The clinical presentation markedly varies from patient to patient, but an early onset carries a more severe phenotype in most cases. Severe hyperbilirubinemia and hemolytic anemia that necessitate phototherapy and/or exchange transfusions for a prolonged period of time are main features of neonatal forms [1] [6], which can appear hours after birth [4]. In fact, early onset of kernicterus or hydrops fetalis can be fatal without appropriate measures [1] [2] [4], while liver disease has been reported as a complication in some patients [6]. On the other hand, individuals can present with mild or moderate anemia in infancy that stabilizes over time, and the diagnosis is often delayed until adulthood, when acute infections or pregnancy exacerbate the condition and cause more severe symptoms [1]. Pregnant women who are unaware of the diagnosis can suffer from preeclampsia, multi-organ dysfuncton due to iron overload, and repeated unexplained pregnancy terminations, in addition to severe anemia [4].

• Splenomegaly

  She is doing well with mild splenomegaly. [ncbi.nlm.nih.gov]

  Symptoms of PKD include: Low count of healthy red blood cells ( anemia ) Swelling of the spleen ( splenomegaly ) Yellow color of the skin, mucous membranes, or white part of the eyes ( jaundice ) Neurologic condition, called kernicterus, that affects [nlm.nih.gov]

• Anemia

  */genetics Anemia, Dyserythropoietic, Congenital*/pathology Anemia, Hemolytic, Congenital Nonspherocytic*/complications Anemia, Hemolytic, Congenital Nonspherocytic*/genetics Anemia, Hemolytic, Congenital Nonspherocytic*/pathology Female Humans Infant [ncbi.nlm.nih.gov]

  […] congenital nonspherocytic hemolytic anemia that has material basis in homozygous or compound heterozygous mutation in the PKLR gene on chromosome 1q22 pyruvate kinase deficiency of red cells hemolytic anemia due to red cell pyruvate kinase deficiency [wikidata.org]

  Specifically, pyruvate kinase deficiency is a common cause of a type of inherited hemolytic anemia called hereditary nonspherocytic hemolytic anemia. [ghr.nlm.nih.gov]

  Newborns may present with prolonged jaundice and anemia. Older children may be pale (due to anemia) and have intermittent episodes of jaundice. [rarediseases.info.nih.gov]

  Abstract Abstract Pyruvate kinase (PK) deficiency (MIM 266200) is the most common enzyme deficiency resulting in hereditary hemolytic anemia. [ommbid.mhmedical.com]

• Splenectomy

  We report a case of recurrent thromboembolic disease and chronic pulmonary hypertension in an adult patient with pyruvate kinase deficiency who underwent splenectomy as a child. [ncbi.nlm.nih.gov]

  Removing the spleen ( splenectomy ) may help reduce the destruction of red blood cells. But, this does not help in all cases. In newborns with a dangerous level of jaundice, the provider may recommend an exchange transfusion. [nlm.nih.gov]

• Fatigue

  A shortage of red blood cells to carry oxygen throughout the body leads to fatigue, pallor, and shortness of breath. [ghr.nlm.nih.gov]

  (pedsFACIT-F), Patient Reported Outcomes Measurement Information System Fatigue (PROMIS Fatigue) changes over time in hemoglobin and markers of hemolysis [ Time Frame: enrollment, annually, up to 2 years ] prevalence and severity of iron overload [ Time [clinicaltrials.gov]

  PKD include: Low count of healthy red blood cells ( anemia ) Swelling of the spleen ( splenomegaly ) Yellow color of the skin, mucous membranes, or white part of the eyes ( jaundice ) Neurologic condition, called kernicterus, that affects the brain Fatigue [nlm.nih.gov]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: January 30, 2019 [patientslikeme.com]

  SIGNS AND SYMPTOMS Fatigue Lethargy Jaundice  Pallor (Paleness of skin)  Dyspnea (Shortness of breath) Tachycardia (Rapid heart rate ). (Grace et al., 2015). 7. HAEMATOLOGICAL IMPLICATIONS Reticulocytosis. [slideshare.net]

• Pallor

  A shortage of red blood cells to carry oxygen throughout the body leads to fatigue, pallor, and shortness of breath. [ghr.nlm.nih.gov]

