The Brief Case: Cases from Mount Sinai Medical Center


Case 1: Atypical hemolytic uremic syndrome in an adult patient

Hyung J. Cho, MD, ACP Member, and Shirley L. Jiang, MD, MPH

The patient

A 72-year-old woman with no medical history presented with 4 days of epigastric pain and bloody diarrhea after eating an undercooked hamburger. Vital signs and basic laboratory tests were normal. Upon examination, her abdomen was tender to palpation without rebound or guarding. Abdominal CT revealed diffuse colitis, and empiric therapy with ceftriaxone and metronidazole was begun.

On hospital day 3, the patient developed hemolytic anemia with decreasing hemoglobin level (11.3 to 9.4 g/dL), increasing bilirubin level (total, 1.0 to 4.0 mg/dL; direct, 0.4 to 1.4 mg/dL), low haptoglobin level (<7 mg/dL), and elevated lactate dehydrogenase level (1,107 μL). Decreasing platelets (176 x 103 cells/μL to 70 x 103 cells/μL) and rising creatinine level (0.78 to 1.50 mg/dL) were also observed. Peripheral blood smear revealed numerous schistocytes. Stool studies were negative for shiga toxin, Escherichia coli O157:H7, Salmonella, Campylobacter, and Yersinia.

Plasmapheresis and steroids were initiated with poor response. Hemodialysis was started on hospital day 8 for progressively worsening renal function. ADAMTS13 level was normal, not suggestive of thrombotic thrombocytopenic purpura (TTP). Eculizumab was started with rapid improvement in platelet count and renal function.

The diagnosis

This case demonstrates an atypical presentation of the hemolytic uremic syndrome (HUS). HUS and TTP are types of thrombotic microangiopathies frequently thought to represent a spectrum of the same disease. HUS is typically a childhood disease and thus often overlooked in the differential diagnosis in adults. HUS and TTP both present with hemolytic anemia, acute renal dysfunction, and thrombocytopenia; HUS often presents with more severe renal dysfunction, while TTP tends to have more prominent neurological symptoms. ADAMTS13 testing can be used to differentiate between HUS and TTP.

HUS can further be divided into “typical” and “atypical” forms. Typical HUS is primarily caused by shiga toxin-producing Escherichia coli (STEC), while atypical HUS is caused by dysregulation of the complement cascade, which can be inherited, acquired, or both. Atypical HUS has a poor prognosis; in one case series, 46% of adults experiencing their first episode of atypical HUS progressed to end-stage renal disease. Negative stool studies for shiga toxin help distinguish the atypical from the typical form. Treatment of either form of HUS is supportive, with red blood cell and platelet transfusions, although the latter may worsen thrombocytopenia and should be used judiciously. Temporary hemodialysis may be necessary and can be discontinued if renal function improves. Therapies such as plasmapheresis and steroids are also used but have little clinical evidence for their effectiveness. Eculizumab, a terminal complement inhibitor, has been shown to significantly improve renal function in atypical HUS.

Pearls

  • Hemolytic uremic syndrome (HUS) should be considered in the differential in adult patients presenting with hemolytic anemia, acute renal dysfunction, and thrombocytopenia; it is also important to consider both “typical” and “atypical” forms of HUS.
  • Eculizumab should be considered in the treatment of atypical HUS if there is poor response to supportive therapy, plasmapheresis, and steroids.

Case 2: Therapeutic plasma exchange in hypertriglyceridemic pancreatitis

Dennis Chang, MD

The patient

A 53-year-old woman with uncontrolled diabetes mellitus presented with worsening epigastric pain for 7 days and was diagnosed with pancreatitis. She reported no alcohol use and earlier that year had undergone a cholecystectomy. She said she had not been adherent with her insulin for the past week. Temperature was 37.6°C, pulse was 110 beats per minute, and blood pressure was 108/68 mm/Hg. Physical examination was normal except for her distended, diffusely tender abdomen. Liver function tests and complete blood count were normal. Triglyceride (11,838 U/L) and lipase (9,708 U/L) levels were markedly elevated; her calcium level was 7.1 mg/dL, and her glucose level was 297 mg/dL.

The patient was treated with a continuous insulin infusion, and on hospital day 2, her lipase (113 U/L) and triglyceride (1,911 mg/dL) levels were substantially improved. However, she continued to be in severe pain despite high doses of analgesics, with no flatus or bowel movements. Repeat CT showed worsening edematous changes around the head of the pancreas with extension to the mesentery and retroperitoneum. Therapeutic plasma exchange (TPE) was immediately started, and the next day her triglyceride level dropped below 500 mg/dL. She had significant improvement in her pain and began passing flatus. She showed continued improvement over the next several days and was discharged home.

