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Thrombotic thrombocytopenic purpura associated with chronic HCV infection
The Egyptian Rheumatologist (2012) 34, 107–110
Egyptian Society for Joint Diseases and Arthritis
The Egyptian Rheumatologist www.rheumatology.eg.net www.sciencedirect.com
CASE REPORTS
Thrombotic thrombocytopenic purpura associated with chronic HCV infection Ayman El Garf a b
a,*
, Wafaa Gaber a, Tamer Elbaz b, Kamal El Garf
a
Department of Rheumatology and Rehabilitation, Faculty of Medicine, Cairo University, Cairo, Egypt Department of Hepatogastroenterology and Endemic Medicine, Cairo University, Cairo, Egypt
Received 17 May 2012; accepted 17 May 2012 Available online 27 June 2012
KEYWORDS Thrombotic thrombocytopenic purpura; Vasculitis; HCV; Interferon
Abstract Background: Thrombotic thrombocytopenic purpura is a potentially lethal microvascular thrombotic disorder. Case presentation: In this study, we report a 32 years old woman who suffered from undifferentiated vasculitis with marked improvement on steroids and cyclophosphamide. Two years later, hepatitis C virus infection was discovered. Decision for interferon therapy was not recommended at this stage and the patient remained stable for the following 7 years. In January 2009, pegylated interferon and ribavirin were started due to worsening of her hepatitis; the treatment was stopped after 12 weeks due to the absence of any virologic response. Fourteen months later, she developed severe uncontrolled thrombotic thrombocytopenic purpura that led eventually to her death. Conclusion: We report this rare case of thrombotic thrombocytopenic purpura that may directly be related to chronic HCV infection rather than to interferon therapy. 2012 Egyptian Society for Joint Diseases and Arthritis. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction Thrombotic thrombocytopenic purpura (TTP) was first described in 1925 as a new disease characterized by unique path* Corresponding author. Address: 45 Dokki Street, Dokki Square, Giza 12311, Cairo, Egypt. Tel.: +20 101770866, 237499101; fax: +20 237616629. E-mail addresses: [email protected], [email protected] (A.E. Garf). Peer review under responsibility of Egyptian Society for Joint Diseases and Arthritis.
Production and hosting by Elsevier
ological findings of hyaline thrombi in many organs [1]. A review of 271 published cases up to 1964 defined the classic pentad of the clinical features of this disease [2]: thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms and signs, renal function abnormalities and fever. Although some studies distinguish between TTP and hemolytic uremic syndrome (HUS), yet the presenting features are similar in most of the patients: thrombocytopenia and microangiopathic hemolytic anemia without another apparent cause and, in many patients, neurologic and/or renal abnormalities [3]. When neurologic manifestations are dominant and acute renal failure is minimal or absent, some consider TTP to be present. On the other hand, when acute renal failure is dominant and neurologic abnormalities are minimal or absent, the disease is considered by some to represent HUS [4].
1110-1164 2012 Egyptian Society for Joint Diseases and Arthritis. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejr.2012.05.001
108
A.E. Garf et al.
The diagnosis of TTP-HUS was supported by the pathologic demonstration of hyaline thrombi in renal biopsy. The disease was usually looked as a fatal disease, however with the routine use of therapeutic plasma exchange, TTP-HUS has changed from a fatal to a curable illness in many cases. The availability of curative treatment necessitates rapid diagnosis and less adherence to the diagnostic criteria. At the present time, only the presence of unexplained thrombocytopenia and microangiopathic hemolytic anemia is required to establish the diagnosis of TTP-HUS and initiate treatment [5]. The pathogenesis of the disease is attributed to the accumulation of the unusually large von Willebrand factor (ULVWF) multimers that lead to platelet clumping and subsequent microvascular thrombosis. The ULVWF multimers primarily synthesized by vascular endothelial cells, are normally rapidly cleaved into smaller protein units by the metalloprotease enzyme ADAMTS 13: A Disintegrin-like And Metalloprotease with ThromboSpondin type 1 repeats [6]. Impairment of ADAMTS 13 activity can be due to its hereditary deficiency. However, in the majority of cases, it is related to acquired auto-antibodies that specifically inhibit ADAMTS 13 function, with subsequent excessive accumulation of the ULVWF and the onset of TTP-HUS [6]. Hereby, we report a rare case of a patient who suffered from TTP as a complication of hepatitis C virus infection. 2. Case presentation A 32 years old woman was first presented to the Rheumatology Department, Cairo University Hospitals, Egypt, in December 2000 for a gradual onset and progressive course of burning pain sensation affecting her hands and feet and a subsequent blackish discoloration of some of her finger tips. On examination, she was mildly hypertensive (140/90 mm Hg)
Table 1
Routine laboratory parameters.
