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A Sweet Source of Abdominal Pain

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 Series, Department of Medicine, Brigham and Womens Hospital, and Harvard Medical School both in Boston. Address reprint requests to Dr. Levy at Brigham and Womens Hospital, Harvard Institutes of Medicine Bldg., Ave. Louis Pasteur (HIM855), Boston, MA 02115, or at blevy@partners.org. N Engl J Med 2011;364:1762-7.
Copyright 2011 Massachusetts Medical Society.

A 25-year-old woman presented to her primary care physician for evaluation of abdominal pain. Her discomfort had begun 6 months earlier and was localized to the right upper quadrant of the abdomen. She described a constant pressure unrelated to food intake that was associated with intermittent nausea and vomiting. She reported no change in urine or stools and no hematochezia, melena, dysphagia, anorexia, increase in abdominal girth, early satiety, or change in weight. She also had no lethargy, fatigue, pruritus, jaundice, night sweats, fever, easy bruising, or bleeding. 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 hepatic origin. The patients medical history was notable for type 1 diabetes mellitus, which had been diagnosed in childhood and was complicated by several episodes of diabetic ketoacidosis, hypothyroidism, psoriasis, and a seizure disorder, as well as juvenile rheumatoid arthritis, which was diagnosed when she was 18 months of age, after the development 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 patients 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-

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titis. She could have autoimmune hepatitis, which is more likely, given her sex and other autoimmune disorders, including type 1 diabetes mellitus, juvenile rheumatoid arthritis, and hypothyroidism. Toxin-induced hepatitis is a possibility and may have been caused by several of her medications, including methotrexate, carbamazepine, glucocorticoids, and nonsteroidal antiinflammatory drugs; she reports no alcohol use. Apart from her work as a nurse, she has no obvious risk factors for viral hepatitis. There is no family history of liver disease, which reduces but does not eliminate the possibility of an inherited disorder, such as hemochromatosis, Wilsons disease, or alpha1antitrypsin deficiency.

