Case 39-2010: a 19-Year-Old Woman with Nausea, Jaundice, and Pruritus Lawrence S

T h e new england journal o f medicine

case records of the massachusetts general hospital

Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

Case 39-2010: A 19-Year-Old Woman with Nausea, Jaundice, and Pruritus Lawrence S. Friedman, M.D., Michael S. Gee, M.D., Ph.D., and Joseph Misdraji, M.D.

Presentation of Case

From the Departments of Medicine Dr. Kerry L. Massman (Medicine): A 19-year-old woman was transferred to this hospi- (L.S.F.), Radiology (M.S.G.), and Pathol- tal because of nausea, jaundice, and pruritus. ogy (J.M.), Massachusetts General Hos- pital; the Departments of Medicine The patient had been well until approximately 2.5 weeks earlier, when malaise, (L.S.F.), Radiology (M.S.G.), and Pathol- vomiting, and upper respiratory symptoms developed, which resolved after 3 days. ogy (J.M.), Harvard Medical School; and Approximately 1 week before admission, pruritus and dark urine developed. She the Department of Medicine, Tufts Uni- versity School of Medicine (L.S.F.) — all noted darkening of her skin, which she attributed to sun exposure. Three days in Boston; and the Department of Medi- later, for a headache, she reportedly took three doses of oxycodone–acetamino- cine, Newton–Wellesley Hospital, New- phen that she received from a friend, pseudoephedrine, and tablets containing a ton, MA (L.S.F.). combination of acetaminophen, aspirin, and caffeine. This article (10.1056/NEJMcpc1005309) Three days before admission, her mother brought her to the emergency depart- was updated on November 16, 2011, at ment at another hospital because of increasing discoloration of her eyes and skin. NEJM.org. She reported generalized malaise, decreased appetite, and a weight loss of approxi- N Engl J Med 2010;363:2548-57. mately 3 kg during the previous month. She did not have diarrhea or abdominal Copyright © 2010 Massachusetts Medical Society. pain. On examination, the vital signs were normal, and the conjunctivae and skin were icteric; the remainder of the examination was normal. Results of a complete blood count, a differential count, and renal-function tests were normal, as were plasma levels of electrolytes, glucose, calcium, alkaline phosphatase, and albumin. The total protein level was 8.2 g per deciliter (reference range, 6.0 to 8.0); other results are shown in Table 1. The patient was advised to avoid alcohol and over- the-counter medications, and she was discharged with a follow-up appointment at a medical clinic 2 days later. The next day, an episode of abdominal pain occurred. At the follow-up appointment the day after that, the patient reported increasing pruritus and nausea. Test- ing for acute Epstein–Barr virus (EBV) infection was negative, and a complete blood count, a differential count, and plasma levels of amylase, lipase, protein, and ammonia were normal; other test results are shown in Table 1. Urinalysis revealed orange, cloudy urine, with a pH of 6.0, a specific gravity of 1.020, 3+ bilirubin, 2+ blood, 1+ protein, and trace amounts of glucose, ketones, and leuko- cytes. Urinalysis also revealed positive nitrites, 2+ squamous cells, and 5 to 10 white cells and 2 to 5 red cells per high-power field, with occasional bacteria; the urobilinogen level was normal. An ultrasonogram of the abdomen showed chole-

2548 n engl j med 363;26 nejm.org december 23, 2010 The New England Journal of Medicine Downloaded from nejm.org by Danielle Klimas on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. case records of the massachusetts general hospital

Table 1. Laboratory Data.*

3 Days before 1 Day before Reference Range, Admission, Admission, Variable Adults† Other Hospital Other Hospital On Admission Activated partial-thromboplastin time 21.0–33.0 29 (ref 24.0–31.6) 27.0 (sec) Prothrombin time (sec) 10.8–13.4 12.6 (ref 8.9–10.6) 14.5 Bilirubin (mg/dl) Total 0.0–1.0 11.6 15.6 16.8 Direct 0.0–0.4 12.0 Aspartate aminotransferase (U/liter) 9–32 869 829 1035 Alanine aminotransferase (U/liter) 7–30 908 931 1176 Salicylate (mg/dl) 7 (ref 10–25) Antibody to hepatitis B surface antigen Equivocal Hepatitis B virus surface antigen Nonreactive Nonreactive Antinuclear antibodies Negative at 1:40 and Positive at 1:40 dilution, nega- 1:160 dilution tive at 1:80 and 1:160 dilu- tions, speckled pattern Antimitochondrial antibodies Negative at 1:20 dilution Negative at 1:20 dilution Anti–smooth-muscle antibodies Negative at 1:20 dilution Positive at 1:80 dilution Antibodies to liver–kidney microsomes (U) <20.1 <20.1

