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Professional societies play a major role in medicine and science. The societies tend to be large with well-developed administrative structures. An additional model, however, is based on small groups of experts who meet regularly in an egalitarian model in order to discuss disease-specific scientific and medical problems. In order to illustrate the effectiveness of this model, the history and practices are examined of a long-standing successful example, the International Liver Pathology Group, better known as the Gnomes. The history shows that groups such as the Gnomes offer a number of important benefits not available in larger societies and nurturing such groups advances science and medicine in meaningful ways. The success of the Gnomes' approach provides a road map for future small scientific groups.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide. Experimental and small clinical trials have demonstrated that angiotensin II blockers (ARB) may be anti-fibrotic in the liver. The aim of this randomised controlled trial was to assess whether treatment with Losartan for 96 weeks slowed, halted or reversed the progression of fibrosis in patients with non-alcoholic steatohepatitis (NASH)., Methods: Double-blind randomised-controlled trial of Losartan 50 mg once a day versus placebo for 96 weeks in patients with histological evidence of NASH. The primary outcome for the study was change in histological fibrosis stage from pre-treatment to end-of-treatment., Results: The study planned to recruit 214 patients. However, recruitment was slower than expected, and after 45 patients were randomised (median age 55; 56% male; 60% diabetic; median fibrosis stage 2), enrolment was suspended. Thirty-two patients (15 losartan and 17 placebo) completed follow up period: one patient (6.7%) treated with losartan and 4 patients (23.5%) in the placebo group were "responders" (lower fibrosis stage at follow up compared with baseline). The major reason for slow recruitment was that 39% of potentially eligible patients were already taking an ARB or angiotensin converting enzyme inhibitor (ACEI), and 15% were taking other prohibited medications., Conclusions: Due to the widespread use of ACEI and ARB in patients with NASH this trial failed to recruit sufficient patients to determine whether losartan has anti-fibrotic effects in the liver., Trial Registration: ISRCTN 57849521.

Background & Aims: Pharmacologic treatments for nonalcoholic steatohepatitis (NASH) are limited. Lifestyle interventions are believed to be effective in reducing features of NASH, although the effect of regular exercise, independent of dietary change, is unclear. We performed a randomized controlled trial to study the effect of exercise on hepatic triglyceride content (HTGC) and biomarkers of fibrosis in patients with NASH., Methods: Twenty-four patients (mean age, 52 ± 14 y; body mass index, 33 ± 6 kg/m 2 ) with sedentary lifestyles (<60 min/wk of moderate-vigorous activity) and biopsy-proven NASH were assigned randomly to groups that exercised (n = 12) or continued standard care (controls, n = 12) for 12 weeks while maintaining their weight. The exercise (cycling and resistance training) was supervised at an accredited sports center and supervised by a certified exercise specialist and recorded 3 times per week on nonconsecutive days. We measured HTGC, body composition, circulating markers of inflammation, fibrosis, and glucose tolerance at baseline and at 12 weeks., Results: Compared with baseline, exercise significantly reduced HTGC (reduction of 16% ± 24% vs an increase of 9% ± 15% for controls; P < .05), visceral fat (reduction of 22 ± 33 cm 2 vs an increase of 14 ± 48 cm 2 for controls; P < .05), plasma triglycerides (reduction of 0.5 ± 1.0 mmol/L vs an increase of 0.3 ± 0.4 mmol/L for controls; P < .05), and γ-glutamyltransferase (reduction of 10 ± 28 U/L - 1 for controls; P < .05). There were no effects of exercise on liver enzyme levels, metabolic parameters, circulatory markers of inflammation (levels of interleukin 6, tumor necrosis factor-α, or C-reactive protein) and fibrosis.-1 for controls; P < .05). There were no effects of exercise on liver enzyme levels, metabolic parameters, circulatory markers of inflammation (levels of interleukin 6, tumor necrosis factor-α, or C-reactive protein) and fibrosis., Conclusions: In a randomized controlled trial, 12 weeks of exercise significantly reduced HTGC, visceral fat, and plasma triglyceride levels in patients with NASH, but did not affect circulating markers of inflammation or fibrosis. Exercise without weight loss therefore affects some but not all factors associated with NASH. Clinical care teams should consider exercise as part of a management strategy of NASH, but weight management strategies should be included. Larger and longer-term studies are required to determine the effects of exercise in patients with NASH. ISRCTN registry.com: ISRCTN16070927., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of clinical and histopathological changes including "simple" steatosis, steatosis with inflammation, steatohepatitis, cirrhosis, and hepatocellular carcinoma. It was initially described in the context of drug-induced liver injury and acute liver disease following jejunoileal bypass surgery, but since the early 1980s it has been widely acknowledged as the hepatic manifestation of metabolic syndrome. It now represents a burgeoning public health crisis and is fast becoming the main indication for liver transplantation in some parts of the world. Its true incidence and prevalence are unknown, although estimates have been made from large imaging studies. Liver biopsy interpretation is still regarded as the gold standard for making accurate diagnoses in NAFLD, but sampling limitations are recognized. Furthermore, clear definitions for key histopathological components have been lacking, resulting in significant interobserver variations in making a diagnosis of steatohepatitis. In this review the authors consider some aspects of classification and variant forms of NAFLD such as that occurring in children. They provide an update on grading and staging systems and histopathological prognostic factors, and address the role of liver biopsy in contemporary clinical care of patients with NAFLD., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

