A 74-Year-Old Woman with Abdominal Pain and Fever

Home , Heparinoid

A SELF-TEST IM BOARD REVIEW DAVID L. LONGWORTH, MO, JAMES K. STOLLER, MD, EDITORS OF CLINICAL PETER MAZZONE, MD CRAIG NIELSEN, MD RECOGNITION Department of Pulmonary and Critical Department of General Internal Care Medicine, Cleveland Clinic Medicine, Cleveland Clinic

A 74-year-old woman with abdominal pain and fever

74-YEAR-OLD WOMAN was transferred pulmonary embolism, and a subsequent pul- from a local hospital for further evalua- monary angiogram was read as normal. A tion and management of abdominal pain with chest CT scan did not reveal anything other fever. than the small bilateral pleural effusions seen The patient had presented to the local on the chest radiograph. A thoracentesis hospital 11 days before with a 1-day history of revealed transudative fluid only. Intravenous bilateral upper-quadrant abdominal pain. She heparin was discontinued. described the pain as a constant ache with Past history. The patient had had essen- intermittent sharper pains accompanied by tial thrombocythemia for 5 years, for which nausea, but she could not identify any precip- she took hydroxyurea until 2 months before itants of the pain. She was also constipated. admission. Hydroxyurea was restarted at the A few days after being admitted to the local hospital because her platelet count was local hospital, the patient had developed a high at 750 x 109/L (normal 150-400 x fever and mild shortness of breath. She was 109/L), but it was stopped 3 days later because treated empirically for a possible pulmonary of mucositis. More than 30 years ago, the infection with a variety of antibiotics (ceftri- patient had been diagnosed with "pernicious Her platelet axone, ticarcillin-clavulanate, erythromycin, anemia. count dropped metronidazole, cefazolin, and vancomycin). Family history was unremarkable. The Blood, urine, and sputum cultures remained patient lived with her husband on a farm, had from 750 to negative throughout her hospitalization. two healthy children, and had not recently 272 x 109/L At the local hospital she had also under- traveled. gone an upper gastrointestinal (GI) series, a in only a few small bowel follow-through, a barium enema, Physical examination days and computed tomography (CT) of the On presentation to our hospital the patient abdomen. These revealed colonic diverticulo- was experiencing diffuse abdominal pain, nau- sis and a dilated gallbladder with no gall- sea, vomiting, fatigue, and sweats. stones. A hepato-iminodiacetic acid scan was On physical examination, the patient reported as suspicious for acute cholecystitis. appeared ill. Her temperature was 38.2°C, CT-guided aspiration of the gall bladder heart rate 102/minute and regular, blood revealed "non-purulent fluid." Cultures of the pressure 123/67 mm Hg, respiratory rate fluid from the gallbladder were negative. A 16/minute, and oxygen saturation 96% by chest radiograph revealed only small bilateral pulse oximetry while receiving oxygen at pleural effusions. 2 L/minute per nasal cannula. She had mild During the barium enema the patient had oral mucositis, decreased basal breath sounds become hypoxic, requiring supplemental oxy- bilaterally, and a grade 2/6 systolic ejection gen and transfer to the intensive care unit. murmur (reported in the past). Her Her physicians started intravenous heparin abdomen was soft with diffuse tenderness therapy empirically while investigations were but without palpable organomegaly or peri- performed. A ventilation-perfusion scan was toneal signs. Her stool was negative for interpreted as showing a low probability of occult blood. She had no focal neurologic

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TABLE 1 At this point our patient had had an upper The patient's laboratory values CI series, a small bowel follow-through, a barium enema, CT scans of the chest and at the time of admission abdomen, a hepato-iminodiacetic acid scan, aspiration and later removal of her gallbladder, TEST VALUE UNITS NORMAL RANGE a pulmonary angiogram, a bone marrow aspi-