Item
Result
HGB (g/dl) WBC (cell/mm3) Staf:Seg Lymphocytes% Platelets (/mm3) ALT (U/L) AST (U/L) S. albumin (g/dl) S. creatinine (mg/dl)
12.3 13.1 1:75 20 327.000 39 38 4.3 0.5
Urine analysis Pus cells /HPF RBC /HPF Proteins Casts Cholesterol (mg/dl) Triglycerides (mg/dl) HDL (mg/dl) LDL (mg/dl) Coagulation profile PT (m second) PC (%) a-PTT (ms) INR
2 0 Nil 0 178 120 61 137 14 97 30 1
and gangrene was seen related to the distal phalanx of her right index, ring and little fingers as well as the distal phalanx of her left index, middle and ring fingers with intact peripheral pulsations. Her complete blood count was normal apart from mild leucocytosis. Her ESR was mildly elevated (40 mm/h), but other lab tests including complete liver biochemical profile, renal profile, coagulation profile and urine analysis were within normal findings as shown in Table 1. ANA was borderline (1/40), homogenous pattern, ANCA, anti-dsDNA, rheumatoid factor, cryoglobulins and anticardiolipin antibodies (IgG and IgM) were negative and lupus anticoagulant had normal values. Arterial duplex was performed on both upper limbs and revealed normal parameters. Abdomino-pelvic ultrasonography showed normal liver and kidneys. The patient was diagnosed as undifferentiated vasculitis and she was given three grams of methyl prednisolone on three successive days, followed by 50 mg of oral prednisolone/day. Intravenous cyclophosphamide pulse (750 mg), started at the fourth day, and then monthly for a total of 6 months. The steroid dose was gradually tapered to a maintenance dose of 10 mg/day. In addition, low dose aspirin and verapamil 40 mg/day were given with marked improvement of her condition. Two years later and during her routine follow up, her liver enzymes were elevated (less than double fold). Serological markers were positive for hepatitis C virus and the qualitative PCR test confirmed the diagnosis. Liver biopsy was performed and revealed mild hepatitis C related necroinflammation with no evidence of fibrosis. Decision for Interferon therapy was not recommended at this stage and the patient remained stable and asymptomatic for the following 7 years on daily maintenance therapy of 10 mg oral prednisolone and liver supportive drugs. In January 2009, during her routine follow up, the patient’s lab tests showed further increase of liver enzymes. A second, liver biopsy revealed progressive increase of the necroinflammatory and fibrotic state of the liver compared to the previous one (grade 5/18 and stage of fibrosis 3/6 by modified Knodell’s score) [7] as shown in (Table 2). Subsequently, we decided to start interferon therapy and pretreatment quantitative PCR was 131339 copies/ml. She received weekly pegylated Interferon alpha2A combined with daily ribavirin 1000 mg/day. However, treatment stopped at 12 weeks due to the bad response to therapy and failure of her quantitative PCR to decline to satisfactory level. The patient was hospitalized in May 2010 for an acute onset of uncontrolled hypertension and rapidly rising serum cre-
Table 2
Liver biopsy according to modified knodell’s score.