* Ref denotes reference range. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. To convert the values for salicylate to millimoles per liter, multiply by 0.07240. † Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.

lithiasis, a thickened gallbladder wall, and a New England. She took no other medications, normal-appearing liver and common bile duct. A did not take herbal supplements, and had no specimen of urine was cultured. The patient was known allergies to medications. She lived with sent to this hospital, arriving shortly after mid- her child and boyfriend in a rural area and had night, and was admitted. stopped working early in her pregnancy. She Three months earlier, the patient had given smoked cigarettes, drank alcohol rarely, and did birth to a healthy child by spontaneous vaginal not use intravenous drugs or eat wild mush- delivery after an uncomplicated, full-term gesta- rooms. She had had no industrial exposures, tion. She breast-fed for 2 months. Prenatal test- recent contacts with ill persons, or trauma. She ing for hepatitis B and C viruses (HBV and HCV) was of mixed European ancestry. Her paternal and the human immunodeficiency virus (HIV) grandmother had died of Laënnec’s cirrhosis, were reportedly negative, and the patient was not her paternal grandfather had died of lung can- informed of any abnormal liver-function tests cer, and maternal relatives had type 2 diabetes during pregnancy. She had migraines, for which mellitus and asthma; there was no other history she took pseudoephedrine and a tablet contain- of liver disease. ing a combination of acetaminophen, aspirin, On examination, the patient was awake, alert, and caffeine as needed. She had had an abnormal and oriented. The blood pressure was 143/83 Papanicolaou smear, for which she was sched- mm Hg; other vital signs were normal. There was uled to undergo colposcopy. Eighteen months marked conjunctival icterus, and the skin was yel- earlier, she had undergone body piercing at a low, with no spider angiomas, palmar erythema, reputable shop; she had never received a blood or telangiectasias. The abdomen was soft, with- transfusion. She had not recently traveled outside out tenderness, distention, or organomegaly.

n engl j med 363;26 nejm.org december 23, 2010 2549 The New England Journal of Medicine Downloaded from nejm.org by Danielle Klimas on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. T h e new england journal o f medicine

Neurologic examination revealed normal speech temic viral infections that may involve the liver, and attention and no asterixis. The remainder of or by drugs or toxic agents, and these must be the examination was normal. Results of a com- ruled out in this case. plete blood count and differential count were normal, as were serum levels of electrolytes, Viral hepatitis glucose, calcium, phosphorus, magnesium, total Viral hepatitis must lead the differential diagno- protein, albumin, globulin, alkaline phosphatase, sis in this case of acute hepatitis. We can essen- amylase, lipase, and ceruloplasmin. Testing was tially rule out acute hepatitis A infection because negative for EBV DNA by polymerase chain reac- of this patient’s negative test for IgM antibody to tion (PCR), cytomegalovirus (CMV) antigenemia, HAV, and acute hepatitis B because of the nega- antibodies to HIV and HCV, and IgM antibodies tive test for hepatitis B surface antigen (HBsAg). to hepatitis A virus (HAV); other test results are Occasionally, a patient with fulminant hepatitis shown in Table 1. Urine testing for pregnancy B will test negative for HBsAg, and antibody to and a toxicology screen were negative. Urinalysis HBsAg (anti-HBs) will appear early in the course revealed orange, clear urine, with a pH of 6.5, a of the infection. In this patient, it is more likely specific gravity of 1.010, 3+ bilirubin, 2+ blood, that the equivocal test for anti-HBs was due to and 20 to 50 white cells and 0 to 2 red cells per waning titers of anti-HBs as a result of vaccina- high-power field; there were few bacteria and tion against HBV in the remote past. The most squamous cells and very few tubular cells per reliable serologic marker of acute hepatitis B — high-power field; and mucin was present. An IgM antibody to hepatitis B core antigen1 — is electrocardiogram was normal. Ultrasonography not reported in the case summary. The absence of the abdomen revealed cholelithiasis, gallblad- of anti-HCV antibodies in this case does not reli- der-wall thickening, and no evidence of common ably rule out acute hepatitis C infection, because bile duct dilatation, pericholecystic fluid, or so- anti-HCV antibodies may not appear for several nographic Murphy sign (the presence of maxi- weeks after the acute presentation. In such cases, mal tenderness elicited over a sonographically the absence of HCV RNA reliably rules out acute localized gallbladder). The hepatic parenchyma hepatitis C. I suspect that a test for HCV RNA was unremarkable, and the hepatic vasculature was sent on admission. was patent. This patient could have a hepatitis-like illness A diagnostic procedure was performed. in association with acute EBV or CMV infection (infectious mononucleosis). In immunocompe- Differential Diagnosis tent hosts, the serum aminotransferase levels are usually no higher than two or three times Dr. Lawrence S. Friedman: Although I did not par- the upper limit of the normal range, and the ticipate in this young woman’s care, I am aware alkaline phosphatase level is characteristically of her diagnosis; the case was presented to me at elevated, in contrast to the findings in this a teaching conference shortly after her hospital- case.2-4 The absence of EBV DNA in the serum ization. May we review the imaging studies? or CMV antigenemia reliably rules out EBV or Dr. Michael S. Gee: An ultrasound examination CMV infection as the cause of this patient’s ill- of the abdomen (Fig. 1) revealed multiple gall- ness. On rare occasions, herpes simplex virus stones and thickening of the gallbladder wall, causes aggressive, life-threatening hepatitis in without evidence of dilatation of the common pregnant women (usually during the third tri- bile duct, pericholecystic fluid, or sonographic mester),5 in the absence of mucocutaneous le- Murphy sign. The hepatic parenchyma was unre- sions. The timing relative to pregnancy and the markable, and the hepatic vasculature (the he- nonfulminant course (thus far) make this diag- patic arteries and the portal and hepatic veins) nosis unlikely. was patent. No ascites was present. Dr. Friedman: The presentation is one of acute Drug- and toxin-induced hepatitis hepatitis, with characteristic clinical and bio- This patient had been taking acetaminophen, chemical features, and the differential diagnosis which is the most common dose-dependent cause is straightforward. Acute hepatitis is often caused of hepatotoxicity; toxic effects may develop either by one of several hepatotropic viruses, by sys- after an overdose, usually in a suicide attempt, or

