Clin J Gastroenterol (2010) 3:237–242 DOI 10.1007/s12328-010-0165-x
Autoimmune hemolytic anemia in treatment-naive chronic hepatitis C infection: a case report and review of literature Robert J. Basseri • Michael T. Schmidt Benjamin Basseri
Received: 6 April 2010 / Accepted: 6 July 2010 / Published online: 6 August 2010 Ó Springer 2010
Abstract The hepatitis C virus (HCV) is the most common blood-borne pathogen and currently infects over two hundred and fifty million individuals worldwide. Chronic HCV infection may result in cirrhosis, hepatocellular carcinoma, and liver failure. An exceedingly rare extrahepatic manifestation of HCV is autoimmune hemolytic anemia (AIHA). We discuss an interesting case of direct Coombs’positive AIHA in a treatment-naive 53-year-old male with a past medical history of HCV cirrhosis, genotype 3a, who presented with fatigue, abdominal pain, and jaundice. Complete blood cell count demonstrated anemia, thrombocytopenia, elevated mean corpuscular hemoglobin and corpuscular volume worrisome for hemolytic anemia. Upon further workup, the patient was found to have increased bilirubin, reticulocyte count, and lactate dehydrogenase with concomitant direct Coombs’-positive test, consistent with the diagnosis of AIHA. A comprehensive workup was conducted to elucidate the underlying etiology of the AIHA, including malignancy, systemic lupus erythematosus (SLE), and medication side-effects. Malignancy was ruled out with an imaging and bone marrow biopsy. SLE was subsequently eliminated with a negative anti-nuclear antibody (ANA), and the patient had never received ribavirin, interferon, cephalosporins or other medications associated with drug-induced immune hemolytic anemia (DI-IHA). While the relationship between DIIHA and HCV is well-described in the literature, primary AIHA in treatment-naive patients is a rare and intriguing
R. J. Basseri M. T. Schmidt Cedars-Sinai Medical Center, Los Angeles, CA, USA B. Basseri (&) 308 Euclid Street, Santa Monica, CA 90402, USA e-mail: [email protected]
extrahepatic manifestation of HCV and only four reports have been described in the literature. Given the prevalence of HCV and this interesting extrahepatic manifestation, HCV testing should be considered in patients presenting with AIHA with an otherwise negative workup and a history of parenteral or lifestyle risk factors. Keywords Autoimmune hemolytic anemia (AIHA) Hepatitis C virus (HCV) Extrahepatic manifestation Treatment-naive
Introduction Hepatitis C virus (HCV) is a blood-borne pathogen that can cause acute and chronic hepatitis and may ultimately lead to cirrhosis, hepatocellular carcinoma, and liver failure . HCV is responsible for approximately 20% of acute hepatitis infections, and the impending risk of chronic infection is overwhelming without antiviral therapy [2, 3]. According to the National Health and Nutrition Examination Survey (NHANES) 2006, HCV is the most common blood-borne infection in the United States and affects 1.6% of the American population [4, 5]. Recent studies demonstrate that HCV-related complications are increasing [6, 7]; HCV is now the leading cause of chronic liver failure and the most common indication for liver transplantation in the United States . The gold standard of care for HCV infection is dual antiviral therapy with ribavarin and interferon. While there are vaccines for hepatitis A and B, and despite a 2006 study where patients successfully formed antibodies to an experimental HCV vaccine deeming immunity to HCV infection, hepatitis C vaccines are still being tested . In addition to the typical complications of HCV infection described above, up to 38%