The hepatic sinusoids comprise a complex of vascular conduits to transport blood from the porta hepatis to the inferior vena cava through the liver. Under normal conditions, portal venous and hepatic artery pressures are equalized within the sinusoids, oxygen and nutrients from the systemic circulation are delivered to the parenchymal cells and differentially distributed throughout the liver acini, and proteins of liver derivation are carried into the cardiac/systemic circulation. Liver sinusoid structures are lined by endothelial cells unique to their location, and Kupffer cells. Multifunctional hepatic stellate cells and various immune active cells are localized within the space of Disse between the sinusoid and the adjacent hepatocytes. Flow within the sinusoids can be compromised by physical or pressure blockage in their lumina as well as obstructive processes within the space of Disse. The intimate relationship of the liver sinusoids to neighbouring hepatocytes is a significant factor affecting the health of hepatocytes, or transmission of the effects of injury within the sinusoidal space. Pathologists should recognize several patterns of injury involving the sinusoids and surrounding hepatocytes. In this review, injury, alterations and accumulations within the liver sinusoids are illustrated and discussed., (© 2014 John Wiley & Sons Ltd.)

Liver transplant biopsies are routinely archived following formalin fixation and paraffin embedding and may provide an additional source of diagnostic information following transcriptomic biomarker analysis. This study was designed to compare gene transcription between resting and stressed biliary cells in culture, these cells after fixation and embedding and archival liver transplant biopsy tissue. The transcription of p21/WAF1 and transforming growth factor (TGF)-β1 showed similar changes in the fresh and embedded liver cells. However, the expression of TGF-β2 was markedly different between the fresh and embedded samples, suggesting that fixation can produce sequence-specific artefacts. Sufficient quantities of pure RNA were recovered from all the liver transplant biopsies to allow complementary DNA production. Measurement of the transcription of all three genes showed variability between the cases. Although the results for individual transcripts should be interpreted with care, these data do suggest the feasibility of performing a larger biomarker discovery studies using archival tissue.

