CASE CONFERENCE hyperthyroidism

An U n u s u a l C a u s e of A b d o m i n a l Pain in a Young W o m a n [Harwood-Nuss AL, Marte] TJ: An unusual cause of abdominal pain in a young woman. Ann Emerg Med May 1991;20:574-582.]

INTRODUCTION Today's case is that of a young woman with abdominal pain. The case illustrates several clinical issues fundamental to emergency medicine. Clearly, in many cases it is appropriate to perform a limited history and physical examination on a woman with abdominal pain. However, our case represents that situation in which a thorough review of systems and complete physical examination are essential to a proper differential diagnosis and treatment plan. This approach has special merit when dealing with the patient with a history of repeated emergency department visits for the same complaint. Another basic issue pertains to the reconciliation of the chief complaint, objective findings, and the working diagnosis. We have attempted to provide specific points of concern in this often difficult but critical reconciliation process. Finally, we discuss a comprehensive differential diagnosis of abdominal pain with emphasis placed on the most common processes and their characteristic clinical features. We believe our case illustrates the issues presented above. The case will be discussed by Ann Harwood-Nuss, MD, FACEP, and Thomas J Martel, MD, from the Division of Emergency Medicine, Department of Surgery, University of Florida Health Science Center-Jacksonville.

Ann L Harwood-Nuss, MD, FACEP Thomas J Martel, MD Jacksonville, Florida From the Division of Emergency Medicine, University of Florida Health Science Center-Jacksonville. Received for publication July 31, 1990. Revision received October 2, 1990. Accepted for publication November 24, 1990. Address for reprints: Ann L HarwoodNuss, MD, FACEP, Division of Emergency Medicine, University of Florida Health Science Center-Jacksonville, 655 West Eighth Street, Jacksorwille, Florida 32209.

CASE PRESENTATION Thomas J Martel, MD: A 25-year-old black woman presented to the ED with intermittent, colicky, right upper-quadrant pain. There was no radiation of the pain, nor were there exacerbating or relieving factors. The pain was occasionally associated with nausea, vomiting, and diarrhea. There had been two ED visits during the preceding three months for the same complaints. However, the pain had increased in intensity during the past four days, resulting in the current visit. The patient also reported fever, chills, night sweats, and a 40-1b weight loss over four months despite a good appetite. She denied hematemesis, melena, or rectal bleeding. Her last menstrual period was four months earlier. Before that time, the patient described normal, regular menses. She had no urinary tract symptoms. She denied the use of over-the-counter medication or prescription drugs. She also denied the use of illicit drugs and alcohol. Her medical history was significant only for sickle cell trait. She had no prior surgery or trauma. The physical examination revealed a thin, poorly nourished, anxious woman not in distress. Her vitals signs were blood pressure of 140/70 m m Hg; pulse, 112; respirations, 22; and temperature, 38.5 C. Examination of the skin revealed it to be warm and dry with no evidence of dehydration, rash, or other lesions. Examination of the head was normal. The neck was supple without adenopathy. A symmetrically enlarged, nontender thyroid gland was palpated. The pulmonary examination was normal. The cardiac examination revealed a regular rhythm with sinus tachycardia and a nonradiating, 2/6 systolic ejection murmur over the left sternal border. The abdomen was soft, flat, and nontender with normal bowel sounds. Murphy's sign was absent, as were flank and costovertebral angle tenderness. The pelvic and rectal examinations were normal. The stool was gna-

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iac-negative. The neurologic examination was normal except for tremulous extremities. The nails were separated from the nail beds (onycholysis). CBC, electrolytes, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, liver function tests, serum amylase, urinalysis, and urinary pregnancy test were obtained (Table 1). Abnormal laboratory values included a white blood cell count of 20,000/ram s (79 leukocytes, 12 lymphocytes, and 10 bands); hematocrit, 29.5%; aspartate aminotransferase, 51 IU/L; and alkaline phosphatase, 207 U/L. A radiograph of the chest and an abdominal obstructive series were normal. The ECG revealed a sinus tachycardia.

Question: What is the differential diagnosis in this patient? Ann Harwood-Nuss, MD, FACEP: The differential diagnosis of right upper-quadrant pain in a young woman is vast 1 (Figure 1). Despite the recent exacerbation, our patient described persistent, i n t e r m i t t e n t abdominal pain of nearly four months' duration. Review of the medical records from the two previous ED visits revealed that the evaluation was focused on the abdominal pain only, with the Tesultant diagnosis of gastroenteritis. During the third ED visit, a careful review of systems elicited associated complaints of anxiety, weight loss, nausea, vomiting, diarrhea, fever, and amenorrhea. This constellation of signs and s y m p t o m s m a n d a t e s a m o d i f i c a t i o n of the s t a n d a r d approach to abdominal pain. Although the customary priority is to exclude s u r g i c a l l y c o r r e c t a b l e causes of abdominal pain (ie, obstruction, perforation, infection, and hemorrhage), the chronicity and intermittency made these less li-kely. In addition, the examination failed to reveal serious peritoneal signs or abnormal pelvic findings. However, other important objective i n f o r m a t i o n obtained from the physical examination and laboratory studies warrant an expanded differential diagnosis: malnourishment, onycholysis of the nails, a heart murmur, an enlarged thyroid, leukocytosis, anemia, and elevated alkaline phosphatase and aspartate aminotransferase. Question: What are the principal di150/575

TABLE 1. Laboratory data Test Electrolytes

Results (Normal Range)

Na K

143 mmol/L (136 - 146 mmol/L) 3.1 mmol/L (3.5 -5.1 retool/L) 107 mmol/L (98 - 106 mmo//L) 24.6 mmol/L (24- 31 mmol/L) 6 mg/dL ( 5 - 25 mg/dL) 0.6 mg/dL (0.5 - 1.4 mg/dL) 85 mg/dL (70 110 mg/dL)

CI HCO3 Blood urea nitrogen Creatinine Glucose

Complete Blood Count WBC Segs Bands Lymphs Hemoglobin Hematocrit Platelets Mean cell volume Mean cell hemoglobin Transferrin Iron Ferritin Amylase Phosphorus Calcium Total protein Albumin Alkaline phosphatase Aspartate aminotransferase Atanine aminotransferase Total bilirubin Prothrombin time Partial thrombin tire Urine !S-HOG

