Light and electron microscopic analysis of liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy

OBJECTIVE: We study liver damage in forty-two patients with rheumatoid arthritis (RA) using light (LM) and electron microscopy (EM) and assess histological changes after four years of treatment with methotrexate (MTX). PATIENTS AND METHODS: liver biopsies (LB) were taken before and after four years of treatment. Patients received weekly doses of between 7.5-15 mg of MTX. RESULTS: Fourteen per cent of the baseline LB presented mild perisinusoidal fibrosis (Roenigk IIIA) and the rest a lower Roenigk grade; EM identified an increase in collagen fibers in the Disse spaces in 50% of baseline LB. Neither microscopy technique revealed histological progression in any of the sequential LB. Variables that correlated with histological abnormalities were patient's age, length of evolution of the disease, alcohol consumption and biochemical data (gammaglutamate transferase and albumin); the cumulative dose of MTX was not correlated with worse histological findings. Correlation between the two microscopy techniques was good, though EM was more sensitive than LM for the detection of fibrosis. CONCLUSIONS: RA patients present with liver damage before treatment with MTX. The alterations are mild. At low doses MTX treatment is safe. In addition to the recommendations of the American College of Rheumatology, other factors associated with liver impairment are patient's age and length of evolution of the RA.     

Longitudinal measurement of methotrexate liver concentrations does not correlate with liver damage,clinical efficacy,or toxicity during a 3.5 year double blind study in rheumatoid arthritis

OBJECTIVES: In patients with rheumatoid arthritis (RA), we examined whether methotrexate (MTX) and MTX polyglutamate accumulation in the liver correlated with clinical efficacy or clinical/laboratory toxicity. We also began preliminary examination of a new histologic index of liver histology (the Iowa Score) relative to the Roenigk grading system. METHODS: Forty patients with RA participated in a prospective, double blind, 3.5 year study of MTX treatment. Liver biopsies, liver MTX and MTX polyglutamate concentrations, laboratory tests, evaluation of disease activity, and evaluation of adverse events were done prospectively at baseline and at 1, 2, and 3.5 years. Biopsies were examined using the Roenigk grading system and an additional histological scoring system. Radiochemical ligand binding assays and HPLC methods were used to measure MTX and MTX polyglutamates. Statistical analysis included ANOVA, linear regression, and logistic regression modeling. RESULTS: No significant changes in the mean values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, albumin, or hemoglobin occurred. A significant percentage of patients had at least one abnormal alkaline phosphatase, AST, or ALT (25 to 52%), although most abnormalities were small and transient. Histological abnormalities did not progress using either the Roenigk or the Iowa score. The last abnormal AST, the number of abnormal AST and ALT, and female sex correlated with histological liver abnormalities (r2 = 0.41) using a new preliminary histologic scoring system (the Iowa Score). Amount of alcohol use correlated with fatty change, and the MTX dose at biopsy was associated with liver histological abnormalities (p = 0.03 and 0.049, respectively). Total liver MTX concentrations were stable from Year 1 to Year 3.5 and the percentage of higher order polyglutamates was relatively high (38 to 56%) relative to monoglutamates. No correlation of these concentrations with clinical response or toxicity, histology, or liver function tests could be documented. CONCLUSION: This analysis describes the accumulation and stabilization of MTX concentrations in the liver and examined correlations between MTX liver concentrations, patient demographics, liver histology, concomitant medications, and disease activity. No such correlations were found, decreasing the likelihood that MTX concentrations in serum would be useful measures to predict significant hepatotoxicity.     

Liver biopsy findings in patients with rheumatoid arthritis undergoing longterm treatment with methotrexate

Ten histological criteria were evaluated semiquantitatively in the liver biopsies of 60 patients with rheumatoid arthritis (RA) before initiation of methotrexate (MTX) and were compared with 40 biopsies taken during MTX treatment (mean cumulative dose 1.322 mg). Mesenchymal changes (Kupffer cell proliferation, portal tract infiltration) and parenchymal alterations (nuclear variability, ballooning, fatty infiltration) were very common without statistically significant difference between the 2 groups. Slight periportal and/or portal fibrosis was present in 25% of patients without statistical difference between groups. Central fibrosis occurred in 13.5-12.5%. We conclude that liver abnormalities in RA are not related to MTX treatment.     