Unlabelled: Liver biopsy is the reference standard for the detection of nonalcoholic steatohepatitis (NASH) within nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify a biomarker of NASH in patients without significant fibrosis. In all, 172 patients from two centers with biopsy-proven NAFLD were included in this study. Eighty-four patients from a single center were included as a derivation cohort and 88 patients from a second center were included as a validation cohort. Serum samples were tested for candidate markers of fibrosis and inflammation alongside hematological and biochemical markers. Among patients without advanced fibrosis, terminal peptide of procollagen III (PIIINP) was the only marker found to be associated with a histological diagnosis of NASH in both cohorts. PIIINP also correlated with the total NAFLD activity score (NAS) and its constituent components (P < 0.001). Area under receiver operating characteristic curve (AUROC) for PIIINP in discriminating between NASH and simple steatosis (SS) was 0.77-0.82 in patients with F0-2 fibrosis and 0.82-0.84 in patients with F0-3 fibrosis. PIIINP was elevated in patients with advanced fibrosis, the overwhelming majority of whom had NASH. When incorporating patients with all degrees of fibrosis from both cohorts, PIIINP was able to discriminate between patients with SS and those with NASH or advanced fibrosis with AUROC 0.85-0.87., Conclusion: PIIINP discriminates between SS and NASH or advanced fibrosis. The use of a single biomarker in this context will be of clinical utility in detecting the minority of patients with NAFLD who have NASH or advanced fibrosis related to NASH., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Unlabelled: The polymorphism, KLF6-IVS1-27A, in the Krüppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development of insulin resistance, central to NAFLD pathogenesis, we genotyped KLF6-IVS1-27 in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified messenger RNA (mRNA) expression of KLF6 and glucokinase (GCK), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine Klf6 knockdown model (DeltaKlf6). Klf6 overexpression studies in a mouse hepatocyte line were utilized to mechanistically link KLF6 with Gck promoter activity. KLF6-IVS1-27Gwt (i.e., less KLF6 splicing) was associated with stepwise increases in FPG and insulin and reduced hepatic insulin sensitivity. KLF6 binds to the liver-specific Gck promoter and activates a GCK promoter-reporter, identifying GCK as a KLF6 direct transcriptional target. Accordingly, in DeltaKlf6 hepatocytes Gck expression was reduced and stable transfection of Klf6 led to up-regulation of Gck. GCK and KLF6 mRNAs correlate directly in human NAFLD tissues and immunohistochemistry studies confirm falling levels of both KLF6 and GCK in fat-laden hepatocytes. In contrast to full-length KLF6, splice variant KLF6-SV1 increases in NAFLD hepatocytes and inversely correlates with glucokinase regulatory protein, which negatively regulates GCK activity., Conclusion: KLF6 regulation of GCK contributes to the development of hepatic insulin resistance. The KLF6-IVS1-27A polymorphism, which generates more KLF6-SV1, combats this, lowering hepatic insulin resistance and blood glucose., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Background: Non-alcoholic fatty liver disease (NAFLD) is principally a disease of middle and old age. Previous studies reported it to be benign in old age, however more recent studies suggest an increased mortality in the >60-year-olds., Objectives: To define the prevalence of risk factors and the laboratory and histological differences between different age groups with NAFLD, in order to confirm/refute findings in previous smaller studies., Methods: Retrospective, cohort study set in a tertiary liver clinic in the UK. 351 consecutive patients with biopsy-proven NAFLD were divided into an older (> or =60), a middle-aged (> or =50 to <60) and a younger (<50) group. Blood pressure, body mass index, serum lipids, glucose, HbA1C, albumin, liver enzymes, bilirubin, mean cell volume (MCV), platelets, and insulin resistance were recorded. In addition, liver biopsy was analyzed for steatosis, inflammation and fibrosis., Results: Older patients had significantly more risk factors (hypertension, obesity, diabetes, hyperlipidaemia). Albumin, alanine aminotransferase (ALT), ALT/aspartate aminotransferase ratio and platelets significantly reduced with advancing age. MCV and alkaline phosphatase significantly increased with increasing age. Older patients had significantly greater fibrosis on biopsy with less percentage fat, with the cirrhotic patients being significantly older than non-cirrhotics. Insulin resistance was similar in younger and older groups., Conclusion: NAFLD affects mainly the middle-aged and the elderly. With advancing age come more risk factors for its development. Older patients show more severe biochemical, haematological and histological changes, with cirrhotics having a significantly greater age than those with milder disease.

Intrahepatic nerves serve important metabolic, sensory and motor functions. Their ontogeny in human liver has not been elucidated. We aimed to characterise the ontogeny of human intrahepatic innervation, to assess its relationship with biliary structures and to examine the distribution and nature of peptidergic nerves during development. We used immunohistochemistry on archival normal human liver tissue from 63 fetuses [8-40 gestational weeks (gw)] and 10 adults with antibodies to pan-neural markers and neuropeptides. Few nerve fibers appeared in portal tracts at 8 gw. Their density increased gradually from 12 gw and reached adult levels at 32-33 gw. Rare intra-acinar nerves, restricted to periportal areas, appeared at 40 gw. Galanin-, somatostatin- and calcitonin-gene-related peptide-positive nerve fibers were noted only in portal tracts from 22, 26 and 32 gw, respectively. In human adult liver, dense portal and intra-acinar neural supply was observed. Human fetal liver contains a neural network distributed mainly in portal tracts with a density that increases progressively towards term. Intra-acinar innervation appears at term, suggesting that is not required for normal liver function during development, while peptidergic nerves are important for intrauterine liver functions. Developmentally regulated expression of galanin and somatostatin may play a role in liver morphogenesis.