2550 n engl j med 363;26 nejm.org december 23, 2010 The New England Journal of Medicine Downloaded from nejm.org by Danielle Klimas on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. case records of the massachusetts general hospital in persons who habitually drink alcohol in at least moderate amounts and ingest moderate thera- A peutic doses (10 to 20 g over a period of 3 days) of acetaminophen.6,7 Patients present with nausea, vomiting, drowsiness, anorexia, vomiting, and fatigue, with marked elevations of the serum aminotransferase levels, often between 2000 and 10,000 U per liter.7 Signs of acute liver failure may ensue. There is no evidence of excessive ingestion or of the use of acetaminophen before the onset of symptoms in this case, although the patient’s medical history may be unreliable. Despite the possible family history of alcoholic liver disease, the clinical presentation is not suggestive of acute alcoholic hepatitis, in which the aspartate amino- B transferase level is often below 300 U per liter and the alanine aminotransferase level is often normal or nearly normal, presumably because of con- comitant pyridoxine deficiency.8,9 This patient did not report exposure to drugs that may cause acute hepatitis on an allergic basis (e.g., nitrofurantoin, minocycline [both of which can lead to autoimmune hepatitis], phe- nytoin, sulfasalazine, and etretinate) or to those that may cause acute hepatitis as a result of sus- ceptibility to drug injury because of genetic or acquired alterations in drug metabolism, cana- C licular secretion, mitochondrial function, or cell- death–receptor signaling (e.g., isoniazid, other antituberculosis drugs, antifungal agents such as ketoconazole and terbinafine, thiazolidinediones, monoamine oxidase inhibitors, selective sero- tonin reuptake inhibitors, and nonsteroidal antiinflammatory drugs).10 Acute hepatic injury may result from ingestion of poisonous mushrooms, including Amanita phylloides or A. verna; drugs of abuse, including cocaine, 3,4-methylenedioxymethamphetamine (“ecstasy”), and phencyclidine (“angel dust”); and various herbal preparations, including ma Figure 1. Abdominal Ultrasonogram. huang (ephedra), jin bu huan, germander, chap- Panel A shows cholelithiasis (arrow), and Panel B shows arral, pennyroyal, skullcap, kava, the nutritional thickening of the gallbladder wall (arrows) to 0.7 cm supplement Herbalife (Herbalife International), (normal, <0.4 cm). Panel C shows the normal ultra- and the weight-loss aid Hydroxycut (Iovate Health sonographic appearance of the hepatic parenchyma, Sciences).11,12 An association between black co- with no evidence of biliary obstruction. hosh and hepatotoxicity has been questioned because of potential inaccuracies in the assess- ments, and illicit drugs and reported no such ment methodology.13 Patients may report no use exposures. of illicit drugs and may not consider herbal rem- edies when questioned about medication use. Wilson’s disease This patient was appropriately questioned about In a person who is younger than 40 years of age the ingestion of wild mushrooms, herbal supple- and has liver disease, Wilson’s disease is always

n engl j med 363;26 nejm.org december 23, 2010 2551 The New England Journal of Medicine Downloaded from nejm.org by Danielle Klimas on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. T h e new england journal o f medicine

