Cases from New York University

Acute intermittent porphyria, thrombotic microangiopathy complicating chemotherapy, and more.


Physician editor: Christopher Sankey, MD, FACP

Deputy physician editor: Benjamin Galen, MD, FACP

Case 1: Acute intermittent porphyria

By Adria R. Simon, BA; Amar Parikh, MD; and Karin M. Warltier, MD

The patient

A 40-year-old woman with a history of acute intermittent porphyria (AIP) presented with diarrhea, vomiting, and leg pain. She had been diagnosed with AIP 1 year earlier, after an episode of acute abdominal pain. Since her diagnosis, she had experienced 3 flares requiring hospitalization, the most recent of which was complicated by myocardial infarction. Previous episodes were successfully treated with hemin infusion. One day before her current admission, the patient noted intermittent, sharp epigastric pain associated with nonbloody and nonbilious emesis; loose stools and diffuse pain in the bilateral distal lower extremities were noted as well.

Upon admission, the patient's vital signs were normal and examination revealed mild tenderness to palpation in the epigastric region. Laboratory testing demonstrated hyponatremia (sodium level, 126 mmol/L) and a mildly elevated lipase level (396 U/L), aspartate aminotransferase level (81 U/L), and alanine aminotransferase level (76 U/L). The spot urine porphobilinogen level returned at 423.9 μmol/L (normal range, less than 8.8 μmol/L) on hospital day 6, confirming an acute attack of AIP. While urine studies were pending, the patient was treated empirically with glucose, hemin, and analgesics. Her sodium level improved, her pain resolved, and she was discharged home with close follow-up with her hematologist.

The diagnosis

The patient's diagnosis is a flare or “attack” of AIP, an autosomal-dominant disorder resulting from an enzymatic deficiency in heme synthesis that leads to abnormal accumulation of pathway intermediates. Symptoms of an attack include severe abdominal pain that is often poorly localized, peripheral neuropathy, and autonomic dysregulation. Central nervous system involvement is also possible, including neuropsychiatric manifestations such as anxiety, agitation, and labile affect. Abdominal examination of a patient with an AIP attack is often unremarkable or demonstrates only mild tenderness, out of proportion to the patient's reported level of pain. Laboratory studies commonly reveal hyponatremia and elevated aminotransferase levels. These findings should increase clinical suspicion of an AIP attack. Elevations in urine porphobilinogen and porphyrin levels, which consist mostly of uroporphyrin and coproporphyrin, can confirm the diagnosis of an acute flare, but it often takes several days to get results, so empiric treatment should be initiated when the clinical suspicion is high.

In an acute attack, total urinary porphyrin excretion is markedly elevated, accompanied by increased levels of porphobilinogen. However, elevated urinary porphyrin levels with a normal porphobilinogen level are associated with other porphyrias that are separate entities from AIP, as well as nonporphyric medical conditions such as liver disease. Therefore, an elevated level of urine porphobilinogen is the only test result required to confirm the diagnosis. In patients with a known diagnosis of AIP and symptoms of a typical attack, repeat testing may not be needed.

Treatment for AIP attacks includes hemin infusion, glucose loading, and pain control. Both hemin infusion and glucose loading result in inhibition of enzymes upstream of the precursor molecules in the heme synthesis pathway and are aimed at reducing further accumulation of heme pathway intermediates. The intermediates or derivatives are hypothesized to be the neurotoxin that leads to symptoms in AIP. While hemin infusion is considered to be more effective, glucose may be initiated in patients with mild attacks or when hemin is not readily available. Clinical endpoints for treatment are based on resolution of symptoms, typically expected within 4 to 5 days.

Pearls

  • The diagnosis of acute intermittent porphyria (AIP) should be considered in patients presenting with recurrent abdominal pain and neuropsychiatric symptoms.
  • Patients with a history of AIP and symptoms consistent with an attack should be empirically treated with hemin infusion with or without glucose loading while awaiting confirmatory testing.

Case 2: Thrombotic microangiopathy complicating chemotherapy

By Joseph Kingsbery, MD, ACP Resident/Fellow Member; Karen Kan, MD; and Nicole Adler, MD, FACP

The patient

A 63-year-old woman with a history of metastatic adenocarcinoma of unknown primary was admitted with 4 weeks of lower-extremity edema, fatigue, and progressive shortness of breath. She had completed a total of 26 cycles of chemotherapy consisting of gemcitabine and oxaliplatin, with the most recent administration 1 month before presentation. Preceding this admission, she was noted to have new-onset hypertension (170/80 mm Hg), anemia (hemoglobin level, 7 g/dL, decreased from a baseline of 9 g/dL), worsening renal insufficiency (creatinine level, 1.8 mg/dL, increased from 1 mg/dL), as well as newly noted blood and protein on urinalysis.