The diagnosis

Hypertriglyceridemia is the third most common cause of pancreatitis behind alcohol and gallstones. Patients with triglyceride levels above 1,000 mg/dL are at risk for development of hypertriglyceridemic pancreatitis (HTGP), and the goal triglyceride level in treatment of HTGP is less than 500 mg/dL. Conventional therapy consists of pain control, intravenous fluids, bowel rest, and insulin (even in nondiabetic patients). Insulin removes the catalyst for the triglyceridemia and also enhances lipoprotein activity, which accelerates chylomicron and very low-density lipoprotein metabolism to glycerol and fatty free acids. A continuous infusion is typically started at 0.1 to 0.3 units/kg per day along with 5% dextrose to maintain a blood glucose level between 150 and 200 mg/dL.

Mounting evidence from case series and case reports shows that therapeutic plasma exchange (TPE), specific apheresis with replacement of plasma with a colloid solution, should be performed as early as possible in patients with HTGP. When TPE is initiated, studies have described rapid improvement in triglyceride levels and symptoms with minimal adverse effects. There are advocates for initiation of TPE within 48 hours of symptom onset in HTGP to achieve best results; this should be considered in patients with signs of organ failure or systemic complications. Current guidelines from the American Society for Apheresis give TPE in HTGP a grade 2C recommendation.

Pearls

  • Hypertriglyceridemia is the 3nd most common cause of acute pancreatitis, and intravenous insulin/dextrose infusions are often necessary.
  • Therapeutic plasma exchange (TPE) is currently believed to be a safe and effective means of rapidly lowering triglyceride levels and reducing symptoms in patients with severe cases of hypertriglyceridemic pancreatitis.

Case 3: Hypoglycemia in a diabetic patient

Tuyet-Trinh N. Truong, MD, ACP Member, and Lisa Lin, MD, ACP Resident/Fellow Member

The patient

An 88-year-old man with type 2 diabetes had presented with hypoglycemia a week previously, with resultant discontinuation of all oral antihyperglycemic agents. He presented again with hypoglycemia and reported progressive fatigue and poor oral intake for the past few weeks. He lived independently, and a home health assistant helped him with medication management. On physical examination, he was a frail elderly man in no distress. His abdomen was soft and without tenderness or masses; there was no jaundice or rash.

Laboratory studies demonstrated normal hepatic function, normal aminotransferase levels, undetectable sulfonylurea and normal beta-hydroxybutyrate levels, and a suppressed endogenous insulin level. His infectious evaluation was also negative. CT of the abdomen and pelvis revealed a mass, 13.4 x 13.4 x 17.5 cm, extending from the gallbladder neck, without evidence of metastasis. Microscopic and immunohistochemical examination of the tissue biopsy were consistent with solitary fibrous tumor (SFT). Serum insulin growth factor-II (IGF-II) level was 523 ng/mL (high normal), and an IGF-I level was not obtained.

While hospitalized, the patient remained persistently hypoglycemic, requiring a continuous infusion of 10% dextrose. He underwent cholecystectomy with complete removal of the mass. Shortly after surgery, he was successfully weaned off the dextrose infusion.

The diagnosis

This patient's presentation and findings are most consistent with Doege-Potter syndrome (DPS). DPS is a rare paraneoplastic syndrome characterized by a solitary fibrous tumor that secrets IGF-II, leading to hypoglycemia. The diagnosis in this case was based on findings of a large solitary fibrous tumor (solitary fibrous tumors larger than 8 to 10 cm have increased risk for yielding paraneoplastic hypoglycemia), low insulin level while hypoglycemic, and the exclusion of other causes of low-insulin hypoglycemia. Available commercial assays for IGF-II level often yield a normal level, while an IGF-II/IGF-I ratio greater than 10 is more diagnostic of DPS.

Solitary fibrous tumors typically originate from intrathoracic pleura but rarely can be extrapleural. In a large retrospective study of 4,000 soft-tissue tumors obtained over 18 years, only 79 solitary fibrous tumors were identified, and 54 of those were intrathoracic in origin. DPS accounts for fewer than 5% of solitary fibrous tumor cases, and surgical resection is currently the definitive treatment.

Pearls

  • Hypoglycemia is common in hospitalized patients, and malignancy should be included as part of the differential diagnosis of recalcitrant hypoglycemia.
  • Doege-Potter Syndrome is rare, but early diagnosis and treatment by surgical resection is almost always curative.