20,000/ram3 (4.5 - 11.0/ram3) 79/ram3 (36 - 66/ram3) 10/mm3 (5 - 11/ram3) 12/mm3 (24 - 44/ram3) 9.1 g/dL (12 - 16 g/dL) 29.5% (37 47%) 322,000/mm3 (140,000 - 440,000/mm3) 65.8 ~,m3 (82 - 101t~m3) 20.9 ng (27 34 ng) 199 mg/dL (204- 360 mg/dL) 8 mg/dL (26 170 mg/dL) 175 ng/mL (10 - 130 ng/mL) 36 U/L (44 - 128 U/L) 5.0 mg/dL (2.6- 4.9 mg/dL) 8.0 mg/dL (8.4 - 10.2 mg/dL) 6.2 g/dL (2.6 4.9 g/dL) 3.4 g/dL ( 3 - 5.5 g/dL) 207 U/L (37 - 106 U/L) 51 IU/L ( 0 - 42 IU/L) 60 U/L (10- 60 U/L) 0.4 mg/dL (0.2 1.0 mg/dL) 12 seconds (11 - 14 seconds) 36 seconds (25 - 38 seconds) Negative

Urinalysis Keione Protein Hemoglobin WBCs RBCs pH Specific gravity Blood culture and sensitivity Cervical (gonorrhea) culture Throat culture Urine culture and sensitivity

agnostic considerations in our patient ?

Dr Martel: In lieu of the right upperquadrant pain, diseases of the hepatoAnnals of Emergency Medicine

Trace Negative Negative O-5/high power field O/high power field 7.0 1.013 No growth No growth No growth No growth

biliary system were considered, including acute cholecystitis, ascending cholangitis, hepatitis, and pancreatitis. C h o l e c y s t i t i s is a c o m m o n disease and was considered because 20:5 May 1991

A B D O M I N A L PAIN H a r w o o d - N u s s & Martel

Pelvic inflammatory disease Ectopic pregnancy Torsion of adnexal structures Ovarian cyst or neoplasm Gastmenteritis Appendicitis Peptic ulcer disease Hepatitis Pancreatitis Cholecystitis Perihepatitis Pneumonia Pyelonephritis or cystitis Nephrolithiasis Metabolic or endocrine in origin Modifiedfrom Reference1.

of the location of the pain, fever, and elevated alkaline phosphatase and aspartate aminotransferase. Historically, however, the patient's pain was not associated with meals, nor were there any food intolerances. There was no history of jaundice. The abdominal examination was unremarkable with a negative Murphy's sign and a nonpalpable gallbladder. The laboratory data revealed minimally elevated alkaline phosphatase and aspartate aminotransferase with normal bilirubin. The m a j o r i t y of cases of acute cholecystitis (90%) are associated with cholelithiasis and obstruction of the cystic duct. 2 The acute obstructive process is characterized by upper abdominal pain, fever, and nausea. Typically, there will be loc a l i z e d p e r i t o n e a l signs. L e u k o cytosis, jaundice, and liver enzyme abnormalities are not usually seen in uncomplicated cholecystitis. Both ultrasound and nuclear hepatobiliary imaging are useful in the diagnosis of acute cholecystitis. Our patient had an abdominal ultrasound performed at the time of her third ED visit, followed by a r a d i o n u c l i d e (HIDA) scan of the biliary system. Both studies were negative. Acute obstructive cholangitis is characterized by right upper-quadrant pain, fever, and jaundice (Charcot's triad). The most c o m m o n etiology is gallstones. The diagnosis is confirmed by e n d o s c o p i c retrograde cholangiopanereatography. 2 In our patient, this diagnosis was not given serious con20:5 May 1991

FIGURE 1. Differential diagnosis of abdominal pain in a woman. sideration in light of the negative HIDA and ultrasound and the fact that this process occurs primarily in the elderly. Hepatitis was briefly considered, but our patient had no known exposure or risk factors for hepatitis. Her liver was normal size and nontender, she was nonicteric, and the liver function studies were inconsistent with a diagnosis of hepatitis. Pancreatitis can cause upper abdominal pain. However, more than 70% of cases r e s u l t f r o m g a l l s t o n e s or chronic alcoholism. Our patient had no history of alcohol abuse, no evidence of gallstones, and no other unusual risk factors for pancreatitis (eg, trauma, viral infection, hyperlipidemia, drug use, or surgery}. A n o n t e n d e r abdomen, normal amylase, and normal ultrasound essentially excluded pancreatitis. Question: What entities involving the gastrointestinal system could be responsible for our patient's clinical picture? Dr Harwood-Nuss: I would consider gastroenteritis, peptic ulcer disease, inflammatory bowel disease ([IBD] Crohn's disease and ulcerative colitis), and an appendiceal abscess. Infectious diarrhea seems u n l i k e l y given the chronic nature of her complaints. However, Campylobacter was considered because it may present with chronic abdominal pain, diarrhea, and weight loss. Furthermore, it is a common cause of recurrent gastroenteritis and may cause gastric erosions and ulceration. 3 The patient's stool was guaiac-negative, and fecal leukocytes were absent. Cultures of the stool for ova, parasites, and Campylobacter were negative. Peptic ulcer disease can cause chronic abdominal pain and weight loss. However, our patient denied a h i s t o r y of p e p t i c ulcers, h e m a temesis, melena, or rectal bleeding. She was on no medication that increases the risk for ulcers. The pain was not related to meals and was not relieved with antacids. During hospitalization, she had upper endoscopy that ruled out peptic ulcer disease. IBD was given serious consideraAnnals of Emergency Medicine

