Agustin Castiella

The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury.

Distinguishing drug‐induced liver injury (DILI) from idiopathic autoimmune hepatitis (AIH) can be challenging. We performed a standardized histologic evaluation to explore potential hallmarks to differentiate AIH versus DILI. Biopsies from patients with clinically well‐characterized DILI [n = 35, including 19 hepatocellular injury (HC) and 16 cholestatic/mixed injury (CS)] and AIH (n = 28) were evaluated for Ishak scores, prominent inflammatory cell types in portal and intra‐acinar areas, the presence or absence of emperipolesis, rosette formation, and cholestasis in a blinded fashion by four experienced hepatopathologists. Histologic diagnosis was concordant with clinical diagnosis in 65% of cases; but agreement on final diagnosis among the four pathologists was complete in only 46% of cases. Interface hepatitis, focal necrosis, and portal inflammation were present in all evaluated cases, but were more severe in AIH (P < 0.05) than DILI (HC). Portal and intra‐acinar plasma cells, rosette formation, and emperiopolesis were features that favored AIH (P < 0.02). A model combining portal inflammation, portal plasma cells, intra‐acinar lymphocytes and eosinophils, rosette formation, and canalicular cholestasis yielded an area under the receiver operating characteristic curve (AUROC) of 0.90 in predicting DILI (HC) versus AIH. All Ishak inflammation scores were more severe in AIH than DILI (CS) (P ≤ 0.05). The four AIH‐favoring features listed above were consistently more prevalent in AIH, whereas portal neutrophils and intracellular (hepatocellular) cholestasis were more prevalent in DILI (CS) (P < 0.02). The combination of portal inflammation, fibrosis, portal neutrophils and plasma cells, and intracellular (hepatocellular) cholestasis yielded an AUC of 0.91 in predicting DILI (CS) versus AIH. Conclusion: Although an overlap of histologic findings exists for AIH and DILI, sufficient differences exist so that pathologists can use the pattern of injury to suggest the correct diagnosis. (Hepatology 2011;)

The prevalence of peptic ulcer not related to Helicobacter pylori or non-steroidal anti-inflammatory drug use is negligible in southern Europe.

Background and Aim.  Helicobacter pylori is the major cause of peptic ulcer disease, but the proportion of H. pylori‐negative peptic ulcers seems to be increasing in developed countries. We investigated the frequency of H. pylori‐negative peptic ulcer without intake of nonsteroidal anti‐inflammatory drugs (NSAIDs) in a Mediterranean European country.

Quantification of iron concentration in the liver by MRI

ObjectiveMeasurement of liver iron concentration is a key parameter for the management of patients with primary and secondary haemochromatosis. Magnetic resonance imaging (MRI) has already demonstrated high accuracy to quantify liver iron content. To be able to improve the current management of patients that are found to have iron overload, we need a reproducible, standardised method that is, or can easily be made, widely available.MethodsThis article discusses the different MRI techniques and models to quantify liver iron concentration that are currently available and envisaged for the near future from a realistic perspective.ResultsT2 relaxometry methods are more accurate than signal intensity ratio (SIR) methods and they are reproducible but are not yet standardised or widely available. SIR methods, on the other hand, are very specific for all levels of iron overload and, what is more, they are also reproducible, standardised and already widely available.ConclusionsFor these reasons, today, both methods remain necessary while progress is made towards universal standardisation of the relaxometry technique.

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

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.