Unlabelled: Patients with nonalcoholic fatty liver disease (NAFLD) and advanced liver fibrosis are at the highest risk for progressing to end-stage liver disease. We constructed and validated a scoring system consisting of routinely measured and readily available clinical and laboratory data to separate NAFLD patients with and without advanced fibrosis. A total of 733 patients with NAFLD confirmed by liver biopsy were divided into 2 groups to construct (n = 480) and validate (n = 253) a scoring system. Routine demographic, clinical, and laboratory variables were analyzed by multivariate modeling to predict presence or absence of advanced fibrosis. Age, hyperglycemia, body mass index, platelet count, albumin, and AST/ALT ratio were independent indicators of advanced liver fibrosis. A scoring system with these 6 variables had an area under the receiver operating characteristic curve of 0.88 and 0.82 in the estimation and validation groups, respectively. By applying the low cutoff score (-1.455), advanced fibrosis could be excluded with high accuracy (negative predictive value of 93% and 88% in the estimation and validation groups, respectively). By applying the high cutoff score (0.676), the presence of advanced fibrosis could be diagnosed with high accuracy (positive predictive value of 90% and 82% in the estimation and validation groups, respectively). By applying this model, a liver biopsy would have been avoided in 549 (75%) of the 733 patients, with correct prediction in 496 (90%)., Conclusion: a simple scoring system accurately separates patients with NAFLD with and without advanced fibrosis, rendering liver biopsy for identification of advanced fibrosis unnecessary in a substantial proportion of patients.

Unlabelled: Primary biliary cirrhosis (PBC) recurs in the allograft after liver transplantation. Study of early tissue changes in the time-course of disease recurrence provides a unique insight into the initial stages of the disease process, which, in nontransplant patients, occurs long before clinical presentation. We describe a patient who developed classical clinical, biochemical, immunological, and histological features of PBC within 9 months after transplantation. Use of tissue from this patient before and during the development of PBC allowed us to identify biliary epithelial cell (BEC) epithelial-mesenchymal transition (EMT) as a key pathogenetic process. BEC expression of S100A4 (an early fibroblast lineage marker established as a robust marker of EMT), vimentin, and pSmad 2/3 [a marker of transforming growth factor beta (TGF-beta) pathway signaling] were identified immunohistochemically in most BECs in liver tissue from this patient at the point of diagnosis of recurrent disease. BEC expression of S100A4 and pSmad 2/3 was seen as early as 24 days after orthotopic liver transplantation (OLT), although no other features of recurrent PBC were present at this time., Conclusion: S100A4, vimentin, and pSmad 2/3 expression in early recurrent PBC after OLT suggests that BEC EMT is occurring (potentially explaining BEC loss) and that this process is driven by TGF-beta. S100A4 expression by BEC appears to occur before the development of any other features of recurrent PBC, suggesting that EMT may be an initiating event.

We have previously provided evidence suggesting that phosphatidic acid, possibly derived from the hydrolysis of phosphatidylcholine by phospholipase D (PLD), is involved in platelet-derived growth factor (PDGF)-mediated increases in extracellular signal-regulated kinase (ERK) activity and DNA synthesis in rat hepatic stellate cells (HSC), the primary fibrogenic cells of the liver. A recent study has shown the presence of P2Y nucleotide receptors on HSC that are coupled to contraction and synthesis of the matrix component, alpha1-procollagen, leading to the suggestion that they may represent a new therapeutic target in the treatment of liver fibrosis. However, although extracellular nucleotides have been shown to stimulate both PLD and ERK, and to elicit proliferation of fibrogenic cells outside the liver, their effect on these parameters in HSC have not yet been investigated. PLD activity was determined by [3H]choline release and [3H]phosphatidylbutanol production, ERK activity by Western blotting, and DNA synthesis by [3H]thymidine incorporation. We report here, for the first time in HSC, that extracellular nucleotides stimulate PLD activity and a sustained activation of ERK. However, in contrast to PDGF, nucleotides had negligible effects on DNA synthesis. Moreover, the effects of PDGF and nucleotides on PLD and ERK were not additive, suggesting activation of the same PLD isoform and pool of ERK. The data demonstrate that nucleotide-stimulated PLD and ERK activities are not coupled to DNA synthesis in HSC. Instead, these responses may be linked to other phenotypic changes associated with activated HSC such as increases in contraction, motility, or extracellular matrix deposition.

