A Sweet Source of Abdominal Pain

T h e new england journal o f medicine

clinical problem-solving

Shari S. Rogal, M.D., M.P.H., Chinweike Ukomadu, M.D., Ph.D., Bruce D. Levy, M.D., and Joseph Loscalzo, M.D., Ph.D.

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors’ commentary follows.

From the Clinical Pathological Conference A 25-year-old woman presented to her primary care physician for evaluation of ab- Series, Department of Medicine, Brigham dominal pain. Her discomfort had begun 6 months earlier and was localized to the and Women’s Hospital, and Harvard Medical School — both in Boston. Ad- right upper quadrant of the abdomen. She described a constant pressure unrelated to dress reprint requests to Dr. Levy at food intake that was associated with intermittent nausea and vomiting. She reported Brigham and Women’s Hospital, Harvard no change in urine or stools and no hematochezia, melena, dysphagia, anorexia, in- Institutes of Medicine Bldg., Ave. Louis Pasteur (HIM855), Boston, MA 02115, or crease in abdominal girth, early satiety, or change in weight. She also had no leth- at [email protected]. argy, fatigue, pruritus, jaundice, night sweats, fever, easy bruising, or bleeding.

N Engl J Med 2011;364:1762-7. Copyright © 2011 Massachusetts Medical Society. Appropriate characterization of abdominal pain is the first step in identifying its cause. It is important to ask about the location of the pain and its quality, duration, relationship to meals, radiation, and any associated symptoms. In this patient, the pain is described as “pressure” in the right upper quadrant of the abdomen and is unrelated to meals; these characteristics decrease the likelihood that disorders of the gallbladder or bowel are the cause. Dyspepsia is a common cause of pain but tends to be intermittent and related to diet. Pain that feels like pressure is common with hepatic capsular stretch and raises the possibility that her discomfort is of An Interactive hepatic origin. Medical Case related to this The patient’s medical history was notable for type 1 diabetes mellitus, which had been Clinical Problem- diagnosed in childhood and was complicated by several episodes of diabetic ketoaci- Solving article is available at dosis, hypothyroidism, psoriasis, and a seizure disorder, as well as juvenile rheuma- NEJM.org toid arthritis, which was diagnosed when she was 18 months of age, after the devel- opment of arthritis in her right ankle and uveitis in both eyes. Her growth was normal despite eventual involvement of arthritis in both ankles and knees. She had been treated with naproxen, methotrexate, and glucocorticoids. Her current medications included carbamazepine, methotrexate, levothyroxine, and insulin. Her cumulative dose of methotrexate was 1.3 g. She reported no use of over-the-counter medications or herbal supplements. She worked as a nurse, was unmarried, and had no children. She smoked seven cigarettes a day and had done so for 10 years. She said she did not use alcohol or illicit drugs and had no history of blood transfusions, no occupational exposure to blood, and no tattoos. She was not sexually active and had no history of sexually transmitted infections. There was no family history of diabetes, arthritis, autoimmune diseases, or liver disease.

Although it is possible that the patient’s nonspecific symptoms are due to gastritis or gastroparesis, her medical history supports a hepatic cause of her abdominal discomfort. Given prior episodes of diabetic ketoacidosis, she may have poorly controlled diabetes, which could have caused steatohepatitis and then hepatomegaly. The nausea and vomiting could be related to diabetes-induced gastroparesis or hepa-