White blood cell count 4.07 X 109/L 4.2-5.4 ration, and multiple cultures, none of which Hemoglobin 9.2 g/dL 12.0-16.0 provided an adequate explanation for her Platelet count 272 x 109/L 150-400 symptoms and fever. Sodium 135 mmol/L 132-148 Potassium 4.5 mmol/L 3.5-5.0 • FEVER OF UNKNOWN ORIGIN Chloride 108 mmol/L 98-110 Carbon dioxide 22 mmol/L 24-32 Which of the following choices is not part Blood urea nitrogen 11 mg/dL 8-25 of the standard definition of fever of Creatinine 1.0 mg/dL 0.7-1.4 1 unknown origin? Glucose 112 mg/dL 65-110

• Temperature greater than 38.3 °C • Fever for at least 3 weeks deficits, TABLE 1 shows her laboratory values at • Fever that defies diagnosis after 1 week of the time of admission. Coagulation studies inpatient investigation were normal. • Fever that cannot be suppressed by Her medications on transfer included antipyretics ticarcillin-clavulanate and heparin in prophy- lactic, subcutaneous doses. The standard definition of fever of unknown origin has been a temperature higher than • HOSPITAL COURSE 38.3 °C for at least 3 weeks that defies diagnosis after 1 week of inpatient investigation. The Fever of We continued to give ticarcillin-clavulanate, ability of antipyretics to suppress the fever is unknown origin performed bone marrow aspiration to assess not part of the definition. the patient's essential thrombocythemia and A new classification scheme divides fever has a new set to look for a cause of her fever, and obtained a of unknown origin into four categories: classic, of criteria general surgery consult. The surgeons believed nosocomial, neutropenic, and HIV-associated. that the patient might have acute cholecysti- In each, the definition differs somewhat from tis and so scheduled her for a laparoscopic the older, standard definition. cholecystectomy the following day. The Classic fever of unknown origin (an patient tolerated the operation well. The ini- unexplained temperature higher than tial pathology study suggested an acute exac- 38.3 °C for at least 2 weeks, or three outpa- erbation of chronic cholecystitis. tient visits, or 3 days in the hospital). There Two days passed, but the patient's condi- are many potential causes. Infectious causes tion did not change significantly. She contin- are numerous (tuberculosis being the most ued to spike fevers with temperatures as high common). If a typical infection cannot be as 39°C and complained of nausea, vomiting, found, occult infections must be considered abdominal pain, and weakness. Blood, urine, (eg, abscesses, osteomyelitis, endocarditis, and sputum cultures remained negative, and prostatitis), as should viral infections (eg, her laboratory values remained about the cytomegalovirus, Epstein-Barr virus) and same. She noted some swelling of her right infections with less common organisms such lower extremity. A duplex ultrasound scan as fungi, Plasmodium (the agents of malaria), revealed a popliteal deep venous thrombosis, or Rickettsia. Some neoplastic diseases can which we monitored by serial duplex ultra- cause fever; the most common being lym- sound examinations. Her bone marrow aspira- phomas, leukemias, renal cell carcinoma, tion results were consistent with the prior and hepatomas. Collagen vascular diseases, diagnosis of essential thrombocythemia. granulomatous disorders, and miscellaneous