Autoimmune hepatitis after treatment with fluvastatin

To the editor: Severe autoimmune diseases have been reported in association with statins (1). Systemic lupus erythematosus, dermatomyositis, pemphigoides and autoimmune hepatitis are well-known side effects described in the literature (2, 3). Statins may produce toxic liver damage too (4, 5). We present herein a case report of a patient treated with fluvastatin, for hypercholesterolemia, who suffered an autoimmune hepatitis during the treatment, very probably triggered by statin ingestion. A 67-year-old patient came to our hospital because of hypertransaminasemia. Previously, he had normal liver enzymes. Four months after treatment with fluvastatin for hypercholesterolemia was initiated, alanine aminotransferase (ALT) values increased to 408 U/l. A study for causes of acute hypertransaminasemia revealed: ALT 791 U/l, aspartate aminotransferase (AST) 476 U/l, glutamyl transpeptidase (GGTP) 1035 U/l, alkaline phosphatase 161 U/l, immunoglobulin M (IgM)-hepatitis A virus (HAV) ( ), hepatitis C virus (HCV) ( ), ribonucleic acid (RNA)-HCV ( ), hepatitis B surface antigen (HbsAg) ( ), HbcAc ( ), Epstein-Barr-IgM ( ), cytomegalovirus (CMV)-IgM ( ) and normal values of a-1-antrypsin, ceruloplasmin, antimitochondrial and smooth muscle antibody (SMA). Antinuclear antibodies were 1/640. Liver ultrasound revealed a hyperechogenic hepatic echostructure, without other findings. After discontinuing the drug the ALT-AST values showed an initial improvement but rose again, hence hepatic biopsy was advised. Liver biopsy showed periportal hepatitis with inflammatory activity (portal and lobulillar grade 2) and moderate portal fibrosis (F2-3). The autoimmune hepatitis score (6) was 11 (because of the hepatotoxic possible effect of fluvastatin) and treatment with corticosteroids was initiated with rapid recovery. Azathioprin was added. A study for human leucocyte antigen (HLA)-DR3 revealed homozygosis. Antithyroid antibodies were present too. A perivascular lymphocitic dermatitis was diagnosed after 1 month of treatment and with good hepatic response. Corticosteroids were gradually stopped. The patient continues on azathioprin 50 mg/day. Liver laboratory data are normal 1 year after diagnosis. Autoimmune hepatitis and toxic hepatitis have been described in association with statins (2–5). The report of severe autoimmune diseases in patients with statin treatment suggest that statins could have an immunomodulator effect (1). Skin reactions may persist for months or years after starting treatment. Our patient presented an autoimmune hepatitis with higher transaminase values after drug discontinuation and with a score of probable autoimmune hepatitis. Skin erythema appeared after steroid treatment was initiated. A DR-3-positive HLA analysis determined that he was genetically predisposed to autoimmune disease and that statins probably played a role as a trigger in the onset of the disease. Therefore when prescribing statins the possibility of hepatic damage, of toxic or autoimmune origin should be taken into account and regular transaminase control should be performed.

Non-invasive methods for liver fibrosis prediction in hemochromatosis: One step beyond

Advances in recent years in the understanding of, and the genetic diagnosis of hereditary hemochromatosis (HH) have changed the approach to iron overload hereditary diseases. The ability to use a radiologic tool (MRI) that accurately provides liver iron concentration determination, and the presence of non-invasive serologic markers for fibrosis prediction (serum ferritin, platelet count, transaminases, etc), have diminished the need for liver biopsy for diagnosis and prognosis of this disease. Consequently, the role of liver biopsy in iron metabolism disorders is changing. Furthermore, the irruption of transient elastography to assess liver stiffness, and, more recently, the ability to determine liver fibrosis by means of MRI elastography will change this role even more, with a potential drastic decline in hepatic biopsies in years to come. This review will provide a brief summary of the different non-invasive methods available nowadays for diagnosis and prognosis in HH, and point out potential new techniques that could come about in the next years for fibrosis prediction, thus avoiding the need for liver biopsy in a greater number of patients. It is possible that liver biopsy will remain useful for the diagnosis of associated diseases, where other non-invasive means are not possible, or for those rare cases displaying discrepancies between radiological and biochemical markers.

Significance of H63D homozygosity in a Basque population with hemochromatosis

Background:  The significance of H63D homozygosity remains uncertain, although it is associated with a tendency for patients to develop iron overload.

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. Fi brosis 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 ( 1,000) a NPV of 75%, and MRI-derived LIC x age (> 480,000) a NPV of 80%. The combina tion 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 nega tive result allows to discard significant fibrosis in 94% of cases. MRI allows a good fibrosis prediction

Celiac disease and hemochromatosis.

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Measurement of Liver Iron Concentration by MRI Is Reproducible

Purpose. The objectives were (i) construction of a phantom to reproduce the behavior of iron overload in the liver by MRI and (ii) assessment of the variability of a previously validated method to quantify liver iron concentration between different MRI devices using the phantom and patients. Materials and Methods. A phantom reproducing the liver/muscle ratios of two patients with intermediate and high iron overload. Nine patients with different levels of iron overload were studied in 4 multivendor devices and 8 of them were studied twice in the machine where the model was developed. The phantom was analysed in the same equipment and 14 times in the reference machine. Results. FeCl3 solutions containing 0.3, 0.5, 0.6, and 1.2 mg Fe/mL were chosen to generate the phantom. The average of the intramachine variability for patients was 10% and for the intermachines 8%. For the phantom the intramachine coefficient of variation was always below 0.1 and the average of intermachine variability was 10% for moderate and 5% for high iron overload. Conclusion. The phantom reproduces the behavior of patients with moderate or high iron overload. The proposed method of calculating liver iron concentration is reproducible in several different 1.5 T systems.