in the differential diagnosis. On occasion, pa- In a young woman, particularly one who is tients present with an illness that resembles taking oral contraceptives or was recently preg- acute hepatitis and is indistinguishable from au- nant, such as this patient, the diagnosis of acute toimmune hepatitis.14 A normal serum cerulo- hepatic-vein thrombosis (the Budd–Chiari syn- plasmin level does not rule out the diagnosis of drome) must be considered. The presentation Wilson’s disease, and characteristic Kayser– usually includes pain in the right upper quadrant Fleischer rings are absent in approximately 50% and new ascites. Aminotransferase levels may rise of patients with a hepatic presentation,15 which is to more than 1000 U per liter, particularly when more common in younger than in older patients. the portal vein is also thrombosed, and high Serum IgG levels are increased, and antinuclear levels that decline slowly are associated with a antibodies (ANA) and anti–smooth-muscle anti- poor prognosis.19 The clinical presentation and bodies may be detected, as they are in autoim- ultrasonographic findings in this case do not mune hepatitis. A fulminant presentation of Wil- suggest acute hepatic-vein thrombosis. son’s disease is often characterized by relatively Ischemic hepatitis is typically associated with low aminotransferase levels (<1500 U per liter) and striking elevations in serum aminotransferase an alkaline phosphatase level that is in the nor- levels, often to values greater than 5000 U per mal range or is low for the patient’s age (because liter, with marked elevations in the serum lac- of displacement of the cofactor zinc by copper); tate dehydrogenase (LDH) level and a ratio of both of these features were seen in this patient. alanine aminotransferase to LDH of less than The combination of a ratio of aspartate amino- 1.5.20 Affected patients are generally older and transferase to alanine aminotransferase of more have had a sudden fall in cardiac output caused than 2.2 and a ratio of alkaline phosphatase to by, for example, an acute myocardial infarction total bilirubin of less than 4 suggests fulminant or arrhythmia, often with preexisting passive Wilson’s disease16; this patient does not meet congestion of the liver. There is nothing to sug- those criteria. A hepatic copper content greater gest ischemia in this case. Infiltration of the than 250 μg per gram of liver (dry weight) is con- liver, as in occasional cases of lymphoma or sidered diagnostic of Wilson’s disease,17 whereas hepatic replacement by metastases, may some- concentrations of less than 40 μg per gram are times present with a biochemical pattern sugges- strong evidence against the diagnosis. Wilson’s tive of acute hepatitis but seems unlikely in this disease remains a consideration in this case. patient.21 Celiac disease is commonly associated with mild elevations in serum aminotransferase Other causes levels, perhaps because of immunologic involve- This patient reported abdominal pain, and ultra- ment of the liver, and may be associated with sonography showed gallstones. Acute obstruc- more severe and advanced liver disease, including tion of the bile duct by a gallstone may be mani- autoimmune hepatitis and primary biliary cirrho- fested as an initial rise in serum aminotransferase sis.22 The clinical onset of celiac disease may oc- levels to more than 1000 U per liter.18 These ele- cur in the postpartum period,23 but acute hepa- vations generally occur in conjunction with bili- titis with jaundice as the presenting feature, as ary pain, return to normal within days, and are in this case, would be an unlikely manifestation. followed by a more gradual rise in the alkaline Pregnancy-specific liver diseases include intra- phosphatase and bilirubin levels if the obstruc- hepatic cholestasis of pregnancy, preeclampsia, tion persists. Our patient’s abdominal pain oc- the HELLP syndrome (hemolysis, elevated liver- curred after the elevation of the serum amino- enzyme levels, and a low platelet count), and transferase levels, and the marked elevation of acute fatty liver of pregnancy. Liver abnormali- bilirubin levels occurred simultaneously with the ties generally resolve promptly after delivery. In elevations in the aminotransferase levels, which this case, the onset of liver disease 2.5 months is a pattern more typical of acute hepatitis than after delivery is inconsistent with pregnancy- of acute biliary obstruction or acute cholecystitis. related liver disease.24 The thickening of the gallbladder wall that was seen on ultrasonography was most likely the re- Autoimmune hepatitis sult of the proximity of the gallbladder to an in- The patient’s clinical, biochemical, and serologic flamed liver. features are consistent with an acute presenta-