Usefulness of the american college of rheumatology recommendations for liver biopsy in methotrexate-treated rheumatoid arthritis patients

Objective. To test the usefulness and cost savings resulting from application of the new American College of Rheumatology (ACR) guidelines for assessing the risk for the development of clinically significant liver disease in rheumatoid arthritis (RA) patients treated with methotrexate (MTX). Methods. One-hundred twelve MTX-treated RA patients were prospectively followed up for MTX hepatotoxicity and underwent liver biopsies according to modified guidelines of the Psoriatic Task Force (PTF). All biopsies were graded according to the Roenigk classification. The new ACR recommendations were then retrospectively applied to test their usefulness and cost-effectiveness in this cohort. Results. Based on the PTF guidelines, 66 patients underwent liver biopsies; a total of 110 liver biopsies were performed. Two patients had biopsy-related complications. Five patients were found to have Roenigk grade IIIB or IV histologic abnormalities. The total cost for this group was $111,380. Applying the new ACR criteria, only 15 patients would have undergone liver biopsies; there would have been a total of 18 biopsies, with no complications. Four of the 5 patients with Roenigk grade IIIB or IV liver abnormalities would have been identified. One patient with insulin-dependent diabetes mellitus (IDDM) who was found to have cirrhosis (Roenigk grade IV) on liver biopsy as a result of use of the PTF guidelines would have been missed with use of the ACR guidelines. The total cost for the group receiving biopsies based on the ACR guidelines would have been $16,956. Overall, the new ACR guidelines had 80% sensitivity and 82% specificity and resulted in a cost savings of $1,430 per patient. Conclusion. The new ACR guidelines on MTX monitoring and biopsy surveillance appear to be clinically useful and result in considerable cost savings. However, 1 IDDM patient with significant liver histologic abnormalities would have been missed. We suggest that IDDM be added to the ACR guidelines as a risk factor for MTX hepatotoxicity.     

Quantitative liver function in patients with rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study

The objectives were to determine quantitative liver function prospectively in patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX), to search for risk factors for a loss of quantitative liver function and to assess the relationship between quantitative liver function and histological staging. A total of 117 patients with RA (ACR criteria, 85 women, mean age 59 yr) had measurements of galactose elimination capacity (GEC), aminopyrine breath test (ABT) and liver enzymes [aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (AP), 7-glutamyl transferase (GGT), bile acids, bilirubin, albumin] before treatment with weekly i.m. MTX injections and every year thereafter. In 16 patients, liver biopsies were performed. Before the introduction of MTX, mean GEC was 6.6 mg/min/kg [5th to 95th percentile (5-95 PC) 5.1- 8.5; reference range 6.0-9.1] and mean ABT was 0.80% kg/mmol (5-95 PC 0.42-1.30: reference range 0.6-1.0). During treatment with MTX [mean weekly dose 11.8 mg (5-95 PC 5.4-20.2), mean observation period 3.8 yr (5-95 PC 0.4-6.9)], significant declines of GEC (-0.12 mg/min/kg per year. t = 3.30, P < 0.002) and ABT (-0.06% kg/mmol per year, t = 4.81, P < 0.001) were observed. Negative correlations were found between the annual change in GEC and GEC at baseline (Rs = -0.40, P < 0.0001), and the annual change in ABT and ABT at baseline (Rs = -0.43, P < 0.0001). No correlations were found between the annual change in GEC or ABT and weekly MTX dose, age or percentage of increased liver enzymes, and no effect of a history of alcohol consumption > 30 g/week became evident. Two patients with Roenigk grade III had impaired quantitative liver function, while 14 patients with Roenigk grades I and II exhibited a high variability of GEC and ABT from normal to abnormal values. The continuous declines in GEC and ABT observed deserve attention in patients with prolonged treatment. Patients with a low GEC or ABT at baseline seem not to be at increased risk for a further loss of quantitative liver function. An impaired GEC or ABT does not necessarily concur with hepatic fibrosis on histological examination.      

Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy followup over long treatment intervals and correlation with clinical and laboratory variables

Objective. To describe liver histopathologic features and ultrastructural changes in a prospectively studied cohort of rheumatoid arthritis (RA) patients receiving long-term methotrexate (MTX) therapy, and to seek correlations between these changes and simultaneously measured laboratory indices of liver function. Methods. This was a long-term, prospective, open observational study. Twenty-seven outpatients with RA who began therapy with MTX and continued treatment for extended periods underwent baseline and followup liver biopsies. One hundred seventy liver biopsy specimens were analyzed by light microscopy (LM) and assessed according to a modified Roenigk score and a newly devised numerical grading system. Ninety-three biopsy specimens were also analyzed by electron microscopy (EM). Blood samples were obtained at 4–6-week intervals for determination of bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), and albumin levels, and the weekly dosage of MTX was adjusted if there were abnormalities in the AST or albumin level. A mean of 6.3 liver biopsies per patient were obtained over a mean followup period of 8.2 years (range 2–13 years). Results. The modified Roenigk score was significantly different from baseline at year 3, when it increased from a mean of 1.8 to 2.3 (P = 0.05) and at year 6, when it increased to 2.4 (P = 0.04), but this was not considered clinically meaningful. No other significant changes from baseline were observed by either LM grading system. No significant progression was observed by EM over the course of the investigation. Increases in serial measurements of AST correlated with both the modified Roenigk score (r = 0.21, P = 0.016) and the numerical rating score (r = 0.19, P = 0.027). Conclusion. Patients with RA who are receiving weekly single-dose oral MTX therapy exhibit little deterioration in hepatic architecture by LM or EM when the dosage of the drug is adjusted for abnormalities in AST and serum albumin, monitored at frequent intervals.     

The long-term effect of methotrexate therapy on the liver in patients with juvenile rheumatoid arthritis

Objective. To determine if the long-term use of methotrexate (MTX) in juvenile rheumatoid arthritis (JRA) is associated with the development of significant liver fibrosis, and to describe the presence of risk factors for liver fibrosis in patients with JRA. Methods. Needle biopsies of the liver were performed on a cross-section cohort of 14 patients with JRA who had received a total cumulative dose of MTX that was either >3,000 mg or >4,000 mg/1.73 m² of body surface area. Biopsy samples were independently graded according to the Roenigk Classification Scale by 2 pathologists. The presence of risk factors for MTX hepatotoxicity, especially biochemical abnormalities reflective of liver injury and alcohol consumption, were assessed. Results. Thirteen biopsy samples (93%) were classified as grade I, and 1 (7%) as grade II; none demonstrated significant fibrosis. However, histologic abnormalities were found in 13 biopsy samples (93%). Only 2 patients (14%) consumed more than 1 alcoholic drink per month. Thirteen patients (93%) had biochemical abnormalities while being treated with MTX, but only 5 patients (36%) had at least 1 determination in which the aspartate or alanine aminotransferase elevation was >3 times the upper limit of normal. Conclusion. Long-term use of MTX for JRA does not appear to be associated with the development of significant liver fibrosis. Although nearly all patients had minor histologic changes, no significant clinical consequences were apparent. A prospective study of a larger population will more accurately define the incidence of MTX-related liver fibrosis and appropriate monitoring guidelines in JRA.     

Liver histology in patients receiving low dose pulse methotrexate for the treatment of rheumatoid arthritis.

The liver histology of 52 patients treated with intermittent low dose pulse methotrexate for rheumatoid arthritis was evaluated using a modification of the Roenigk grading system. Patients studied had had an average of 3.2 years of treatment or had received 1.7 g methotrexate. No patient had cirrhosis; 15 (29%) patients had evidence of mild fibrosis. Histological abnormalities were not predicted by liver function test changes, with the exception that hypoalbuminaemia occurred in 60% of those with grade IV (modified criteria) findings. The need for liver biopsy in patients with rheumatoid arthritis treated with methotrexate before two years or 1500 mg of treatment has not been established. Whether serial liver biopsies will be needed beyond this time has yet to be determined.     

Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury

BACKGROUND AND AIMS: Hepatotoxicity, especially liver fibrosis, is the major concern with long-term, 'low-dose' oral methotrexate (MTX) therapy for psoriasis. The histological features are non-specific and resemble those of non-alcoholic steatohepatitis (NASH). Moreover, most of the risk factors of MTX-induced liver injury are also associated with NASH. In this study, we investigate whether NASH contributes to the prevalence and progression of MTX-induced liver injury in patients receiving MTX for psoriasis. METHODS: Clinical details, including MTX dosage schedules and risk factors for liver injury, was documented for 24 patients on long-term MTX therapy for psoriasis. Serial liver biopsies were graded according to the Roenigk classification scale and a recently proposed grading and staging system for NASH. RESULTS: Thirteen of the 17 patients who had a NASH-like pattern of liver injury also had the risk factors for NASH obesity and/or diabetes, and all had progressive liver injury. The other four patients had no risk factors, but a mean cumulative dose of 6.5 g. Seven patients, who did not have a NASH-like pattern of injury, had a mean cumulative dose of 3.8 g. There was a positive correlation between the cumulative dose, risk factors and progression when the biopsies were scored by the modified grading and staging classification for NASH, but not with the Roenigk system. CONCLUSIONS: Non-steatohepatitis, probably aggravated by MTX, is an important cause of liver injury in patients on long-term, 'low-dose' MTX treatment for psoriasis. In addition, MTX alone can cause a NASH-like pattern of injury that is at least, in part, caused by a higher cumulative dose.     

Clinical liver disease in patients with rheumatoid arthritis taking methotrexate.

Between 1981 and 1989, 3 of 134 patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) developed clinically significant hepatic dysfunction and showed histologic evidence of severe liver disease (fibrosis and cirrhosis). Factors identified in these patients that may have been linked to liver toxicity included diabetes, congestive heart failure and Felty's syndrome. In the patient group that received a post-MTX liver biopsy, pulmonary fibrosis and obesity were significantly associated with hepatic fibrosis/cirrhosis. Severe liver disease may occur in patients with RA treated with low dose MTX (less than 3%). Early liver biopsy is recommended in selected cases.     

Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples

Twenty-nine patients with active rheumatoid arthritis receiving long-term oral weekly methotrexate (MTX) therapy were studied to determine the extent of their hepatic architectural changes. Liver biopsies (n = 101) were performed in all patients before the initiation of MTX therapy, after 2 years, and annually thereafter (mean duration of therapy 53 months). The hepatic histologic grade (5-point scale) in 25 patients increased (worsened) (mean +/- SEM change 0.84 +/- 1.02; P = 0.001). Fibrosis, confirmed by trichrome staining, developed in 14 of 27 patients (52%). A history of alcohol consumption prior to starting MTX correlated significantly with subsequent worsening of the liver biopsy grade (r = 0.55, P = 0.0054). Alcohol intake prior to study entry, elevated weight at MTX initiation, and dose and duration of MTX were significantly associated with the development of fibrosis. Elevations in serum aspartate aminotransferase levels at 29-53 months of therapy correlated with the increase in hepatic histologic grade at the 3-year biopsy (r = 0.50, P = 0.04) and 4-year biopsy (r = 0.58, P = 0.03). We conclude that long-term MTX therapy in rheumatoid arthritis patients results in a statistically significant worsening in hepatic histologic grade, with common development of mild fibrosis. We do not consider these changes to be clinically significant at present.     

Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis.

BACKGROUND: Methotrexate (MTX) use is associated with hepatic fibrosis in psoriasis patients. To monitor this serial liver biopsies were performed. The Fibroscan and the Fibrotest are two novel, non-invasive methods that might be able to assess MTX-induced hepatic fibrosis. AIM: Evaluating the accuracy and feasibility of the Fibroscan and Fibrotest to detect significant MTX-induced liver fibrosis in psoriasis patients. Methods: We assessed 24 psoriasis patients who had a recent liver biopsy during MTX use. The results from the Fibroscan and Fibrotest were compared with liver histology. RESULTS: Fibroscan values (n=20) ranged between 3.3 and 18.4 kPa (median value 6.4 kPa) and correctly identified 88% of the patients without significant liver fibrosis (Metavir score /=F2, Fibrotest >0.31). CONCLUSION: In this population, Fibrotest accurately predicted the presence of significant liver fibrosis while the Fibroscan accurately predicted the absence of significant liver fibrosis in MTX users. This suggests that a combination of Fibrotest and Fibroscan should prospectively be evaluated in monitoring and detecting significant MTX-induced liver fibrosis in psoriasis patients.     