tion, although it is more common in whites. It usually presents in the third and fourth decades of life with intermittent abdominal pain, diarrhea, fever, weight loss, and anemia, features also found in our patient. Ulcerative colitis is a diffuse, inflammatory disease of the mucosal lining of the colon and rectum. Abdominal pain, weight loss, bloody diarrhea, and anemia are the usual features. Ulcerative colitis is often associated with the extracolonic manifestations of rash, arthralgias, and liver disease. 3 The physical examination and laboratory data are nonspecific and nondiagnostic. Crohn's disease involves chronic, relapsing segmental disease of the intestine, although any part of the gastrointestinal tract may be affected from the oral cavity to the anus. Typically, the disease is one of recurrent abdominal pain, often located in the right lower quadrant. 3 Associated complaints include diarrhea, melena, fever, malaise, and arthralgias. Crohn's disease may present with fistulas, fissures, strictures, right lower-quadrant mass, or intestinal obstruction. It is not unusual for the initial diagnosis to be that of acute appendicitis. Usually, however, the physical examination and laboratory studies are nonspecific. IBD is often a diagnosis of exclusion because there are no diagnostic markers. However, abdominal radiography, endoscopy, sigmoidoscopy, and barium studies may all be suggestive of IBD. The diagnosis is made by tissue biopsy. IBD was excluded in our patient during her h o s p i t a l i z a t i o n w i t h p a n e n doscopy, air contrast barium enema, and sigmoidoscopy, all of which were negative. An intra-abdominal abscess walled off by i n f l a m m a t o r y adhesions is possible after perforation of the intestinal tract, ruptured appendix, hematogenous seeding in an i m m u n o compromised host, or prior surgery. The patient with an abdominal abscess is usually febrile with constant pain. Most seek medical attention within the first week of abscess formation. An abdominal abscess may be difficult to diagnose, often requiring special imaging studies. Plain abdominal films, ultrasound, computed tomography, gallium scan, and indium scans may be useful diagnostic studies. An abdominal abscess was consid576/151

ABDOMINAL PAIN Harwood-Nuss & Martel

ered in our patient as the cause of her chronic abdominal pain, fever, and leukocytosis. Abdominal radiographs and ultrasound performed in the ED were negative. Abdominal computed tomography done after admission to the hospital was also normal. Diseases of the urinary tract were also briefly considered, including cystitis, pyelonephritis, and ureterolithiasis. None of these entities was thought to be likely. There was no history of urologic disease, instrumentation, or voiding complaints. There was no costovertebral angle, flank, or suprapubic tenderness. A normal urinalysis and subsequent negative urine culture further eliminated these from serious consideration. However, intrarenal and perirenal abscesses are often characterized by an insidious course, delay in diagnosis, and significant mortality.2 Intrarenal abscess may occur as a complication of acute pyelonephritis or hematogenous seeding, especially of Staphyloccus aureus. A perinephric abscess usually occurs as the result of rupture of an intrarenal abscess. Delayed diagnosis is common, with symptoms often exceeding 14 days. 2 Fever, flank pain, flank mass, anemia, and leukocytosis are typical features of a perinephric abscess. The urinalysis m a y or may not show pyuria. Ultrasound and computed tomography permit early diagnosis. Our patient denied any of the recognized predisposing factors (ie, urinary tract obstruction, diabetes mellitus, and urinary calculi) and had a normal ultrasound and computed tomography. T h e r e p r o d u c t i v e s y s t e m , of course, is always of concern in young women with abdominal pain. The presence of ectopic pregnancy must be considered. A normal pelvic exa m i n a t i o n and a n e g a t i v e u r i n e [3-HCG pregnancy test excluded this diagnosis. Many primary ovarian tumors are asymptomatic and discovered only on routine pelvic examination. Symptoms usually relate to the size of the mass. At age 25, our patient was not likely to have a germ cell tumor. Ovarian epithelial neoplasm is a disease primarily of perimenopausal and menopausal women, with the median age in the late 50s to early 60s. A normal pelvic examination and ultrasound further diminished ovarian disease from consideration. 152/577

Pelvic inflammatory disease was thought to be unlikely with normal abdominal and pelvic examinations. In addition, cervical cultures showed no growth. Perihepatitis was also Considered. This disease, caused by dissemination of Chlamydia trachomatis or gonococcal pelvic infection, can be difficult to diagnose because of the absence of diagnostic markers. Supporting features include a history of sudden onset of sharp, often pleuritic right upper-quadrant abdominal pain. Physical findings include fever and tenderness under the right costal margin. The pelvic examination may be normal or reveal signs of pelvic inflammatory disease. Liver function studies may be abnormal. Our patient related no history of recent or remote pelvic infection and had unremarkable abdominal and pelvic exa m i n a t i o n s and negative cervical cultures. Dr Martel: Disease of the lung or pleura may cause right upper-quadrant pain. Right lower-lobe pneumonia occasionally causes irritation of the diaphragm, resulting in right upper-quadrant pain. However, our patient had no pulmonary symptoms and a normal pulmonary examination. A n o r m a l chest radiograph eliminated the diagnosis of pneumonia. The patient gave a history of sickle cell trait, confirmed by review of a prior h e m o g l o b i n electrophoresis. Sickle cell trait results from the inheritance of one Hb S gene and one Hb A gene. An individual who is hete r o z y g o u s for sickle cell a n e m i a (sickle cell trait) is usually asymptomatic, not anemic, and has a normal life expectancy. 4 However, there are three rare but well-documented complications of sickle cell trait that should be considered: painless microh e m a t u r i a from inadequately perfused renal papillae, splenic infarct, and painful crisis. The latter two occur in conditions of low a m b i e n t oxygen or severe acidosis, s The absence of hematuria and the chroni c i t y of our p a t i e n t ' s c o m p l a i n t s made these complications of sickle cell trait unlikely. Hodgkin's disease and other lymphomas could be responsible for fever, abdominal pain, night sweats, weight loss, and anemia in a young adult. The absence of lymphadenopAnnals of Emergency Medicine

athy and a normal abdominal computed tomography and chest radiograph excluded this diagnosis. Q u e s t i o n : Could an endocrine disease account for our patient's clinical picture? Dr Harwood-Nuss: Most comprehensive lists of the differential diagnoses of abdominal pain include the broad category of " e n d o c r i n e and metabolic." Diabetic ketoacidosis m a y present with abdominal pain. The mechanism is obscure. Our patient had normal blood sugar and serum carbon dioxide, which made this an unlikely diagnosis. Acute porphyria and lead poisoning should also be considered because there are some features of each that were present in our patient. The porphyrias are inherited and acquired disorders resulting from deficiencies in enzymes of the heme b i o s y n t h e t i c pathway, z The clinical manifestations of acute porphyria include abdominal pain and neurologic manifestations. The abd o m i n a l pain is u s u a l l y c o l i c k y (80%) and associated with an ileus. Nearly half of all patients present with n e u r o p s y c h i a t r i c manifestations. Proximal muscle weakness, urinary retention, generalized seizures, diminished deep tendon reflexes, hypertension, and tachycardia are also seen. 2 The porphyrias are rare but should be considered. A bedside test during an acute attack involves the m i x i n g of urine w i t h Ehrlich's aldehyde reagent. Details of this test may be found elsewhere. 2 A l t h o u g h lead p o i s o n i n g m a y cause abdominal pain, none of the other manifestations of lead poisoning was present in our patient. Lead poisoning in adults results from occupational exposure in more than 92% of all cases. Our patient was unemployed and had no known exposure to nonoccupational sources of lead (ie, home-distilled whiskey, lead bullets, etc). Our final diagnostic possibility, thyrotoxicosis, could account for our p a t i e n t ' s c o n s t e l l a t i o n of signs, symptoms, and supportive data. The two previous ED evaluations focused on a single system (abdomen) and a single chief complaint (abdominal pain). The failure to recognize and reconcile subtle associated signs and symptoms led to erroneous diagnosis and improper management. Our pa20:5 May 1991

