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Smith AI, Royston CMS, Sedman PC. Stapled and non-stapled laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair: a prospective randomised trial. Surg Endosc 1999; 13: 804–06. 3 Wright D, O’Dwyer PJ. The learning curve for laparoscopic hernia repair. Semin Laparosc Surg 1998; 5: 227–32. 4 Rattner DW. Inguinal herniorrhaphy: for surgical specialists only? Lancet 1999; 354: 175–76. 5 Liem MSL, Van der Graaf Y, Van Steensel CJ, et al. Comparison of conventional anterior surgery and laparoscopic surgery for inguinal hernia repair. N Engl J Med 1997; 336: 1541–47.

Commentator’s reply Sir—I am not surprised that the MRC Trial Group report 1 and my accompanying commentary have provided further fuel to the controversy about the role of laparoscopic inguinal herniorrhaphy. Your correspondents point out some of the deficiencies in the trial, while at the same time expressing the biases of the respective authors. Faisal Abbasakoor and colleagues praise the plug and patch technique, but many surgeons have had the unpleasant experience of having to remove plugs that migrated, impinged on the genitofemoral or ilioinguinal nerve, or incited an intense fibrotic reaction resulting in a painful groin mass. Several new dual component prostheses (consisting of a preperitoneal sheet of mesh connected to an anterior piece of mesh designed to lie in the floor of the inguinal canal) may mitigate this difficulty, although the objective data to support this claim do not yet exist. I concur fully with Danie Fölscher and co-workers that there is concern about the relative skill and experience of the surgeons in laparoscopic herniorrhaphy compared with open herniorrhaphy. As I stated, that laparoscopic herniorrhaphy fared as well as it did under these circumstanes is surprising. M J Notaras points out the simplicity and safety of open herniorrhaphy under local anaesthesia with conscious sedation. There is little question that repair of first time unilateral hernias is accomplished safely and cost-effectively by this standard approach. However, as comfortable as this technique is for the surgeon, patients who have had both a laparoscopic and an open herniorrhaphy almost universally report less pain and disability after laparoscopic repair. Although surgeons in the UK may choose an open herniorrhaphy for themselves,2 those in American cities where expert laparoscopic surgeons are available are

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increasingly choosing laparoscopic hernia repairs for themselves.3 When I began doing laparoscopic hernia repairs I held the views expressed by Notaras and Abbasakoor. Surgical colleagues at my own institution continue to hold these views. However, patients’ response to laparoscopic herniorrhaphy has been so favourable that I doubt this operation is heading for the “inevitable extinction” that Notaras proclaims. David W Rattner Division of General and Gastrointestinal Surgery, Massachusetts General Hospital, Boston, MA 02114, USA (e-mail: [email protected]) 1

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The MRC Laparoscopic Groin Hernia Trial Group. Laparoscopic versus open repair of groin hernia: a randomised comparison. Lancet 1999; 354: 185–90. Williams N, Scott A. Conventional or laparoscopic inguinal hernia repair? The surgeon’s choice. Ann R Coll Surg Engl 1999; 81: 56–57. Rattner DW. Physicians’ choice for their own inguinal hernia repairs. J Laparoendosc Adv Surg Tech (in press).

Non-alcoholic steatohepatitis Sir—Oliver James and Christopher Day, in their excellent May 15 on non-alcoholic commentary1 steatohepatitis (NASH), review in detail the mechanisms that can cause this condition and justly emphasise the strong association with insulin resistance, central obesity, and increased supply of fatty acids to the liver. These associations may explain the recent findings of the National Health and Nutrition Examination Survey (NHANES-3), which showed a prevalence of 2·6% of raised alanine aminotransferase concentrations. However, in their discussion of the various treatments James and Day fail to mention the possible efficacy of simple measures aimed at improving the associated metabolic abnormalities. We have evaluated2 48 consecutive patients referred to our gastroenterology unit for chronically (>6 months) raised liver enzymes with clinical, ultrasound, and histological findings consistent with fatty infiltration of the liver and no data suggesting any other specific cause. Most (39, 81%) patients were overweight or obese and had increased waist circumference, which closely relates to visceral fat. Only five (10%) patients had normal glucose tolerance. Type 2 diabetes was found in 21 (44%), 14 (29%) had impaired glucose tolerance, and eight (17%) were hyperinsulinaemic. 41 (85%) had hypertriglyceridaemia, low serum HDL