470 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 66 • NUMBER 8 SEPTEMBER 1999 Downloaded from www.ccjm.org on October 6, 2021. For personal use only. All other uses require permission. causes such as drug fever, gout, cirrhosis, TABLE 2 recurrent pulmonary emboli, and metabolic Causes of primary adrenal disorders round out the list. insufficiency Nosocomial fever of unknown origin (an unexplained temperature higher than Anatomic destruction 38.3°C in a hospitalized patient in whom Idiopathic Autoimmune fever was not present at admission; there Adrenoleukodystrophy must be at least 3 days of investigation with Infections 2 days of culture incubation). Investigation Tuberculosis should focus on sites where occult infec- Fungal Viral tions might be sequestered, such as intravas- Infiltration cular lines, sinuses (with nasogastric tubes), Metastatic disease prosthetic devices, acalculous cholecystitis, Amyloid and Clostridium difficile colitis. Drugs and Sarcoid transfusion-related fevers must also be con- Hemorrhage sidered. Waterhouse-Friderichsen syndrome Neutropenic fever of unknown origin (a Antiphospholipid syndrome temperature higher than 38.3 °C in a patient Heparin-induced thrombocytopenia with a neutrophil count lower than 500/pL Metabolic failure Congenital adrenal hyperplasia after 3 days of investigation with 2 days of cul- Cytotoxic agents ture incubation). All types of infections, Drugs including fungal, viral, and gram-positive and gram-negative bacterial organisms, must be considered. A cause of the fever is often not found. In general, patients do well with sup- • ADRENAL INSUFFICIENCY portive care, including empiric antimicrobial Which of the following laboratory find- therapy, while awaiting a rise in the neu- 2 ings is consistent with a diagnosis of pri- trophil count. mary adrenal insufficiency? In spite of HIV-associated fever of unknown origin persistent (a temperature higher than 38.3°C for more • Increased serum sodium than 4 weeks for outpatients or 3 days of in- • Increased serum chloride vomiting, her hospital investigation with 2 days of culture • Increased serum carbon dioxide potassium level incubation). HIV itself, Mycobacterium avium • Increased serum potassium intracellular, toxoplasmosis, tuberculosis, remained 4.5 Pneumocystis carinii pneumonia, cryptococcus, Failure of the adrenal glands may be either histoplasmosis, non-Hodgkin lymphoma, and primary or secondary. drug fever are just some of the many diagnos- tic possibilities. The differential diagnosis Primary adrenal insufficiency depends on the degree of immunosuppression, More than 150 years ago, Richard Addison as reflected by the CD4+ count. described primary adrenal insufficiency as "general languor and debility, remarkable fee- Hospital course (continued) bleness of the heart's action, irritability of the The patient's condition did not change. In stomach, and a peculiar change of the color of spite of persistent vomiting her sodium level the skin." It is rare and affects both sexes was 134 mmol/L, potassium 4-5 mmol/L, and equally, across all age groups. CO2 20 mmol/L. (With persistent vomiting Causes of primary adrenal insufficiency one would expect the potassium level to fall can be divided into those leading to anatomic and the C02 to rise.) destruction of the glands (more than 90% of Given the above findings and her per- the glands' volume must be destroyed before sistent GI complaints and weakness, we symptoms of adrenal insufficiency appear) and considered the possibility of adrenal insuffi- those resulting from metabolic failure of the ciency. gland (TABLE 2).