of this patient population may develop one or more extrahepatic manifestations of HCV . These extrahepatic manifestations of HCV may develop in the skin (vitiligo) , eyes, joints, immune system (Sjo¨gren syndrome) , nervous system and kidneys. A rare and novel extrahepatic manifestation of HCV is autoimmune hemolytic anemia (AIHA). After an extensive literature search, only four reports of AIHA in treatment-naive HCV patients have been reported [13–16]. AIHA is an extravascular hemolysis of red blood cells (RBCs) in the spleen, in conjunction with the bone marrow’s inability to compensate for such destruction. AIHA manifests as anemia, reticulocytosis, erythroid hyperplasia of the bone marrow, elevated bilirubin and lactate dehydrogensase (LDH), as well as reduced haptoglobin. AIHA is ultimately confirmed with a direct Coombs’ test. While drug-induced immune hemolytic anemia (DI-IHA) secondary to ribavarin and interferon treatment in HCV patients is well-described in the literature [17, 18], very few cases of AIHA in HCV treatment-naive patients have been reported worldwide. In a large national cohort of HCV-infected US veterans, Chiao et al.  observed an increased risk of developing AIHA secondary to HCV infection (1.7-fold) and treatment (2.4-fold), independently. The proposed hypothesis is that interferon transforms the RBC membrane and causes an accelerated autoimmune reaction, ultimately resulting in RBC destruction and the development of AIHA . Furthermore, interferon’s innate immunomodulatory effects may exacerbate underlying autoimmunity . Moreover, anti-microbial treatment for spontaneous bacterial peritonitis (SBP) with cephalosporins may also result in DI-IHA [22, 23] whereby the drug alters the immune system, thereby creating autoantibodies to RBCs and resulting in a similar presentation to AIHA. Viruses, including HCV, can trigger an autoimmune response via antigenic mimicry and result in the loss of tolerance [24, 25]. More specifically, HCV infection can stimulate other autoimmune processes and thus catalyze subsequent autoantibody production . For example, HCV has been linked with the development of idiopathic thrombocytopenic purpura (ITP). HCV may bind to human CD-81 receptors on platelet membranes and result in HCVinduced destruction of platelets [27, 28], and the virus may also infiltrate and replicate within megakaryocytes, leading to their destruction . Given the prevalence of HCV infection—approximately 250 million people worldwide —and this interesting extrahepatic manifestation, HCV testing may be considered in patients presenting with AIHA with an otherwise negative workup and history of parenteral or lifestyle risk factors. Here, we report an interesting case of direct Coombs’-positive AIHA in a treatment-naive HCV patient.
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Case description History of present illness A 53-year-old male with a past medical history of HCV cirrhosis, genotype 3a, presented to our medical center with complaints of fatigue, yellowing of his eyes, and 7 days of right upper quadrant abdominal pain. On admission the patient denied shortness of breath, chest pain, change of bowel habits, fever, chills, night sweats, dizziness or weakness. HCV had been diagnosed 3 years prior to presentation and likely contracted via blood transfusion in 1986, secondary to blood loss sustained in a motor vehicle accident. The disease course included cirrhosis and associated esophageal varices, portal hypertensive gastropathy, and spontaneous bacterial peritonitis. He also had a past medical history of anxiety, panic attacks, and seizures (he experienced one episode of generalized seizure in 2007). His outpatient medications included: lasix 20 mg PO daily, spironolactone 100 mg PO daily, potassium chloride 10 mEq PO daily, omeprazole 20 mg daily, nadolol 20 mg PO daily and diazepam 2.5 mg PO daily. He has a 15 packyear smoking history, and denied any history of alcohol consumption, illicit drug use, or family history of hematological or liver disease. Physical examination The patient is a pleasant, mildly jaundiced male in no apparent distress with normal vital signs upon admission. His physical examination revealed scleral icterus, abdominal distention, right upper quadrant tenderness to palpation, negative Murphy’s sign, gynecomastia, and diffuse spider angiomata. No