per deciliter (53.0 mol per liter), and glucose 217 mg per deciliter (12 mmol per liter). The level of alanine aminotransferase was 443 U per liter (normal range, 7 to 52), aspartate aminotransferase 218 U per liter (normal range, 9 to 30), alkaline phosphatase 145 U per liter (normal range, 38 to 118), total bilirubin 0.5 mg per deciliter (8.6 mol per liter), total protein 7.4 mg per deciliter, albumin 4.4 g per deciliter, and globulin 3.0 mg per deciliter. Amylase and lipase levels were normal. The white-cell count was 6630 per cubic millimeter, with a normal differential count; hematocrit 38.5%, with a mean corpuscular volume of 110 fl and a red-cell distribution width of 14.6%; and platelet count 383,000 per cubic millimeter. Levels of vitamin B12 and folic acid were normal. The inOn 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 eleute, 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 ravenous pressure was not elevated. Examination tio of blood urea nitrogen to creatinine, and hyof 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 conor guarding. Murphys 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 subwith 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 inflamdence of ascites. Examination of the skin revealed mation and fibrosis. Given her history of autoimscaly 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 deposilesions, palmar erythema, leg edema, or spider tion disease merits consideration, given the presangiomata. 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 BuddChiari 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 Gauchers 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 reliter, 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. Aldeciliter (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 associated hepatitis is often severe. Wilsons disease occurs in young adults and should be considered in any patient younger than 40 years of age with unexplained hepatitis. A decreased ceruloplasmin level and Kayser Fleischer rings (brownish copper deposits around the iris) are characteristic findings but are not universally present. She has no neuropsychiatric symptoms and no family history to suggest a diagnosis of Wilsons disease, but these features are absent in many cases. Ceruloplasmin is an acute-phase reactant and thus may be falsely normal or even elevated in patients with Wilsons disease. If this disorder is suspected, screening for urinary copper levels is warranted. The elevated mean corpuscular volume in this patient is probably related to the medications she takes specifically, methotrexate or carbamazepine. The elevated ratio of blood urea nitrogen to creatinine suggests mild volume depletion, probably the result of inadequately controlled diabetes mellitus. The patients serum iron level was 104 mg per deciliter (18.6 mol per liter), total iron-binding capacity 392 g per deciliter (70.2 mol per liter), ferritin 141 g per liter, and thyrotropin 5.9 IU per liter. Her total cholesterol level was 195 mg per deciliter (5.0 mmol per liter), triglycerides 458 mg per deciliter (5.2 mmol per liter), high-density lipoprotein cholesterol 60 mg per deciliter (1.6 mmol per liter), and low-density lipoprotein cholesterol 98 mg per deciliter (2.5 mmol per liter). The glycated hemoglobin level was 12.4%. The erythrocyte sedimentation rate was 21 mm per hour. Serologic tests for viral hepatitis were positive for hepatitis B surface antibody, negative for hepatitis B surface antigen and core antibody, and negative for hepatitis C antibody. The antinuclear antibody titer was 1:20, with a diffuse pattern. Tests for antimitochondrial antibody and anti smooth-muscle antibody were negative. The serum ceruloplasmin and urinary copper levels were normal, as were the results of an ophthalmologic examination. The level of alpha1-antitrypsin was also normal. Doppler ultrasonography of the abdomen showed hepatomegaly, with no fatty infiltration or vascular abnormalities and normal echogenicity. The kidneys were normal with respect to echogenicity but were enlarged, both measuring 13.9 cm in length.
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The serologic findings rule out chronic hepatitis B and C, and the positive result for hepatitis B surface antibody is consistent with prior vaccination. Iron overload is unlikely, given the normal iron studies; the aminotransferase levels are also higher than in typical cases of iron-overload disease. Primary biliary cirrhosis can cause hepatomegaly, but the normal test result for alkaline phosphatase and the negative result for antimitochondrial antibody are inconsistent with this diagnosis. At this point, a liver biopsy would be required to rule out a number of possible diagnoses, but they appear to be clinically unlikely. These diagnoses include steatohepatitis, alpha1antitrypsin deficiency, autoimmune hepatitis, inherited glycogen storage disorders, Gauchers disease, and secondary amyloidosis. If the patient was fasting at the time of blood draw, her elevated triglyceride level is probably related to her hyperglycemia, as part of the metabolic syndrome. Nonalcoholic fatty liver disease is also associated with this syndrome and could underlie the elevated aminotransferase levels. However, there was no evidence of hepatic steatosis on ultrasonography, which is highly sensitive for marked fatty infiltration but less sensitive when there is less steatosis or when obesity precludes adequate imaging. The normal alpha1-antitrypsin level and the absence of a family history of liver or lung disease argue against alpha1-antitrypsin deficiency. The normal levels of globulins, the negative result for antismooth-muscle antibody, and the low titer for antinuclear antibody make autoimmune hepatitis unlikely. The concomitant enlargement of the patients liver and kidneys points to infiltrative disease. An inherited glycogen storage disorder is inconsistent with her age at presentation, the absence of cirrhosis, and the presence of hyperglycemia rather than hypoglycemia. Gauchers disease can be diagnosed in adults, but the deposition of glucocerebroside in the liver, spleen, and bone marrow characteristically causes not only hepatomegaly but also splenomegaly, anemia, and thrombocytopenia. Although amyloidosis could be secondary to juvenile rheumatoid arthritis, the primary abnormality would be expected to cause a greater elevation in alkaline phosphatase than in the aminotransferases. Given the patients history of poorly controlled diabetes and the presence of hepatomegaly, pain, nausea, and elevated aminotransferases, the most likely innejm.org may 5, 2011