2552 n engl j med 363;26 nejm.org december 23, 2010 The New England Journal of Medicine Downloaded from nejm.org by Danielle Klimas on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. case records of the massachusetts general hospital tion of autoimmune hepatitis, a disorder of un- Table 2. Simplified Scoring System for the Diagnosis of Autoimmune known cause characterized by inflammation of Hepatitis.* the liver, hypergammaglobulinemia, and the presence of autoantibodies.25,26 Although the on- Feature Score set is often insidious, with fatigue and hyperbili- Autoantibodies 27 rubinemia, a fulminant presentation that mim- Antinuclear antibodies or anti–smooth-muscle antibodies ics acute viral hepatitis, as seen in this patient, ≥1:40 dilution +1 has been recognized.28 There is no specific diagnostic test for autoimmune hepatitis. The diag- ≥1:80 dilution +2 nosis requires that other chronic liver diseases Antibodies to liver–kidney microsome type 1, ≥1:40 dilution +2 with similar features be ruled out. These include Antibodies to soluble liver antigen, positive +2 chronic viral hepatitis, drug-induced liver dis- Serum IgG level ease, nonalcoholic fatty liver disease, Wilson’s disease, primary biliary cirrhosis, and primary >Upper limit of the normal range +1 sclerosing cholangitis. An international panel has >1.1 times upper limit of the normal range +2 codified the diagnostic criteria,28,29 and a scor- Histologic findings on liver biopsy ing system for making the diagnosis has been Compatible with autoimmune hepatitis +1 developed that is based on four components: the Typical of autoimmune hepatitis +2 serum IgG level, the presence and level of autoantibodies, the absence of viral markers, and his- Absence of markers for viral hepatitis +2 tologic features on liver biopsy (Table 2).30,31 Aggregate score indicating definite diagnosis ≥7 Autoimmune hepatitis is classified as type 1 or Aggregate score indicating probable diagnosis 6 type 2 on the basis of characteristic autoantibodies (Table 3).30 In the United States, 11 to 23% of * Data are from Czaja.30 cases of chronic liver disease are attributable to autoimmune hepatitis.28,32 It is not clear whether the initial presentation Dr. Andrew S. deLemos (Gastroenterology): I was in this patient was affected by recent pregnancy. the consulting fellow and saw the patient in the In general, pregnancy has been reported to amelio- emergency room. We favored a diagnosis of auto rate autoimmune hepatitis, presumably because of immune hepatitis for the reasons that Dr. Fried- increases in estrogen levels and a resulting cyto- man has already indicated and thus recommend- kine shift from a type 1 to a type 2 helper T-cell ed an ultrasound-guided liver biopsy, which was antiinflammatory profile.33 Flares of the disease performed by an interventional radiologist the occur in 12 to 21% of patients during pregnancy, same day. but this may be due to a reduction in immunosuppressive therapy.34,35 Because of decreases in Clinical Diagnosis estrogen levels, postpartum flares are more common, occurring in 12 to 86% of patients.33,35,36 Autoimmune hepatitis. The diagnostic procedure in this case should be a liver biopsy. The finding of characteristic Dr. Lawrence S. Friedman’s histologic features, including interface hepatitis, Diagnosis would suggest a probable diagnosis of autoimmune hepatitis, and the diagnosis would be Autoimmune hepatitis. considered definite if characteristic antibodies were found in the serum. Testing for tissue cop- Pathological Discussion per levels should also be done to rule out Wil- son’s disease. A response to immunosuppressive Dr. Joseph Misdraji: The biopsy specimen (Fig. 2A) therapy would provide additional confirmation shows panlobular hepatitis, with inflammation, of the diagnosis and a therapeutic benefit. necrotic hepatocytes, and disarray of the hepatic Dr. Nancy Lee Harris (Pathology): Dr. deLemos, plates involving the entire lobule, from portal would you tell us the thinking of the clinical tract to central vein. Cholestasis was noted in the team at the time of the diagnostic procedure? lobules. Clusters of plasma cells were seen in por-

n engl j med 363;26 nejm.org december 23, 2010 2553 The New England Journal of Medicine Downloaded from nejm.org by Danielle Klimas on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. T h e new england journal o f medicine

Table 3. Classification of Autoimmune Hepatitis.*

Feature Type 1 Type 2 Characteristic autoantibodies Anti–smooth-muscle, antinuclear Antibodies to liver–kidney microsome type 1 Associated autoantibodies Atypical pANCA; antibodies to actin Antibodies to liver cytosol type 1, soluble asialoglycoprotein receptor, liver antigen chromatin, soluble liver antigen Putative autoantigen Unknown CYP2D6 Age Infants to elderly Children (2 to 14 yr of age)† Female sex (%) 78 89 Patients with concurrent immune 38 34 diseases (%) Typical concurrent autoimmune Autoimmune thyroiditis, Graves’ Autoimmune thyroiditis, vitiligo type 1, diseases disease, ulcerative colitis diabetes mellitus, APECED Organ-specific antibodies (%) 4 30 Elevated immunoglobulins +++ + Glucocorticoid-responsive +++ ++

* Data are from Czaja.28 APECED denotes autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy, CYP2D6 cytochrome P-450 2D6, and pANCA perinuclear antineutrophil cytoplasmic antibodies. † In Germany and France, 20% of adult patients with autoimmune hepatitis have type 2; it is uncommon in adults in the United States.