1762 n engl j med 364;18 nejm.org may 5, 2011 The New England Journal of Medicine Downloaded from nejm.org by alieh pourdast on March 11, 2013. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. clinical problem-solving titis. She could have autoimmune hepatitis, which per deciliter (53.0 μmol per liter), and glucose 217 is more likely, given her sex and other autoim- mg per deciliter (12 mmol per liter). The level of mune disorders, including type 1 diabetes melli- alanine aminotransferase was 443 U per liter (nor- tus, juvenile rheumatoid arthritis, and hypothy- mal range, 7 to 52), aspartate aminotransferase roidism. Toxin-induced hepatitis is a possibility 218 U per liter (normal range, 9 to 30), alkaline and may have been caused by several of her med- phosphatase 145 U per liter (normal range, 38 to ications, including methotrexate, carbamazepine, 118), total bilirubin 0.5 mg per deciliter (8.6 μmol glucocorticoids, and nonsteroidal antiinflamma per liter), total protein 7.4 mg per deciliter, albu- tory drugs; she reports no alcohol use. Apart from min 4.4 g per deciliter, and globulin 3.0 mg per her work as a nurse, she has no obvious risk fac- deciliter. Amylase and lipase levels were normal. tors for viral hepatitis. There is no family history The white-cell count was 6630 per cubic millime- of liver disease, which reduces but does not elim- ter, with a normal differential count; hematocrit inate the possibility of an inherited disorder, such 38.5%, with a mean corpuscular volume of 110 fl as hemochromatosis, Wilson’s disease, or alpha1- and a red-cell distribution width of 14.6%; and antitrypsin deficiency. platelet count 383,000 per cubic millimeter. Levels of vitamin B12 and folic acid were normal. The in- On physical examination, the patient was a thin, ternational normalized ratio was 0.9. anicteric woman who was not in acute distress. She was afebrile; her pulse was 109 beats per min- The most significant abnormalities are the ele- ute, blood pressure 122/90 mm Hg, weight 46 kg vated hepatic enzyme levels; the patient also has (101 lb), and height 152 cm (60 in.). The jugular a high mean corpuscular volume, an elevated ra- venous pressure was not elevated. Examination tio of blood urea nitrogen to creatinine, and hy- of the heart and lungs was unremarkable. The ab- perglycemia. The differential diagnosis at this domen was nondistended and soft, with normal point includes common causes of chronic liver bowel sounds. She had mild tenderness on palpa- injury: drug-induced hepatitis, viral hepatitis, and tion in the right upper quadrant, with no rebound inherited iron-overload disorder. Also under con- or guarding. Murphy’s sign was absent. The liver sideration is nonalcoholic fatty liver disease — was palpable 3 to 4 cm below the costal margin, specifically, nonalcoholic steatohepatitis, a sub- with a measured span of 14 cm at the midclavicu- type of nonalcoholic fatty liver disease in which lar line. The edge of the liver was smooth. The fatty infiltration of the liver is accompanied by spleen was not palpable, and there was no evi- evidence of other liver injury, including inflam- dence of ascites. Examination of the skin revealed mation and fibrosis. Given her history of autoim- scaly plaques on her scalp, ears, and the extensor mune disorders, autoimmune hepatitis is also a surfaces of her arms and legs. She had no vesicular concern. In addition, acquired glycogen deposi- lesions, palmar erythema, leg edema, or spider tion disease merits consideration, given the pres- angiomata. The results of neurologic examina- ence of type 1 diabetes mellitus. Less common tion, including mental status, were normal. causes of hepatitis and hepatomegaly include thyroid disease, celiac sprue, the Budd–Chiari Physical examination reveals an enlarged liver syndrome, and deposition diseases of the liver, but no evidence of an enlarged spleen, making it such as amyloidosis, sarcoidosis, and Gaucher’s less likely that the patient has severe portal hyper- disease. tension from cirrhosis or an infiltrative process The possibility of drug-induced hepatitis (both of which are common causes of hepato- should be assessed by obtaining a thorough megaly and splenomegaly). Congestive hepatopa- medical history of the patient and her family, thy is also unlikely, given her normal cardiovas- with attention to over-the-counter medications cular examination. and herbal supplements (e.g., kava, pennyroyal, comfrey, and germander). In addition, her use of Laboratory studies showed that the sodium level medications with potential hepatotoxic effects was 137 mmol per liter, potassium 4.1 mmol per raises some concerns. Methotrexate has been re- liter, chloride 97 mmol per liter, bicarbonate 31 ported to cause liver injury, but her cumulative mmol per liter, blood urea nitrogen 29 mg per dose of less than 1.5 g makes this unlikely. Al- deciliter (10.4 mmol per liter), creatinine 0.6 mg though carbamazepine can cause hepatitis, it also

