inflammatory bowel disease. The immunomodulatory ef-fects are thought to be mediated via the active metabolite,6-thioguanine (11). These agents have been shown to beeffective in treating active disease, maintaining remission,closing fistulae, and sparing steroids in the adult population(1, 2). However, these beneficial effects may take severalmonths to occur (11).

A recent article by Markowitz et al. (12) supports the useof 6-mercaptopurine early in the disease course in a pedi-atric population with moderate to severe Crohn’s disease.Patients had significant improvement in clinical outcome at12 months, with fewer patients experiencing disease relapseand less cumulative steroid dose relative to the patients whoreceived standard medical therapy. 6-Mercaptopurine iswell tolerated by most people, and with the first publishedreports of 6-mercaptopurine in inflammatory bowel diseaseappearing 30 yr ago, it does not appear to be associated withany significant long term sequelae when used in the doses of1–1.5 mg/kg/day (1).

Infliximab, a chimeric monoclonal antibody directedagainst tumor necrosis factor � has proven effective incontrolled trials of patients with medically refractorymoderate to severe Crohn’s disease (3, 4). Infliximab wasshown to be safe and effective in the short term treatmentof medically refractory Crohn’s disease in a pediatricpopulation and also showed a prolonged duration of re-sponse in those patients who received the infliximabinfusion earlier in the disease course (13). Preliminarydata from a multicenter, prospective, placebo-controlledtrial of repeat dosing of Remicade in patients with in-flammatory Crohn’s disease demonstrate that repeat dosingis well tolerated by most patients and those patients receiv-ing multiple infusions were twice as likely to be in remissionthan those receiving placebos at 30 wk (14). Long termefficacy and safety remain important, as yet unansweredquestions.

Our case demonstrates a rapid clinical response to earlyuse of infliximab and 6-mercaptopurine in an adolescentwith Crohn’s colitis that had been refractory to ASA agentsand antibiotics. Our patient achieved clinical remissionwithout receiving any steroids. Recent studies suggest thatearly use of immunomodulatory therapy and biologicalagents may alter the natural history of Crohn’s disease (15,16). Our experience in this patient supports the early ag-gressive use of infliximab to achieve prompt remission andavoid steroid-related complications. Early use of infliximabrequires further investigation in a prospective controlledtrial comparing it to steroids.

Kimberly Persley, M.D.Ellen Scherl, M.D.Peter Rubin, M.D.

Mount Sinai Medical CenterNew York, New York

REFERENCES

1. Present D, Korelitz B, Wisch N, et al. Treatment of Crohn’sdisease with 6MP: Long term, randomized, double-blindstudy. N Engl J Med 1980;308:981–7.

2. Pearson D, May G, Fick G, Sutherland L. Azathioprine and6MP in Crohn’s disease: A metanalysis. Ann Intern Med1995;123:132–42.

3. Targan S, Hanauer S, Deventer S, et al. A short-term study ofchimeric monoclonal antibody cA2 to tumor necrosis factoralpha for Crohn’s disease: Crohn’s Disease cA2 Study Group.N Engl J Med 1997;337:1029–35.

4. Present D, Rutgeerts P, Targan S, et al. Infliximab for thetreatment of fistulas in patients with Crohn’s disease. N EnglJ Med 1999;340:1398–1405.

5. Summers R, Switz D, Sessions J, et al. National CooperativeCrohn’s Disease Study: Results of drug treatment. Gastroen-terology 1979;77:847–69.

6. Present DH. How to do without steroids in inflammatorybowel disease. Inflamm Bowel Dis 2000;6:48–57.

7. Lichtenstein GR. Treatment of fistulizing Crohn’s disease.Gastroenterology 2000;119:1132–47.

8. Kelts DG, Grand RJ, Shen G, et al. Nutritional basis of growthfailure in children and adolescents with Crohn’s disease. Gas-troenterology 1979;75:720–7.

9. Hyams JS, Treem WR, Carey DE, et al. Comparison of col-lagen propeptides as growth markers in children with inflam-matory bowel disease. Gastroenterology 1991;100:971.

10. Sadeghi-Nejad A, Senior B. The treatment of ulcerative colitisin children with alternate-day corticosteroids. Pediatrics 1969;43:840–4.

