Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry.

OBJECTIVES: The hepatotoxic potential of statins is controversial. The objectives of this study were to describe the relative frequency of hepatotoxicity caused by statins and the phenotypes found in Spain. PATIENTS AND METHODS: The incidence of hepatotoxicity attributed to statins in the Spanish Hepatotoxicity Registry (REH) were studied and compared with those attributed to other drugs. RESULTS: Between April 1994 and August 2012, the REH included a total of 858 cases of which 47 (5.5 %) were attributed to statins. Of these, 16 were due to atorvastatin (34 %); 13 to simvastatin (27.7 %); 12 to fluvastatin (25.5 %); 4 to lovastatin (8.5 %) and 2 to pravastatin (4.3 %). Statins represented approximately half of the cardiovascular group which occupied 3rd place (10 %), after anti-infectious agents (37 %) and central nervous system drugs (14 %). The hepatocellular pattern was predominant, especially in the simvastatin group (85%), the cholestatic/mixed pattern was more frequent with fluvastatin (66 %) and had a similar distribution to atorvastatin. Patients with statin-induced toxicity were older (62 years versus 53 years, p < 0.001) and more often demonstrated anautoimmune hepatitis phenotype (8.5 % versus 1.4 %, p < 0.003). CONCLUSIONS: Statins are not a common cause of hepatotoxicity in Spain. Atorvastatin is the statin involved in the greatest number of incidents. The liver injury pattern varies among the different statins. The hepatitis phenotype with autoimmune features appears to be a characteristic signature of statin-induced hepatotoxicity.

Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis.

BACKGROUND & AIMS: Multiple instances of DILI in the same patient with drugs of similar structure or function as well as completely unrelated drugs are not well understood and poorly documented. We have sought evidence of the frequency and characteristics of patients who have experienced two DILI episodes due to different drugs. METHODS: All cases of DILI systematically collected in the Spanish DILI Registry between 1994 and 2009 were retrieved. Data on demographics, clinical, laboratory and pathological findings, and outcome were analyzed. RESULTS: Nine patients (mean age 67 years, four women) out of 742, 1.21%, had evidence of two DILI episodes caused by different drugs. In four cases DILI was associated with structurally related drugs and in an additional two cases the drugs had a common target. In another case, unrelated antibiotics were implicated. In only two cases, the two drugs/herbals were not related in structure or function. All but one patient exhibited hepatocellular damage. The type of damage was consistent in both DILI episodes. Four cases presented as autoimmune hepatitis (AIH) in the second episode. CONCLUSIONS: Multiple episodes of DILI in association with different drugs occur infrequently. In each individual, the type of injury was similar during the two DILI episodes, regardless of the causative drug. Second episodes of DILI are more likely to be associated with features of AIH. It remains uncertain if this is drug-induced unmasking of true AIH or DILI with autoimmune features. These cases illustrate the dilemma faced by clinicians in distinguishing these possibilities.

Are hepatocellular carcinoma surveillance programs effective at improving the therapeutic options.

AIM: to evaluate whether the current surveillance programs (ultrasonography and alpha-fetoprotein testing every six months) are successful in detecting patients in the early stages. MATERIAL AND METHODS: the health records of all patients diagnosed with hepatocellular carcinoma in Donostia Hospital between 2003 and 2005 were reviewed retrospectively. Eighty-five patients (11 women and 74 men) were included in the study and demographic data, risk factors and clinical data were obtained. Patients were split into two groups according to whether or not they had been included in a surveillance program. RESULTS: seventy per cent of patients of the surveillance group is diagnosed in early stage opposite to 26.7% of patients in no surveillance group (p < 0.05). Thirteen patients cannot receive curative treatment in spite of the diagnosis in early stage (9 in the surveillance group and 4 in the no surveillance group. The global sensibility of the surveillance program in our series is 95%. CONCLUSIONS: current hepatocellular carcinoma surveillance programs, which comprise six-monthly ultrasonography and alpha-fetoprotein tests, are highly sensitive and effective. These programs result in the detection of hepatocellular carcinoma in its early-stages, when potentially curative treatment may be offered.