cholesterol concentration, or both. We noted that dietary intervention, supplemented by oral hypoglycaemic or lipid-lowering drugs as needed, and follow-up (median 24 months) resulted not only in a moderate weight loss, decreased fasting blood glucose, and improved serum lipid profile, but also in a substantial reduction in serum liver enzymes in 46 (96%), which became normal in more than half the patients. The improvement in liver enzymes was not associated with initial metabolic or histological findings (such as inflammation or fibrosis). Thus, fatty infiltration of the liver and its more severe form NASH are strongly associated with many features of insulin resistance syndrome and have a high potential for reversibility once the metabolic profile abnormalities are improved. This reversal can be readily accomplished by following simple dietary and drug interventions. Such therapeutic measures have an additional and important benefit of lowering the increased risk for cardiovascular diseases associated with insulin resistance syndrome. 3 *Hilla Knobler, Ami Schattner Hebrew University and Hadassah School of Medicine, Jerusalem 91120, Israel 1

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James O, Day C. Non-alcoholic steatohepatitis: another disease of affluence. Lancet 1999; 353: 1634–36. Knobler H, Schattner A, Zhornicki T, et al. Fatty liver—an additional and treatable feature of the insulin resistance syndrome. QJM 1999; 92: 73–79. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dislipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173–94.

Sir—In their commentary,1 Oliver James and Christopher Day called NASH “another disease of affluence” because of its close association with obesity in western countries. In a series of 528 liver biopsies in severely obese individuals (428 female, 100 male; mean age 36·2 [SD 10·5] years; mean body mass index [BMI] 42·6 [6·8] kg/m2) who had gastroplasty, fatty deposition was seen in 391 (74%) of the biopsy specimens, and were scored as mild (160, 41%), moderate (125, 32%), or severe (106, 27%).2 The prevalence of steatosis was significantly higher in men than in women (91 vs 70%, p<0·001) and in diabetic than in non-diabetic patients (89 vs 69%, p<0·001). Steatosis severity was positively associated with BMI (p=0·002), fasting hyperglycaemia (p=0·007), hypertriglyceridaemia, (p=0·002), and hyperinsulinaemia

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(p=0·003). Thus, liver steatosis can be regarded as part of the insulin resistance or metabolic syndrome.3 We have also reported4 in a cohort of 505 obese patients who had gastroplasty that the prevalence and severity of all biological abnormalities associated with the metabolic syndrome significantly regressed after a mean weight loss of 32 (SD 16) kg and a mean follow-up of 26 (14) months after bariatric surgery. For instance, the prevalence of hyperglycaemia fell from 35% to 21% (p=0·004), that of hyperinsulinaemia from 58% to 32% (p=0·004), that of low HDL cholesterol from 44% to 35% (p=0·05), and that of hyperfibrinogenaemia from 43% to 20% (p=0·003).4 Furthermore, we showed5 in a subset of obese women that recovery of ideal body weight after gastroplasty was accompanied by return to normal of insulin secretion, clearance, and action on glucose metabolism. 69 patients of the initial cohort who had a liver biopsy before gastroplasty had a second procedure 27 (15) months after bariatric surgery, in the course of a mandatory surgical procedure.2 After a mean weight loss of 32 (19) kg, a remarkable reduction in liver fatty scores was noted: 45% of the biopsy specimens were classified as normal (vs 13% at baseline, p<0·001), and pure fatty changes were still seen in only 38% of the patients (vs 83% before weight loss, p<0·001). In addition, the severity of the steatosis was significantly (p<0·001) reduced. However, a significant increase of hepatitis was recorded (26% of specimens after vs 14% before gastroplasty, p<0·05). As James and Day discuss, we do not exclude that the rapid mobilisation of fatty acids or cytokines from adipose tissue, as a result of drastic weight reduction after restrictive gastroplasty, may be toxic for the liver and result in mild lobular hepatitis in some individuals, despite the overall regression of pure steatosis recorded in most patients. NASH may indeed be regarded as another disease of affluence since its presence in severe obesity can be reversed, at least in part, by weight loss. In this respect, the regression of liver steatosis parallels the correction of the classic biological markers of the metabolic syndrome associated with insulin resistance, another disease of affluence. Françoise H Luyckx, *André J Scheen, Pierre J Lefèbvre