  […] healthy red blood cells ( anemia ) Swelling of the spleen ( splenomegaly ) Yellow color of the skin, mucous membranes, or white part of the eyes ( jaundice ) Neurologic condition, called kernicterus, that affects the brain Fatigue, lethargy Pale skin ( pallor [nlm.nih.gov]

  SIGNS AND SYMPTOMS Fatigue Lethargy Jaundice  Pallor (Paleness of skin)  Dyspnea (Shortness of breath) Tachycardia (Rapid heart rate ). (Grace et al., 2015). 7. HAEMATOLOGICAL IMPLICATIONS Reticulocytosis. [slideshare.net]

• Family History of Anemia

  A familial history of anemia may be obtamed in congenital hemolytic icterus. spheroidocytosis and inSplenomegaiy, creased fragility are characteristic. The toxic hemoglobinemias’4 must be considered. [kundoc.com]

• Dyspnea

  SIGNS AND SYMPTOMS Fatigue Lethargy Jaundice  Pallor (Paleness of skin)  Dyspnea (Shortness of breath) Tachycardia (Rapid heart rate ). (Grace et al., 2015). 7. HAEMATOLOGICAL IMPLICATIONS Reticulocytosis. [slideshare.net]

  Chronic hemolytic anemia can lead to unusually pale skin (pallor), yellowing of the eyes and skin (jaundice), extreme tiredness (fatigue), shortness of breath (dyspnea), and a rapid heart rate (tachycardia). [ghr.nlm.nih.gov]

  Subjectively the patient felt much stronger, had a return of libido and experienced no dyspnea. [kundoc.com]

  […] clinical spectrum of presentation of a Patent Ductus Arteriosus (PDA) in adult may range from no sign and symptom which is incidentally found on routine physical exam or Transthoracic Echocardiogram (TTE) for other purposes, to patients who present with dyspnea [thefreelibrary.com]

• Failure to Thrive

  We describe 6-month-old American girl with red cell pyruvate kinase (PK) deficiency, failure to thrive, and marked hypertriglyceridemia (=1500 mg/dL). The hyperlipidemia resolved with hypertransfusion therapy. [ncbi.nlm.nih.gov]

  […] to thrive ) Gallstones, usually in the teens and older People with severe anemia may need blood transfusions. [nlm.nih.gov]

  Children may have signs of anaemia, growth delay and failure to thrive. [patient.info]

• Tachycardia

  SIGNS AND SYMPTOMS Fatigue Lethargy Jaundice  Pallor (Paleness of skin)  Dyspnea (Shortness of breath) Tachycardia (Rapid heart rate ). (Grace et al., 2015). 7. HAEMATOLOGICAL IMPLICATIONS Reticulocytosis. [slideshare.net]

  Chronic hemolytic anemia can lead to unusually pale skin (pallor), yellowing of the eyes and skin (jaundice), extreme tiredness (fatigue), shortness of breath (dyspnea), and a rapid heart rate (tachycardia). [ghr.nlm.nih.gov]

  Among the symptoms of pyruvate kinase deficiency are: Mild to severe hemolytic Anemia Cholecystolithiasis Tachycardia Hemochromatosis Icteric sclera Splenomegaly Leg ulcers Jaundice Fatigue Shortness of breathThe level of 2,3-bisphosphoglycerate is elevated [en.wikipedia.org]

  On return to work he noticed weakness, easy fatigability and tachycardia on slight exertion. In August, 1947, he again had an upper respiratory infection accompanied by chills and fever. [kundoc.com]

• Jaundice

  She responded to conservative management, the jaundice clearing and the altered liver function showing a steady return to normal. Pyruvate kinase deficiency may cause pregnancy-associated jaundice. [ncbi.nlm.nih.gov]

  Newborns may present with prolonged jaundice and anemia. Older children may be pale (due to anemia) and have intermittent episodes of jaundice. [rarediseases.info.nih.gov]

  See your provider if: You have jaundice (this is a symptom of many severe illnesses). You have a family history of this disorder and are planning to have children. [nlm.nih.gov]