[Porphyria cutanea tarda. An analysis of HFE gene mutations, hepatitis viruses, alcohol intake, and other risk factors in 54 patients from Guipúzcoa, Basque Country, Spain]. / Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco.

AIM: To study the frequency of HFE gene mutations (C282Y, H63D, S65C) in a group of 54 sporadic PCT patients and in a group of healthy controls (blood donors) from Guipúzcoa, Spain. We studied the association of PCT with HCV, HBV, alcohol abuse, and other established risk factors. METHODS: The analysis of mutations was made by PCR. Allelic and genotypic frequencies were compared. Probability was determined and a Chi-squared test was performed. RESULTS: No association was observed between C282Y mutation and PCT (5.76 vs. 5% in controls). A high H63D mutation frequency was observed in PCT (34.25%) but was not statistically significant (controls 29.31%) because of the high prevalence of this mutation in the Basque general population. The S65C mutation was lower in PCT than in controls. There is a similar presence for H63D heterozygosis in PCT (38.8 vs. 38.8%). HCV association was observed in 35.18% of patients with PCT. HBV infected 7.4% of patients. Heavy alcohol intake (> 60 g/day) was present in 55.55% of patients. No HIV-infected patients were detected. The study of other risk factors revealed only one of the five women with PCT taking estrogens. CONCLUSION: Our results found no relevant role for C282Y and H63D mutations. External factors such as HCV and alcohol could be determinant in the development of PCT in the Basque population.

[Utility of various non-invasive methods for fibrosis prediction among Basque Country patients with phenotypic hemochromatosis]. / Utilidad de los diferentes métodos no invasivos de predicción de fibrosis hepática en pacientes del País Vasco con hemocromatosis fenotípica.

OBJECTIVE: To determine whether the product of multiplying age by liver iron concentration (LIC) (fibrosis index; cut-off, 480,000), platelets, transaminases, and ferritin values are related to the risk of high grade fibrosis. METHODS: A retrospective study of 32 patients with hereditary hemochromatosis (HH) with phenotypic expression. All patients had a liver biopsy with LIC. RESULTS: In 7 patients a magnetic resonance imaging (MRI) scan (1.5 T) was obtained with LIC following Alustiza's protocol. Liver biopsy: fibrosis grade (F) 0-2 in 23 patients; F 3-4 in 9. Fibrosis index (FI) showed a specificity of 68%, sensitivity of 85.7%, positive predictive value (PPV) of 42.8%, and negative predictive value (NPV) of 94.4% for high-grade fibrosis. Platelet count ( < 200,000) revealed a NPV of 94.7% for F3-4. Aspartate transaminase (AST) levels above the upper limit of normal showed a NPV of 94.4%; ferritin levels (> 1,000) a NPV of 75%, and MRI-derived LIC x age (> 480,000) a NPV of 80%. The combination of FI (either by biopsy or MRI) with transaminases, and of platelets with transaminases revealed a NPV of 100%. CONCLUSIONS: FI > 480,000 and platelets < 200,000 have the highest sensitivity for high-degree fibrosis prediction. A negative result allows to discard significant fibrosis in 94% of cases. MRI allows a good fibrosis prediction.

Selective sphincteroplasty of the papilla in cases at risk due to atypical anatomy.

AIM: To analyze the indications, efficacy and safety of sphincteroplasty in our centre. METHODS: A retrospective study of sphincteroplasty in 53 cases of papilla at high risk was performed in 2004-2006. The procedure consisted of duodenoscopy with Olympus TJF 145 Videoduodenoscope, approach to the biliary tract using a catheter with a guidewire, and dilatation of the papilla with a dilatation balloon catheter using a syringe with a manometer for control of the filling pressure. RESULTS: The indications included intradiverticular papilla in 26 patients (49%), stenosis of a previous sphincterotomy in 19 patients (35.8%), small size of the papilla in 4 patients (7.5%), Billroth II gastrectomy in 3 patients (5.6%), and coagulopathy in one patient (1.9%). The efficacy was 97.8%, with all the calculi extracted from the common bile duct in 84.4% of the patients, even though 21 of the patients (39.6%) had calculi with a diameter equal to or greater than 10 mm. Seven patients (13.2%) presented complications: haemorrhage in 1 patient (1.9%) and mild pancreatitis in 6 patients (11.3%). The mean hospital stay in case of complications was of 3 +/- 0.63 d. CONCLUSION: Sphincteroplasty is highly effective, with a complication rate similar to that of sphincterotomy, furthermore, the complications are of low clinical importance. The use of the 10 mm balloon makes it possible to extract calculi with a diameter of over 15 mm and to extract more than 3 calculi without increasing the rate of complications and reduces the need to resort to lithotripsy or rescue sphincterotomy.

