BONE MARROW NECROSIS: A RARE COMPLICATION OF HERBAL TREATMENT WITH HYPERICUM PERFORATUM (ST. JOHN’S WORT)

Hypericum perforatum L (St John’s wort) is a member of the Hypericum genus, which includes some of the most widely used herbal substances (8,19). This plant possesses antimicrobial properties and is used to treat depression; however, it has been implicated in drug interactions (4,12,16). Herbal remedies can alter a patient’s hematological status and cause abnormal blood cell count results (1), but the impact of St. John’s wort on bone marrow is unknown. In this case report, we describe a patient who developed fatal bone marrow necrosis associated with use of St. John’s wort.

Serum biochemistry analysis on admission revealed total bilirubin 4.9 mg/dL, direct bilirubin 3.4 mg/dL, serum albumin 3.1 g/dL, blood urea nitrogen 22 mg/dL, creatinine 1.0 mg/dL, lactate dehydrogenase 202 IU/L, alanine aminotransferase 404 IU/L, and aspartate aminotransferase 97 IU/L. By the third day of hospitalization, the levels of these two liver enzymes had dropped to 68 IU/L and 30 IU/L, respectively. Cytokine levels (IL-1b, IL-2R, IL-6, IL-8, IL-10, TNF-alpha) in plasma were analyzed by using chemiluminescent method and immulite hormon autoanalyser (Diagnostic Product Corporation, IL, USA). All cytokine levels in plasma except IL-1b were found to be higher than normal range (Tab. 1). Serologic testing was also done on the first day of hospitalization. The results for hepatitis B and C viruses, human immunodeficiency viruses (HIV) -1 and -2, parvovirus B19, Epstein-Barr virus (EBV) immunoglobulin (Ig) M, herpes simplex viruses 1 and 2, cytomegalovirus IgG and IgM, rubella, Brucella spp., typhoid fever, syphilis, and Toxoplasma IgM were all negative.
On the second day of hospitalization, chest radiography and abdominal computed tomography showed nothing remarkable. Computed tomography of the paranasal sinuses revealed sinusitis on the right side. Electrocardiography showed sinus tachycardia (rate 120 beats/min). Abdominal ultrasound was normal. Multiple blood, bone marrow and urine cultures were also done on day 2, and none of these showed growth. A culture of material from the oropharynx grew mixed flora, and the majority of the isolates were Klebsiella spp. and Enterobacter spp. The hemoglobin level decreased from 10 to 6 g/dL within 3 days, and schistocytes were seen in peripheral blood smear on day 3, which reflects microangiopathic hemolytic anemia.
Based on the abnormal findings on the complete blood cell count and the peripheral smear, the bone marrow of the posterior iliac crest was aspirated and biopsied on the third day of hospitalization. The aspirate showed marrow necrosis, with only a few mononuclear cells and histiocytes preserved. Detailed histopathologic examination of the bone marrow revealed marked decreased numbers of hemapoietic cell series, which are megakaryocytic, erythroid and myeloid series, and cellularity was 15%. Focal bone marrow necrosis was estabilished with necrotic cells and fat necrosis. There were no phagocytic activity and necrotic cell debris around the necrotic focus. With these findings the 92 diagnosis was hypocellular bone marrow with focal necrosis ( Figure 1). The patient received meropenem (Meronem ® , Astra-Zeneca) 6 g/day and amikacin (Mikasin ® , Abfar) 1 g/day before and after the diagnosis was established. Repeat blood testing on the second and third days of treatment showed that the neutropenia was becoming more severe. The patient developed progressive dysphagia. Endoscopic examination of the esophagus showed candidal esophagitis. To manage the bone marrow necrosis and associated clinical signs, we initiated treatment with granulocyte colony-stimulating factor (filgrastim, Neupogen ® , Roche) 48 U/day, a 400 mg/kg bolus of intravenous I g (Endobulin S/D ® , Baxter) to suppress cytokines, and amphotericin B (Fungizone ® , Bristol-Myers Squibb) 100 mg/day. However, there was no response to treatment, and the patient died of cardiac arrest on the eighth day of hospitalization.

Discussion
The most prominent finding in this case was bone marrow necrosis. It has been reported that beside agranulocytosis, anemia and thrombocytopenia can be observed (90% and 80% respectively) in patients with bone marrow necrosis (11). In our case with agranulocytosis, thrombocytopenia developed following microangiopathic hemolytic anemia, which often occures in the case of bone marrow necrosis (7,10). Necrosis of normal hematopoietic elements with gelatinous transformation has been described in patients with hematooncological disease, adenocarcinoma, typhoid fever, systemic lupus erythematosus and tuberculosis (7,9,14,15). Other causes of marrow necrosis include vasoocclusive crisis, direct damage to bone and radiation, and toxins (9,14,15). However, our patient had neither the classic features nor serologic evidence of any of these diseases. The patient had no history of exposure to any other chemical or potential toxins.
There are two explanations for this patient's dramatic illness. First, the condition may have been initiated by an infection that resulted in histiocytic proliferation and macrophage reactivation with excessive cytokine release. Epstein-Barr virus, cytomegalovirus, parvovirus B19, HIV-1 and -2, and herpes virus are the most common causes of histiocytic proliferation and inhibition of normal hematopoietic cells in adults (5). Epstein-Barr virus infection has a number of different oral manifestations. Affected patients frequently develop cervical lymphadenopathy and may exhibit palatal petechiae, but erosions and ulcers are not typical. Cytomegalovirus usually does not cause oral ulceration (3,5). In our case, the absence of any risk factors for HIV infection made this diagnosis unlikely. Further, all the serology results for viral disease were negative.
A second possible explanation is bone marrow necrosis, and elevated liver enzymes might have been unexplained toxic effects of the St. John's wort the patient was taking for depression. Use of herbal preparations is increasing globally in parallel with alternative medicine. St. John's wort is one of several herbal products used to treat depression (4,8). Previous studies have shown that Hypericum spp. have a number of biological activities. Hypericin, a derivative and the active compound of St. John's wort, is known to have antioxidant and antimicrobial activity (2,6,13,17). Two reports suggest that St. John's wort has anticancer activity, and that it may act by inducing apoptosis and inhibition of cell growth (19). Other research indicates that this herb may also affect drug metabolism by inducing the cytochrome P 450 enzyme (12). St. John's wort has in vitro immunomodulatory effects on lymphocytes, and may alter cytokine release (10,18). The presence of high plasma cytokine levels in our case might reflect such immunological effects that can lead to bone marrow necrosis.
Herbal remedies are used throughout the world, and this report highlights a rare association of herb use and bone marrow necrosis. This case underlines the need for better assessment of the safety of these products.