Background: Pathologists are often faced with the dilemma of whether to recommend continuation of methotrexate therapy for psoriasis within the context of an existing pro-fibrogenic risk factor, in this instance, patients with genetic hemochromatosis., Case Presentations: We describe our experience with two male psoriatic patients (A and B) on long term methotrexate therapy (cumulative dose A = 1.56 gms and B = 7.88 gms) with hetero- (A) and homozygous (B) genetic hemochromatosis. These patients liver function were monitored with routine biochemical profiling; apart from mild perivenular fibrosis in one patient (B), significant liver fibrosis was not identified in either patient with multiple interval percutaneous liver biopsies; in the latter instance this patient (B) had an additional risk factor of partiality to alcohol., Conclusion: We conclude that methotrexate therapy is relatively safe in patients with genetic hemochromatosis, with no other risk factor, but caution that the risk of fibrosis be monitored, preferably by non-invasive techniques, or by liver biopsy.

In the absence of satisfactory cell culture systems for hepatitis C virus (HCV), virtually all that is known about the proteins of the virus has been learned by the study of recombinant proteins. Characterization of virus proteins from patients with HCV has been retarded by the low virus titre in blood and limited availability of infected tissue. Here, the authors have identified a primary infection in a liver transplanted into an immunodeficient patient with chronic HCV. The patient required re-transplant and the infected liver, removed 6 weeks after the initial transplant, had a very high titre of HCV, 5 x 10(9) International Units (IU) per gram of liver. The density distribution of HCV in iodixanol gradients showed a peak at 1.04 g x ml(-1) with 73 % of virus below 1.08 g x ml(-1). Full-length HCV RNA was detected by Northern blotting and the ratio between positive- and negative-strand HCV RNA was determined as 60. HCV was partially purified by precipitation with heparin/Mn(2+) and a single species of each of the three structural proteins, core, E1 and E2, was detected by Western blotting. The molecular mass of core was 20 kDa, which corresponds to the mature form from recombinant sources. The molecular mass of glycoprotein E1 was 31 kDa before and 21 kDa after deglycosylation with PNGase F or endoglycosidase H. Glycoprotein E2 was 62 kDa before and 36 kDa after deglycosylation, but E2-P7 was not detected. This was in contrast to recombinant sources of E2 which contain E2-P7.

Several distinct conditions are characterized by a reduction in the number of small and medium-sized intrahepatic bile ducts. These diseases are associated with progressive cholestasis, which in turn leads to biliary fibrosis and ultimately cirrhosis. The best-characterized ductopenic condition in adulthood is primary biliary cirrhosis (PBC) for which there is now strong evidence of an autoimmune cause. The antigenic targets are epitopes on proteins of the 2-oxoacid dehydrogenase complex within mitochondria. Some of these proteins appear to be aberrantly expressed at the surface of cholangiocytes in PBC. The basis for the breakdown in tolerance remains uncertain, although there is recent evidence to indicate that apoptosis may play a key role at early stages in the pathogenesis of the disease. Related conditions include autoimmune overlap syndromes and AMA-negative PBC (autoimmune cholangitis). Primary sclerosing cholangitis is clinically and histologically distinct, although there is evidence that it also may have an immune-mediated cause. Ductopenia may also arise on the basis of drug-induced injury; the best example of this is progressive cholestasis complicating chlorpromazine therapy.

