Erythrocyte Pyrimidine 5’-Nucleotidase Deficiency With Portal Vein Thrombosis:A Case Report And Review Of The Literature And Clinical Analysis Of 357 Cases Of Pancytopenia In The Department Of Hematology,Qilu Hospital

PART I Erythrocyte pyrimidine 5’-nucleotidase deficiency with portal vein thrombosis:a case report and review of the literatureBackground and Objective:Erythrocyte pyrimidine 5’-nucleotidase(P5’N)deficiency is thought to be the third most common red cell enzymopathy,after glucose-6-phosphate dehydrogenase and pyruvate kinase deficiencies.Pyrimidine 5’-nucleotidase catalyzes the dephosphorylation of pyrimidine nucleotides,preventing an accumulation of excess nucleotides in the mature red cells.Defects in nucleotide metabolism may result in a shortened erythrocyte lifespan and consequent hemolytic anemia.P5’N deficiency is transmitted as an autosomal recessive trait,and it can also be acquired as a result of lead poisoning,β-thalassemia and so on.The clinical manifestation of congenital P5’N deficiency is moderate,and there are a lot of undiscovered cases.The epidemiology of P5’N deficiency is unknown yet.We analyze the clinical features and differential diagnose of P5’N deficiency in order to facilitate the early diagnose of this disease.Materials and methods:We reported a newly diagnosed case of P5’N deficiency and performed a search on Pubmed and CNKI using the following terms ’pyrimidine 5’-nucleotidase deficiency’,’ Erythrocyte Enzymopathies ’,’ Hemolysis anemia’.We reviewed dozens of related literatures to summarize the clinical features and known gene mutation of P5’N deficiency.Case report:A 26-year-old man was admitted to the hospital because of hepatosplenomegaly and thrombocytopenia for 20 years.The patient had frequent episodes of hematemesis and melena,and was diagnosed as ’portal hypertension’.Nothing abnormal was detected in liver biopsy.Work-up revealed an elevated prothrombin time(PT),reduced white-cell count and platelet count.The results of liver-function tests were nearly normal except elevated bilirubin,and tests for viral hepatitis,autoimmune hepatitis and rheumatic disease were all negative.Nothing abnormal was found in the bone marrow examination too.Kaiser-Fleischer ring was not presented,and ceruloplasmin and serum cuprum were normal.Abdomen ultrasound showed portal hypertension,portal vein thrombosis,splenomegaly and ascites.Portal vein ultrasound revealed the cavernous transformation of portal vein.CTA showed portal vein thrombosis and the cavernous transformation,tortuosity and varicosity of splenic vein,liver cirrhosis,splenomegaly,and ascites.Coagulation factor Ⅴ and Ⅶ,PC,and ATIII were all reduced,but the mutation examination of genes related to bleeding and coagulation showed no significance.Coombs test.Ham test and other hemolytic tests were all negative.Heinz body,HbA2,Hemoglobin electrophoresis were all negative,too.Surprisingly,the activity of β-glucosidase was reduced using dry blood spots analysis,but GBA gene mutation analysis was negative.Ultimately,analysis of erythrocyte enzymes revealed significant result that the activity of P5’N was positive.Literature review:We reviewed dozens of related literatures since 1974,less than 100 patients have been reported yet.The clinical and hematological features of P5’N deficiency are not distinctive,mild to moderate anemia and splenomegaly are common findings.The hallmark of this deficiency is the presence of marked basophilic stippling in the red cells.Hemolytic anemia due to P5’N deficiency has been related to mutations in the NT5C3 gene,which is located in chromosome 7 p15-p14.The P5’N-1 gene consists of 10 exons and is about 50kb long.About 26 different mutations of P5’N-1 gene have been so far described in 30 unrelated families.No specific therapy for P5’N deficiency is available,and the treatment of this disease is,therefore,based on supportive measures.Splenectomy does not arrest hemolysis and has been reported to be of clinical benefit only in rare cases.Conclusions:P5’N deficiency is a rare non-spherocytic hemolytic anemia,which is usually characterized by mild-to-moderate hemolytic anemia associated with the accumulation of high concentrations of pyrimidine nucleotides within the erythrocytes.About 26 different mutations of P5’N-1 gene have been so far described in 30 unrelated families.The treatment of this disease is based on supportive measures.The blood film gives a strong clue on the diagnosis when marked basophilic stippling is presented.The diagnosis ultimately depends upon the demonstration of high concentrations of pyrimidine nucleotides and a reduced P5’N-1 activity in red blood cells.Basophilic stippling occasionally occurring in other congenital or acquired conditions,such as β-thalassemia trait,some hemoglobin variants,sideroblastic anemia or lead poisoning.So we should consider the possibility of P5’N deficiency when making the diagnosis of chronic hemolytic anemia.PART Ⅱ Clincal analysis of 357 cases of pancytopenia in the department of hematology,Qilu HospitalObjective:Pancytopenia means simultaneous reduction of three tangible components in peripheral blood.The diagnosis of pancytopenia is crucial for PCP and has profound significance for the treatment and prognosis.In our research,we summarize clinical data of 357 pancytopenia cases in the Department of