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seems unlikely to be the culprit here, since the The serologic findings rule out chronic hepatitis associated hepatitis is often severe. B and C, and the positive result for hepatitis B Wilson’s disease occurs in young adults and surface antibody is consistent with prior vaccina- should be considered in any patient younger tion. Iron overload is unlikely, given the normal than 40 years of age with unexplained hepatitis. iron studies; the aminotransferase levels are also A decreased ceruloplasmin level and Kayser– higher than in typical cases of iron-overload dis- Fleischer rings (brownish copper deposits around ease. Primary biliary cirrhosis can cause hepato- the iris) are characteristic findings but are not megaly, but the normal test result for alkaline universally present. She has no neuropsychiatric phosphatase and the negative result for antimito- symptoms and no family history to suggest a chondrial antibody are inconsistent with this di- diagnosis of Wilson’s disease, but these features agnosis. At this point, a liver biopsy would be are absent in many cases. Ceruloplasmin is an required to rule out a number of possible diagno- acute-phase reactant and thus may be falsely nor- ses, but they appear to be clinically unlikely. mal or even elevated in patients with Wilson’s These diagnoses include steatohepatitis, alpha1- disease. If this disorder is suspected, screening antitrypsin deficiency, autoimmune hepatitis, in- for urinary copper levels is warranted. The ele- herited glycogen storage disorders, Gaucher’s dis- vated mean corpuscular volume in this patient is ease, and secondary amyloidosis. If the patient probably related to the medications she takes — was fasting at the time of blood draw, her elevat- specifically, methotrexate or carbamazepine. The ed triglyceride level is probably related to her hy- elevated ratio of blood urea nitrogen to creati- perglycemia, as part of the metabolic syndrome. nine suggests mild volume depletion, probably Nonalcoholic fatty liver disease is also associated the result of inadequately controlled diabetes with this syndrome and could underlie the ele- mellitus. vated aminotransferase levels. However, there was no evidence of hepatic steatosis on ultrasonogra- The patient’s serum iron level was 104 mg per phy, which is highly sensitive for marked fatty deciliter (18.6 µmol per liter), total iron-binding infiltration but less sensitive when there is less capacity 392 µg per deciliter (70.2 µmol per liter), steatosis or when obesity precludes adequate im- ferritin 141 µg per liter, and thyrotropin 5.9 µIU aging. The normal alpha1-antitrypsin level and per liter. Her total cholesterol level was 195 mg per the absence of a family history of liver or lung deciliter (5.0 mmol per liter), triglycerides 458 mg disease argue against alpha1-antitrypsin deficien- per deciliter (5.2 mmol per liter), high-density li- cy. The normal levels of globulins, the negative poprotein cholesterol 60 mg per deciliter (1.6 result for anti–smooth-muscle antibody, and the mmol per liter), and low-density lipoprotein cho- low titer for antinuclear antibody make autoim- lesterol 98 mg per deciliter (2.5 mmol per liter). mune hepatitis unlikely. The glycated hemoglobin level was 12.4%. The The concomitant enlargement of the patient’s erythrocyte sedimentation rate was 21 mm per liver and kidneys points to infiltrative disease. hour. Serologic tests for viral hepatitis were posi- An inherited glycogen storage disorder is incon- tive for hepatitis B surface antibody, negative for sistent with her age at presentation, the absence hepatitis B surface antigen and core antibody, and of cirrhosis, and the presence of hyperglycemia negative for hepatitis C antibody. The antinuclear rather than hypoglycemia. Gaucher’s disease can antibody titer was 1:20, with a diffuse pattern. be diagnosed in adults, but the deposition of Tests for antimitochondrial antibody and anti– glucocerebroside in the liver, spleen, and bone smooth-muscle antibody were negative. The se- marrow characteristically causes not only hepa- rum ceruloplasmin and urinary copper levels were tomegaly but also splenomegaly, anemia, and normal, as were the results of an ophthalmologic thrombocytopenia. Although amyloidosis could examination. The level of alpha1-antitrypsin was be secondary to juvenile rheumatoid arthritis, also normal. Doppler ultrasonography of the ab- the primary abnormality would be expected to domen showed hepatomegaly, with no fatty infil- cause a greater elevation in alkaline phosphatase tration or vascular abnormalities and normal than in the aminotransferases. Given the pa- echogenicity. The kidneys were normal with re- tient’s history of poorly controlled diabetes and spect to echogenicity but were enlarged, both the presence of hepatomegaly, pain, nausea, and measuring 13.9 cm in length. elevated aminotransferases, the most likely in-