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Most cases of anatomic adrenal destruc- mal response consists of a stimulated Cortisol tion are idiopathic, although half of patients level greater than 18 |ig/dL and at least 7 with idiopathic anatomic destruction have f-ig/dL higher than at baseline. circulating adrenal antibodies. Some of these Treatment. Education is an important destroy the adrenal glands directly while oth- part of any comprehensive treatment program. ers block the binding of ACTH. These The patient should wear a medic alert autoimmune forms of primary adrenal insuffi- bracelet. A glucocorticoid (hydrocortisone ciency are part of both type 1 (characterized 25-37.5 mg/day or prednisone 7.5 mg/day) by mucocutaneous candidiasis, hypoparathy- should be given in divided doses, with the roidism, and adrenal insufficiency) and type 2 larger portion in the morning. A mineralocor- (thyroiditis, type 1 diabetes mellitus, and ticoid is often needed as well, even if the adrenal insufficiency) polyglandular autoim- patient takes in ample sodium (3-4 g per day). mune syndromes. Fludrocortisone 0.05 to 0.2 mg/day usually suf- The next most common causes of anatom- fices. The baseline doses are adjusted on the ic destruction are infections (tuberculosis, fun- basis of clinical status, blood pressure, and gal, viral, opportunists in AIDS), invasion by electrolyte levels. tumors, surgery, hemorrhage with necrosis, During illness the glucocorticoid dose may and invasion by nonmalignant processes need to be increased to two to five times that (amyloid, sarcoid). at baseline. After major surgery, five to 10 Metabolic failure is rare. Congenital times the maintenance dose should be given adrenal hyperplasia, cytotoxic agents, and in divided doses and tapered by approximately drugs that act as enzyme inhibitors fall into 20% to 30% per day, depending on the post- this category. operative course. Sodium intake and fludro- Symptoms and signs of primary adrenal cortisone levels may need to be increased dur- insufficiency vary in spectrum and severity, ing times of heavy exercise in hot weather. depending on the duration and degree of adrenal hypofunction. Frequently seen are weakness, Secondary adrenal insufficiency Mild adrenal weight loss, GI complaints, abnormal pigmen- Secondary adrenal insufficiency may be due to insufficiency tation of the skin and mucous membranes, isolated ACTH deficiency, a panhypopituitary hypotension, syncope, and vitiligo. disorder, or exogenous corticosteroids. Most of can only be Laboratory findings. Early on, only the the symptoms and signs are the same as in pri- diagnosed by cosyntropin stimulation test may be abnormal. mary adrenal insufficiency, but patients with With more advanced disease, serum levels of secondary adrenal insufficiency have near- ACTH sodium, chloride, and CO2 are often low, and normal aldosterone levels and generally do stimulation potassium is often high. ("Increased serum not have excess pigmentation, severe dehy- potassium" is the correct answer to QUESTION 2, dration, or hyperkalemia. Thus, mineralocor- above.) Decreased renal blood flow may lead ticoid replacement is unnecessary. to elevated vasopressin and angiotensin II levels (the reason for low sodium). Mild hyper- Hospital course (continued) calcemia can be seen, for reasons that are A cosyntropin stimulation test was performed. unclear. Electrocardiographic and electroen- The baseline level of Cortisol was 6.4 1-lg/dL cephalographic findings are nonspecific. (normal morning range 3.4-26.9), and the Normocytic anemia and moderate eosinophil- stimulated level was 6.1 |ig/dL (normal > 18 ia (10% to 20%) are frequent. and at least 7 |-lg/dL higher than at baseline). In mild adrenal insufficiency all values Glucocorticoid replacement was given, and may overlap with normal. Thus, the diagnosis the patient's fever, GI symptoms, and labora- can only be made by corticotropin (ACTH) tory abnormalities quickly disappeared. stimulation testing. The screening cosyn- Although the patient's original presenta- tropin stimulation test is performed by giving tion was probably due to cholecystitis, the per- 0.25 mg cosyntropin intravenously or intra- sistence of her fever after cholecystectomy, the muscularly and measuring the Cortisol level at finding of adrenal insufficiency, and the reso- baseline, 30 minutes, and 60 minutes. A nor- lution of her symptoms (including fever) after

474 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 66 • NUMBER 8 SEPTEMBER 1999 Downloaded from www.ccjm.org on October 6, 2021. For personal use only. All other uses require permission. glucocorticoid replacement confirm the diagnosis of adrenal insufficiency as the cause of her fever. This is indeed a rare cause of fever of unknown origin. The question remained: Why did the patient develop adrenal insufficiency? Two findings gave some insight into the cause: the rapid drop in platelets from approximately 750 x 109/L to 272 x 109/L after only a few days of hydroxyurea therapy, and the finding of a below-the-knee DVT. Because the patient had received heparin, we decided to investigate the possibility of heparin-induced thrombocytopenia leading to hemorrhage and necrosis of the adrenal glands.

• HEPARIN-INDUCED THROMBOCYTOPENIA

Which of the following is not true of 3 heparin-induced thrombocytopenia?

• There are two types • The nonimmune type is readily reversible • The IgG-mediated immune type leads to a substantial risk of thrombotic complications • The immune type of heparin-induced thrombocytopenia is usually seen within Paradoxically, 12 hours of starting heparin heparin-induced