Item
Score
Result
Portal Inflammation Periportal Inflammation Lytic parenchymal Foci Confluent necrosis Degree of steatosis Granulomas Dysplastic changes Malignant Changes Final Score: Necroinflammatory Final score: stage of fibrosis
(0–4) (0–4) (0–4) (0–6) (0–100%) +ve or ve +ve or ve +ve or ve (0–18) (0–6)
2 1 2 0 10% ve –ve –ve 5 3
Thrombotic thrombocytopenic purpura associated with chronic HCV infection atinine. On admission, her blood pressure was 180/110 mm Hg and she had bilateral lower limb edema. Her creatinine rose from 1.1 to 8.1 mg/dl within few days. Her hemoglobin level was 11.9 gm/dl and platelet count 185 · 103/mm3, with consumed C3 (C3 = 0.7 g/L with reference normal value 0.9–1.8 g/L) and normal C4. Her ESR was 25 at first hour. We proceeded to high resolution CT chest that unmasked the presence of mild bilateral pleural and pericardial effusion, left basal focal areas of small infarctions, mild bronchiectasis and chronic pericarditis. Echocardiography revealed mild mitral and tricuspid regurgitation, dilated left atrium, mild pericardial effusion and normal pulmonary artery pressure. Abdominal ultrasonography documented the presence of mild hepatomegaly, moderate ascites and grade II nephropathy. To complete her assessment, renal biopsy was done. It showed thrombi within the vessels, hydropic degeneration of the tubules, focal glomerular atrophy with hyaline cast formation and edematous interstitium as well as diffuse cellular infiltrates (mainly lymphocytes). Renal biopsy confirmed the diagnosis thrombotic microangiopathy (TMA) (Figs. 1 and 2). Aiming to save the life of the patient, hemodialysis started and the patient received 3 g of methyl prednisolone on three successive days followed by one pulse of cyclophosphamide (500 mg) on the 4th day. Few days, later her hemoglobin dropped to 5.9 g/dl. Abdomino-pelvic ultrasonography showed a large perinephric hematoma related to the site of biopsy around the left kidney and extending to pelvis. CT abdomen confirmed the diagnosis (Fig. 3) and for this problem surgical embolization was done. In spite of this regimen, marked deterioration of the general condition was progressive. Her laboratory tests showed a rapid progressive decline of platelet count (from 150 · 103/mm3 to 16 · 103/mm3), marked leucopenia (1000/mm3) and reticulocytic count up to 15.7%. A peripheral blood film showed large number of schistocytes. Coomb’s test was negative while D-Dimer and FDPs were weakly positive. Microscopic analysis of urine showed hematuria (RBC > 100/HPF), pyuria (WBC > 75/HPF), proteinuria (+++) as well as hyaline and granular casts. Plasma exchange (plasmapheresis) was initiated, with initial good response. Serum creatinine declined to 2 mg/dl and platelet
109
Figure 2 Renal biopsy stained with H&E. The red arrow points to obsolescent part of a glomerulus. The blue arrow points to hydropic degeneration of the tubules with evidence of tubulitis. The black arrow points to edematous interstitium with diffuse mild infiltrate mainly (lymphocytes). The yellow arrow points to the subintimal mucoid deposits and marked thickening of the blood vessel wall. The green arrow points to the hyaline cast formation.
Figure 3 CT abdomen. The yellow arrows point to the normal kidney. The red arrow points to the large perinephric hematoma.
count rose to 190 · 103/mm3. G-CSF was given to the patient with subsequent increases of the TLC to 7400/mm3. Ten days later; the patient started to develop high grade fever (40 C), septic work up failed to find an underlying etiology and broad spectrum antibiotics were given. HIV antibodies were also negative. Moreover, the patient developed an attack of hematemesis, bleeding per rectum; gastroscopy revealed a superficial gastric ulcer and another deep active duodenal ulcer. Hemoglobin dropped again to 4 g/dl, repeated blood transfusion and intravenous proton pump inhibitors were infused. Due to worse general condition of the patient, plasmapheresis was paused, and repeated plasma infusion was used. We planned to give B-cell depletion therapy (Rituximab) after improvement of the general condition, but unfortunately her general condition progressively deteriorated and eventually the patient passed away. Figure 1 Renal biopsy stained with mason trichrome stain. The red arrow points to a thrombus within a vessel, the green arrow points to a hyaline cast. The blue arrow points to hydropic degeneration of the tubules with evidence of tubulitis. The black arrow points to edematous interstitium with diffuse mild infiltrate mainly (lymphocytes).