On admission, the patient's vital signs were as follows: temperature, 97.9 °F; heart rate, 88 beats/min; respiratory rate, 18 breaths/min; blood pressure, 167/81 mm Hg; and oxygen saturation, 98% on room air. On physical exam, she was alert and oriented and was cachectic but in no acute distress. The cardiopulmonary exam was unremarkable. Her skin was warm and without petechiae. There was 1+ pitting edema to the knees bilaterally.

Admission laboratory testing revealed a serum lactate dehydrogenase (LDH) level of 1,643 U/L (normal range, 313 to 618 U/L), a haptoglobin level of 10 mg/dL (normal range, 30 to 200 mg/dL), and a platelet count of 111,000 cells/µL from a baseline of 300,000 cells/µL (normal range, 150,000 to 400,000 cells/µL). A peripheral blood smear showed 2 to 3 schistocytes per high-powered field. Complement levels were normal, and Coombs testing was negative. Fibrinogen, international normalized ratio, and prothrombin time were all within normal limits. Urine protein to creatinine ratio was 9,599 mg/g. ADAMTS13 level was 57% (normal is greater than 67%).

The patient was treated with transfusions of packed red blood cells and antihypertensive medications. Over the course of her admission, her platelet count and creatinine level stabilized, and she was discharged to follow-up with her oncologist. Over the following 3 months, creatinine level and platelet count returned to normal. The patient died of metastatic adenocarcinoma 15 months after initial presentation to the hospital.

The diagnosis

The patient's clinical course and laboratory results were consistent with a diagnosis of thrombotic microangiopathy (TMA) secondary to chemotherapy. It is unclear whether this was due to gemcitabine alone or to its combination with oxaliplatin. TMA is a rare but serious complication associated with chemotherapeutic agents. Gemcitabine-associated TMA most often occurs in adenocarcinomas. The risk of development of this complication is dose-related, with increasing risk when the number of doses exceeds 18.

The diagnosis of chemotherapy-induced TMA was made based on several features. First, laboratory abnormalities associated with TMA include thrombocytopenia, hemolytic anemia with schistocytes on peripheral smear, increased LDH level, decreased haptoglobin level, and renal dysfunction. In addition, new onset of hypertension is suggestive of gemcitabine-associated TMA. ADAMTS13 levels in these patients are often reduced, but not to the degree that is seen in inherited thrombotic thrombocytopenic purpura, which typically is less than 5%. Fibrinogen, prothrombin time, and coagulation studies were normal, which aided in differentiating TMA from alternative diagnoses, including disseminated intravascular coagulation.

When the agent responsible is withdrawn, most patients have a remission of TMA. There are little data on whether chemotherapy-induced TMA has any prognostic implications for disease recurrence or mortality, although the discontinuation of a therapeutic agent may affect future treatment decisions and the ability to control disease progression.

Pearls

  • Gemcitabine is a common chemotherapeutic drug that can rarely cause thrombotic microangiopathy (TMA).
  • Clinical features of gemcitabine-induced TMA include new-onset hypertension, thrombocytopenia, hemolytic anemia with schistocytes on peripheral smear, increased lactate dehydrogenase level, decreased haptoglobin, renal dysfunction, and a mild to moderately decreased ADAMTS13 level.

Case 3: Disseminated gonococcal arthritis with systemic lupus erythematosus

By Jennifer Johnson, MS, RN, and Katherine Hochman, MD

The patient

A 44-year-old woman with history of systemic lupus erythematosus (SLE) complicated by pleurisy and thrombocytopenia on belimumab presented with a 10-day history of a new migratory polyarthritis. Her pain started in her left wrist and was noted in her right wrist 1 day later and in her right shoulder after 2 more days. Of note, she reported that this presentation was not typical of her lupus, which usually involved pleurisy. Without seeking medical attention, she presumed a lupus flare and began a course of prednisone, 30 mg, with no improvement. One day later, she noted pain in her right hip. She presented to an outpatient clinic, where she was found to have leukocytosis. A right shoulder arthrocentesis was unsuccessful. One day later, she developed left ankle pain and sought medical evaluation.