rash, joint tenderness, oral ulcers, hepatosplenomegaly or lymphadenopathy were appreciated on examination. Laboratory White blood cell count was 5.7 thousand cells/mL (normal range 4–11 thousand cells/mL), hemoglobin 8.3 g/dL (12–16 g/dL) and hematocrit 25.2% (37–47%). Mean corpuscular volume was 112.4 fL (80–100 fL), mean corpuscular hemoglobin 40.2 pg/cell (27–31 pg/cell), and platelet count 47,000/lL (150,000–400,000/lL). Basic metabolic panel was within normal limits, indirect bilirubin was 14.3 mg/dL (0.1–1.0 mg/dL), reticulocyte count 9.6% (0.5–1.5%), haptoglobin \6 mg/dL (27–139 mg/dL), LDH 392 U/mL (3.5–4.5 U/mL), negative for cryoglobulins, and direct Coombs’ test was positive. Total bilirubin was 24.3 mg/dL (0–0.3 mg/dL), AST 24 IU/L (5–43 IU/L), ALT 45 IU/L (5–60 IU/L), alkaline phosphatase 57 IU/L (30–115 IU/L) and lipase 116 U/L (0–110 U/L). Anti-nuclear
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9 10 11 12 13 14 15 16 17 18 19
Day of Hospitalization
Fig. 1 Peripheral smear. This demonstrated the variability of RBC morphology seen in AIHA consisting of schistocytes, burr cells, polychromatic cells, microcytes and a single macrocytic cell displaying coarse basophilic stipling
Fig. 3 Hemoglobin response to steroid therapy. This shows hemoglobin levels throughout hospitalization. Upon diagnosis of AIHA, prednisone 75 mg PO daily was initiated (day 5 as exemplified by the leftmost line). Prednisone 75 mg PO daily was continued until day 13 when the patient’s hemoglobin reached the target of 10 mg/dL (arrow). Prednisone was changed to 60 mg PO daily, with a stabilization of hemoglobin. The patient was discharged on prednisone 60 mg PO daily for 1 week with subsequent taper
Pathology Peripheral smear demonstrated the variability of RBC morphology seen in AIHA consisting of schistocytes, burr cells, polychromatic cells, microcytes and a single macrocytic cell displaying coarse basophilic stipling (Fig. 1). Bone marrow biopsy was performed to rule out leukemia and lymphoma as the underlying etiology for the patient’s AIHA. Examination demonstrated erythroid hyperplasia with normal megakaryocytes, lymphocytes, eosinophils and mature plasma cells. No tumor, granulomata, or lymphoma were noted. Imaging A chest radiograph and computed tomography (CT) did not demonstrate any underlying mass, lymphadenopathy or changes of the bony thorax. Workup to rule out underlying malignancy continued with magnetic resonance imaging (MRI) and CT of the abdomen with contrast, which both illustrated a shrunken and nodular liver consistent with cirrhosis, and without any mass or lymphadenopathy (Fig. 2). Fig. 2 MRI of the abdomen. This was performed before and after the use of intravenous gadolinium enhancement. These images demonstrates a nodular contour and heterogeneity of a shrunken cirrhotic liver, without any mass or lymphadenopathy
antibody (ANA), anti-double strand DNA antibody, and anti-smooth muscle [which are suggestive of systemic lupus erythematosus (SLE)], were negative.
Treatment course AIHA was diagnosed based on the constellation of the patient’s clinical presentation, laboratory data, and peripheral smear. A comprehensive workup was conducted to evaluate for possible etiologies of AIHA, which include malignancy, SLE, and medication side-effects. Malignancy
was ruled out with imaging and bone marrow biopsy. SLE was subsequently eliminated with a negative ANA, and the patient had never received ribavirin, interferon, cephalosporins or any other medications associated with DI-IHA. On day 5 of hospitalization high-dose oral prednisone (75 mg PO daily) was administered, and was continued at this dose until the patient’s hemoglobin reached the target of C10 g/dL (day 13, Fig. 3). The patient was discharged on an oral prednisone taper (60 mg PO daily: total 7 days, then 40 mg PO daily: 7 days, 20 mg PO daily: 7 days, 10 mg PO daily: 7 days, and then a maintenance dose of 10 mg PO every other day with complete resolution of anemia 4 months after discharge.