3. Discussion In the current study, the diagnosis of TTP was essentially based on the presence of: hemolytic anemia with excess schis-
110 tocytes and negative Coomb’s test in peripheral blood, fever up to 40 C with a negative septic workup, thrombocytopenia, and renal biopsy that revealed thrombi within the blood vessels. Neurologic manifestations were not encountered in our patient. Many previous studies showed that fever, neurologic and renal involvement were not consistent in all patients, especially during the early stage of the disease. The association of microangiopathic hemolytic anemia and unexplained thrombocytopenia was sufficient to suspect TTP and to initiate plasma therapy [5]. The clinical setting and association at presentation of 206 patients with suspected TTP-HUS collected between 1996 and 2004, from the Oklahoma TTP-HUS Registry revealed that most cases were idiopathic (37%), followed by drug-associated (13%), autoimmune disease (13%), infection (9%), pregnancy/postpartum (7%), bloody diarrhea prodrome (%6), and hematopoietic cell transplantation (4%) [8]. Although most cases of post-infectious TTP-HUS occur after an episode of bloody diarrhea caused by Shiga toxin-producing Escherichia coli 0157:H7 [9], rare cases have developed this disorder after a pneumococcal infection [10]. As regard viral infections, TTP-HUS has been reported with HIV infection and attributed to direct endothelial injury [11]. A HUSlike syndrome has been reported with the use of high dose valacyclovir prophylaxis (8 g/day) against cytomegalovirus infection in patients with advanced HIV infection [12]. In the setting of HCV infection, TTP-HUS was rarely reported, usually in relation to pegylated interferon (PEG-IFN) therapy; one case developed suddenly at 16th week during the PEGIFN course, while the other one has been reported one month after the end of a long term PEG-IFN course [13,14]. One patient with HCV-related liver cirrhosis was complicated by fetal TTP following the development of an ADAMTS13 inhibitor [15]. In addition, a simultaneous refractory TTP and membranoproliferative glomerulonephritis associated with HCV infection and successfully treated with rituximab have been also reported, without any apparent relation to IFN therapy [16]. 4. Conclusion Our case is unique, there was no evidence of cirrhosis and the duration between the end of the short course PEG-IFN therapy and onset of TTP-HUS was more than one year; that raises the possibility of direct implication of chronic HCV in the pathogenesis of TTP-HUS. HCV infection itself has been associated with multiple autoimmune phenomena. It is possible that HCV infection can alter the immune system response and induce anti-ADAMTS13 antibody formation leading to an episode of TTP. In addition, some patients may have a preexisting deficiency or defect of ADAMTS13 putting them at even higher risk for development of this complication. In conclusion, we here report a case TTP associated with chronic HCV infection, that seems to be unrelated to interferon therapy; TTP should be considered among the extrahepatic manifestations of chronic HCV infection.
A.E. Garf et al. Consent Written informed consent was obtained from the patient’s relative for publication of this Case report and any accompanying images.
