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White Blood Cells (WBC) – What About You Need To Know

White blood cells (WBC) are a heterogeneous group of nucleated cells that can be found in circulation for at least a period of their life. Their normal concentration in the blood varies between 4000 and 10,000 per microliter.

White white blood cells (WBC) are a heterogeneous group of nucleated cells that can be found in circulation for at least a period of their life. Their normal concentration in the blood varies between 4000 and 10,000 per microliter. Blood cells (WBC) are a heterogeneous group of nucleated cells that can be found in circulation for at least a period of their life. Their normal concentration in the blood varies between 4000 and 10,000 per microliter. They play a most important role in phagocytosis and immunity and therefore in defense against infection

Technique

Leukocytes can be evaluated through several techniques of varying complexity and sophistication. Both quantitative and qualitative properties can be assessed in the laboratory.

The simplest test is the WBC count and differential. White cells can be counted manually in specially designed chambers (Neubauer) or with automated counters. The latter are widely used, offering the advantage of higher accuracy and speed over manual techniques. To determine the differential, a drop of blood is thinly spread over a glass slide, air dried, and stained with a Romanofsky stain, most commonly the Wright or May-Grunewald-Giemsa technique. Two hundred cells are then counted and classified. Machines have been developed to perform automated differential counts, but they are still inferior to manual techniques as far as reliability and ability to discover morphologic abnormalities.

The absolute number of each type of WBC, often more informative than its proportion, can be calculated if the differential and the total number of leukocytes per volume unit are known.

Many of the conditions affecting the WBC can be diagnosed from studying the peripheral smear, but it may be necessary to evaluate the bone marrow for a better investigation. Bone marrow can be aspirated from the posterior iliac crest or the sternum. A core biopsy can be obtained percutaneously from the iliac crest. Biopsies allow assessment of the architecture of the marrow. Touch preparations can be made at the time the core bone marrow is obtained. Clumps of metastatic epithelial cancer cells can be recognized easily with this technique.

When evaluating a bone marrow specimen, note must be made of the overall cellularity and of the presence and proportion of normal bone marrow elements of abnormal hematopoietic cells or extrinsic cells. Myeloid precursors are two- to fourfold more numerous than erythroid precursors.

Occasionally, the morphologic examination is not sufficient to differentiate among cells of myeloid, monocyte, or lymphoid origin. Histochemistry can be helpful in this regard. In principle it identifies differences in the cellular content of different substances, mainly cytoplasmic enzymes. Among those most commonly used are:

  • Leukocyte peroxidase, which is present in myeloid cells and ANLL (acute nonlymphoblastic leukemia) blasts. It plays a role in the killing of bacteria. It is not found in ALL (acute lymphoblastic leukemia) cells.
  • Leukocyte alkaline phosphatase is found in the more mature cells of the myeloid series, bands and neutrophils. It is useful for the differential diagnosis between CML (chronic myelocytic leukemia) where it is low, from leukemoid reactions, where it is normal.
  • Sudan Black B is a lipid stain positive in the neutrophilic granules of precursors and mature granulocytes. It is also found in ANLL but not ALL blasts.
  • Periodic acid–Schiff (PAS) demonstrates the presence of polysaccharides. Neutrophilic granules stain with this technique. Lymphocytes may have PAS-positive granules. PAS is negative in ANLL blasts, but ALL blasts may show a variable positivity.
  • Acid phosphatase. Macrophages and osteoclasts possess this enzyme. T cell ALL blasts and hairy cells are also positive. Acid phosphatase is tartrate resistant in hairy cell leukemia.
  • Leukocyte esterases are found in monocytes and neutrophils in varying concentrations. Alpha naphtyl esterase is strongly positive in monocytes and weakly positive in neutrophils. The reverse is true for AS-D chloroacetate esterase. These enzymes are useful to differentiate the monocytic from granulocytic precursors in ANLL.
  • Terminal deoxynucleotidyl transferase (TdT) is present in thymocytes and lymphocyte precursors. It is positive in most patients with ALL, except for the rare B-cell ALL. It is absent in ANLL.

Histochemical stains can sometimes be difficult to interpret even in the most experienced hands, especially when leukemic blasts are undifferentiated enough to make a morphologic diagnosis difficult.

Surface markers refer to a group of membrane properties that are useful to differentiate B from T lymphocytes. Many of these techniques utilize antibodies to detect the presence of the marker.

  • Ia is an antigen present in mouse B lymphocyte precursors. It is also found on myeloid cells. An Ia-like antigen is present in human cells.
  • Common ALL antigen (CALLA) is described on ALL cells.
  • Surface immunoglobulins (sIg) are synthesized and carried attached to the membrane of B lymphocytes. Most commonly they belong to the IgM class.
  • Receptors for the Fc fragment of immunoglobulins are also found on the membrane of B and T lymphocytes and monocytes.
  • Complement receptors are present in lymphocytes and peripheral blood monocytes.
  • Mouse rosettes are formed by B lymphocytes in the presence of mouse erythrocytes.

Several tests identify T cells. Sheep erythrocytes attach to the surface of T lymphocytes, forming characteristic rosettes. Monoclonal antibodies able to identify subsets of T cells are now available. For instance, CD4 (Ortho Company) identifies helper T cells, and CD8 identifies cytotoxic and suppressor T cells.