A B D O M I N A L PAIN H a r w o o d - N u s s & Martel

TABLE 2. Frequency of common symptoms and signs of hyperthyroidism Symptoms

Reported Frequency (%)

Nervousness

80

99

Increased sweating Heat intolerance

50 41

91 89

Palpitations

63

89

Dyspnea on effort

66

81

Fatigue and weakness

44 - 88

Weight loss Increased appetite

52 11

Eye symptoms Hyperdefecation

85 65 55

12

33

Thyroid enlargement

37

100

Thyrdd bruit Exophthatmos

28 - TT 49 - 62

Signs

Lid retraction

38

Lid lag Hyperkinesis

48 - 62 39 - 80

Tremor

40

Hands (hot, moist)

7 2 - 76

Tachycardia (> 90) Atrial fibrillation

58 100 10 - 38

gT

Modified from Spaulding SW, Uliger R, in Felig P (ed): Endocrinology and Metabolism New York, McGraw Hill Book Co, 1981, p 308

tient had endured an illness for three months, characterized not only by abdominal pain but also by progressive and persistent nausea, vomiting, diarrhea, weight loss, fever, chills, night sweats, and amenorrhea. On closer questioning, our patient also admitted to several months of heat intolerance, emotional lability, and inability to sleep. The examination revealed the following pertinent findings: an undernourished, anxious y o u n g w o m a n with fever, tachyca~Jia, a heart murmur, thyroid mass, onycholysis, and a fine tremor of the extremities. Abnormal laboratory studies included a hematocrit of 29%, a WBC count of 20,000/cu 3, and elevated aspartate aminotransferase and alkaline phosphatase.

HYPERTHYROIDISM First described by Parry in 1786, and further elucidated by Graves in 1835, hyperthyroidism is a clinical syndrome associated with numerous disease states, s Hyperthyroidism is common in the United States, with 20:5 May 1991

80% to 90% of all cases resulting from Graves' disease (toxic diffuse goiter). Toxic nodular goiters and thyroiditis account for the remainder.2, 5 Graves' disease affects nearly 1.9% of all women with a peak incidence in the third and fourth decades of life. There is also a strong familial component. There is no explanation for the strong female preponderance (7 to 10:1) of this disease. 5 The etiology of Graves' disease is unknown, but it is thought to be a disease of disordered i m m u n i t y . Stimulation of the thyroid possibly o c c u r s f r o m a c i r c u l a t i n g , nonthyroid-stimulating hormone thyroid s t i m u l a t o r w i t h IgG i m m u n o globulin acting against the thyroid plasma membrane.S, 6 True hyperthyroidism is caused by an increase in the synthesis and release of thyroid h o r m o n e s from the .thyroid gland. 5 Thyrotoxicosis may also be either drug induced or, infrequently, resulting from an iodine load. Factitious or iatrogenic thyrotoxicosis, the ingestion of excess thyroid hormone, is seen, often in medical personnel. 5 The ingestion may also be accidental or through food sources. Amiodorone is rich in iodine and may cause iodine-induced thyrotoxicosis. These latter causes may be distinguished by a low uptake of administered radioactive iodine (RAI uptake).5, 7 Iodine-induced hyperthyroidism is u n c o m m o n in the United States. s Typically, it occurs in the patient with an underlying subclinical goiter or thyroid adenoma. In these situations, the occult disease is uncovered by t h e a d m i n i s t r a t i o n of large amounts of iodine.S,7 The RAI uptake may be falsely low in the presence of an iodine load, most often during imaging with iodine-containing contrast agents. The potential exists for interference in subsequent diagnostic testing and therapy with iodine. Adequate t r e a t m e n t m a y be achieved with ~3-adrenergic blocking agents only, although a n t i t h y r o i d agents may be necessary in more severely affected patients, s Question: What are the clinical manifestations of hyperthyroidism? Dr Martel: The clinical manifestations are those of hypermetabolism from excessive quantities of circulating thyroid hormone. The actions of Annals of Emergency Medicine

the excessive thyroid hormone most prominently affect the cardiovascular and central n e r v o u s systems, although the degrees of influence may vary (Table 2).2,5,7 In its classic form, hyperthyroidism has distinct clinical features, but it may occasionally be a great imitator of other disorders. In particular, the elderly may demonstrate predominant constitutional, cardiovascular, p s y c h i a t r i c , musculoskeleta], or gastrointestinal manifestations. This subtype of hyperthyroidism, apathetic hyperthyroidism, was first recognized by Lahey in 1931 and is characterized by apathy, listlessness, weakness, weight loss, dry skin, and often signs of other clinical disease, s Graves' disease is most often seen in young women, with the typical patient in her middle 20s. Graves' disease m a y cause c h r o n i c complaints and is frequently misdiagnosed unless the patient presents with classic ocular, dermatologic, and cardiovascular findings. As a result, it is c o m m o n for the "typical patient" to have been symptomatic for six to 12 months before a diagnosis is made. s Central nervous system manifestations are prominent, including nervousness, anxiety, fatigue, and emotional lability. Other common complaints include palpitations, dyspnea on exertion, heat intolerance, neck swelling, and oligomenorrhea or amenorrhea, s Gastrointestinal symptoms of hyperthyroidism are nonspecific: nausea, v o m i t i n g , loose stools, and weight loss despite a good appetite. The physical examination of the patient with Graves' disease usually reveals an anxious, nervous patient. A low-grade fever may be present, but the body temperature is usually norreal. In young patients, a tachycardia is almost always found, s Systolic blood pressure is elevated with a widened pulse pressure. The skin is warm and smooth; pretibial "myxedema" and alopecia may be noted. Occasionally, o n y c h o l y s i s of the fourth and fifth fingers or clubbing is seen. There may be a fine tremor of the fingers and tongue as well as muscle weakness, hyperactive reflexes, and unsustained clonus. A l t h o u g h a n y k i n d of h y p e r thyroidism can cause ocular signs, the characteristic feature of Graves' disease is proptosis. Exophthalmic goiter is considered by many to be 578/153