HFE gene mutations analysis in Basque hereditary haemochromatosis patients and controls.

C282Y/C282Y genotype is the prevalent genotype in Hereditary Haemochromatosis (HH), however, other genotypes have been associated with the disease. The objective of our study was to analyse the frequency of the three main mutations of HFE gene in HH patients and controls from the Basque population with differential genetic characteristics. Thirty five HH patients and 116 controls were screened for C282Y, H63D and S65C mutations using a PCR-RFLP technique. The association of HLA-A and-B alleles and HFE mutations was also studied in Basque controls. The frequency of C282Y homozygotes in the group of patients was only 57%. The rest of the patients presented heterogeneous genotypes, including compound heterozygotes: 11% of them were C282Y/H63D; and 2.85% were H63D/S65C. H63D or S65C heterozygotes had a frequency of 11% and 2.85 respectively and 5.71% patients lacked any mutation The high frequency of H63D in the healthy Basque population is confirmed in this study. A considerable incidence of S65C is observed either in controls and in HH (3%) or in iron overloaded patients. The peculiar genetic characteristics of Basques could explain the heterogeneity of genotypes in HH patients of this group. Further studies should be carried out to confirm these findings although the implication of other genetic or external factors in the development of HH is suggested.

Influence of Helicobacter pylori infection and eradication on blood lipids and fibrinogen.

BACKGROUND: An association between Helicobacter pylori infection and heart disease has been suggested. A potential mechanism may be inflammation-induced atherogenic changes of lipoproteins, but epidemiological studies have provided conflicting results. METHODS: In a prospective multicentre study, 830 patients submitted for endoscopy and H. pylori testing were evaluated. Of the 686 H. pylori-positive patients, 487 received and 199 did not receive eradication treatment. Serum lipids and plasma fibrinogen were measured at baseline in all patients and 3 months later in those initially positive for H. pylori. RESULTS: H. pylori had no influence on baseline lipid or fibrinogen levels. Increases in high-density lipoprotein cholesterol were observed in 368 patients who received eradication treatment and in 193 untreated patients: 0.06 mmol/L (P=0.000) and 0.07 mmol/L (P=0.009), respectively. Similar minor increases in total cholesterol and triglycerides occurred in both groups. Lipid changes were related to symptom relief and a reduction in smoking. Eradication therapy was associated with a minor decrease in plasma fibrinogen irrespective of the resolution of infection. CONCLUSIONS: H. pylori has no influence on blood lipids or fibrinogen. Both the eradication of infection and symptomatic treatment without eradication are associated with minor lipid changes related to symptom relief and lifestyle modifications. Thus, the inflammatory changes associated with H. pylori are unlikely to affect lipoprotein or fibrinogen metabolism.

Hypertransaminasaemia and Addison's disease.

A 37-year-old man with hypertransaminasaemia, astenia, anorexia and weight loss is presented. After a search for the usual causes of hypertransaminasaemia, without a positive result, finally Addison's disease was diagnosed. This is an association that is very rarely published.

[Ticlopidine-induced cholestatic hepatitis. A case report]. / Hapatitis colestásica por ticlopidina. Presentatión de un nuevo caso.

A 74-year-old man with cholestatic hepatitis after 3 months of taking ticlopidine is presented herein. Viral serology and autoantibodies were negative. There was no evidence of biliary tree obstruction. After ticlopidine was discontinued, liver tests were normal in 3 months. We review the other cases published in the literature.

