found to be increased in PH, and the measurement of NOS mRNA expression in different organs suggest that the splanchnic vascular system is a major source of NO release. Consequently, NO could play a role in the development of the splanchnic hyperaemia, collateral circulation and portal hypertensive gastropathy. Furthermore, increased generation of NO in central circulation likely accounts for pulmonary vasorelaxation and cardiac dysfunction found in cirrhosis. By contrast, PH-associated endothelial dysfunction seems to invalidate the capability of intrahepatic and intrarenal vasculature to produce NO. A deficient NO release in these vascular territories might contribute to enhancement of PH and development of the hepatorenal syndrome. Overall NO hyperproduction is either the cause (induction of iNOS) or the consequence (stimulation of ecNOS) of the hyperdynamic syndrome. This incertitude results from the yet undefined significance of mild and transitory activation of the endotoxin-cytokines axis for iNOS induction and contradictory data on specific iNOS and ecNOS activities. A contribution of each isoform of NOS to pathogenesis of the hyperdynamic syndrome probably depends on the model of PH in animal studies and the aetiology or severity of cirrhosis in human studies.

Aminoguanidine reverses aortic hyporeactivity to noradrenaline in portal vein-ligated rats.

To evaluate the role of the inducible and endothelial constitutive nitric oxide synthase in vascular hyporeactivity to vasopressors in portal hypertension, in vitro experiments were performed on intact and endothelium-denuded isolated thoracic aortic rings from portal vein-ligated and sham-operated rats in control conditions, in the presence of aminoguanidine alone, considered to be a selective inhibitor of the inducible nitric oxide synthase, and of aminoguanidine and the nonselective nitric oxide synthase inhibitor N(G)-nitro-L-arginine. In control conditions, hyporeactivity to noradrenaline was observed in both rings with and without endothelium from portal hypertensive versus sham-operated rats. In the rings with endothelium, aminoguanidine reverted this hyporeactivity in portal hypertensive rats. N(G)-Nitro-L-arginine caused an additional shift to the left of the concentration-response curves to noradrenaline in portal hypertensive and a similar shift in sham-operated rats. In the endothelium-denuded rings, aminoguanidine caused no significant changes in portal hypertensive rats, whereas a significant shift to the right in the sham-operated rats was noted, however similar as the shift in the time controls not preincubated with aminoguanidine. No significant further changes were observed after preincubation with the two inhibitors. The endothelium-dependent relaxations to acetylcholine were attenuated in portal hypertensive versus sham-operated rats; addition of aminoguanidine shifted the relaxation curves to the left in portal hypertensive but not in sham-operated rats. These results provide indirect evidence for an increased activity of the inducible nitric oxide synthase in the intact aortic rings but not in the endothelium-denuded rings from portal vein-ligated rats, where other factors seem to be responsible for the observed hyporeactivity to noradrenaline. The endothelial constitutive nitric oxide synthase in rings from portal vein-ligated rats shows a reduced activity which is alleviated after inhibition of the inducible enzyme by aminoguanidine.

Serum aminotransferase levels and histological disease in chronic hepatitis C.

The reliability of serum aminotransferase (ASAT and ALAT) levels, currently used in deciding on performing liver biopsy and to assess interferon therapy in chronic hepatitis C has been questioned. In Belgium, interferon therapy is actually only reimbursed for treatment of chronic hepatitis C when serum aminotransferase levels are more than twice the upper limit of normal. The aim of the present study was to assess the relationship between serum aminotransferase levels and histological severity of chronic hepatitis C. Sixty-seven liver biopsies from 51 different patients with chronic hepatitis C and presenting with elevated ASAT and/or ALAT levels, were retrospectively evaluated using the original terminology (minimal hepatitis, chronic persistent hepatitis, chronic active hepatitis, cirrhosis), the Knodell score and the components of the Bianchi-Gudat score, where grading (portal inflammation, piecemeal necrosis, intra-acinar necrosis and inflammation) and staging components (fibrosis/ cirrhosis) are quantitated separately. The correlation between amino-transferase levels measured at or near to the biopsy date and histological criteria were evaluated using Spearman's rank correlation. About one third of the patients, including patients with chronic active hepatitis and cirrhosis, presented with ASAT and ALAT levels less than twice the upper limit of normal. ASAT levels correlated with originally determined histological severity, the numerical Knodell score and the numerical scores for piecemeal necrosis, for intra-acinar necrosis and inflammation and for fibrosis in the Bianchi-Gudat score. ALAT levels correlated only with intra-acinar necrosis and inflammation. It is concluded that limiting interferon therapy to patients with aminotransferase levels over twice the upper limit of normal excludes a large proportion of patients from potentially curative treatment. ASAT levels are more useful than ALAT to assess the histological severity of the disease, probably because this mitochondrial enzyme is present in higher quantities in the liver as compared to the cytosolic ALAT, and is more released when tissue damage is more severe.

Hepatotoxicity after a short course of low-dose pyrazinamide.

We report on a patient who developed extensive centrolobular liver necrosis after a treatment with low-dose (25 mg/kg/d) pyrazinamide for only 4 weeks, combined with rifampicin, 600 mg/d). In the past, the patient already developed severe aminotransferase elevations under isoniazid treatment. After prompt withdrawal of the drugs, a gradual decline of the aminotransferases was observed. No signs of hepatic failure developed. Pyrazinamide has to be used with caution, even in low-dose, especially when combined with rifampicin.