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synonymous with Graves' disease. 7 Eye signs are present in more than 50% of patients with Graves' disease and include lid lag, stare, a widened palpebral fissure, and proptosis.2, s However, eye signs may be mild or absent.5, 7 Thyroid enlargement is common and may be the initial clue to diagnosis, although in the elderly, the thyroid may be normal size. In Graves' disease, both lobes are moderately enlarged and symmetric. A thyroid bruit may be audible due to increased vascularity of the gland. Cardiovascular findings are common and may dominate the initial clinical picture; they include sinus tachycardia, atrial flutter and fibrillation, systolic murmur, and a gallop rhythm. 7 The abdominal examination is unremarkable except for a small percentage of patients with an enlarged spleen.Z,5, 7 Question: What laboratory abnormalities are seen in hyperthyroidism? Dr Harwood-Nuss: In 5% to 20% of patients with hyperthyroidism, physiologic, biochemical, and serologic abnormalities may be found, reflecting excessive thyroid hormone action on various tissues. The most common abnormalities include a modest anemia, lymphocytosis, and granulocytopenia. Calcium concentration may be increased. Hepatic dysfunction is c o m m o n in moderate-to-severe thyrotoxicosis with decreased protein, increased direct bilirubin, and elevated serum aspartate aminotransferaae and alkaline phosphatase.2,5, 6 The chemical abnormalities seen in our patient are consistent with hyperthyroidism. Question: Our patient had predominantly gastrointestinal complaints. What are the usual gastrointestL al manifestations of hyperthyroidism? Dr Nartel: Gastrointestinal symptoms are relatively common but nonspecific and depend not only on the severity of the disease but also on the age of the patient. 6 Symptoms include anorexia, nausea, vomiting, w e i g h t loss, and f r e q u e n t bowel movements. 9 Increased motility is the most frequent effect of hyperthyroidism on the gastrointestinal tract, with gastric and small- and large-bowel hypermotility present in 154/579

as many as 92% of patients.6, 7 The mechanism of increased gastric motility is unclear. The clinical effects of the hypermotility include rapid gastric emptying and frequent bowel m o v e m e n t s . C h r o n i c n a u s e a and vomiting are infrequent complaints, present in only 10% to 15% of patients, possibly resulting from gastric hypermotility and decreased gastric emptying. There is an increased incidence of gastritis and achlorhydria (73%) compared w i t h the general population.6, lo Hyperdefecation occurs in 20% to 40% of patients. Frank diarrhea is rare. 6 Berstein and Siurala each postulated steatorrhea as the etiology of hyperdefecation, noting a return to n o r m a l fecal fat p e r c e n t a g e after treatment (Siurala et al Io and Berstein and Ridingll). Constipation has been reported in 4% to 30% of hyperthyroid patients, possibly resulting from increased bowel tone and motility. Weight loss is seen in 75% to 85% of patients, despite a normal or increased appetite; increased appetite has been reported in 10% to 65% of patients. 6 In younger patients, increased appetite is characteristic, but anorexia and extensive weight loss m a y occur in older persons or in younger patients with severe disease. 6 Rapid resolution of symptoms resulting from gastritis, achlorhydria, and hypermotility occurs with treatment before the return of a euthyroid state. 6 Normal motility returns with the resumption of a 'euthyroid state. Question: Is abdominal pain considered an unusual manifestation of hyperthyroidism? Dr Harwood-Nuss: Since Graves' disease was first described, certain gastrointestinal manifestations of hyperthyroidism (nausea, weight loss, and h y p e r d e f e c a t i o n ) h a v e b e e n reported. 9,12-16 In 1931, Verbrycke reported that abdominal pain was present in 47% of h y p e r t h y r o i d patients, is In 1956, Chapman and Maloof described symptoms of chronic abdominal pain, weight loss, and vomiting in a patient with hyperthyroidism. 17 However, in 1974, Palmer and Beardwell observed that most gastrointestinal symptoms related to bowel f u n c t i o n (diarrhea, nausea, and vomiting) and that abd o m i n a l p a i n w a s s e l d o m deAnnals of Emergency Medicine

scribed. 12 They went on to report three cases involving middle-aged adults with abdominal pain mimicking intra-abdominal emergencies.12 More recently, Coe et al described a case of apathetic hyperthyroidism presenting as an abdominal emergency. 9 At present, the prevailing medical opinion appears to contend that protracted abdominal pain is an unusual m a n i f e s t a t i o n of h y p e r t h y r o i d ism. 16,18,!9 It is unclear why abdominal pain is no longer considered a c o m m o n m a n i f e s t a t i o n of hyperthyroidism, as it was in the early part of this century. One possible reason pertains to earlier diagnosis and t r e a t m e n t of the disease. 16 Some have suggested that the onset of abdominal pain is not present in uncomplicated h y p e r t h y r o i d i s m but may actually herald the onset of thyroid storm. 6,2° The etiology of abdominal pain remains unknown, but it responds rapidly to a n t i t h y r o i d medications and ~3-adrenergic blocking agents.5,1a, 16 H y p e r t h y r o i d i s m and thyroid storm should be considered in the differential diagnosis of abdominal pain with chronic nausea, vomiting, and diarrhea. Question: What is thyroid storm? Dr Nartel: Approximately 1% of individuals with hyperthyroidism will develop thyroid storm. The diagnostic line between the two may be nebulous because the pathophysiology of thyroid storm does not differ from that of hyperthyroidism. 5 Thyroid storm usually occurs after a recent superimposed stress or infection, but it can occur spontaneously or after iodine-131 therapy.2,5, 2° T h y r o i d storm is suggested in the setting of a patient with k n o w n thyrotoxicosis who develops exaggerated or severe signs and s y m p t o m s of thyrotoxicosis. Precise criteria for thyroid storm are not well defined. Some authorities describe thyroid storm as the onset of fever, altered m e n t a l status (delirium, obtundation, or psychosis), and dysfunctions of the cardiovascular and gastrointestinal systems. 5 Although Utiger believes that there are no fixed criteria for diagnosis, he lists the following as suggestive of thyroid storm: fever, tachycardia, nausea, vomiting, abdominal pain, and cardiac failure as well as the manifestations of less se20:5 May 1991

A B D O M I N A L PAIN H a r w o o d - N u s s & Martel

FIGURE 2. Laboratory diagnosis of hyperthyroidism. THBR refers to the thyroid hormone binding ratio (formerly termed T 3 or T 4 uptake). TSH-IMA refers to the serum TSH measured by an immunometric assay that can discriminate between normal and suppressed as well as elevated TSH concentrations. From Larsen PR: Cecil Textbook of Medicine, ed. 18.