References [1] Moschowitz E. An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries. Arch Intern Med 1925;36:89–93. [2] Amorosi E, Ultmann J. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine 1966;45:139–59. [3] Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 2003;14(4):1072–81. [4] Veyradier A, Obert B, Houllier A, et al. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood 2001;98(6):1765–72. [5] George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006;354(18):1927–35. [6] Fujikawa K, Suzuki H, McMullen B, et al. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood 2001;98(6):1662–6. [7] Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696–9. [8] Terrell DR, Williams LA, Vesely SK, et al. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J Thromb Haemost 2005;3(7):1432–6. [9] Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 2005;365(9464):1073–86. [10] Begue R, Dennehy PH, Peter G. Hemolytic uremic syndrome associated with Streptococcus pneumoniae. N Engl J Med 1991;325(2):133–4. [11] Alpers CE. Light at the end of the TUNEL: HIV-associated thrombotic microangiopathy. Kidney Int 2003;63(1):385–96. [12] Bell WR, Chulay JD, Feinberg JE. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine (Baltimore) 1997;76:369–80. [13] Lyoda K, Kato M, Nakagawa T, et al. Thrombotic thrombocytopenic purpura developed suddenly during interferon treatment for chronic hepatitis C. J Gastroenterol 1998;33(4):588–92. [14] Kitano K, Gibo Y, Kamijo A, et al. Thrombotic thrombocytopenic purpura associated with pegylated-interferon alpha-2a by an ADAMTS13 inhibitor in a patient with chronic hepatitis C. Haematologica 2006;91(8 Suppl):ECR34. [15] Yagita M, Uemura M, Nakamura T, Matsumoto M, Fujimura Y, et al. Development of ADAMTS13 inhibitor in a patient with hepatitis C virus-related liver cirrhosis causes thrombotic thrombocytopenic purpura. J Hepatol 2005;42:420–1. [16] Mak S, Lo K, Lo M, et al. Refractory thrombotic thrombocytopenic purpura and membranoproliferative glomerulonephritis successfully treated with rituximab: a case associated with hepatitis C virus infection. Hong Kong Med 2009;J 15:201–8.
Egyptian Society for Joint Diseases and Arthritis
The Egyptian Rheumatologist www.rheumatology.eg.net www.sciencedirect.com
CASE REPORTS
Thrombotic thrombocytopenic purpura associated with chronic HCV infection Ayman El Garf a b
a,*
, Wafaa Gaber a, Tamer Elbaz b, Kamal El Garf
a
Department of Rheumatology and Rehabilitation, Faculty of Medicine, Cairo University, Cairo, Egypt Department of Hepatogastroenterology and Endemic Medicine, Cairo University, Cairo, Egypt
Received 17 May 2012; accepted 17 May 2012 Available online 27 June 2012
KEYWORDS Thrombotic thrombocytopenic purpura; Vasculitis; HCV; Interferon
Abstract Background: Thrombotic thrombocytopenic purpura is a potentially lethal microvascular thrombotic disorder. Case presentation: In this study, we report a 32 years old woman who suffered from undifferentiated vasculitis with marked improvement on steroids and cyclophosphamide. Two years later, hepatitis C virus infection was discovered. Decision for interferon therapy was not recommended at this stage and the patient remained stable for the following 7 years. In January 2009, pegylated interferon and ribavirin were started due to worsening of her hepatitis; the treatment was stopped after 12 weeks due to the absence of any virologic response. Fourteen months later, she developed severe uncontrolled thrombotic thrombocytopenic purpura that led eventually to her death. Conclusion: We report this rare case of thrombotic thrombocytopenic purpura that may directly be related to chronic HCV infection rather than to interferon therapy. 2012 Egyptian Society for Joint Diseases and Arthritis. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction Thrombotic thrombocytopenic purpura (TTP) was first described in 1925 as a new disease characterized by unique path* Corresponding author. Address: 45 Dokki Street, Dokki Square, Giza 12311, Cairo, Egypt. Tel.: +20 101770866, 237499101; fax: +20 237616629. E-mail addresses: [email protected], [email protected] (A.E. Garf). Peer review under responsibility of Egyptian Society for Joint Diseases and Arthritis.
Production and hosting by Elsevier
ological findings of hyaline thrombi in many organs [1]. A review of 271 published cases up to 1964 defined the classic pentad of the clinical features of this disease [2]: thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms and signs, renal function abnormalities and fever. Although some studies distinguish between TTP and hemolytic uremic syndrome (HUS), yet the presenting features are similar in most of the patients: thrombocytopenia and microangiopathic hemolytic anemia without another apparent cause and, in many patients, neurologic and/or renal abnormalities [3]. When neurologic manifestations are dominant and acute renal failure is minimal or absent, some consider TTP to be present. On the other hand, when acute renal failure is dominant and neurologic abnormalities are minimal or absent, the disease is considered by some to represent HUS [4].
1110-1164 2012 Egyptian Society for Joint Diseases and Arthritis. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejr.2012.05.001
108
A.E. Garf et al.