• Murphy's Sign

  sign positive • Extremities—Chronic leg ulcers Causes • Medical conditions, such as acute leukemia, preleukemia and refractory sideroblastic anemia, as well as complications from chemotherapy, can cause an acquired pyruvate kinase deficiency. [namrata.co]

  sign Chronic leg ulcers Cazzola M. [emedicine.medscape.com]

• Hydrops Fetalis

  The authors report a case of hydrops fetalis due to severe pyruvate kinase deficiency, the most unusual clinical manifestation of this disease. [ncbi.nlm.nih.gov]

• Frontal Bossing

  bossing • Jaundice • Abdomen—Splenomegaly mild to moderate, upper right quadrant tenderness, Murphy sign positive • Extremities—Chronic leg ulcers Causes • Medical conditions, such as acute leukemia, preleukemia and refractory sideroblastic anemia, as [namrata.co]

  Other physical effects of PKD can include smaller head size and the forehead appearing prominent and rounded (called frontal bossing). If a child with PKD has their spleen removed, their growth tends to improve. [medical-dictionary.thefreedictionary.com]

  The following are evident in pyruvate kinase deficiency: Mild to severe anemia Symmetrical growth delay Failure to thrive Cholecystolithiasis: Usually after the first decade of life but possibly in childhood Frontal bossing Icteric sclera Mild to moderate [emedicine.medscape.com]

• Irritability

  Fecal transplant is used to treat gut infections and is now being studied as a treatment for obesity, urinary tract infections, irritable bowel syndrome and more. [nytimes.com]

Observation of clinical signs and symptoms in early life must rise suspicion toward PKD as the underlying cause, but several steps in workup should be made in order to solidify the diagnosis. Firstly, a detailed patient history with an emphasis on the familial presence of the disease or similar symptoms is pivotal, but family history may not always be positive, which may present as a significant challenge for the physician to further pursue the diagnosis [1]. Secondly, a thorough laboratory workup consisting of a complete blood count (CBC), bilirubin levels, Coomb's test and a peripheral blood smear to confirm non-spherocytic hemolytic anemia should be performed. Specifically, a normal mean corpuscular hemoglobin concentration (MCHC), increased red cell distribution width (RDW) and increased reticulocyte count (in addition to anemia) are highly suggestive of PKD, and these tests must be used to distinguish this disorder from hereditary spherocytosis and glucose-6-phosphate dehydrogenase deficiency [2]. To confirm PKD, either genetic testing that will reveal the site of the mutation, or quantitative evaluation of enzymatic activity, which is now more commonly performed due to its wide availability, are required [1] [4].

• Erythroblast

  In addition, bone marrow ultrastructural studies showed dyshemopoietic changes in all blood cell lines and especially in erythroblasts. [ncbi.nlm.nih.gov]

  Erythroblasts were elevated at 242/100 white blood cells. At 5 hours of life, lactate dehydrogenase reached 5411 U/L and conjugated bilirubin 57 µmol/L (45% of total bilirubin). The patient developed generalized edema over a few hours. [pediatrics.aappublications.org]

  In basophilic erythroblasts, both PK-R and PK-M2 are expressed. [dx.doi.org]

• Anisocytosis

  Peripheral blood smear showed polychromasia, anisocytosis, tear drop cells, fragmented eyrtrocytes, and target cells. [ncbi.nlm.nih.gov]

  Anisocytosis and polychromatophilia of moderate degree were noted on the stained smear. [kundoc.com]

• Macrocytic Anemia

  Kang, Microcytic, Normocytic, and Macrocytic Anemias, Non‐Neoplastic Hematopathology and Infections, (65-88), (2012). [dx.doi.org]

• Reticulocytes Increased

  Char10C mice also display a reduction in anemia phenotypes associated with the PklrG338D mutation including decreased splenomegaly, decreased circulating reticulocytes, increased density of mature erythrocytes, increased hematocrit, as well as decreased [ncbi.nlm.nih.gov]

• Heinz Bodies

  Heinz bodies and spherocytes are absent. Osmotic fragility testing may serve as a useful screen for PKD. Unlike hereditary spherocytosis, PKD autohemolysis does not correct with the addition of glucose. [clinicaladvisor.com]