Serum T44- THBR

I

FreeT4 index

I

I Elevated I

I

Normal or equivocal

I

Hyperthyroidism (unless.T4to Ts conversionEs inhibited)

SerumT3 I

I

Elevated

I

Normal or equivocal

I

I

T4to T3 conversion inhibited

I

T4 to T3 conversion normal

I

I

Hyperthyroid (probable)

I

Ts-thyrotoxicosis

Euthyroid (probable)

f I

Thyroid-stimulatinghurmone-immunometricassay(TSH-IMA) or thyrotropin-releasinghormone(TRH)test

Normal or increased r Euthyroid: No autonomous function

vere hyperthyroidism. Mental status abnormalities m a y include marked anxiety, occasional psychosis, confusion, and c o m a . 2 As m e n t i o n e d above, some believe that the acute onset of severe abdominal pain may herald thyroid storm.6, ~o Despite the lack of consensus on definition, thyroid s t o r m m u s t be r e c o g n i z e d as a p o t e n t i a l l y lifethreatening medical emergency with a m o r t a l i t y of 20% to 40%. 5 The diagnosis is clinical because there are no laboratory markers. Standard thyroid function studies do not distinguish between thyrotoxicosis and thyroid storm. The patient with thyroid storm has elevated thyroxine (T3) and t r i i o d o t h y r o n i n e (T4) levels but no more so than in hyperthyroidism. 20:5 May 1991

I

Subnormalbasal TSH or no TSH releaseafterTRH

I

Hyperthyroidism or autonomous thyroid function

Question: Did the patient have findings compatible with thyroid storm? Dr Martel: We believe that our patient demonstrated features compatible with thyroid storm. In addition to signs and s y m p t o m s of severe thyrotoxicosis, our patient had abdominal pain, fever, nausea, and vomiting. Question: W h a t thyroid f u n c t i o n screening studies should be ordered in the ED on the patient with suspected hyperthyroidism? Dr Martel: The initial screening test for hyperthyroidism is the free T4 index. The majority of patients with h y p e r t h y r o i d i s m will have an elevated T 4 index. 5 In equivocal situations, a t h y r o i d - s t i m u l a t i n g horm o n e - i m m u n o m e t r i c a s s a y will Annals of Emergency Medicine

help. A history and laboratory abnorm a l i t i e s c o m p a t i b l e w i t h hyperthyroidism preclude the necessity of a radioactive iodine uptake and thyroid s c a n to e s t a b l i s h the diagnosis, s,z (See Figure 2 for the laboratory diagnosis of hyperthyroidism.) Question: What is the treatment for severe hyperthyroidism and thyroid storm? Dr Martel: Treatment should be aggressive, w i t h appropriate cardiac monitoring, IV fluids, and supplemental oxygen. 2 It is important to reduce fever with a cooling blanket and acetaminophen. Aspirin should be avoided because it can displace thyroid hormone from thyroglobulin. A careful search for precipitating events should be done in the ED. Specific pharmacologic intervention includes a n t i t h y r o i d drugs, s o d i u m iodide, propranolol, and glucocorticoids 22 (Figure 3). The first phase of t r e a t m e n t involves the administration of f3-adrenergic b l o c k i n g agents. A l t h o u g h p l a s m a c a t e c h o l a m i n e concentrations are normal in hyperthyroidism, the blockage of ~3-adrenergic receptors by propranolol or other f3-antagonists may result in prompt, symptomatic i m p r o v e m e n t before a decrease in serum thyroid hormones. Propranolol decreases pulse rate and cardiac output, but it does not alter the basal metabolic rate. 5 The second phase involves the int e r r u p t i o n of T 3 p r o d u c t i o n to achieve a euthyroid state. The inhibition of peripheral T 4 conversion to T3 is a critical step in treatment because T3 is the biologically active form of thyroid hormone. Suppression of the conversion can be accomplished with propranolol, glucocorticoids, and propylthiouracil. Suppression of the elevated thyroid h o r m o n e secretion rate is accomplished with the antithyroid drugs 580/155

ABDOMINAL PAIN H a r w o o d - N u s s & Martel

propylthiouracil and methimazole, s T 3 levels can be lowered by inhibiting thyroid h o r m o n e p r o d u c t i o n within the gland, preventing thyroid h o r m o n e release from the gland, blocking the peripheral tissue iodination of T 3 and T4, blocking the adrenergic effects of thyrotoxicosis, surgical resection of the gland, or radioiodine. The agents used to accomplish both phases are discussed below.22,23

Antithyroid Drugs Propylthiouracil and methimazole are the two antithyroid agents approved for use in the United States. Each can control most causes of thyrotoxicosis, but the remission after t r e a t m e n t is d i s c o n t i n u e d is unpredictable. 22 These drugs are actively concentrated in the thyroid. 24 In the thyroid, these drugs inhibit iodide binding to the thyroglobulin from forming monoiodotyrosine and diiodotyrosine and inhibit the coupling reaction of monoiodotyrosine and diiodotyrosine from forming T 3 and T 4. This leads to a depletion of thyroid hormone within the gland. Propylthiouracil also inhibits the peripheral conversion of T 4 to T3, giving it a mild therapeutic advantage over methimazole.5, 25 These agents have been reported to decrease circulating thyroid-stimulating antibody titers in patients with Graves' disease.

Methimazole is tenfold more potent than propylthiouracil and has a longer duration of action. The dose of methimazole is 30 to 60 mg/day; it can be administered orally or rectally. Propylthiouracil is rapidly absorbed from the g a s t r o i n t e s t i n a l tract; the usual dose is 100 to 200 mg by mouth or nasogastric tube every six to eight hours. Propylthiouracil is also the drug of choice in thyroid storm because of its ability to block p e r i p h e r a l T 4 - t o - T 3 conversion; the dosage for propylthiouracil during thyroid storm is 400 mg orally every six hours, as Although both methimazole and propylthiouracil cross the placenta, propylthiouracil is favored in the treatment of pregnant women. Adverse drug reactions for each include arthralgias, rash, fever, benign transient leukopenia, hepatitis, and vasculitis. Agranulocytosis represents the most serious side effect, but it is rare. 5 156/581

FIGURE 3. Management of patients with thyroid storm. From Larsen PR: Cecil Textbook of Medicine, ed 18.