affluence. Lancet 1999; 353: 1634–36. Luyckx FH, Desaive C, Thiry A, et al. Liver abnormalities in severely obese subjects: effects of drastic weight loss after gastroplasty. Int J Obesity 1998; 22: 222–26. 3 Marceau P, Biron S, Hould F-S, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999; 84: 1513–17. 4 Luyckx FH, Scheen AJ, Desaive C, Dewé W, Gielen JE, Lefèbvre PJ. Effects of gastroplasty on body weight and related biological abnormalities in morbid obesity. Diab Metab 1998; 24: 355–61. 5 Letiexhe MR, Scheen AJ, Gérard PL, Desaive C, Lefèbvre PJ. Postgastroplasty recovery of ideal body weight normalizes glucose and insulin metabolism in obese women. J Clin Endocrinol Metab 1995; 89: 393–99.

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Authors’ reply Sir—We are grateful for the supportive comments of Hilla Knobler and Ami Schattner, and Françoise Luyckx and colleagues. Both groups refer to very recent studies1,2 published after we had written our commentary. Knobler and colleagues’ report 1 included 48 patients with chronically raised liver enzymes and fatty liver shown on ultrasonography, in whom other specific causes of liver disease had been excluded. Of the 16 patients who underwent liver biopsy eight seem to have had fatty liver alone with no inflammation or fibrosis. These workers suggest that weight loss and lowering of HDL cholesterol after diet and, where indicated, hypoglycaemic or lipid-lowering drugs, led to improvement in liver enzymes in those with fatty liver alone and those with fibrosis or inflammation on biopsy, although no repeat liver biopsies were done. This sensible pragmatic approach should, however, be examined in a controlled trial, with monitoring of liver histology in patients with NASH before firm conclusions can be drawn. We were pleased that Luyckx and colleagues support the metabolic syndrome as a disease of affluence notion for NASH. The studies that they cite add to those suggesting that weight loss does lead to improvement, not only in fatty liver but also in other aspects of the metabolic syndrome. However, like Luyckx and colleagues, we would draw attention to the fact that sudden striking weight loss—for example after gastroplasty—may lead to worsening of liver enzymes and possibly to liver failure. *O F W James, C P Day

Departments of Clinical Chemistry, *Medicine, Surgery and Anatomopathology, CHU Sart Tilman, B-4000 Liège, Belgium (e-mail: [email protected])

Centre for Liver Research, School of Clinical Medical Sciences, University of Newcastle upon Tyne NE2 4HH, UK

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James O, Day C. Non-alcoholic steatohepatitis: another disease of

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Knobler H, Schattner A, Zhornicki T, et al. Fatty liver—an additional and

treatable feature of the insulin resistance syndrome. QJM 1999; 92: 73–79. 2 Marceau P, Biron S, Hould F-S, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999; 84: 1513–17.