tal areas (Fig. 2B). A periodic acid–Schiff stain this patient, the tissue copper level was slightly with diastase digestion (Fig. 2C) reveals numer- elevated, at 54 μg per gram (reference range, 10 ous ceroid-laden macrophages in the centrilobu- to 35), a finding that may be seen in many forms lar area, which are indicative of lobular injury of liver disease, but it was well below the 250 μg and hepatocyte necrosis. A trichrome stain (Fig. per gram that is expected in Wilson’s disease. 2D) reveals expanded portal tracts but no evi- Dr. deLemos: After the biopsy, the patient was dence of chronic scarring. The biopsy findings admitted to the medical service. That night, ab- are diagnostic of severe panlobular hepatitis, with dominal pain developed, along with a systolic features that are suggestive of an acute presenta- blood pressure of 70 mm Hg that was associated tion of autoimmune hepatitis, although other with bradycardia. A computed tomographic scan causes of acute hepatitis, particularly viral hepa- revealed fluid in the abdomen, which was consis- titis due to hepatitis A virus cannot be ruled out. tent with hemoperitoneum. The hematocrit was Studies of the histology of the liver in pa- 22%, and the patient received 2 units of packed tients who have an acute presentation of autoim- red cells. She was taken urgently to the vascular mune hepatitis have shown that these livers of- interventional radiology suite and underwent ten have lobular inflammation superimposed on successful embolization of an actively bleeding portal and periportal hepatitis and frequently branch of the right hepatic artery. have bridging fibrosis or even cirrhosis, features Treatment with 60 mg of prednisone daily that suggest that the acute presentation repre- was begun after the results of the liver biopsy sents a flare of subclinical chronic disease.37,38 were reported on hospital day 1. Additional tests However, autoimmune hepatitis can also have a ordered on admission (Table 1) were negative for histologic appearance identical to acute viral HCV RNA and positive for ANA and anti– hepatitis, as in this case, without evidence of smooth-muscle antibody, features that were con- chronic disease.39 In these cases, the presence of sistent with the more common type 1 autoim- numerous plasma cells is suggestive of acute mune hepatitis. The serum IgG level was 1393 autoimmune hepatitis, although other entities mg per deciliter (reference range, 614 to 1295). that are associated with numerous plasma cells, On the third day, the level of aspartate amino- such as hepatitis A, need to be ruled out.39 In transferase was 413 U per liter, alanine amino-

2554 n engl j med 363;26 nejm.org december 23, 2010 The New England Journal of Medicine Downloaded from nejm.org by Danielle Klimas on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. case records of the massachusetts general hospital

A B

C D

Figure 2. Liver-Biopsy Specimen. The liver-biopsy specimen (Panel A, hematoxylin and eosin) reveals panlobular hepatitis, with mononuclear inflammation, hepatocyte necrosis, and disarray of the hepatic plates spanning the entire lobule, from the portal tract (arrow) to the central vein (arrowhead). At high magnification (Panel B, hematoxylin and eosin), the portal inflammation consists largely of mononuclear cells and numerous plasma cells (arrowheads). Periodic acid–Schiff staining after diastase digestion (Panel C) reveals numerous clusters of ceroid-laden macrophages (arrowheads) in the vicin- ity of the central vein (arrow). These lesions mark the sites of hepatocyte necrosis. Trichrome staining (Panel D) reveals an expanded portal tract (arrow) but no bridging fibrosis or cirrhosis; the central vein is also shown (arrowhead). transferase 222 U per liter, alkaline phosphatase after the diagnosis, the patient became pregnant 86 U per liter, and total bilirubin 5 mg per deci- and discontinued the azathioprine; the aspartate liter (85.5 μmol per liter). The dose of predni- aminotransferase and alanine aminotransferase sone was reduced to 40 mg per day, and the levels then began to rise, so we reinstituted aza- patient was discharged. Ten days after dis- thioprine, thinking that the risk of recurrent charge, the alanine aminotransferase level was disease outweighed the potential risk to the 81 U per liter, and the aspartate aminotransfer- child. ase level was normal. At that time, the adminis- Dr. Harris: Dr. Friedman, can you tell us what tration of 50 mg of azathioprine daily was be- the patient’s autoimmune hepatitis score would gun, with tapering of prednisone to 10 mg daily. have been? Four months after discharge, results of the pa- Dr. Friedman: I calculate a score of 7. The patient’s liver-function tests were normal. The ad- tient had an anti–smooth-muscle antibody titer ministration of azathioprine was gradually in- of 1:80 (2 points), an elevated IgG level (1 point), creased to the goal dose of 2 to 2.5 mg per an absence of viral hepatitis (2 points), and kilogram of body weight, and prednisone was typical histologic findings on biopsy (2 points). tapered and discontinued. Approximately 1 year This makes the diagnosis definite.