Discussion We report a unique treatment-naive 53-year-old male patient with a past medical history of HCV cirrhosis, genotype 3a, who presented to our medical center with complaints of fatigue, jaundice, and right upper quadrant abdominal pain. Coombs’ test confirmed the diagnosis of AIHA, and underlying etiologies of AIHA were eliminated. Thus, it is believed that HCV induced AIHA. Chronic HCV infection can lead to cirrhosis, hepatocellular carcinoma and ultimately liver failure. Extrahepatic manifestations of chronic HCV infection include myriad organ systems, such as the immune system in the case of AIHA. AIHA is a rare extravascular hemolytic anemia whereby the immune system prematurely destroys its own RBCs at a rate that the bone marrow is unable to compensate. There appears to be a significant relationship between the incidence of AIHA and age, as the majority of patients affected are of middle age or elderly, as with our patient. Other risk factors associated with AIHA include female gender, underlying malignancy and SLE. Up to 20% of patients with SLE experience AIHA during their lifetime . The differential diagnosis of AIHA includes DI-IHA. As only 15-20% of patients with HCV infection experience clearance of the virus and normalization of liver function tests without treatment [32, 33], dual therapy with ribavarin and interferon has become the cornerstone of treatment . Unfortunately, antiviral therapy is associated with numerous side-effects, including immune hemolytic anemia. De Franceschi et al. hypothesized that the underlying oxidative mechanism of ribavarin promotes immune-mediated hemolysis . Numerous case reports have described DI-IHA in the HCV patient population secondary to antiviral therapy [35–39]. Contrastingly, the link between AIHA and HCV in treatment-naive patients has, to date, only been described in 4 reports worldwide [7–10].
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Patients affected with acute or severe anemia frequently present with pale conjunctivae, general pallor and can experience fatigue, tachycardia, weakness, dizziness, and dyspnea. Furthermore, timely recognition of AIHA is imperative as these patients are at risk for myocardial infarction, pulmonary edema, and fatal cardiac arrythmia . In addition, hemolysis can increase bilirubin, leading to the formation of gallstones and causing right upper quadrant abdominal pain. The evaluation of AIHA entails complete blood count, complex metabolic panel, liver function tests, radiographic imaging, bone marrow biopsy, and ANA. The objectives of treating AIHA include slowing the destruction of RBCs, elevating the RBC count, and ultimately treating the underlying etiology of AIHA. Corticosteroid therapy—the first-line treatment to quell the autoimmune process—should be initiated and titrated accordingly to reverse the patient’s anemia. Ramos-Casals et al.  showed that patients with HCV-associated AIHA had a higher incidence of autoimmune disease and cryoglobulinemia, and a good response to corticosteroid therapy; nevertheless, these individuals had poorer prognosis than HCV-associated thrombocytopenia. Furthermore, HCV-associated blood dyscrasias occurred more frequently in females and patients with cirrhosis. We present an interesting case of a male without cryoglobulinemia or a known autoimmune disorder who experienced AIHA secondary to the hepatitis C virus. Intravenous immunoglobulin (IVIG) is the second-line treatment in patients in which steroid therapy fails; unfortunately, IVIG successfully reverses AIHA in only 40% of patients receiving such therapy and can be quite cumbersome, as the procedure is time-consuming and must be repeated every three weeks until remission is accomplished [42, 43]. AIHA is an extravascular process whereby destruction of RBCs occurs in the spleen. Thus, splenectomy may be a curative measure for patients who fail IVIG and steroid treatment. Immunosuppressive therapy is the final line of treatment for AIHA and is reserved for those patients who do not respond to steroid medication, IVIG or splenectomy. Medication successfully used so far includes azathioprine and cyclophosphamide [44, 45]. Blood transfusions are not indicated in AIHA, as the introduction of foreign RBCs in the setting of heightened autoimmunity may exacerbate hemolysis [46, 47]. In summary, while ribavirin and interferon-associated DI-IHA are well-described in the literature, AIHA in treatment-naive patients is a rare and intriguing manifestation of HCV and has only been described in a handful of cases worldwide. Diagnosis requires a hypervigilant review of the peripheral smear, imaging, bone marrow biopsy and the meticulous evaluation of laboratory data. Given the prevalence of hepatitis C and this novel extrahepatic
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manifestation, HCV testing may be considered in patients presenting with AIHA who have an otherwise negative workup and a history of parenteral or lifestyle risk factors. Conflict of interest The authors declare that there is no potential conflict of interest or funding related to this article.
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