Sir—In their commentary, Oliver James and Christopher Day 1 present an update overview of NASH and provide a consensus that in addition to simple steatosis, a second hit capable of inducing necrosis, inflammation, and fibrosis is required for the development of NASH. We completely agree with this consensus. In our experience, tamoxifen induces liver steatosis (liver/spleen ratio <0·9) in 36% of breast cancer patients 2 and NASH emerges among them. 3 We also agree with the idea that oxidative stress and subsequent lipid peroxidation is a potential risk to deteriorate mitochondria in NASH through excessive free hepatic iron. We assessed plasma ferritin concentration in 51 patients with adjuvant tamoxifen. Plasma ferritin was higher than 90 ng/mL in 11 of 21 patients with liver steatosis, but in only two of 30 patients without liver steatosis (figure). ␹2 test and Fisher’s exact test in two-cell classification showed excessive plasma ferritin in adjuvant tamoxifen patients with liver steatosis (p=0·0006). Body-mass index (BMI) was significantly higher in patients with liver steatosis than that in patients without liver steatosis (25·2 kg/m 2 [SD 2·2] vs 22·0 kg/m2 [mean 2·7], p<0·0001). Seven of ten patients with BMI greater than 25 kg/m2 or 17 of 27 patients with BMI greater than 23 kg/m2 had liver steatosis, whereas only five of 24 patients with BMI less than 23 kg/m2 had this disorder. With a cut-off value of 23 kg/m2, BMI was a risk factor for liver steatosis with adjuvant tamoxifen (p=0·042). During the 1980s, NASH was recognised as a common complication of jejunoileal bypass surgery and as an adverse reaction to several drugs. In the past 5 years, it has become the third most common liver disease in North America. However, NASH with adjuvant tamoxifen is underdetected. 5-year therapy with adjuvant tamoxifen for breast cancer outweighs the risk to cirrhosis, but NASH may cryptogenically progress to cirrhosis.4 For this reason, we believe it important to improve awareness of the disorder to prevent the progression of steatosis to NASH and cirrhosis in patients on adjuvant tamoxifen, since coadministration of bezafibrate provides beneficial effects on tamoxifen-induced NASH.3

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Plasma ferritin concentration and liver/spleen ratio in patients receiving adjuvant tamoxifen *Computed tomography values (Housfield units).

Liver biopsy was undertaken in seven of 21 patients receiving adjuvant tamoxifen with liver steatosis, and NASH was shown in six patients. Five of the six patients with NASH had BMI below 28 kg/m2 and none had diabetes mellitus or hyperlipidaemia, even though a high proportion of NASH is associated with obesity, type 2 diabetes, or hyperlipidaemia. 1 Regular computed tomography or ultrasonography and laboratory tests are recommended to rule out liver metastasis and monitor liver steatosis as a risk factor for NASH during adjuvant tamoxifen. *Toshiji Saibara, Saburo Onishi, Yasuhiro Ogawa, Shouji Yoshida, Hideaki Enzan Departments of *Medicine, Radiology, and Pathology, Kochi Medical School, Nankoku 783-8505, Japan 1

James O, Day C. Non-alcoholic steatohepatitis: another disease of affluence. Lancet 1999; 353: 1634–36. 2 Ogawa Y, Murata Y, Nishioka A, Inomata T, Yoshida S. Tamoxifen-induced fatty liver in patients with breast cancer. Lancet 1998; 351: 725. 3 Saibara T, Onishi S, Ogawa Y, Yoshida S, Enzan H. Bezafibrate for tamoxifeninduced non-alcoholic steatohepatitis. Lancet 1999; 353: 1802. 4 Oien KA, Moffat D, Curry GW, et al. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet 1999; 353: 36–37.

Sir—In the conclusion of their c o m m e n t a r y 1 Oliver James and Christopher Day cite the findings of a pilot study indicating that the insulinsensitising drug troglitazone might be of therapeutic value for NASH. Whether the drug is being proposed for treatment of glucose intolerance or diabetes, or as a more general assault on insulin resistance, is not clear. There are important safety issues about troglitazone, the first of a new class of drugs—(the which was t h i a z o l i d i n e d i o n e s )2