11. Dubinsky M, Lamothe S, Yang H, et al. Pharmacogenomicsand metabolic measurement for 6-mercaptopurine therapy ininflammatory bowel disease. Gastroenterology 2000;118:705–13.

12. Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of6MP and prednisone in children with newly diagnosedCrohn’s disease. Gastroenterology 2000;119:895–902.

13. Kugathasan S, Werlin S, Martinez A, et al. Prolonged durationof response to infliximab in early but not late pediatric Crohn’sdisease. Am J Gastroenterol 2000;95:3189–94.

14. Hanauer SB, Lichtenstein JF, et al. Maintenance infliximab(Remicade) is safe, effective and steroid-sparing in Crohn’sdisease: Preliminary results from the Accent I Trial. Gastro-enterology 2001;A99.

15. Baert FJ, D’Haens GR, Peeters M, et al. Tumor necrosisfactory a antibody (infliximab) therapy profoundly down-reg-ulates the inflammation in Crohn’s ileocolitis. Gastroenterol-ogy 1999;116:22–8.

16. D’Haens G, Deventer S, Hogezand RV, et al. Endoscopic andhistological healing with infliximab anti-tumor necrosis factorantibodies in Crohn’s disease: A European multicenter trial.Gastroenterology 1999;116:1029–34.

Reprint requests and correspondence: Ellen Scherl, M.D., 12East 86th Street, New York, NY 10028.

Received June 12, 2001; accepted June 13, 2001.

Hypoxic Hepatitis Related to ProfoundAnemia: How Low Can You Go?TO THE EDITOR: Hypoxic hepatitis due to severe hypox-emia has been described in the setting of acute exacerbation

3445AJG – December, 2001 Letters to the Editor

of chronic respiratory failure (1–3), obstructive sleep apnea(4, 5), and carbon monoxide poisoning (6). We describe, toour knowledge, the first reported case of what we believe tobe hypoxic hepatitis related to profound anemia in theabsence of hypotension.

A 47-yr-old white male with cerebral palsy presented tothe emergency room with increased weakness and lethargyof a few weeks duration. He denied aspirin, nonsteroidalanti-inflammatory drugs, or alcohol. He had no past historyof GI, liver, or cardiopulmonary disease. His medicationswere phenobarbital and phenytoin. On examination, he waspale and obtunded and had Kussmaul’s respirations. He wasafebrile, with a blood pressure of 110/80. Cardiopulmonaryexamination was otherwise normal. The abdomen was be-nign, without hepatosplenomegaly. There were no stigmataof chronic liver disease. Rectal examination revealed brownstool strongly positive for occult blood.

Hb was 1.8 g/dl and Hct 6.8%, with a mean corpuscularvolume of 56. Iron indices and ferritin were consistent withiron deficiency anemia. A severe lactic acidemia waspresent with an arterial pH of 6.8, bicarbonate of 4, andpCO2 of 28. AST was 2234 U/L, ALT 975 U/L, and LDH2746 U/L. Bilirubin and ALP were normal. PT was 21 s andPTT was 54 s. Lactate levels were elevated. No otheretiology of liver dysfunction was found. There was noevidence of sepsis.

The patient was resuscitated with oxygen and blood trans-fusions. Endoscopy revealed a large hiatal hernia and a largeCameron ulcer. Liver biochemistries, PT, and PTT normal-ized rapidly, within 6 days of resuscitation.

We propose that profound anemia with resultant de-creased hepatic oxygenation was the major etiological factorof our patient’s hepatitis. Animal studies have suggestedthat extreme hypoxemia could result in necrosis of centri-lobular hepatocytes. In patients with respiratory failure, arelationship was shown between the degree of arterial hy-poxemia and the increase in serum transaminase levels (2,3). Consistent with this mechanism, hypoxic hepatitis hasbeen reported in patients with carbon monoxide poisoning(6) and with obstructive sleep apnea (4, 5).