1764 n engl j med 364;18 nejm.org may 5, 2011 The New England Journal of Medicine Downloaded from nejm.org by alieh pourdast on March 11, 2013. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. clinical problem-solving filtrative process is glycogenic hepatopathy, an acquired hepatic glycogen storage disease that may A occur in patients with poorly controlled type 1 diabetes. A liver biopsy is warranted to confirm the diagnosis.

A liver biopsy was performed, and the results were consistent with glycogenic hepatopathy (Fig. 1). The patient was treated with aggressive insulin therapy. Within 6 months, levels of glycated hemoglobin had decreased from more than 12% to 8%, and her abdominal symptoms and hepatic biochemical abnormalities had resolved. B The administration of insulin for aggressive glucose control typically results in normalization of liver biochemical values and resolution of symptoms in patients with glycogenic hepatopathy. Pa- tients in whom this diagnosis is suspected may be treated empirically with intensive insulin therapy to see whether their symptoms and the results of liver-function tests improve; however, liver biopsy remains the definitive diagnostic test for distinguishing this entity from nonalcoholic steatohepatitis or drug-induced hepatitis. C Commentary

This case demonstrates the importance of distinguishing causes of hepatitis. After an initial evaluation that uncovered elevated levels of liver enzymes and an enlarged liver, major considerations included drug-induced hepatitis, nonalcoholic fatty liver disease, and infiltrative diseases. Drug-induced hepatitis is common, although a definitive diagnosis can be difficult because biopsy findings can be nonspecific. A particu- lar concern in this case was the possibility of Figure 1. Liver-Biopsy Specimen Liver Showing methotrexate-induced liver disease. A retrospec- Histologic and Biochemical Features of Glycogenic tive cohort study of patients with rheumatic or Hepatopathy. psoriatic arthritis showed that 43% of patients Hematoxylin-and-eosin staining (Panel A) reveals clear had at least one hepatic biochemical abnormal- cytoplasm, normal portal tracts, no fibrosis, and glyco- genation of the nuclei (arrow), findings that may be ity. The patients with rheumatic arthritis received seen in glycogen storage disease, glycoprotein or gly- a median cumulative dose of 3.6 g of methotrex- colipid storage diseases, glycogenic hepatopathy, and ate, and higher doses were associated with a steatosis. Periodic acid–Schiff staining is markedly higher frequency of biochemical abnormalities.1 positive for the presence of glycogen (Panel B). With Although more data are needed to assess the the addition of diastase, which digests pure glycogen but not glycoproteins or glycolipids, periodic acid– risk of cirrhosis that is associated with metho- Schiff staining is lost (Panel C), confirming the pres- trexate, the risk is considered to be low. In a ence of pure glycogen within the hepatocytes. Images large study, the 5-year cumulative incidence of courtesy of Dr. Dominique Coco, Brigham and Women’s cirrhosis and liver failure among patients with Hospital, Department of Pathology. rheumatic arthritis who took methotrexate was