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voluntarily withdrawn from the UK by its distributors shortly after introduction in 1997. This action followed reports of severe hepatotoxicity in patients with type 2 diabetes that resulted in death or liver transplantation. In 1999, the UK Medicines Control Agency rejected an application for its reintroduction. In the USA, where troglitazone remains available, the product information sheet has been amended after a review by the Food and Drug Administration; the drug is contraindicated in patients with active liver disease or serum transaminase concentrations greater than 1·5 times the upper limit of the normal range. 3 Whether other thiazolidinediones (rosiglitazone and pioglitazone) will have any hepatotoxic effects is not known with certainty. So far, reports about the latter agent are reassuring. 2 Metformin, another drug that improves insulin action, should also be used with caution in patients with NASH because of the potential increased risk (albeit small) of lactic a c i d o s i s .4 In such patients, the selection of antidiabetic drugs is an important therapeutic consideration. It could perhaps be argued on theoretical grounds that thiazolidinediones merit further cautious evaluation in patients with NASH. However, evidence of safety in the presence of liver disease should be a prerequisite. Another important point is that reduced sensitivity to insulin and glucose intolerance are features of others forms of chronic liver disease.5 It is unclear whether the insulin resistance associated with NASH is a non-specific biochemical abnormality. Careful selection and characterisation of patients and appropriate control groups are needed to clarify this point. Andrew J Krentz Department of Diabetes and Endocrinology, Southampton General Hospital, Southampton SO16 6YD, UK 1

James O, Day C. Non-alcoholic steatohepatitis: another disease of affluence. Lancet 1999; 353: 1634–36. 2 Day C. Thiazolidinediones: a new class of oral antidiabetic drugs. Diabet Med 1999; 16: 179–92. 3 Donnelly R. FDA reviews troglitazone. Diabet Obesity Metab 1999; 1: 65–66. 4 Sulkin T, Bosman D, Krentz AJ. Contraindications to metformin therapy in patients with NIDDM. Diabet Care 1997; 20: 925–28. 5 Krentz AJ. Insulin resistance. BMJ 1996; 313: 1385–89.

Antioxidants and Friedreich’s ataxia Sir—Pierre Rustin and colleagues (Aug 7, p 477)1 report that the lipidsoluble antioxidant idebenone could protect heart muscle from ironinduced damage in three patients with Friedreich’s ataxia over 4–9 months of follow-up. They also suggest that the application of antioxidants, such as ascorbate or glutathione, might actually be harmful because they reduce the mitochondrial iron overload from the Fe3+ to Fe2+ oxidation state, such that it can catalyse more oxygen radical formation. It seems plausible that cardiomyopathy in Friedreich’s ataxia could be favourably modified by careful choice of antioxidant drugs. Successful treatment of abnormalities of antioxidant metabolism in a 21-year-old woman with Friedreich’s ataxia after a 13-month follow-up has been described by Helveston and colleagues. 2 Comparison of pretreatment versus post-treatment whole blood concentrations after a 13-month follow-up showed an increase in selenium, in the antioxidant enzyme activity of glutathione peroxidase (GPX) and in glutathione reductase (GTR). An abnormally high lipid peroxide index (a measure of free radical activity) was also correctable. This regimen arrested further neurological decline with improvements in proprioceptive and vibratory sensation in her legs and in ambulation and ataxia. 3 Selenium deficiency in Friedreich’s ataxia probably reflects an increased demand for, and turnover of, antioxidant enzymes or their cofactors associated with the chronic oxidative burden. Selenium is required for GPX activity in the detoxification of peroxides, whereas GTR regenerates glutathione, a ubiquitous cellular reductant required for GPX activity. If a similar selenium deficiency and aberrant GPX activity can be shown in heart biopsy samples from patients with Friedreich’s ataxia, then simple selenium supplementation would become a logical option in this disease in which hypertrophic cardiomyopathy is the most frequent eventual cause of death. Michael J Fryer Department of Biology, John Tabor Laboratories, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK (e-mail: [email protected]) 1

Rustin P, von Kleist-Retzow J-C, Chantrel-Groussard K, Sidi D, Munnich A, Rotig A. Effect of idebenone

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