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filtrative process is glycogenic hepatopathy, an acquired hepatic glycogen storage disease that may 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. 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. Patients 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 om men ta r y
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 particular concern in this case was the possibility of methotrexate-induced liver disease. A retrospective cohort study of patients with rheumatic or psoriatic arthritis showed that 43% of patients had at least one hepatic biochemical abnormality. The patients with rheumatic arthritis received a median cumulative dose of 3.6 g of methotrexate, and higher doses were associated with a higher frequency of biochemical abnormalities.1 Although more data are needed to assess the risk of cirrhosis that is associated with methotrexate, the risk is considered to be low. In a large study, the 5-year cumulative incidence of cirrhosis and liver failure among patients with rheumatic arthritis who took methotrexate was
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Figure 1. Liver-Biopsy Specimen Liver Showing Histologic and Biochemical Features of Glycogenic Hepatopathy. Hematoxylin-and-eosin staining (Panel A) reveals clear cytoplasm, normal portal tracts, no fibrosis, and glycogenation of the nuclei (arrow), findings that may be seen in glycogen storage disease, glycoprotein or glycolipid storage diseases, glycogenic hepatopathy, and steatosis. Periodic acidSchiff staining is markedly positive for the presence of glycogen (Panel B). With the addition of diastase, which digests pure glycogen but not glycoproteins or glycolipids, periodic acid Schiff staining is lost (Panel C), confirming the presence of pure glycogen within the hepatocytes. Images courtesy of Dr. Dominique Coco, Brigham and Womens Hospital, Department of Pathology.

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estimated at 1 case per 1000 patients.2 Similarly, a retrospective cohort study including 25 patients with juvenile rheumatoid arthritis showed no correlation between the cumulative methotrexate dose and fibrosis, and none of the patients studied had high-grade fibrosis over the course of longterm follow-up.3 Recommendations regarding indications for biopsy in patients taking methotrexate are inconsistent, and there are no guidelines for patients with juvenile rheumatoid arthritis. The current guidelines of the American College of Rheumatology for patients with rheumatic arthritis who are taking methotrexate recommend measurement of liver enzyme levels every 4 to 8 weeks; biopsy is recommended if the results of 6 of 12 monthly tests are abnormal (or 5 of 9 tests if testing is performed every 6 weeks); the guidelines do not recommend performance of biopsy on the basis of the cumulative dose.4 It is important to distinguish between glycogenic hepatopathy and hepatic steatosis for the purposes of treatment and assessment of prognosis. In glycogenic hepatopathy, glycemic control can be achieved with adequate insulin therapy. Nonalcoholic steatohepatitis is more difficult to

treat; weight loss and correction of hypertriglyceridemia and hyperglycemia are recommended, and certain medications (including insulin-sensitizing agents, statins, ursodiol, pentoxifylline, and vitamin E) have been used.5 Nonalcoholic steatohepatitis is increasingly recognized as a cause of cirrhosis. In one study of 103 patients, 37% had histologic progression to cirrhosis, 34% had no change, and 29% had regression.6 With treatment, glycogenic hepatopathy has a more benign course. In the largest case series, 2 of 14 patients were found to have mild fibrosis on biopsy.7 Although biopsy is the only way to distinguish the two conditions definitively, biopsy is not necessary if empirical treatment leads to biochemical and symptomatic improvement. First described in 1930 by Mauriac8 as hepatic glycogenosis, the entity now called glycogenic hepatopathy is characterized by hepatic glycogen deposition in patients with poorly controlled type 1 diabetes mellitus. The original syndrome was described in children and included three features also present in this case hepatomegaly, abdominal pain, and abnormal levels of liver enzymes but also included hypercho-

Glycogen synthase phosphatase (deactivated)

Glucose Insulin

Glycogen synthase phosphatase

Glycogen synthase phosphorylase

Glucagon

Glycogen synthase (activated)

Glucose

Glucose-1-phosphate

Glycogen

Glycogen phosphorylase

Glucagon

Figure 2. Mechanism of Glycogen Storage in the Liver. RETAKE: 1st AUTHOR: Rogal In the presence of insulin and excess glucose, glycogen synthase phosphatase is activated as dephosphorylated glyco2nd 3rd gen synthase. Dephosphorylated FIGURE: 2 ofglycogen synthase is required for the conversion of glucose-1-phosphate (activated) 2 Revised to glycogen. The thick arrows highlight the effects of glucose and excess insulin on glycogen formation. In contrast, ARTIST: ts SIZE glucagon stimulates the phosphorylation of glycogen synthase, leading to increased glycogenolysis. Adapted from 6 col 7 Combo 4-C H/T TYPE: Line Torbenson et al. 33p9
AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully.