Hypoxic hepatitis has been most commonly described inpatients with severe hypoxemia due to acute on chronicrespiratory failure. Henrion et al. (1) performed hemody-namic studies in patients with hypoxic hepatitis due to acuteon chronic respiratory failure. They compared these to agroup of patients with acute respiratory failure not associ-ated with hypoxic hepatitis, and to patients with ischemichepatitis due to congestive heart failure (1). The patientswith acute on chronic respiratory failure complicated byhypoxic hepatitis had the lowest mean pO2. As expected, thepatients with congestive heart failure had low cardiac indi-ces and elevated systemic vascular resistance. In contrast,the elevated pCO2 in the patients with respiratory failurewas associated with lower systemic vascular resistance andgreater cardiac indices. Hepatic blood flow is proportional to

cardiac output; it is reduced in ischemic hepatitis due tocongestive heart failure, but not in hypoxic hepatitis due tosevere hypoxemia (1). Thus, ischemic hepatitis in patientswith congestive heart failure is generally associated withdecreased cardiac indices and reduced hepatic blood flow,and not necessarily with as prominent a drop in pO2. Incontrast, hypoxic hepatitis in respiratory failure is generallyassociated with extremely severe hypoxemia, but preservedhepatic blood flow. Central venous pressure was elevated inpatients with hypoxic hepatitis due to acute and chronicrespiratory failure compared to patients with acute respira-tory failure not associated with hypoxic hepatitis. Thus,passive congestion of the liver may contribute to a predis-position to hypoxic hepatitis in patients with acute onchronic respiratory failure.

Our patient had no pulmonary or cardiac disease. Hedeveloped severe lactic acidemia associated with profoundanemia in the absence of hypotension. The development oflactic acidemia in this setting implies tissue hypoxia. He wasastoundingly anemic—to a degree that would critically af-fect the blood’s oxygen-carrying capacity. How low can yougo? We feel our patient’s hepatic dysfunction was due toreduced oxygen delivery to the liver causing a hypoxichepatitis. The patient’s rapid rise and fall in transaminases,LDH, PT, and PTT are characteristic of ischemic or hypoxichepatitis. They were synchronous with the profound anemia(Hb, 1.8) and severe lactic acidemia (pH, 6.8; bicarbonate,4). The liver dysfunction resolved rapidly after lifesavingresuscitation with oxygen and blood transfusion. When clin-ical and laboratory features are typical and when othercauses of acute hepatitis are excluded, liver biopsy is notmandatory for the diagnosis.

We propose that severely reduced hepatic oxygenationrelated to profound anemia is the major etiological factorcausing hypoxic hepatitis. Other possible contributory fac-tors include intravascular volume contraction secondary toGl blood loss, increased hepatic centrizonal oxygen require-ment due to cytochrome P450 inducers (phenobarbital andphenytoin), and transient cardiac dysfunction due to severeacidemia.

In summary, we describe what we believe to be the firstreported case of hypoxic hepatitis related to profound ane-mia. We propose that severely reduced hepatic oxygen de-livery caused by profound anemia is the major etiologicalfactor.

Andrew Okas, D.O.Joseph Kowalczyk, M.D.

Robert Stein, M.D.Douglas Lee, M.D.

Charles Berkelhammer, M.D.Division of Gastroenterology

Christ HospitalUniversity of Illinois

Oak Lawn, Illinois

3446 Letters to the Editor AJG – Vol. 96, No. 12, 2001

REFERENCES

1. Henrion J, Minette P, Colin L, et al. Hypoxic hepatitis causedby exacerbation of chronic respiratory failure: A case-con-trolled hemodynamic study in 117 consecutive cases. Hepatol-ogy 1999;29:427–33.

2. Refsum HE. Arterial hypoxemia, serum activities of GOT, GPTand LDH, and centrilobular liver cell necrosis in pulmonaryinsufficiency. Clin Sci 1963;25:369–74.

3. Refsum HE. Severe arterial hypoxemia and liver cell necrosis inpatients with pulmonary insufficiency. Acta Med Scand 1964;176:473–8.

4. Henrion J, Colin L, Schapira M, et al. Hypoxic hepatitis causedby severe hypoxemia from obstructive sleep apnea. J ClinGastroenterol 1997;24:245–9.

5. Mathurin P, Durand F, Ganne N, et al. Ischemic hepatitis due toobstructive sleep apnea. Gastroenterology 1995;109:1682–4.