Case 4: Vitamin B12 deficiency presenting as hemolytic anemia

Maria Anaizza Aurora Reyna, MD

The patient

A 69-year-old woman with no medical history presented with 3 days of jaundice and reported increased forgetfulness. She reported no fever, chills, nausea, vomiting, abdominal pain, weight loss, or abnormal bleeding. There were no changes in bowel or bladder habits. She said she took no medications, and there was no history of drug and alcohol use. Physical examination was remarkable only for icteric sclera. There was no hepatosplenomegaly, lymphadenopathy, or rash. The neurologic exam was unremarkable.

Laboratory analysis showed macrocytic anemia (hemoglobin level, 7.1 g/dL; mean corpuscular volume, 134 fL) and mild thrombocytopenia (90 x 10 to the 3rd cells/μL). Review of the peripheral blood smear demonstrated the presence of schistocytes. The reticulocyte count was 3.5% with reticulocyte index of 0.8. A complete metabolic panel was normal except for elevated total bilirubin level of 2.3 mg/dL, with direct bilirubin level of 0.5 mg/dL. Additional laboratory testing revealed a low haptoglobin level (<7 mg/dL) and elevated lactate dehydrogenase (LDH) level (7,737 U/L). Direct Coombs testing was negative. Folate level, coagulation profile, G6PD screening, and hemoglobin fraction were normal. The vitamin B12 level was strikingly low (29 pg/mL), and homocysteine and methylmalonic acid levels were elevated, confirming the presence of vitamin B12 (cobalamin) deficiency. Intrinsic factor antibody testing was positive. Pernicious anemia was diagnosed, and the patient was started on intramuscular vitamin B12 treatment with improvement of thrombocytopenia and hemolysis.

The diagnosis

This patient was diagnosed with hemolytic anemia secondary to vitamin B12 deficiency, ultimately confirmed by response to treatment. The presence of anemia, thrombocytopenia, and schistocytosis in this patient with mental status changes raised the possibility of a microangiopathic hemolytic anemia due to thrombotic thrombocytopenic purpura (TTP). However, these features occur in the context of vitamin B12 deficiency as well.

Vitamin B12 is required for synthesis of deoxyribonucleic acid and normal cell division of hematopoietic cells in the bone marrow; deficiency of this vitamin leads to ineffective erythropoiesis, resulting in intramedullary destruction of erythrocytes. Death and lysis of immature nucleated red cells in the bone marrow leads to elevated LDH levels, low haptoglobin, and a microangiopathic-appearing peripheral smear.

Cobalamin deficiency was more likely than TTP as the cause of this patient's hemolytic anemia for the following reasons: The inappropriate reticulocyte response (reticulocyte index <2) signifies decreased red blood cell production; the disproportionately high LDH level (>4 times normal) argues against the peripheral hemolysis of TTP; the relatively mild elevation in indirect bilirubin level is related to impaired hemoglobin synthesis; and the relatively preserved platelet count is higher than would be expected for TTP.

Pearls

  • Vitamin B12 deficiency should be considered in the differential diagnosis of hemolytic anemia.
  • The presence of microangiopathic hemolytic anemia with higher LDH level and platelet counts with low reticulocyte index should prompt the physician to screen for cobalamin deficiency.

Case 5: Prosthetic valve endocarditis

Joshua Allen-Dicker, MD, MPH, ACP Member, and Shira F. Grock, MD

The patient

A 71-year-old man with a medical history of rheumatic heart disease and bioprosthetic aortic and mitral valve replacements 3 months prior to admission presented with fever and shortness of breath for 2 days. Review of systems was positive for 3 weeks of fatigue. Initial vital signs included a temperature of 39.2°C, respiration of 25 breaths per minute, a pulse of 149 beats per minute, and oxygen saturation of 98% on 2 L of supplemental oxygen. Blood pressure was normal.

Physical examination was significant for decreased breath sounds at the lung bases bilaterally and a grade III/VI systolic murmur heard loudest at the right sternal border. Initial laboratory testing showed a leukocyte count of 17,400 cells/μL. Chest radiography revealed moderate right and small left pleural opacities. Blood cultures were drawn, and the patient was given IV fluids along with cefepime and vancomycin for presumed sepsis.

After only 13 hours, blood cultures grew gram-positive cocci in pairs and chains. Transthoracic echocardiogram (TTE) revealed a normal ejection fraction, moderate right ventricular dysfunction, and no evidence of valvular vegetation. The positive blood cultures were ultimately identified as Streptococcus mitis. Subsequent transesophageal echocardiogram (TEE) revealed vegetations on all 3 cusps of the bioprosthetic aortic valve with associated aortic root abscess extending into the ascending aorta. The patient underwent reoperative sternotomy with aortic root replacement without subsequent complication.