The diagnosis of TTP-HUS was supported by the pathologic demonstration of hyaline thrombi in renal biopsy. The disease was usually looked as a fatal disease, however with the routine use of therapeutic plasma exchange, TTP-HUS has changed from a fatal to a curable illness in many cases. The availability of curative treatment necessitates rapid diagnosis and less adherence to the diagnostic criteria. At the present time, only the presence of unexplained thrombocytopenia and microangiopathic hemolytic anemia is required to establish the diagnosis of TTP-HUS and initiate treatment [5]. The pathogenesis of the disease is attributed to the accumulation of the unusually large von Willebrand factor (ULVWF) multimers that lead to platelet clumping and subsequent microvascular thrombosis. The ULVWF multimers primarily synthesized by vascular endothelial cells, are normally rapidly cleaved into smaller protein units by the metalloprotease enzyme ADAMTS 13: A Disintegrin-like And Metalloprotease with ThromboSpondin type 1 repeats [6]. Impairment of ADAMTS 13 activity can be due to its hereditary deficiency. However, in the majority of cases, it is related to acquired auto-antibodies that specifically inhibit ADAMTS 13 function, with subsequent excessive accumulation of the ULVWF and the onset of TTP-HUS [6]. Hereby, we report a rare case of a patient who suffered from TTP as a complication of hepatitis C virus infection. 2. Case presentation A 32 years old woman was first presented to the Rheumatology Department, Cairo University Hospitals, Egypt, in December 2000 for a gradual onset and progressive course of burning pain sensation affecting her hands and feet and a subsequent blackish discoloration of some of her finger tips. On examination, she was mildly hypertensive (140/90 mm Hg)
Table 1
Routine laboratory parameters.
Item
Result
HGB (g/dl) WBC (cell/mm3) Staf:Seg Lymphocytes% Platelets (/mm3) ALT (U/L) AST (U/L) S. albumin (g/dl) S. creatinine (mg/dl)
12.3 13.1 1:75 20 327.000 39 38 4.3 0.5
Urine analysis Pus cells /HPF RBC /HPF Proteins Casts Cholesterol (mg/dl) Triglycerides (mg/dl) HDL (mg/dl) LDL (mg/dl) Coagulation profile PT (m second) PC (%) a-PTT (ms) INR
2 0 Nil 0 178 120 61 137 14 97 30 1
and gangrene was seen related to the distal phalanx of her right index, ring and little fingers as well as the distal phalanx of her left index, middle and ring fingers with intact peripheral pulsations. Her complete blood count was normal apart from mild leucocytosis. Her ESR was mildly elevated (40 mm/h), but other lab tests including complete liver biochemical profile, renal profile, coagulation profile and urine analysis were within normal findings as shown in Table 1. ANA was borderline (1/40), homogenous pattern, ANCA, anti-dsDNA, rheumatoid factor, cryoglobulins and anticardiolipin antibodies (IgG and IgM) were negative and lupus anticoagulant had normal values. Arterial duplex was performed on both upper limbs and revealed normal parameters. Abdomino-pelvic ultrasonography showed normal liver and kidneys. The patient was diagnosed as undifferentiated vasculitis and she was given three grams of methyl prednisolone on three successive days, followed by 50 mg of oral prednisolone/day. Intravenous cyclophosphamide pulse (750 mg), started at the fourth day, and then monthly for a total of 6 months. The steroid dose was gradually tapered to a maintenance dose of 10 mg/day. In addition, low dose aspirin and verapamil 40 mg/day were given with marked improvement of her condition. Two years later and during her routine follow up, her liver enzymes were elevated (less than double fold). Serological markers were positive for hepatitis C virus and the qualitative PCR test confirmed the diagnosis. Liver biopsy was performed and revealed mild hepatitis C related necroinflammation with no evidence of fibrosis. Decision for Interferon therapy was not recommended at this stage and the patient remained stable and asymptomatic for the following 7 years on daily maintenance therapy of 10 mg oral prednisolone and liver supportive drugs. In January 2009, during her routine follow up, the patient’s lab tests showed further increase of liver enzymes. A second, liver biopsy revealed progressive increase of the necroinflammatory and fibrotic state of the liver compared to the previous one (grade 5/18 and stage of fibrosis 3/6 by modified Knodell’s score) [7] as shown in (Table 2). Subsequently, we decided to start interferon therapy and pretreatment quantitative PCR was 131339 copies/ml. She received weekly pegylated Interferon alpha2A combined with daily ribavirin 1000 mg/day. However, treatment stopped at 12 weeks due to the bad response to therapy and failure of her quantitative PCR to decline to satisfactory level. The patient was hospitalized in May 2010 for an acute onset of uncontrolled hypertension and rapidly rising serum cre-
Table 2
Liver biopsy according to modified knodell’s score.