6. Watson A, Williams R. Anoxic hepatitis and intestinal injuryfrom carbon monoxide poisoning. BMJ 1984;289:1113.

Reprint requests and correspondence: Charles Berkelhammer,M.D., 9921 Southwest Highway, Oak Lawn, IL 60453.

Received Nov. 30, 2000; accepted June 26, 2001.

Liver-Kidney Microsomal Antibody–Positive Autoimmune Hepatitis in theUnited StatesTO THE EDITOR: We read with interest the article byDuchini et al. (1) reporting five cases of liver-kidney mi-crosomal antibodies type-1 (LKM1)–positive autoimmunehepatitis (AIH) in the western United States, and we agreewith their concluding remark that clinicians should be awareof this condition. We would like, however, to make a fewcomments:

● It is often claimed, as in the present article, that LKM1-positive AIH is rare or even absent in the United States.To support this claim, Duchini et al., and others beforethem, refer to a study by Lindgren et al. (2, 3). This workwas performed in Sweden, on 367 Swedish patients (3).The study was conducted to test an as yet not validatedassay for the detection of LKM1. None of the patientstested with the new assay was positive for LKM1 byconventional immunofluorescence assay. Not surpris-ingly, all of the patients were negative with the new assay.A single LKM1-positive control serum was used as ref-erence, and this is hardly sufficient to validate a newassay. As implied by the authors, LKM1 is not soughtroutinely in the United States in patients with inflamma-tory liver disease, and this is a more likely explanation forits rarity in the United States than the fact that is notdetectable in Sweden (3). Based on the Swedish articlethe authors go on to state that LKM1-positive AIH is rarein Northern Europe: the article with the largest cohort ofLKM1-positive patients with AIH describing clinical fea-tures, response to treatment, and long term follow-up inthis condition comes from the United Kingdom, arguablylocated in Northern Europe (4).

● It is not surprising that a mean of 3 yr from onset ofsymptoms elapsed before the diagnosis of AIH was madein the five patients described by Duchini et al., when apublication as authoritative as the New England Journalof Medicine claims in a “clinical practice” article thatautoantibody determination is unnecessary for the diag-nosis of AIH (5). As stated by an international panelconvened to define criteria for the diagnosis of AIH,non–organ-specific autoantibodies (antinuclear antibod-ies/anti–smooth muscle antibodies for type 1 AIH andanti-LKM1 antibodies for type 2 AIH) remain disease-defining hallmarks (6). LKM1, conventionally detectedby the subjective technique of immunofluorescence, is notuncommonly mistaken for antimitochondrial antibody.Czaja et al. (7) reported that adult patients originallyclassified as affected by antimitochondrial antibody–posi-tive AIH, on retesting were found to be seropositive forLKM1. After the discovery of cytochrome P450IID6(CYP2D6) as the molecular target of LKM1, ELISAswith high sensitivity and specificity are becoming com-mercially available, and their routine use in laboratoriesmay overcome the current difficulty in the diagnosis ofLKM1-positive AIH.

● LKM1-positive AIH is typical of children and youngadults. The disease frequently starts acutely and, apartfrom its occasional presentation as fulminant liver failure,responds satisfactorily to immunosuppression, thoughtreatment may need to be continued for life. In our expe-rience, correct diagnosis followed by early treatment iscompatible with long term transplant-free survival, indi-cating that the presence of this autoantibody should beactively sought in young patients with inflammatory liverdisease (4). These patients should be referred to experi-enced pediatric/adult hepatogastroenterology centers formanagement. Only �10% will then need referral to atransplant center (4).

Dimitrios-Petrou Bogdanos, M.D.Giorgina Mieli-Vergani, M.D.

Diego Vergani, M.D.

Institute of HepatologyUniversity College London

Department of Child HealthKing’s College Hospital

London, United Kingdom

REFERENCES1. Duchini A, McHutchison JG, Pockros PJ. LKM-positive auto-

immune hepatitis in the western United States: A case series.Am J Gastroenterol 2000;95:3238–41.

2. Cerny A, Chisari FV. Pathogenesis of chronic hepatitis C:Immunological features of hepatic injury and viral persistence.Hepatology 1999;30:595–601.

3. Lindgren S, Braun HB, Michel G, et al. Absence of LKM-1antibody reactivity in autoimmune and hepatitis-C-related

3447AJG – December, 2001 Letters to the Editor