Hematology,Qilu Hospital and analyze etiology proportion and clinical characteristics of pancytopenia,to provide diagnosis strategies for physicians.Materials and methods:The date of 357 patients with newly diagnosed PCP in the Department of Hematology.Qilu Hospital between January 2015 and January 2017 are reviewed.The patients who had at least twice tested blood routine:Hb<100g/L,WBC<4.0×109/L,PLT<100×109/L,and without special treatment such as radiotherapy and chemotherapy would be diagnosed as PCP.And we summarize the clinical characteristics of PCP by retrospective analysis.Results:1.In our research,the etiology of pancytopenia in 357 patients as follows:there are 286(80.11%)cases of hematologic diseases,and 17(4.76%)cases of non-hematologic diseases and 54(15.13%)cases of unknown cause,(1)The etiological proportion of non-hematologic diseasesAmong 17 cases of non-hematologic diseases which cause pancytopenia,there are 5(1.40%)cases of hypersplenism,3(0.84%)cases of rheumatic diseases,4(1.12%)cases of infection,2(0.56%)cases of drug,3(0.84%)cases of bone marrow metastasis.(2)The etiological proportion of hematologic diseasesAmong 286 cases of hematologic diseases which cause pancytopenia,there are 87(24.37%)cases of acute leukemia,59(16.53%)cases of aplastic anemia,44(12.33%)cases of myelodysplastic syndrome,9(2.52%)cases of megaloblastic anemia,17(4.76%)cases of hemophagocytic syndrome,12(3.36%)cases of lymphoma.8(2.24%)cases of paroxysmal nocturnal hemoglobinuria,3(0.84%)cases of autoimmune hemolytic anemia,10(2.80%)cases of immune-related pancytopenia,8(2.24%)cases of multiple myeloma,4(1.12%)cases of primary myelofibrosis,3(0.84%)cases of acute arrest of hemopoiesis,8(2.24%)cases of primary immune thrombocytopenia,5(1.40%)cases of idiopathic cytopenia of uncertain significance,3(0.84%)cases of hairy cell leukemia,3(0.84%)cases of macroglobulinemia,2(0.56%)cases of pure red cell aplasia,1(0.28%)cases of POEMS syndrome.(3)The comparison of constituent ratio of the etiology between adult group and older group.Among the patients who have been diagnosed clearly in this study,there are 163 cases in adult group and 85 cases in older group.And there is no difference between this two groups in the constituent ratio of the etiology of pancytopenia(X2= 1.20,P>0.05).2.The clinical manifestations of PCP mainly include anemia,bleeding and infection.Among 357 cases of PCP,there are 265(74.23%)cases having symptoms of anemia.Feebleness(59.66%),fever(34.17%),and dizziness(21.00%)are common reasons for consulting.3.The characteristics of the blood routine examination of PCPComparing the MCV,MCH,MCHC of the morphological classification of the anemia,AA and AL are nonnocytic anemia,MegA is macrocytic anemia,and MDS can be either the normocytic or the macrocytic anemia.The extent of the reduction of the blood cells varied among the different causes of PCP.The extremely severe reduction of white blood cells usually does not occur in the benign diseases of the hematopoietic system.Apart from the ITP.the extremely severe reduction of platelets usually does not occur in the benign diseases of the hematopoietic system.In our research,the collected cases do not have the extremely severe anemia except several cases of AL.The majority of AA patients has simultaneous reduction of three tangible components in peripheral blood to similar degree,while the degree of the reduction of blood cells in diseases such as MDS and PNH is usually varied.4.The characteristics of the bone marrow examination of PCPThe bone marrow of the non-hematologic diseases usually have no specific manifestation except bone marrow metastasis,so we need history,clinical manifestation and relative examinations to make exact diagnosis.Meanwhile,the bone marrow examination of the benign diseases of hematopoietic system is not enough for the diagnosis.In general,the bone marrow of the refractory and malignant diseases has specific manifestation,such as the blast cells in bone marrow of AL.The biopsy of bone marrow of the patients who were considered suffering MDS or PMF is necessary and significant for the diagnosis.Conclusion:1.The etiology of pancytopenia are complex.In our research,we summarize 23 kinds of diseases which can cause pancytopenia.The causes of pancytopenia can be roughly divided for four categories:benign diseases of hematopoietic system;malignant diseases of hematopoietic system;refractory diseases of hematopoietic system;Non-hematopoietic system diseases.2.In our research,hematologic diseases are primary cause,and account for 80.11%of the PCP cases.Among these hematologic diseases,acute leukemia(24.37%),aplastic anemia(16.53%)and myelodysplastic syndrome(12.33%)are most common causes.3.The clinical manifestations of PCP,besides the symptoms of the primary diseases,mainly include anemia,bleeding and infection.In our research,feebleness,fever,and dizziness are common reasons for consulting.4.The extent of the reduction of blood cells and the morphological classification of the anemia in PCP patients provide the proofs and clues.Bone marrow puncture is the important examination methods in the diagnosis process.The smear and biopsy of bone marrow should be analyzed at the same time in some situations and bone marrow puncture for several times and in several positions could be necessary to figure out the correct causes.