The diagnosis

This patient's diagnosis is clearly prosthetic valve endocarditis (PVE). Within 5 years of valve surgery, 3% to 6% of patients develop PVE. Bioprosthetic and mechanical valves have equal risk of endocarditis 1 year after surgery, with minimally increased risk in bioprosthetic valves after this time period. TTE did not reveal evidence of vegetation, but the sensitivity of TTE for infective endocarditis is only 30% to 60%. In cases with high clinical suspicion, TEE remains the gold standard for the diagnosis of endocarditis as well as detection of complications such as abscess formation and valvular perforation.

The 2006 American College of Cardiology/American Heart Association guidelines recommend surgical intervention for patients with PVE displaying signs of heart failure, valvular dehiscence, or abscess formation. Other considerations for surgery include persistent bacteremia, recurrent emboli, or relapsing infection. In comparison to more robust data on surgical interventions for native valve endocarditis, recommendations for PVE are largely based on expert opinion and limited observational data. These data specifically suggest a mortality benefit for early surgery over medical therapy in patients who have developed complications associated with endocarditis (e.g., abscess, heart failure, valve dehiscence). Given his significant burden of disease, our patient was referred for surgical intervention.

Pearls

  • Transthoracic echocardiogram is only 30% to 60% sensitive for detection of vegetations in infective endocarditis.
  • Recommendations for surgical intervention in patients with prosthetic valve endocarditis include signs of heart failure, valvular dehiscence, or abscess formation.

Case 6: Sulfasalazine-induced DRESS syndrome

Tao Xu, MD

The patient

A 29-year-old man with ulcerative colitis presented with 5 weeks of fever and rash. His rash was originally noted on his face and subsequently spread to his chest, abdomen, and legs. There was no associated pruritus, blistering, or pain. One week after the onset of symptoms, his outpatient clinician ordered laboratory testing, which demonstrated leukocytosis and liver function test abnormalities. The patient was instructed to discontinue sulfasalazine, which had been started for ulcerative colitis 3 weeks earlier. His rash progressed along with the onset of bloody diarrhea, and he was admitted to the hospital.

On admission, the patient was afebrile and tachycardic. Physical examination was significant for a diffuse nonvesicular, macular erythematous rash, with patchy scaling. The rash involved the face, torso, and bilateral upper and lower extremities, sparing the palms and soles. No changes were seen in the oropharynx, although lateral nontender submandibular lymphadenopathy was noted.

Laboratory results were significant for leukocytosis with bandemia, atypical lymphocytes, and no peripheral eosinophilia. Aminotransferase levels were markedly elevated, with an aspartate aminotransferase level of 1,164 U/L and an alanine aminotransferase level of 1,716 U/L. Acute viral hepatitis serologies were negative. CT imaging of the abdomen did not reveal hepatomegaly, biliary dilation, or gallstones. Biopsy of the liver was consistent with drug-induced liver injury.

The diagnosis

The patient was diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome is a drug-induced immune response, diagnosed by a constellation of clinical symptoms and laboratory abnormalities. Recognizing this syndrome is important given the mortality rate can reach 10% in unrecognized cases. It is essential to obtain a history of exposure to one of the many drugs that are associated with this syndrome (most commonly antiepileptics and sulfonamides).

The typical presentation of DRESS syndrome includes fever, lymphadenopathy, diffuse morbilliform eruption, and facial edema. The onset of symptoms is characteristically late, occurring 2 to 6 weeks after initiation of the offending medication. Associated laboratory abnormalities include leukocytosis with eosinophilia or atypical lymphocytosis; although the acronym of the syndrome includes eosinophilia as a key feature, an atypical lymphocytosis is often found instead of eosinophilia. Increased serum aminotransferase levels are also common, and HHV-6 serology is often positive. At least 1 organ is involved in 90% of cases, and the liver is the most common.

Treatment is withdrawal of the offending drug and supportive therapy. Topical corticosteroids can be used in cases with significant pruritus. Systemic corticosteroids are recommended for patients with severe renal or pulmonary involvement but have no benefit in patients with severe liver involvement. Antiviral treatment is not routinely recommended except for patients with severe complications from viral reactivation. This patient received IV fluids and nonsteroidal topical emollient, with gradual improvement in liver enzymes and rash.

Pearls

  • Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced immune response, diagnosed by a constellation of clinical symptoms and laboratory abnormalities; despite the acronym, atypical lymphocytes are often found instead of eosinophilia.
  • Treatment centers on removal of the offending agent and supportive care; systemic corticosteroids have shown benefit only in severe renal or pulmonary involvement in DRESS syndrome.