Prevalence of coeliac disease in unexplained chronic hypertransaminasemia.

OBJECTIVE: To determine the prevalence of coeliac disease amongst the population with unexplained chronic hypertransaminasemia in our region. PATIENTS AND METHODS: A prospective study was carried out on 147 consecutive patients with chronic hypertransaminasemia, having previously discarded alcoholic cause, hepatotoxic drugs, B, C and Delta viral infections, autoimmune hepatitis, primary biliary cirrhosis, Jemochromatosis, alfal-antitrypsin deficiency, Wilson's disease, congestive liver and illicit drug use. Serum Ig A to gliadin and endomysium antibodies were determined. Intestinal biopsy was carried out in cases those positive for one or both antibodies. RESULTS: One patient was positive for both IgA to gliadin and to endonisyum antibodies, whereas another three patients were positive to IgA to gliadin only. A duodenal biopsy proved normal in two, a total villous atrophy in one and subtotal atrophy in other. CONCLUSIONS: 1. The prevalence of coeliac disease amongst the population with unexplained chronic hypertransaminasemia in our region is 1.4%. 2. In our region, screening for coeliac disease in unexplained chronic hypransaminasemia should take a secondary place.

[Primary melanoma of the esophagus. 2 new cases]. / Melanoma primario de esófago. Dos nuevos casos.

Primary melanoma of the esophagus is rare. Until 1990, eight cases had been reported in Spain. We report two patients, 50 and 61-year-old men. Melanomas were located in the distal esophagus and were polypoid (5-6 cm), pediculated and pigmented. Endoscopic biopsy was diagnostic in both cases. Fontana staining technique and monoclonal HMB-45 and S-100 antibodies were used. A revision of clinical characteristics, treatment and survival of the patients with primary melanoma of the esophagus in our country is made.

Treatment of achalasia with botulinum toxin.

UNLABELLED: We studied the efficacy of local injections of botulinum toxin in the treatment of patients with achalasia. Four patients diagnosed of achalasia using manometric, radiologic and endoscopic criteria, were treated with botulinum toxin (80 U) injected directly into lower esophageal sphincter (LES), via a sclerotherapy injector. Response to treatment was assessed by changes in symptom scores and LES pressure. All determinations were repeated after 10, 30, 90, 120 and 180 days of treatment. The patients improved after the initial injection. This improvement was accompanied by improved relaxation of the LES. Two patients relapsed after 30 and 65 days and the other two patients remained symptom-free 5 months after treatment. CONCLUSION: Botulinum toxin is probably a safe and effective alternative for the treatment of achalasia and should be considered in patients in whom pneumatic dilation has failed or who are poor surgical candidates. Long-term evaluation of the safety and efficacy of botulinum toxin in the treatment of achalasia is required.

[Hepatotoxicity caused by cloxacillin]. / Hepatotoxicidad por cloxacilina.

We describe acute mixed hepatitis (cholestatic and hepatocellular) in two women probably induced by cloxacillin. Viral causes, autoimmune hepatitis, biliary tree obstruction and other risk factors were excluded. After discontinuation of the drug evolution was favorable and clinical signs and hepatic laboratory tests became normal in both cases. We also review the literature about hepatotoxicity induced by anti-Staphylococci semisynthetic penicillins.

[Chronic anemia and intestinal pseudoobstruction as presentation form of hamartomatous polyp of the Vater's ampulla]. / Anemia crónica y suboclusión intestinal como forma de presentación de un pólipo hamartomatoso de la ampolla de Vater.

We report the case of a 70-year-old female with chronic anemia and intestinal pseudoobstruction from a large hamartomatous polyp of the ampulla of Vater. The patient had been operated by obstructive jaundice of possible biliary etiology and a cholecystojejunostomy was performed. Later, due to cholangytis of unknown etiology cholecystectomy and choledochoduodenostomy were done. The polyp was resected by surgery.