Upon presentation, her temperature was 101.5 °F and her pulse was 117 beats/min. She had a limited range of motion of the right shoulder and left ankle, which were significantly swollen. Skin exam was normal. Her sexual history was significant for intermittent bacterial vaginosis, a monogamous relationship with a male partner, and no prior sexually transmitted illnesses. She did not report dysuria or purulent vaginal discharge. An arthrocentesis of the left ankle revealed 85,000 white blood cells and no crystals. Laboratory testing was significant for negative blood cultures, normal peripheral leukocyte count, double-stranded DNA of 44 IU/mL, C4 complement level of 15 mg/dL, C3 complement level of 80 mg/dL, and creatinine level of 0.7 mg/dL. Polymerase chain reaction nucleic acid testing revealed Neisseria gonorrhea in the urine. This was subsequently corroborated by cultures from the left ankle arthrocentesis. It was later determined that the patient's partner had not been monogamous, and he was notified of the test results. The patient was discharged home to complete a 2-week course of ceftriaxone.

The diagnosis

The patient's diagnosis is septic arthritis secondary to disseminated gonococcal infection (DGI). The prevalence of DGI in patients with SLE is not reported in the literature. However, risk factors for DGI include female gender, age less than 40 years, sexual exposure, and complement deficiency. Furthermore, treatment with belimumab, a human monoclonal antibody that inactivates the B-cell activator factor, contributes to risk of infection. Even with an existing diagnosis of SLE, septic arthritis must be considered as part of the differential in every patient with joint pain. In addition, there are 3 elements in this patient's history that should prompt the clinician to consider DGI: The symptoms were not consistent with her typical SLE flare, the joint pain was described as a migratory arthritis (consistent with DGI), and the patient had a history of bacterial vaginosis, which put her at risk for sexually transmitted diseases. In addition, joint destruction from any reason, including SLE arthritis, is a risk factor for joint infection.

Pearls

  • Septic arthritis should be considered in a patient with joint pain and swelling, especially in patients with concomitant inflammatory joint disease.
  • Risk factors for both disseminated gonococcal infection and systemic lupus erythematosus include female gender, age less than 40 years, complement deficiency, and immunosuppressive medication.

Case 4: Gastric heterotopic pancreatic “rest”

By Jennifer Mulliken, MD, ACP Resident/Fellow Member, and Aron Mednick, MD, ACP Member

The patient

A 27-year-old man with a history of Meckel's diverticulum (resected at age 12) presented with diffuse abdominal pain and nausea for 5 days. His pain was sharp and “stabbing” with radiation to the back. Upon presentation, the patient was afebrile with a pulse of 72 beats/min, blood pressure of 128/81 mm Hg, respiratory rate of 18 breaths/min, and oxygen saturation of 99% on room air. Physical examination revealed severe tenderness to palpation throughout the abdomen, most pronounced in the epigastric region. Laboratory evaluation was most notable for a lipase level of 1,455 U/L (reference range, 23 to 300 U/L) and normal triglycerides. A basic metabolic panel was within normal limits, and liver function tests revealed a total bilirubin level of 1.2 mg/dL (reference range, 0.0 to 1.0 mg/dL). An autoimmune evaluation, including IgG4 and anti-nuclear antibody testing, was unrevealing.

An ultrasound of the right upper quadrant was negative for cholelithiasis or biliary ductal dilatation. A CT of the abdomen and pelvis was notable for a normal-appearing pancreas; however, a gastric mass was incidentally noted. Endoscopic evaluation confirmed the presence of a submucosal tumor measuring 4 × 2 cm within the greater curvature of the stomach, and biopsy of the mass showed ectopic pancreatic tissue. The patient ultimately underwent a partial gastrectomy with subsequent resolution of his abdominal pain and normalization of serum lipase levels. No alternative etiologies of pancreatitis were discovered.

The diagnosis

This patient presented with acute idiopathic pancreatitis of a heterotopic pancreatic mass, also known as a “pancreatic rest.” Ectopic pancreatic tissue can rarely be found within any portion of the gastrointestinal tract but is most common in the stomach, duodenum, and jejunum. Deposits of heterotopic pancreas tissue arise during fetal development, and the majority of patients with this condition remain asymptomatic for life. Clinically significant masses are typically greater than 1.5 cm and may cause epigastric pain, abdominal fullness, nausea, vomiting, and diarrhea. Symptoms often arise in the setting of gastric or duodenal outlet obstruction.

Heterotopic pancreatic tissue is subject to the same pathologic processes as orthotopic pancreatic tissue; acute pancreatitis, chronic pancreatitis, pseudocyst formation, and acute hemorrhage with necrosis have all been reported. When pancreatic rests become symptomatic, surgical resection is curative. Malignant transformation can occur but is rare.

Pearls

  • Heterotopic pancreatic tissue, also known as a “pancreatic rest,” can occur within any portion of the gastrointestinal tract.
  • While largely asymptomatic, pancreatic rests can yield nonspecific gastrointestinal symptoms and are subject to the same pathology as orthotopic pancreatic tissue.