Background: Alcohol is the main cause of chronic liver disease. The Enhanced Liver Fibrosis (ELF) test is a serological biomarker for fibrosis staging in chronic liver disease, however its utility in alcohol-related liver disease warrants further validation. We assessed the diagnostic and prognostic performance of ELF in alcohol-related liver disease.Methods: Observational cohort study assessing paired ELF and histology from 786 tertiary care patients with chronic liver disease due to alcohol (n = 81) and non-alcohol aetiologies (n = 705). Prognostic data were available for 64 alcohol patients for a median of 6.4 years. Multiple ELF cut-offs were assessed to determine diagnostic utility in moderate fibrosis and cirrhosis. Survival data were assessed to determine the ability of ELF to predict liver related events and all-cause mortality.Results: ELF identified cirrhosis and moderate fibrosis in alcohol-related liver disease independently of aminotransferase levels with areas under receiver operating characteristic curves of 0.895 (95% CI 0.823-0.968) and 0.923 (95% CI 0.866-0.981) respectively, which were non-inferior to non-alcohol aetiologies. The overall performance of ELF was assessed using the Obuchowski method: in alcohol = 0.934 (95% CI 0.908-0.960); non-alcohol = 0.907 (95% CI 0.895-0.919). Using ELF < 9.8 to exclude and ≧ 10.5 to diagnose cirrhosis, 87.7% of alcohol cases could have avoided biopsy, with sensitivity of 91% and specificity of 85%. A one-unit increase in ELF was associated with a 2.6 (95% CI 1.55-4.31, p < 0.001) fold greater odds of cirrhosis at baseline and 2.0-fold greater risk of a liver related event within 6 years (95% CI 1.39-2.99, p < 0.001).Conclusions: ELF accurately stages liver fibrosis independently of transaminase elevations as a marker of inflammation and has superior prognostic performance to biopsy in alcohol-related liver disease. [ABSTRACT FROM AUTHOR]

Professional societies play a major role in medicine and science. The societies tend to be large with well-developed administrative structures. An additional model, however, is based on small groups of experts who meet regularly in an egalitarian model in order to discuss disease-specific scientific and medical problems. In order to illustrate the effectiveness of this model, the history and practices are examined of a long-standing successful example, the International Liver Pathology Group, better known as the Gnomes. The history shows that groups such as the Gnomes offer a number of important benefits not available in larger societies and nurturing such groups advances science and medicine in meaningful ways. The success of the Gnomes' approach provides a road map for future small scientific groups. [ABSTRACT FROM AUTHOR]

Abstract: Hepatocellular carcinoma (HCC) is a major world health problem. Screening and diagnosis of early lesions of HCC allows prompt treatment to improve clinical outcomes. Early lesions of HCC include premalignant lesions and small HCCs. The former consists of hepatocellular cytological changes (large cell change, small cell change and iron-free foci), dysplastic foci and dysplastic nodules (low-grade and high-grade); while the latter is subdivided into early HCC and progressed HCC. There is significant overlap in pathological and radiological features between high-grade dysplastic nodules and early HCC making a precise diagnosis demanding even among experts. Various conventional and emerging potential diagnostic markers have been evaluated in assisting pathological diagnosis of early HCC. Translation of the concept of early HCC to daily clinical practice in term of diagnosis and tumour staging is challenging to clinicians, radiologists and pathologists. [Copyright &y& Elsevier]

Considers the structure and function of hepatic stellate cells (HSC) in the liver. Cell biology of HSC; Functions of HSC; Relationship of HSC to other cell types.

Background: Dermatologists, or pathologists, occasionally need to decide whether or not to continue methotrexate therapy in a patient with an identifiable risk factor for liver fibrosis, in this instance heterozygous α1-antitrypsin deficiency. Case Presentation: We relate our experience with an elderly male patient, diagnosed as having α1-antitrypsin deficiency on a liver biopsy, genotypically confirmed as PiMZ. He had been receiving methotrexate for psoriasis for 17 years with a cumulative dose of 7,200 mg. He was monitored by biochemical profiling and interval (10) liver biopsies. Non-specific changes were seen on liver histology although grade 1 liver fibrosis was seen in his last 2 biopsies. Conclusion: We suggest that methotrexate therapy is relatively safe in patients with heterozygous α1-antitrypsin deficiency, with no other risk factor. We however advise that the risk of fibrosis should be monitored and that the patient receives appropriate counselling. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]