[Primary vascular tumors of the liver. Analysis of a series of 20 cases]. / Tumores vasculares primitivos del hígado. Análisis de una serie de veinte casos.

Twenty patients with one or several primary hepatic vascular tumours were studied. Three of them had an angiosarcoma and the other seventeen had twenty nine hepatic haemangiomas. From these seventeen patients, six corresponded to a giant cavernomatous haemangioma. Symptoms, diagnostic methods and treatment of patients with angiosarcoma (3 cases), giant cavernomatous haemangioma (6 cases) and haemangiomas with size less than 4 cm (11 cases) are separately analyzed. We report our series and a critical revision of diagnosis and treatment of these tumours is made.

Pyogenic liver abscesses of bacterial origin. A study of 45 cases.

OBJECTIVE: to determine the clinical, microbiological, diagnostic and therapeutic characteristics of pyogenic liver abscesses of bacterial origin. METHODS: retrospective analysis of pyogenic liver abscesses diagnosed at the Aránzazu Hospital in San Sebastián (northern Spain) between 1989 and 1998. RESULTS: we studied 45 patients with pyogenic liver abscesses of bacterial origin (30 men, 15 women, mean age 61 years 11 months). The site of the liver abscess was biliary in 28.9% of the patients, portal in 11.1%, and unknown in 33.3%. Elevated erythrocyte sedimentation rate (95.5%), leukocytosis (86.7%) and fever (82.2%) were the most frequent clinical and laboratory findings. The abscesses were solitary in 55. 5% of the patients. Echography was diagnostic in 68.4% of patients, and computed tomography was diagnostic in 100%. Cultures of pus from the abscess and blood were positive in 77.1% and 50% respectively. Of the abscesses diagnosed as being of bacterial origin, 44.4% involved multiple organisms. Escherichia coli and Streptococcus milleri were the germs isolated most frequently. Percutaneous drainage was done in 22 patients (48.9%), with satisfactory results in 18. Overall mortality related with abscesses was 15.5%. CONCLUSIONS: the clinical presentation of pyogenic liver abscess did not vary during the study period. Computed tomography is fundamental for diagnosis and treatment. Percutaneous drainage associated with early antibiotic therapy is the treatment of choice.

AIDS-associated cholangiopathy in a series of ten patients.

OBJECTIVE: To present the clinical, biological, radiologic and cholangiographic findings in patients with clinical suspicion of AIDS associated cholangiopathy in our hospital. PATIENTS AND METHODS: We have revised the clinical charts of 10 patients admitted in our hospital from 1991 to 1995. RESULTS: Ultrasonography and/or abdominal CT were carried out on all the patients. Biliary tract dilatation was observed in 11 cases. From the 12 ERCP, biliary tract was fulfilled in 11. In 5 cases papillary stenosis was diagnosed, sclerosing cholangitis in 2, normal biliary tract in 3 and acute cholangitis in one case. Sphincterotomy was done in 5 patients, with clinical improvement. In one case, another sphincterotomy was needed because of reestenosis. CONCLUSIONS: ERCP is very important in the diagnosis of AIDS associated cholangiopathy. Endoscopic sphincterotomy relieves abdominal pain in these patients. Cholangiopathy occurs in very immunocompromised HIV positive patients. Survival is very short.

[Cholestatic acute hepatitis induced by amoxycillin-clavulanic acid combination. Role of ursodeoxycholic acid in drug-induced cholestasis]. / Hepatitis colestásica aguda secundaria a amoxicilina-ácido clavulánico. Papel del ácido ursodesoxicólico en la colestasis inducida por drogas.

We report two cases of acute hepatotoxicity after treatment with amoxicillin-clavulanic. Viral hepatitis serology and autoantibodies were negative. Biliary tree obstruction and other etiologies were excluded. After discontinuation of the drug the evolution was favorable with clinical improvement and normalization of liver tests. Liver biopsy made in one patient showed cholestasic hepatitis with hepatocellular necrosis and other patient was treated with ursodeoxycholic. Also, we analyse potential utility of ursodeoxycholic acid administration in toxic cholestasis.