n engl j med 363;26 nejm.org december 23, 2010 2555 The New England Journal of Medicine Downloaded from nejm.org by Danielle Klimas on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. T h e new england journal o f medicine

Dr. Friedman reports receiving royalties from Elsevier USA Anatomical Diagnosis and UpToDate. No other potential conflict of interest relevant to this article was reported. Severe panlobular hepatitis, with features that Disclosure forms provided by the authors are available with were consistent with the acute onset of autoim- the full text of this article at NEJM.org. We thank Drs. Anna Rutherford, Raymond Chung, Peter mune hepatitis. Noseworthy, and David Sykes (Medicine) for contributions to This case was presented at the Medicine Case Conference, the case history and preparation of the conference and manu- December 11, 2009. script.

References 1. Servoss JC, Friedman LS. Serologic ed. Sleisenger & Fordtran’s gastrointesti- 22. Rubio-Tapia A, Murray JA. The liver in and molecular diagnosis of hepatitis B nal and liver disease: pathophysiology/ celiac disease. Hepatology 2007;46:1650-8. virus. Clin Liver Dis 2004;8:267-81. diagnosis/management. 9th ed. Philadel- 23. Malnick SD, Atali M, Lurie Y, Fraser 2. Feld JJ, Heathcote EJ. Hepatitis caused phia: Elsevier Saunders, 2010:1447-59. G, Geltner D. Celiac sprue presenting by other viruses. In: Feldman M, Fried- 12. Teschke R, Schulze J. Risk of kava during the puerperium: a report of three man LS, Brandt LJ, eds. Sleisenger & hepatotoxicity and the FDA consumer ad- cases and a review of the literature. J Clin Fordtran’s gastrointestinal and liver dis- visory. JAMA 2010;304:2174-5. Gastroenterol 1998;26:164-6. ease: pathophysiology/diagnosis/manage- 13. Teschke R, Bahre R, Genthner A, 24. Hay JE. Liver disease in pregnancy. ment. 9th ed. Philadelphia: Elsevier Saun- Fuchs J, Schmidt-Taenzer W, Wolff A. Sus- Hepatology 2008;47:1067-76. ders, 2010:1343-50. pected black cohosh hepatotoxicity — 25. Czaja AJ. Autoimmune hepatitis after 3. Shaukat A, Tsai HT, Rutherford R, challenges and pitfalls of causality as- liver transplantation and other lessons of Anania FA. Epstein-Barr virus induced sessment. Maturitas 2009;63:302-14. self-intolerance. Liver Transpl 2002;8:505- hepatitis: an important cause of cholesta- 14. Milkiewicz P, Saksena S, Hubscher 13. sis. Hepatol Res 2005;33:24-6. SG, Elias E. Wilson’s disease with super- 26. Manns MP, Vergani D. Autoimmune 4. Wreghitt TG, Teare EL, Sule O, Devi imposed autoimmune features: report of hepatitis. Semin Liver Dis 2009;29:239-40. R, Rice P. Cytomegalovirus infection in two cases and review. J Gastroenterol 27. Kenny RP, Czaja AJ, Ludwig J, Dickson immunocompetent patients. Clin Infect Hepatol 2000;15:570-4. ER. Frequency and significance of anti- Dis 2003;37:1603-6. 15. Merle U, Schaefer M, Ferenci P, Strem- mitochondrial antibodies in severe chron- 5. Czartoski T, Liu C, Koelle DM, mel W. Clinical presentation, diagnosis ic active hepatitis. Dig Dis Sci 1986;31: Schmechel S, Kalus A, Wald A. Fulmi- and long-term outcome of Wilson’s dis- 705-11. nant, acyclovir-resistant, herpes simplex ease: a cohort study. Gut 2007;56:115-20. 28. Czaja AJ. Autoimmune hepatitis. In: virus type 2 hepatitis in an immunocom- 16. Korman JD, Volenberg I, Balko J, et al. Feldman M, Friedman LS, Brandt LJ, eds. petent woman. J Clin Microbiol 2006;44: Screening for Wilson disease in acute liver Sleisenger & Fordtran’s gastrointestinal 1584-6. failure: a comparison of currently avail- and liver disease: pathophysiology/diag- 6. Kaplowitz N. Acetaminophen hepa- able diagnostic tests. Hepatology 2008;48: nosis/management. 9th ed. Philadelphia: toxicity: what do we know, what don’t we 1167-74. Elsevier Saunders, 2010:1461-76. know, and what do we do next? Hepatol- 17. Ferenci P, Steindl-Munda P, Vogel W, 29. Alvarez F, Berg PA, Bianchi FB, et al. ogy 2004;40:23-6. et al. Diagnostic value of quantitative he- International Autoimmune Hepatitis Group 7. Zimmerman HJ, Maddrey WC. Acet- patic copper determination in patients Report: review of criteria for diagnosis of aminophen (paracetamol) hepatotoxicity with Wilson’s disease. Clin Gastroenterol autoimmune hepatitis. J Hepatol 1999;31: with regular intake of alcohol: analysis Hepatol 2005;3:811-8. 929-38. of instances of therapeutic misadventure. 18. Patwardhan RV, Smith OJ, Farmelant 30. Czaja AJ. Autoimmune hepatitis — Hepatology 1995;22:767-73. [Erratum, Hep- MH. Serum transaminase levels and cho- part B: diagnosis. Expert Rev Gastroen- atology 1995;22:1898.] lescintigraphic abnormalities in acute terol Hepatol 2007;1:129-43. 8. Cohen JA, Kaplan MM. The SGOT/ biliary tract obstruction. Arch Intern Med 31. Hennes EM, Zeniya M, Czaja AJ, et al. SGPT ratio — an indicator of alcoholic 1987;147:1249-53. Simplified criteria for the diagnosis of liver disease. Dig Dis Sci 1979;24:835-8. 19. Rautou PE, Moucari R, Cazals-Hatem autoimmune hepatitis. Hepatology 2008; 9. Ludwig S, Kaplowitz N. Effect of pyri- D, et al. Levels and initial course of serum 48:169-76. doxine deficiency on serum and liver alanine aminotransferase can predict out- 32. Boberg KM, Aadland E, Jahnsen J, transaminases in experimental liver inju- come of patients with Budd-Chiari syn- Raknerud N, Stiris M, Bell H. Incidence ry in the rat. Gastroenterology 1980;79: drome. Clin Gastroenterol Hepatol 2009; and prevalence of primary biliary cirrho- 545-9. 7:1230-5. sis, primary sclerosing cholangitis, and 10. Teoh NC, Chitturi S, Farrell GC. Liver 20. Whitehead MW, Hawkes ND, Hains autoimmune hepatitis in a Norwegian disease caused by drugs. In: Feldman M, worth I, Kingham JG. A prospective study population. Scand J Gastroenterol 1998; Friedman LS, Brandt LJ, eds. Sleisenger & of the causes of notably raised aspartate 33:99-103. Fordtran’s gastrointestinal and liver dis- aminotransferase of liver origin. Gut 33. Czaja AJ. Special clinical challenges in ease: pathophysiology/diagnosis/manage- 1999;45:129-33. autoimmune hepatitis: the elderly, males, ment. 9th ed. Philadelphia: Elsevier Saun- 21. Friedman LS, Ross AS. The liver in pregnancy, mild disease, fulminant on- ders, 2010:1413-46. systemic disease. In: Schiff ER, Sorrell set, and nonwhite patients. Semin Liver 11. Lewis JH. Liver disease caused by an- MF, Maddrey WC, eds. Schiff’s diseases Dis 2009;29:315-30. esthetics, toxins, and herbal preparations. of the liver. Philadelphia: Lippincott Wil- 34. Schramm C, Herkel J, Beuers U, Kan- In: Feldman M, Friedman LS, Brandt LJ, liams & Wilkins, 2007:329-48. zler S, Galle PR, Lohse AW. Pregnancy in