Immediate supportive care is mandatory in neonates who develop severe and life-threatening forms of deficiency, mainly through phototherapy and/or repeated transfusions and iron chelation if overload is suspected [1] [8]. Folate supplementation is recommended in all patients, especially pregnant women, as its requirements are higher due to profound hemolysis. Splenectomy is a more concrete therapeutic measure that alleviates the need for blood transfusions and increases both hemoglobin and reticulocyte count [1] [8]. Some authors suggest that partial splenectomy may be even more beneficial, mainly because of the emergence of antibiotic-resistant pneumococcal strains that can cause fatal infection in splenectomized patients [1]. Long-term prophylaxis against Streptococcus pneumoniae is often recommended and daily administration of amoxicillin, cephalexin, or amoxicillin-clavulanic acid in infancy and childhood should be carried out, but pneumococcal and meningococcal vaccination is equally important for prevention of infections [9]. Hematopoietic stem cell transplantation (HSCT) has shown curative effects in a patient who received marrow from an HLA-identical PK-normal sibling [4] [8], which suggests that it might be used as a definite therapeutic method, but its efficacy remains to be solidified. Recent studies have elucidated the potential role of gene therapy, due to its potent efficacy in animal models, but its introduction in human medicine is yet to occur [10].

The severity of PKD does not directly influence patient outcomes, but it was shown that the onset of symptoms in neonatal period carries a higher risk for death, having in mind the fact that hyperbilirubinemia and hemolytic anemia can be severe enough to require rapid and frequent transfusions [1]. For this reason, an early diagnosis can be life-saving if recognized on time.

More than 200 mutations of the pyruvate kinase liver and red blood cell (PK-LR) gene, located on chromosome 1q21 [5], have been described in literature [2], and missense mutations seem to be most common [1] [5]. The cause of these mutations, however, remains unknown. PKD is transferred through an autosomal recessive mode of inheritance, and the clinical presentation develops either in homozygous (individuals in whom both copies of the PK-LR gene are mutated), or in compound heterozygotes (inheritance of one mutant PK gene from their father and a different PK mutation from their mother) [2].

Studies have estimated that PKD occurs in approximately 51 per 1 million Caucasians, or 1 in 10,000-20,000, according to different reports [1] [2]. A strong suspicion of underreporting exists, most likely due to undiagnosed PKD that causes intrauterine or early death, failed recognition or even misdiagnosis [1]. Various population groups have shown markedly higher rates of this condition, most prominent being the Amish community in Pennsylvania and Ohio in the United States and individuals of North European ancestry [1] [2] [6], suggesting that ethnicity and demographic factors (such as consanguineous marriages) influence its frequency [2]. Other risk factors have not been established, but the emotional stress, pregnancy and presence of acute infections have been established as symptom triggers in adulthood [1].

Pyruvate kinase (PK) is an enzyme responsible for conversion of phosphoenolpyruvate (PEP) to pyruvate, the last step in the glycolysis pathway that allows entry of pyruvate into the TCA cycle from which ATP is obtained [1]. In the setting of PK mutations that render its ability to perform this function, however, ATP depletion occurs, primarily in erythrocytes. As a result, further glycolysis is impaired due to inhibition of hexokinase by 2,3-diphosphoglycerate (2,3-DPG), causing profound disruption of iron metabolism and a shorter life-span of erythrocytes [4]. Additionally, RBC production is defective because maturation of erythroid progenitor cells is affected by reduced PK function [4]. These pathological events lead to non-spherocytotic hemolytic anemia and consequent hypebilirubinemia, hallmarks of PKD [3]. Interestingly, the increase in 2,3 DPG, causes enhanced delivery of oxygen to the tissues, which is why anemia can often be compensated and tolerated for a prolonged period of time, or until certain events (infections or pregnancy) trigger its reappearance [8]. Although deficiency of pyruvate kinase also develops in hepatocytes, these cells possess the ability to produce the enzyme in sufficient concentrations to overcome the deficiency, thus shifting the clinical presentation to RBC-related pathology [5].

Prenatal testing of babies conceived by couples with known PK mutations is one of the most important preventive strategies in reducing the risk for complications by early initiation of therapy [4] [7], while counselling may be a valuable strategy as well. To prevent the occurrence of PKD, however, is still not possible, as the cause that triggers the mutations remains unknown.