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estimated at 1 case per 1000 patients.2 Similarly, treat; weight loss and correction of hypertriglyc- a retrospective cohort study including 25 patients eridemia and hyperglycemia are recommended, with juvenile rheumatoid arthritis showed no cor- and certain medications (including insulin-sensi- relation between the cumulative methotrexate dose tizing agents, statins, ursodiol, pentoxifylline, and fibrosis, and none of the patients studied and vitamin E) have been used.5 Nonalcoholic had high-grade fibrosis over the course of long- steatohepatitis is increasingly recognized as a term follow-up.3 Recommendations regarding in- cause of cirrhosis. In one study of 103 patients, dications for biopsy in patients taking methotrex- 37% had histologic progression to cirrhosis, 34% ate are inconsistent, and there are no guidelines had no change, and 29% had regression.6 With for patients with juvenile rheumatoid arthritis. treatment, glycogenic hepatopathy has a more The current guidelines of the American College of benign course. In the largest case series, 2 of 14 Rheumatology for patients with rheumatic ar- patients were found to have mild fibrosis on thritis who are taking methotrexate recommend biopsy.7 Although biopsy is the only way to dis- measurement of liver enzyme levels every 4 to tinguish the two conditions definitively, biopsy is 8 weeks; biopsy is recommended if the results of not necessary if empirical treatment leads to 6 of 12 monthly tests are abnormal (or 5 of 9 tests biochemical and symptomatic improvement. if testing is performed every 6 weeks); the guide- First described in 1930 by Mauriac8 as “he- lines do not recommend performance of biopsy patic glycogenosis,” the entity now called glyco- on the basis of the cumulative dose.4 genic hepatopathy is characterized by hepatic It is important to distinguish between glyco- glycogen deposition in patients with poorly con- genic hepatopathy and hepatic steatosis for the trolled type 1 diabetes mellitus. The original syn- purposes of treatment and assessment of progno- drome was described in children and included sis. In glycogenic hepatopathy, glycemic control three features also present in this case — hepa- can be achieved with adequate insulin therapy. tomegaly, abdominal pain, and abnormal levels Nonalcoholic steatohepatitis is more difficult to of liver enzymes — but also included hypercho-

Glycogen synthase phosphatase (deactivated)

Glucose Glycogen synthase Glycogen synthase Glucagon Insulin phosphatase phosphorylase

Glycogen synthase (activated)

Glucose Glucose-1-phosphate Glycogen

Glycogen phosphorylase

Glucagon

Figure 2. Mechanism of Glycogen Storage in the Liver. AUTHOR: Rogal RETAKE: 1st In the presence of insulin and excess glucose, glycogen synthase phosphatase is activated2nd as dephosphorylated glycogen synthase. Dephosphorylated FIGURE:(activated)2 of glycogen 2 synthase is required for the conversion3rd of glucose-1-phosphate Revised to glycogen. The thick arrows highlightARTIST: thets effects of glucose and excess insulin on glycogen formation. In contrast, SIZE glucagon stimulates the phosphorylation of glycogen synthase, leading to increased6 col glycogenolysis. Adapted from 7 Torbenson et al. TYPE: Line Combo 4-C H/T 33p9 AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully.

1766 JOB: 362xxn engl j med 364;18 nejm.org mayISSUE: 5, 2011xx-xx-10 The New England Journal of Medicine Downloaded from nejm.org by alieh pourdast on March 11, 2013. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. clinical problem-solving lesterolemia and growth delay; since that time, This activation promotes glycogen storage in the this entity has been increasingly recognized among liver and blocks glycogenolysis. both children9 and adults10,11 with type 1 diabe- Our patient had both hepatic and renal en- tes. In the case series of 14 patients with biopsy- largement. Although most glycogen storage oc- proven glycogenic hepatopathy, all the patients curs in the liver and in muscle, some glycogen is had type 1 diabetes, and 13 had abnormal liver- stored in the kidney.15 It is plausible that the renal function tests.7 All 9 patients who were evaluated enlargement in this case was attributable to gly- with imaging had hepatomegaly, and all 6 who cogen deposition, but we cannot be certain; we were tested for glycated hemoglobin had elevat- are not aware of other reports of renal enlarge- ed levels. Pain in the right upper quadrant of the ment in glycogenic hepatopathy. abdomen, nausea, or vomiting was present in Treatment involves the use of adequate doses 8 of the 14 patients, whereas steatosis was pres- of insulin to achieve rigorous glucose control; ent in only 2 — findings that distinguish glyco- this approach has been shown to be effective in genic hepatopathy from nonalcoholic fatty liver children8 and in adults.11 In the published re- disease. Other reports have revealed similar find- ports, pain in the right upper quadrant, nausea, ings.11-14 The prevalence of glycogenic hepatopa- vomiting, hepatomegaly, and laboratory abnor- thy among people with diabetes is unknown. malities have been reversed in as few as 4 weeks In the pathophysiological process of the dis- with adequate insulin therapy.9,10,12 This case calls order, the concomitant presence of insulin and attention to glycogenic hepatopathy as an under- excess glucose increases glycogen storage in the recognized but reversible cause of infiltrative liver. Insulin activates glycogen synthase phospha- liver disease in patients with type 1 diabetes. tase, which dephosphorylates and activates gly- No potential conflict of interest relevant to this article was reported. cogen synthase, an enzyme required for the con- Disclosure forms provided by the authors are available with version of glucose-1-phosphate to glycogen (Fig. 2). the full text of this article at NEJM.org.