Iodide Although the production of thyroid hormone rapidly ceases with propylthiouraci], it may be necessary to administer potassium iodide to block the release of stored thyroid hormone. Sodium iodide, Lugol's solution, and super saturated potassium iodide solution (SSKI) have long been used for the treatment of thyrotoxicosis. Today, these agents are prim a r i l y used as adjuncts to antithyroid drugs, for the treatment of thyroid storm, after radioactive iodine treatment, and before thyroidectomy surgery. The iodides prevent the release of thyroid hormones from the gland by decreasing thyroglobulin breakdown, decreasing iodide trapping by the gland, and, to a lesser degree, interfering with the production of thyroid hormone. In the treatment of thyroid storm, the iodides should be used but only after a dose of propylthiouracil has been given. Iodide is usually administered one hour after the propylthiouracil.22,26Y The dosage for potassium iodide (Lugol's solution with 8 mg iodide/drop) is 1 mL orally every eight hours. SSKI may be given in a dosage of from three to ten drops per day. 27 Sodium iodide may be administered intravenously in a close of 1 g every 8 hours. 27 These drugs are contraindicated m patients with toxic nodules or toxic nodular goiters because of the risk of iodide-induced hyperthyroidism. They are c o n t r a i n d i c a t e d in pregnancy because of fetal goiter formation. Adverse drug reactions include rash, sialadenitis, and fever.

f3-Adrenergic Blocking Agents Propranolol or other f3-receptor antagonists are used for symptomatic relief of thyrotoxieosis and thyroid storm before a decrease in serum thyroid hormone levels. Propranolol results in improvement in tachycardia, tremors, heat intolerance, and anxiety. 28 Propranolol is used as an adjunctive agent and should not be used as the sole therapy for thyrotoxic patients. ~3-Adrenergic blocking agents may not be necessary for mild cases of hyperthyroidism. The dose of propranolol is 40 to. 120 mg Annals of Emergency Medicine

Diagnostic Serum T3 and T4 concentrations, resin or charcoal m3 uptake Appropriate evaluation for underlying precipitating causes such as infection, acute surgical abdomen, central nervous system lesions, or psychologic trauma Baseline WBC and differential, electrolytes, calcium, phosphorus Plasma cortisol

Therapeutic iV fluids -- dextrosewith or without electrolytesas indicated, multivitamins Propylthiouracil 400 mg every six hours (by nasogastric tube, if necessary) to inhibit thyroid hormone synthesis and block T4 to T3 conversion

Sodium iodide 250 mg every six hours (oral or IV) Hydrocortisone 50 to 100 mg every six hours IV External cooling and acetaminophen (300 to 600 mg) every four to six hours for severe hyperpyrexia (do not use salicylates, which increase free thyroid hormones and oxygen consumption) Propranolol -- in patients without asthma, chronic bronchitis, or nonarrhythmia-relatedcongestive heart failure 10 to 40 mg may be given every four to six hours orally; a slow IV infusion of 1 mg/min for two to ten minutes with careful monitoring of blood pressure and ECG may be used if orat therapy is not feasible; propranolol may precipitate pulmonary edema in a few patients with hyperthyroidism; reserpine or guanethidine would not appear to have any advantages over propranolol in this situation. Oxygen may be helpful. Digitalis glycosides should be used for therapy of congestive failure and for blockade of a rapid ventricular response to an atrial tachyarrhythmia. 3Appropriate treatment of precipitating event

orally four times a day. In thyroid storm, 2 to 10 mg IV propranolol may be given at the rate of 1 mg/min. Relative c o n t r a i n d i c a t i o n s include asthma, obstructive lung disease, congestive heart failure, and pregnancy.

Steroids Corticosteroid therapy is used primarily to aid the body's ability to handle the stress of thyroid storm, but it may also decrease peripheral conversion of T 4 t o T 3. Hydrocortisone IV 50 to 100 rng every six hours and prednisone 20 to 50 mg twice a day are most frequently used in thyroid storm. 20:5 May 1991

A B D O M I N A L PAIN Harwood-Nuss & Martel

TABLE 3. Thyroid studies Test Thyroxine (T4) free T4 total Thyroid binding globulin Thyroglobulin antibody titer Microsomal antibody thyroid titer Thyroid stimulating hormone T3 radioimmunoassay

Results (Normal Range) 10.0 ng/dL (0,7- 2.0 ng/dL) 19.8 ng/dL (4.5 ~ 12 ng/dL) 18.0 p.g/mL (16 34 p.g/mL) 10 (0 20) 25,600 (0 99) < 1.5 MIV/mL (0.5.5 MIV/mL) 198 ng/dL (80- 200 ng/dL)

Question: What is the appropriate disposition for the patient with hyperthyroidism? Dr Martel: The patient with severe hyperthyroidism and any patient in w h o m thyroid s t o r m is suspected should be admitted for supportive care and a n t i t h y r o i d m e d i c a t i o n s . Supportive care alone may result in d r a m a t i c a m e l i o r a t i o n of the patient's symptoms. Consultation with the endocrinology service is important because the patient will need long-term care. Question: What c o n s t i t u t e s longterm therapy for Graves' disease? Dr Harwood-Nuss: There is no ideal long-term therapy for Graves' disease because the underlying cause is unknown.2, s Its course is characterized by spontaneous remission, occurring in 25% of patients per year for the first several years. 2 Unfortunately, it is impossible to accurately predict who will have a remission. Long-term therapy m a y involve three options: continued antithyroid drugs in anticipation of a possible remission, surgery, or radioiodine (13lI). With surgery, hyperthyroidism rarely recurs, but 50% to 60% of patients ultimately become hypothyroid. Radioiodine (131I) treatment is also associated with a significant incidence of hypothyroidism. No therapy is ideal, and the choice