2556 n engl j med 363;26 nejm.org december 23, 2010 The New England Journal of Medicine Downloaded from nejm.org by Danielle Klimas on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. case records of the massachusetts general hospital

autoimmune hepatitis: outcome and risk breastfeeding? Scand J Gastroenterol 38. Nikias GA, Batts KP, Czaja AJ. The na- factors. Am J Gastroenterol 2006;101:556- 2007;42:986-91. ture and prognostic implications of auto- 60. 37. Burgart LJ, Batts KP, Ludwig J, Nikias immune hepatitis with an acute presenta- 35. Tan J, Surti B, Saab S. Pregnancy and GA, Czaja AJ. Recent-onset autoimmune tion. J Hepatol 1994;21:866-71. cirrhosis. Liver Transpl 2008;14:1081-91. hepatitis: biopsy findings and clinical 39. Crapper RM, Bhathal PS, Mackay IR, 36. Werner M, Björnsson E, Prytz H, et al. correlations. Am J Surg Pathol 1995;19: Frazer IH. ‘Acute’ autoimmune hepatitis. Autoimmune hepatitis among fertile 699-708. [Erratum, Am J Surg Pathol 1995; Digestion 1986;34:216-25. women: strategies during pregnancy and 19:1341.] Copyright © 2010 Massachusetts Medical Society.

Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends, shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens, and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced, averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the Case Record. The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail [email protected].

n engl j med 363;26 nejm.org december 23, 2010 2557 The New England Journal of Medicine Downloaded from nejm.org by Danielle Klimas on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.