Pyruvate kinase deficiency (PKD) is characterized by insufficient ability of red blood cells (and hepatocytes to a certain extent) to utilize the tricyclic acid (TCA) cycle for energy generation due to deficiency of pyruvate kinase, an enzyme involved in the last step of glycolysis - conversion of phosphoenolpyruvate to pyruvate [1]. Deficiency stems from mutations of the PK liver and red blood cell (PK-LR) gene located on chromosome 1q21 [1]. They are transferred through an autosomal recessive pattern of inheritance [2]. As a result of these mutations, red blood cells are unable to maintain their structural integrity within the body, leading to hemolysis and the appearance of hemolytic anemia and hyperbilirubinemia that usually develop shortly after birth [2] [3]. Iron toxicity that mimics hemochromatosis in children and adults, as well as chronic fatigue can be reported [4]. Hemolytic anemia may be mild and compensated, in which case the diagnosis is often delayed until adulthood, or it may require frequent exchange transfusions, and fatal cases of PKD due to hydrops fetalis and kernicterus are not uncommon [4] [5]. For this reason, a thorough diagnostic workup is necessary in order to identify the condition early on. Information regarding family history is the key steps in making a presumptive diagnosis, as the condition invariably requires the presence of symptoms in either parents or close relatives [1]. Moreover, epidemiologic data show that certain groups are affected by much higher rates of PKD compared to the general population (such as the Amish population living in the United States, especially in the states of Pennsylvania and Ohio, and individuals of Northern European descent) [1] [2] [6], further emphasizing the role of a complete patient history. To confirm PKD, molecular testing is required. Initially, genetic testing to determine mutations of PK-LR was performed, but its infrequent availability and cost led to the introduction of quantitative PK enzyme testing, now considered to be the gold standard in the diagnostic protocol [1] [7]. Treatment of PKD depends on the severity of hyperbilirubinemia and anemia, but immediate symptomatic care is mandatory in the majority of patients [4]. Splenectomy (either partial or total) has proven to be of significant benefit for severe forms of PKD. The procedure markedly increases the risk for pneumococcal infection, necessitating long-term prophylaxis with antibiotics [1] [4]. Hematopoietic stem cell transplantation (HSCT) has resulted in cure for only one patient [1] [8], meaning that that targeted therapy is yet to be discovered.

Pyruvate kinase deficiency (PKD) is a genetic disorder that is seen in approximately 1 in 10,000-20,000 individuals, and is characterized by inability of red blood cells (and liver cells to a lesser extent) to produce energy from glucose due to deficiency of the enzyme pyruvate kinase that is involved in this process. As a result, red blood cells are unable to survive and break down at an increased rate, causing severe anemia and jaundice. Symptoms may start as early as hours after birth, and can range to mild to life-threatening anemia and markedly increased bilirubin responsible for jaundice (hyperbilirubinemia) that require immediate therapeutic measures in the form of phototherapy and/or blood transfusions. Patients who develop a milder clinical course may be undiagnosed until adulthood, when acute infections, stress or pregnancy usually trigger severe anemia. Recurrent unexplained miscarriages can be reported in undiagnosed women who are trying to conceive, while pre-eclampsia and multi-organ dysfunction can ensue during pregnancy in the absence of a timely diagnosis. To confirm PKD as the cause of underlying symptoms, it is necessary to perform a complete blood count (CBC), assess the levels of bilirubin and conduct a peripheral blood smear that will reveal bursting erythrocytes in the absence of other abnormalities. Genetic testing and measurement of enzyme activity, however, are necessary to make the diagnosis and exclude other similar disorders as possible causes (such as hereditary spherocytosis and glucose-6-phosphate dehydrogenase deficiency). Treatment principles rely on immediate supportive care and splenectomy in severe cases, which has proven to be of significant benefit in reducing the rate of red blood cell destruction and improving the overall condition of the patient. Bone marrow transplantation provided curative effects under very specific conditions, but treatment of patients with PKD still rests on symptomatic care. The prognosis depends on a timely diagnosis and early initiation of treatment, which is why physicians must consider this condition as the cause of unexplained jaundice and anemia in newborns, but also in adults. One of the ways to prevent complications from the disorder is prenatal testing of babies conceived by PKD-positive parents, allowing sufficient time for preparation of therapy.

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