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lesterolemia and growth delay; since that time, this entity has been increasingly recognized among both children9 and adults10,11 with type 1 diabetes. In the case series of 14 patients with biopsyproven glycogenic hepatopathy, all the patients had type 1 diabetes, and 13 had abnormal liverfunction tests.7 All 9 patients who were evaluated with imaging had hepatomegaly, and all 6 who were tested for glycated hemoglobin had elevated levels. Pain in the right upper quadrant of the abdomen, nausea, or vomiting was present in 8 of the 14 patients, whereas steatosis was present in only 2 findings that distinguish glycogenic hepatopathy from nonalcoholic fatty liver disease. Other reports have revealed similar findings.11-14 The prevalence of glycogenic hepatopathy among people with diabetes is unknown. In the pathophysiological process of the disorder, the concomitant presence of insulin and excess glucose increases glycogen storage in the liver. Insulin activates glycogen synthase phosphatase, which dephosphorylates and activates glycogen synthase, an enzyme required for the conversion of glucose-1-phosphate to glycogen (Fig. 2).
References 1. Amital H, Arnson Y, Chodick G, Shalev V. Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate. Rheumatology (Oxford) 2009;48:1107-10. 2. Walker AM, Funch D, Dreyer NA, et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arthritis Rheum 1993;36:329-35. 3. Hashkes PJ, Balistreri WF, Bove KE, Ballard ET, Passo MH. The relationship of hepatotoxic risk factors and liver histology in methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr 1999;134: 47-52. 4. Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. Arthritis Rheum 1994; 37:316-28. 5. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-85.

No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This activation promotes glycogen storage in the liver and blocks glycogenolysis. Our patient had both hepatic and renal enlargement. Although most glycogen storage occurs in the liver and in muscle, some glycogen is stored in the kidney.15 It is plausible that the renal enlargement in this case was attributable to glycogen deposition, but we cannot be certain; we are not aware of other reports of renal enlargement in glycogenic hepatopathy. Treatment involves the use of adequate doses of insulin to achieve rigorous glucose control; this approach has been shown to be effective in children8 and in adults.11 In the published reports, pain in the right upper quadrant, nausea, vomiting, hepatomegaly, and laboratory abnormalities have been reversed in as few as 4 weeks with adequate insulin therapy.9,10,12 This case calls attention to glycogenic hepatopathy as an underrecognized but reversible cause of infiltrative liver disease in patients with type 1 diabetes.

6. Adams LA, Sanderson S, Lindor KD,

Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005;42:132-8. 7. Torbenson M, Chen YY, Brunt E, et al. Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus. Am J Surg Pathol 2006;30:50813. 8. Mauriac P. Gros ventre, hepatomegalie, troubles de la croissance chez les enfants diabetiques traites depuis plusieurs annes par linsuline. Gaz Hebd Med Bourdeaux 1930;26:402-10. 9. Munns CF, McCrossin RB, Thomsett MJ, Batch J. Hepatic glycogenosis: reversible hepatomegaly in type 1 diabetes. J Paediatr Child Health 2000;36:449-52. 10. Nakamuta M, Ohashi M, Goto K, Tanabe Y, Hiroshige K, Nawata H. Diabetes mellitus-associated glycogen storage hepatomegaly: report of a case and review of the Japanese literature. Fukuoka Igaku Zasshi 1993;84:354-8.

11. Chatila R, West AB. Hepatomegaly

and abnormal liver tests due to glycogenosis in adults with diabetes. Medicine (Baltimore) 1996;75:327-33. 12. Abaci A, Bekem O, Unuvar T, et al. Hepatic glycogenosis: a rare cause of hepatomegaly in Type 1 diabetes mellitus. J Diabetes Complications 2008;22:325-8. 13. Olsson R, Wesslau C, William-Olsson T, Zettergren L. Elevated aminotransferases and alkaline phosphatases in unstable diabetes mellitus without ketoacidosis or hypoglycemia. J Clin Gastroenterol 1989;11:541-5. 14. Sayuk GS, Elwing JE, Lisker-Melman M. Hepatic glycogenosis: an underrecognized source of abnormal liver function tests? Dig Dis Sci 2007;52:936-8. 15. Cersosimo E, Ajmal M, Naukam RJ, Molina PE, Abumrad NN. Role of the kidney in plasma glucose regulation during hyperglycemia. Am J Physiol 1997;272: E756-E761.
Copyright 2011 Massachusetts Medical Society.

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