20:5 May 1991

must be tailored to the individual patient. Lifelong follow-up is important to ensure that hyperthyroidism has not recurred and that hypothyroidism has not developed.2, 5 HOSPITAL C O U R S E In the ED, we made a presumptive diagnosis of G r a v e s ' disease w i t h probable early thyroid storm. Our patient received IV fluids, propylthiouracil 400 mg orally, propranolol 4 mg IV, hydrocortisone 50 mg IV, and sodium iodide 250 mg orally. Cultures were o b t a i n e d of the blood, urine, throat, and cervix. Thyroid function studies and a hepatitis profile were ordered. The patient was admitted to the medicine service. During her hospitalization, an abdominal c o m p u t e d tomography, sigmoidoscopy, upper panendoscopy, and air c o n t r a s t b a r i u m e n e m a were performed and interpreted as normal. The patient was continued on propranolol, prednisone, and propylthiouracil. She experienced rapid resolution of her abdominal pain, fever, tremors, and anxiety. Cultures of the t h r o a t , urine, blood, and c e r v i x showed no growth. Hepatitis profile and e n z y m e - l i n k e d i m m u n o a d s o r bent assay were negative. The thyroid studies revealed free T 4 level of 10.0 ng/dL (normal, 0.7 to 2.0 ng/dL); thyroid binding globulin, 18 ng/mL (normal, 16 to 34 ng/mL}; microsomal thyroid antibody titer, 25,600 (normal, 0 to 99); and thyroid stimulating hormone, 1.5 IU/mL (normal, 0 to 5.5 IU/mL) (Table 3). The patient was discharged on propylthiouracil and propranolol. The first outpatient visit revealed her to be asymptomatic.

(eds}: Cecil Textbook of Medicine, ed 18. Philadelphia, WB Sauuders, 1988, p 1315. 6. Saeed-us-Zafar M: The thyroid, in Berk JE (ed]: Bockus Gastroenterologja Philadelphia, WB Saunders, 1985, p 4624-4628. 7. Spaulding SW, Lippes H: Hyperthyroidism: Causes, clinical features, and diagnosis, in Symposium on Thyroid Disease. Med Cfin North Am. Philadelphia, WB Saunders, vo[ 69, 1985, p 937-951. 8. Lahey FH: Non-activated (apathetic I type of hyperthyroidism. N Engl f Med 1931;204:747 748. 9. Coe NP, Page DV¢; Friedmann P, et al: Apathetic thyrotoxicosis presenting as an abdominal emergency: A diagnosis pitfall. South Med J 1982;75:175-178. 10. Siurala H, Julkunen H, Lamberg BA, et al: Gastroin testinal tract in hyperthyroidism before and after treatment. Stand f Gastroentero] 1966;1:79 85. ll. Berstein A, Riding WD: Hyperthyroidism and steatorrhoea. Postgrad Med J 1970;46:318 320. t2. Palmer HM, Beardwell CG: Hyperthyroidism presenting with acute abdominal symptoms. Practitioxler 1974;212:239-243. 13. Kassirer JP, Kopeland RI: A surprising cause of abdominal pain, anorexia, vomiting, and weight loss. Hasp Pratt 1985;21 26. I4. Scarf M: Gastrointestinal manifestations of hyperthyroidism. J Lab Clin Med 1935;2:1253-1258. 15. Verbrycke JR: Masked gastrointestinal hyperthyroidism. JAMA 1931;97:513 517. 16. Dreyfuss AI: Protracted epigastric pain and vomiting as a presentation of thyrotoxicosis. J Clir7 Gastroenterol 1984;6:435-436. 17. Chapman EM, Maloof F: Bizarre clinical manifestations of hyperthyroidism. N EngI J Med 1956;254:1 5. 18. Snyder SM, Ruskin P: Thyrotoxicosis and abdomi nal pain. JAMA 1981;266:330. 19. Abate SF, Ferlano GP: Hyperthyroidism as a rare cause of "false acute abdomen." Minerva Med 1982;73: 797 800. 20. Hoffenberg R: Thyroid emergencies, in Sonksen PH, Lowy C (eds): Endocrine and metabolic emergencies. Clin Endocrinol Metab 1980;9:503. 21. Ingbar S: M a n a g e m e n t of emergencies: Thyroid storm. N EngI J Med 1966;274:1252-1254. 2Z. Cooper DS, Ridgway EC: Clinical management of patients with hyperthyroidism, in Symposium on Thyroid Disease. Med Clin North Am. Philadelphia, WB Saunders, 1985, vol 69, p 937-951. 23. Raber J: The pharmacotherapy of thyroid storm. Drug Inteil Clin Pharm 1980~14:344-352. 24. Marchant B, Alexander WD, Lazarus JH, et al: The accumulation of 35-S antithyroid drugs by the thyroid gland. J Clin Endocrinof I972;34:847-85l.

1. Brennan DF, Harwood-Nuss AL: Postpartum abdominal pain. Ann Emerg Med 1989;18:83-89.

25. Geffner DL, Azukizavoca M: PTU blocks extrathyroidal conversion of T~ to T~ and augments thyrotropin secretion. Man f Clin Invest 1975;55:224.

2. Utiger RD: Diseases of the thyroid gland, in Kelley WN (ed): Textbook of Internal Medicine, ed 1. Philadelphia, JB Lippincott, 1989, p 2178-2184.

26. Sitar DS, Hunninghake DB: Pharlnacokinetics of PTU in man after a single oral dose. f Clin Endocrinol 1975;40:26 29.

3. Zenilman ME, Becket JM: Gastroenterological emergencies, in Gastroenterology Clinics of North America. Philadelphia, WB Saunders, 1988, p 387.

27. Roth RN, McAuliffe MJ: Hyperthyroidism and thyroid storm, in Endocrine and Metabolic Emergencies. Emerg Med Cfin North Am. Philadelphia, WB Saunders, 1989, p 873.

REFERENCES

4. Galloway S, Harwood Nuss AL: Sickle celi anemia. J Emer,g Mad 1988;6:213-226. 5. Larsen PR: The thyroid, in Wyngaarden JB, Smith LH

Annals of Emergency Medicine

28. Grossman W, Robin NI, Johnson LW, et al: Effects of beta blockade on the peripheral manifestations of thyrotoxicosis. Am] Intern Med I971;74:875-879.

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An unusual cause of abdominal pain in a young woman.

CASE CONFERENCE hyperthyroidism An U n u s u a l C a u s e of A b d o m i n a l Pain in a Young W o m a n [Harwood-Nuss AL, Marte] TJ: An unusual cau...
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