Hepatotoxicity in patients with juvenile idiopathic arthritis receiving longterm methotrexate therapy

OBJECTIVE: To evaluate hepatotoxicity in patients with juvenile idiopathic arthritis (JIA) receiving methotrexate (MTX) therapy with doses of 20-30 mg/m2 of body surface area. METHODS: We graded the histology of percutaneous liver biopsies from 34 patients with JIA receiving longterm (> 2.4 years) MTX therapy at the Rheumatism Foundation Hospital, Heinola, Finland, using the Roenigk classification scale. Medical records of the patients with JIA were retrospectively analyzed. RESULTS: Of 10 patients with MTX doses >/= 20 mg/m2, 4 had grade II, 5 had grade I histology, and one specimen with extensive steatosis as the only pathologic finding could not be classified. All 24 patients treated with low dose MTX had grade I histology. No specimen showed fibrosis or cirrhosis. In 2 patients with grade II histology, extensive portal tract inflammation resolved when MTX was discontinued for 6 months. CONCLUSION: Aggressive medical treatment of JIA with MTX at 20-30 mg/m2 with concomitant disease modifying antirheumatic drugs and corticosteroids may contribute to minor liver abnormalities that seem to be reversible.     

Hepatitis with bridging fibrosis and reversible hepatic insufficiency in a woman with rheumatoid arthritis taking methotrexate

A patient with seropositive rheumatoid arthritis developed ascites while taking weekly doses of methotrexate (MTX). Her serum transaminase and albumin levels were normal. A liver biopsy revealed chronic hepatitis with bridging fibrosis and piecemeal necrosis. Upon discontinuation of MTX, her ascites resolved, and her arthritis became more active. This is the third report of reversible hepatic decompensation associated with prolonged MTX therapy in patients with rheumatoid arthritis.     

A prospective analysis of liver biopsies in rheumatoid arthritis patients receiving long term methotrexate therapy

Summary Baseline and sequential liver biopsies were performed in ten patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) for more than 4 years. Liver biopsies were performed in all patients before the initiation of MTX therapy and were repeated after reaching a cumulative dose of 1500 mg or more. In four patients a third biopsy was performed 3 years after the first one. No significant worsening of hepatic architecture was found in any of our patients after 4 to 71/2 years of MTX therapy. No correlations between histologic findings and various clinical or pharmacological variables could be found. Our results suggested that prolonged MTX administration in RA patients did not cause severe hepatic abnormalities.     

Massive intrahepatic hemorrhage following routine liver biopsy in a patient with rheumatoid arthritis treated with methotrexate.

Massive intrahepatic hemorrhage occurred in a patient with rheumatoid arthritis (RA) after a routine liver biopsy done to assess possible methotrexate (MTX) hepatotoxicity. Major complications of liver biopsy occur about once in every 600 biopsies, and mortality from liver biopsy has been reported. Life threatening hepatic toxicity occurs rarely during low dose MTX administration, and it is unclear whether routine liver biopsies identify patients at high risk for these complications. Until the relative risks of liver biopsy and serious MTX liver toxicity are better defined, the use of routine liver biopsies should be recommended only after careful consideration of potential procedural complications in patients with RA treated with MTX.     

Hepatic fibrosis with the use of methotrexate for juvenile rheumatoid arthritis

Methotrexate (MTX) is currently under study for use in juvenile rheumatoid arthritis. One complication of MTX is hepatotoxicity. Although liver function tests may be abnormal with its use, in this setting they do not correlate well with the development of hepatic fibrosis. Periodic liver biopsy is required to monitor for the hepatotoxic changes secondary to MTX. We describe and discuss the case of a 17-year-old woman who developed evidence of hepatic fibrosis after 3 years of MTX therapy.     

Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis

PURPOSE: Beginning in the 1980s, methotrexate has been used successfully to treat rheumatoid arthritis. The magnitude and severity of short- and long-term methotrexate toxicity, however, have not been adequately investigated. Our study was performed to determine the prevalence of hepatotoxicity in patients with rheumatoid arthritis receiving long-term methotrexate therapy. PATIENTS AND METHODS: We conducted a retrospective, computer-assisted review of all Duke University Medical Center patients undergoing liver biopsy for methotrexate monitoring from January 1979 to January 1988. A total of 538 biopsies were performed in 399 patients, 259 of whom had inflammatory arthritis (210 with rheumatoid arthritis, 47 with psoriatic arthritis, and two with seronegative spondyloarthropathy). RESULTS: No evidence of cirrhosis was defined in the cohort with rheumatoid arthritis; however, six patients with rheumatoid arthritis had histologic changes of fibrotic liver disease (prevalence of 2.9 percent in the group with rheumatoid arthritis) while taking methotrexate. Five of the six patients were obese and three had glucose intolerance or overt diabetes mellitus, and one person admitted to alcohol usage. Only one patient with fibrotic liver disease had elevated liver function test results, and no person showed a declining serum albumin level at the time of biopsy. Sixty-one patients with rheumatoid arthritis underwent multiple samplings (44 with two, 13 with three, and four with four biopsies). Fourteen of these patients showed progressive hepatic disease, whereas four patients improved. CONCLUSION: Although the prevalence of methotrexate hepatotoxicity in this large cohort of patients with rheumatoid arthritis was low, a small but definite risk of hepatic fibrosis, not predictable by laboratory screening, still exists.     

Methotrexate therapy in rheumatoid arthritis. A two year prospective follow-up

Summary One hundred and thirty seven rheumatoid arthritis (RA) patients refractory to D-penicillamine and some of them (15%) refractory to other slow active drugs were treated with oral methotrexate (MTX) (10–15mg weekly). After 12–24 months of treatment, 94 and 74 patients respectively showed a significant improvement as judged by duration of morning stiffness (p<0.0001), grip strength (p<0.0001), degree of joint swelling (p<0.01) and tenderness (p<0.0001) compared to pre-treatment values. This clinical improvement was also associated with a decrease of erythrocyte sedimentation rate (p<0.0001), decrease of C-reactive protein (p<0.0001) and with improvement of anaemia (p<0.05). No changes were seen in rheumatoid factor titres. Seventy-four of the patients were followed for up to 24 months. Thirty-one of them (23%) had complete remission and 43 (31%) had an excellent response. Adverse drug reaction during MTX therapy included: elevated liver enzymes in 34 patients, mucosal ulcers in 21, nausea and vomiting in 8, diarrhoea in 4, leukopenia in 2, interstitial pneumonitis in one, intestinal bleeding in one and finally septic arthritis in another patient. The majority of these side effects were resolved without sequelae. However, 15 patients (11%) with adverse drug reactions had to discontinue the treatment. Forty-one of our patients who received a cumulative mean dose of MTX of 1550.5±235.5 mg underwent a percutaneous liver biopsy. Ten patients had normal tissue, 12 had minimal changes, 13 nonspecific changes and 6 patients had mild fibrosis. We conclude that MTX therapy in refractory RA patients appears to be effective, but requires close monitoring for toxicity. Hepatotoxicity with fibrosis and cirrhosis due to long term MTX therapy may be relatively uncommon in RA patients.     

Nonalcoholic fatty liver disease: Improvement in liver histological analysis with weight loss

The effect of significant weight loss on nonalcoholic fatty liver disease remains unclear. In this case series of 36 selected obese patients, we examined the effect of weight loss on nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. These 36 patients (11 males, 25 females) had paired liver biopsies, the first at the time of laparoscopic adjustable gastric band placement and the second after weight loss. Second biopsies were obtained from two groups: those requiring a subsequent laparoscopic procedure (n = 19) and those with index biopsy score of 2 or greater for zone 3-centric hepatic fibrosis (n = 17). All biopsies were scored, blinded to the patient's identity and clinical condition, for individual histological features and for NASH stage and grade. Initial biopsies demonstrated NASH in 23 patients and steatosis in 12 patients. Repeat biopsies were taken at 25.6 +/- 10 months (range, 9-51 months) after band placement. Mean weight loss was 34.0 +/- 17 kg, and percentage of excess weight loss was 52 +/- 17%. There were major improvements in lobular steatosis, necroinflammatory changes, and fibrosis at the second biopsy (P <.001 for all). Portal abnormalities remained unchanged. Only four of the repeat biopsies fulfilled the criteria for NASH. There were 18 patients with an initial fibrosis score of 2 or more compared with 3 patients at follow-up (P <.001). Those with the metabolic syndrome (n = 23) had more extensive changes before surgery and greater improvement with weight loss. In conclusion, weight loss after surgery provides major improvement or resolution of obesity and metabolic syndrome-associated abnormal liver histological features in severely obese subjects.