Two types of heparin-induced thrombocytope- FIGURE 1. Axial and coronal T1-weighted thrombo- nia have been described: an early, benign, read- MRI images showing increased density of cytopenia ily reversible, "nonimmune" type and a later, the adrenal glands (arrows) typical of more-serious "immune" type that is mediated adrenal hemorrhage. increases the by IgG and that paradoxically leads to a sub- risk of stantial risk of thrombotic complications. arterial ("white clot syndrome") thromboses The immune type of heparin-induced being noted. Bleeding complications have thrombosis thrombocytopenia has an estimated incidence also been described but are much less frequent of 1% at 7 days and 3% at 14 days. It usually and important than the thrombotic complica- arises 5 to 15 days after starting heparin (not tions. within 12 hours, as listed in the question Platelet counts usually reach a nadir of above), but may occur sooner if the patient between 20 and 150 x 109/L, but they return has taken heparin previously. to baseline within 1 week of stopping heparin. This disorder is caused by IgG and IgM A fall in the platelet count without overt antibodies directed against heparin-platelet thrombocytopenia may be noted—in itself an factor 4 complexes, leading to immune indication to stop heparin treatment. platelet destruction. The antibodies may also Heparin-associated antiplatelet antibody tests activate the endothelium by binding to are assays of platelet activation that look for platelet factor 4 on endothelial cell surface platelet aggregation in the presence of heparin. The net result is a highly prothrom- heparin. An enzyme-linked immunosorbent botic state. Patients have a risk of thrombosis assay has been developed that detects the tar- that is 37 times normal, with both venous and get antigen on the platelets.

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As editors, we'd like you The main treatment is to stop the heparin. As a substitute, warfarin has been used but has to look into every issue, uncertain efficacy, and the white clot syn- every page of the drome may require surgery if severe. Danaparoid (a heparinoid with little cross- Cleveland Clinic Journal reactivity), ancrod (a proteinase obtained from snake venom that specifically breaks of Medicine. down fibrinogen), and argatroban have been We'd like to know... used with some success. Recently, the direct thrombin inhibitor lepirudin has been approved for use in this condition. 1 Out of every 4 issues, how many do you read or look through? Multiple case reports have documented Here's our goal: heparin-induced thrombocytopenia leading to H'4of4 • 3 of 4 • 2 of 4 D1of4 adrenal hemorrhagic necrosis. Adrenal vein thrombosis is frequently found in these cases. It is felt that this is the inciting event, with 2 How do you read or look through an average issue? subsequent necrosis and hemorrhage of the Here's our goal: adrenal glands. EfRead cover to cover • Read articles of interest and look through remaining pages Hospital course (continued) • Read table of contents and articles of interest only The patient's abdomen was imaged again • Skim or look through quickly with an MRI study, revealing enlarged, dense adrenal glands consistent with bilateral 1). We put it in writing... adrenal hemorrhage (FIGURE A heparin- please put it in writing for us. associated antiplatelet antibody test was pos- We want to hear from you. itive. Heparin was discontinued and the patient's platelet count rose to 441 X 109/L within 2 days. She was discharged home in CLEVELAND CLINIC JOURNAL OF MEDICINE good condition. The Cleveland Clinic Foundation 9500 Euclid Avenue, NA32 Diagnosis Cleveland, Ohio 44195 • Cholecystitis • Primary adrenal insufficiency from PHONE 216.444.2661 necrosis and hemorrhage secondary to FAX 216.444.9385 heparin-induced thrombocytopenia syn- [email protected] drome. SH

M SUGGESTED READING

Delhumeau A, Granry JC. Heparin-associated thrombocytopenia [letter], Crit Care Med 1992; 20:1192. Gelfand J, Dinarello C. Fever of unknown origin. In: Fauci A, editor. Harrison's Principles of Internal Medicine. 14th ed. McGraw-Hill, 1998:780-785. Hirsh J, Raschke R, et al. Heparin: mechanism of action, phar- macokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1995; 108(Suppl):258S-275S. Souied F, Pourriat JL, et al. Adrenal hemorrhagic necrosis related to heparin-associated thrombocytopenia. Crit Care Med 1991; 19(2):297—299. Werbel S, Ober K. Acute adrenal insufficiency. Endocrinol Metab Clin North Am 1993; 22(2):303-328.

ADDRESS: Craig Nielsen, MD, Department of Internal Medicine, P39, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

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