Item
Score
Result
Portal Inflammation Periportal Inflammation Lytic parenchymal Foci Confluent necrosis Degree of steatosis Granulomas Dysplastic changes Malignant Changes Final Score: Necroinflammatory Final score: stage of fibrosis
(0–4) (0–4) (0–4) (0–6) (0–100%) +ve or ve +ve or ve +ve or ve (0–18) (0–6)
2 1 2 0 10% ve –ve –ve 5 3
Thrombotic thrombocytopenic purpura associated with chronic HCV infection atinine. On admission, her blood pressure was 180/110 mm Hg and she had bilateral lower limb edema. Her creatinine rose from 1.1 to 8.1 mg/dl within few days. Her hemoglobin level was 11.9 gm/dl and platelet count 185 · 103/mm3, with consumed C3 (C3 = 0.7 g/L with reference normal value 0.9–1.8 g/L) and normal C4. Her ESR was 25 at first hour. We proceeded to high resolution CT chest that unmasked the presence of mild bilateral pleural and pericardial effusion, left basal focal areas of small infarctions, mild bronchiectasis and chronic pericarditis. Echocardiography revealed mild mitral and tricuspid regurgitation, dilated left atrium, mild pericardial effusion and normal pulmonary artery pressure. Abdominal ultrasonography documented the presence of mild hepatomegaly, moderate ascites and grade II nephropathy. To complete her assessment, renal biopsy was done. It showed thrombi within the vessels, hydropic degeneration of the tubules, focal glomerular atrophy with hyaline cast formation and edematous interstitium as well as diffuse cellular infiltrates (mainly lymphocytes). Renal biopsy confirmed the diagnosis thrombotic microangiopathy (TMA) (Figs. 1 and 2). Aiming to save the life of the patient, hemodialysis started and the patient received 3 g of methyl prednisolone on three successive days followed by one pulse of cyclophosphamide (500 mg) on the 4th day. Few days, later her hemoglobin dropped to 5.9 g/dl. Abdomino-pelvic ultrasonography showed a large perinephric hematoma related to the site of biopsy around the left kidney and extending to pelvis. CT abdomen confirmed the diagnosis (Fig. 3) and for this problem surgical embolization was done. In spite of this regimen, marked deterioration of the general condition was progressive. Her laboratory tests showed a rapid progressive decline of platelet count (from 150 · 103/mm3 to 16 · 103/mm3), marked leucopenia (1000/mm3) and reticulocytic count up to 15.7%. A peripheral blood film showed large number of schistocytes. Coomb’s test was negative while D-Dimer and FDPs were weakly positive. Microscopic analysis of urine showed hematuria (RBC > 100/HPF), pyuria (WBC > 75/HPF), proteinuria (+++) as well as hyaline and granular casts. Plasma exchange (plasmapheresis) was initiated, with initial good response. Serum creatinine declined to 2 mg/dl and platelet
109
Figure 2 Renal biopsy stained with H&E. The red arrow points to obsolescent part of a glomerulus. The blue arrow points to hydropic degeneration of the tubules with evidence of tubulitis. The black arrow points to edematous interstitium with diffuse mild infiltrate mainly (lymphocytes). The yellow arrow points to the subintimal mucoid deposits and marked thickening of the blood vessel wall. The green arrow points to the hyaline cast formation.