References 1. Amital H, Arnson Y, Chodick G, Sha- 6. Adams LA, Sanderson S, Lindor KD, 11. Chatila R, West AB. Hepatomegaly lev V. Hepatotoxicity rates do not differ in Angulo P. The histological course of non- and abnormal liver tests due to glyco- patients with rheumatoid arthritis and alcoholic fatty liver disease: a longitudi- genosis in adults with diabetes. Medicine psoriasis treated with methotrexate. Rheu- nal study of 103 patients with sequential (Baltimore) 1996;75:327-33. matology (Oxford) 2009;48:1107-10. liver biopsies. J Hepatol 2005;42:132-8. 12. Abaci A, Bekem O, Unuvar T, et al. He- 2. Walker AM, Funch D, Dreyer NA, et 7. Torbenson M, Chen YY, Brunt E, et al. patic glycogenosis: a rare cause of hepato- al. Determinants of serious liver disease Glycogenic hepatopathy: an underrecog- megaly in Type 1 diabetes mellitus. J Dia- among patients receiving low-dose meth- nized hepatic complication of diabetes betes Complications 2008;22:325-8. otrexate for rheumatoid arthritis. Arthri- mellitus. Am J Surg Pathol 2006;30:508- 13. Olsson R, Wesslau C, William-Olsson tis Rheum 1993;36:329-35. 13. T, Zettergren L. Elevated aminotransfer- 3. Hashkes PJ, Balistreri WF, Bove KE, 8. Mauriac P. Gros ventre, hepatomega- ases and alkaline phosphatases in unsta- Ballard ET, Passo MH. The relationship of lie, troubles de la croissance chez les en- ble diabetes mellitus without ketoacidosis hepatotoxic risk factors and liver histolo- fants diabetiques traites depuis plusieurs or hypoglycemia. J Clin Gastroenterol gy in methotrexate therapy for juvenile annes par l’insuline. Gaz Hebd Med Bour- 1989;11:541-5. rheumatoid arthritis. J Pediatr 1999;134: deaux 1930;26:402-10. 14. Sayuk GS, Elwing JE, Lisker-Melman 47-52. 9. Munns CF, McCrossin RB, Thomsett M. Hepatic glycogenosis: an underrecog- 4. Kremer JM, Alarcon GS, Lightfoot RW MJ, Batch J. Hepatic glycogenosis: revers- nized source of abnormal liver function Jr, et al. Methotrexate for rheumatoid ar- ible hepatomegaly in type 1 diabetes. tests? Dig Dis Sci 2007;52:936-8. thritis: suggested guidelines for monitor- J Paediatr Child Health 2000;36:449-52. 15. Cersosimo E, Ajmal M, Naukam RJ, ing liver toxicity. Arthritis Rheum 1994; 10. Nakamuta M, Ohashi M, Goto K, Ta- Molina PE, Abumrad NN. Role of the kid- 37:316-28. nabe Y, Hiroshige K, Nawata H. Diabetes ney in plasma glucose regulation during 5. Sanyal AJ, Chalasani N, Kowdley KV, mellitus-associated glycogen storage hep- hyperglycemia. Am J Physiol 1997;272: et al. Pioglitazone, vitamin E, or placebo atomegaly: report of a case and review of E756-E761. for nonalcoholic steatohepatitis. N Engl J the Japanese literature. Fukuoka Igaku Copyright © 2011 Massachusetts Medical Society. Med 2010;362:1675-85. Zasshi 1993;84:354-8.

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