Figure 3 CT abdomen. The yellow arrows point to the normal kidney. The red arrow points to the large perinephric hematoma.
count rose to 190 · 103/mm3. G-CSF was given to the patient with subsequent increases of the TLC to 7400/mm3. Ten days later; the patient started to develop high grade fever (40 C), septic work up failed to find an underlying etiology and broad spectrum antibiotics were given. HIV antibodies were also negative. Moreover, the patient developed an attack of hematemesis, bleeding per rectum; gastroscopy revealed a superficial gastric ulcer and another deep active duodenal ulcer. Hemoglobin dropped again to 4 g/dl, repeated blood transfusion and intravenous proton pump inhibitors were infused. Due to worse general condition of the patient, plasmapheresis was paused, and repeated plasma infusion was used. We planned to give B-cell depletion therapy (Rituximab) after improvement of the general condition, but unfortunately her general condition progressively deteriorated and eventually the patient passed away. Figure 1 Renal biopsy stained with mason trichrome stain. The red arrow points to a thrombus within a vessel, the green arrow points to a hyaline cast. The blue arrow points to hydropic degeneration of the tubules with evidence of tubulitis. The black arrow points to edematous interstitium with diffuse mild infiltrate mainly (lymphocytes).
3. Discussion In the current study, the diagnosis of TTP was essentially based on the presence of: hemolytic anemia with excess schis-
110 tocytes and negative Coomb’s test in peripheral blood, fever up to 40 C with a negative septic workup, thrombocytopenia, and renal biopsy that revealed thrombi within the blood vessels. Neurologic manifestations were not encountered in our patient. Many previous studies showed that fever, neurologic and renal involvement were not consistent in all patients, especially during the early stage of the disease. The association of microangiopathic hemolytic anemia and unexplained thrombocytopenia was sufficient to suspect TTP and to initiate plasma therapy [5]. The clinical setting and association at presentation of 206 patients with suspected TTP-HUS collected between 1996 and 2004, from the Oklahoma TTP-HUS Registry revealed that most cases were idiopathic (37%), followed by drug-associated (13%), autoimmune disease (13%), infection (9%), pregnancy/postpartum (7%), bloody diarrhea prodrome (%6), and hematopoietic cell transplantation (4%) [8]. Although most cases of post-infectious TTP-HUS occur after an episode of bloody diarrhea caused by Shiga toxin-producing Escherichia coli 0157:H7 [9], rare cases have developed this disorder after a pneumococcal infection [10]. As regard viral infections, TTP-HUS has been reported with HIV infection and attributed to direct endothelial injury [11]. A HUSlike syndrome has been reported with the use of high dose valacyclovir prophylaxis (8 g/day) against cytomegalovirus infection in patients with advanced HIV infection [12]. In the setting of HCV infection, TTP-HUS was rarely reported, usually in relation to pegylated interferon (PEG-IFN) therapy; one case developed suddenly at 16th week during the PEGIFN course, while the other one has been reported one month after the end of a long term PEG-IFN course [13,14]. One patient with HCV-related liver cirrhosis was complicated by fetal TTP following the development of an ADAMTS13 inhibitor [15]. In addition, a simultaneous refractory TTP and membranoproliferative glomerulonephritis associated with HCV infection and successfully treated with rituximab have been also reported, without any apparent relation to IFN therapy [16]. 4. Conclusion Our case is unique, there was no evidence of cirrhosis and the duration between the end of the short course PEG-IFN therapy and onset of TTP-HUS was more than one year; that raises the possibility of direct implication of chronic HCV in the pathogenesis of TTP-HUS. HCV infection itself has been associated with multiple autoimmune phenomena. It is possible that HCV infection can alter the immune system response and induce anti-ADAMTS13 antibody formation leading to an episode of TTP. In addition, some patients may have a preexisting deficiency or defect of ADAMTS13 putting them at even higher risk for development of this complication. In conclusion, we here report a case TTP associated with chronic HCV infection, that seems to be unrelated to interferon therapy; TTP should be considered among the extrahepatic manifestations of chronic HCV infection.
A.E. Garf et al. Consent Written informed consent was obtained from the patient’s relative for publication of this Case report and any accompanying images.
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