Chemotaxis and phagocytic function of neutrophils can be evaluated in the laboratory. The skin window technique is semiquantitative but has the advantage of simplicity. An abrasion is created in the epidermis and covered for a few hours with a glass coverslide that is then stained and evaluated for attached granulocytes. More complicated in vitro systems have been devised, most of which are based on the ability of neutrophils to traverse a certain obstacle to reach an attracting stimulus.

Phagocytosis and killing abilities can also be evaluated in vitro. These techniques are cumbersome and not universally available. The simplest way to assess the function of the cellular (T cell) immune system is delayed cutaneous hypersensitivity. Several antigens (PPD, mumps, histoplasmin, candida) can be injected intradermally, usually in the forearm. An area of induration appears after 48 hours if the reaction is positive. The ability of the patient to become sensitized to a new substance can also be tested, utilizing a compound to which the patient has had no previous exposure, like dinitrochlorobenzene (DNCB). In vitro techniques rely on stimulating the proliferation of T cells in culture with specific mitogens (concanavalin A, phytohemagglutinin) or antigens.

Humoral immunity can be investigated by measuring the end product of the B system, the immunoglobulins. In electrophoresis, serum proteins are separated in an electric field. Separation is obtained because the electric charge of the protein molecules varies. Protein can be better characterized and quantified by immunoelectrophoresis. Serum proteins are first separated in an electric field and then react with antibodies introduced in the support medium. Each arch of precipitation can then be identified and measured.

Technique

Leukocytes can be evaluated through several techniques of varying complexity and sophistication. Both quantitative and qualitative properties can be assessed in the laboratory.

The simplest test is the WBC count and differential. White cells can be counted manually in specially designed chambers (Neubauer) or with automated counters. The latter are widely used, offering the advantage of higher accuracy and speed over manual techniques. To determine the differential, a drop of blood is thinly spread over a glass slide, air dried, and stained with a Romanofsky stain, most commonly the Wright or May-Grunewald-Giemsa technique. Two hundred cells are then counted and classified. Machines have been developed to perform automated differential counts, but they are still inferior to manual techniques as far as reliability and ability to discover morphologic abnormalities.

The absolute number of each type of WBC, often more informative than its proportion, can be calculated if the differential and the total number of leukocytes per volume unit are known.

Many of the conditions affecting the WBC can be diagnosed from studying the peripheral smear, but it may be necessary to evaluate the bone marrow for a better investigation. Bone marrow can be aspirated from the posterior iliac crest or the sternum. A core biopsy can be obtained percutaneously from the iliac crest. Biopsies allow assessment of the architecture of the marrow. Touch preparations can be made at the time the core bone marrow is obtained. Clumps of metastatic epithelial cancer cells can be recognized easily with this technique.

When evaluating a bone marrow specimen, note must be made of the overall cellularity and of the presence and proportion of normal bone marrow elements of abnormal hematopoietic cells or extrinsic cells. Myeloid precursors are two- to fourfold more numerous than erythroid precursors.

Occasionally, the morphologic examination is not sufficient to differentiate among cells of myeloid, monocyte, or lymphoid origin. Histochemistry can be helpful in this regard. In principle it identifies differences in the cellular content of different substances, mainly cytoplasmic enzymes. Among those most commonly used are:

  • Leukocyte peroxidase, which is present in myeloid cells and ANLL (acute nonlymphoblastic leukemia) blasts. It plays a role in the killing of bacteria. It is not found in ALL (acute lymphoblastic leukemia) cells.
  • Leukocyte alkaline phosphatase is found in the more mature cells of the myeloid series, bands and neutrophils. It is useful for the differential diagnosis between CML (chronic myelocytic leukemia) where it is low, from leukemoid reactions, where it is normal.
  • Sudan Black B is a lipid stain positive in the neutrophilic granules of precursors and mature granulocytes. It is also found in ANLL but not ALL blasts.
  • Periodic acid–Schiff (PAS) demonstrates the presence of polysaccharides. Neutrophilic granules stain with this technique. Lymphocytes may have PAS-positive granules. PAS is negative in ANLL blasts, but ALL blasts may show a variable positivity.
  • Acid phosphatase. Macrophages and osteoclasts possess this enzyme. T cell ALL blasts and hairy cells are also positive. Acid phosphatase is tartrate resistant in hairy cell leukemia.
  • Leukocyte esterases are found in monocytes and neutrophils in varying concentrations. Alpha naphtyl esterase is strongly positive in monocytes and weakly positive in neutrophils. The reverse is true for AS-D chloroacetate esterase. These enzymes are useful to differentiate the monocytic from granulocytic precursors in ANLL.
  • Terminal deoxynucleotidyl transferase (TdT) is present in thymocytes and lymphocyte precursors. It is positive in most patients with ALL, except for the rare B-cell ALL. It is absent in ANLL.

Histochemical stains can sometimes be difficult to interpret even in the most experienced hands, especially when leukemic blasts are undifferentiated enough to make a morphologic diagnosis difficult.

Surface markers refer to a group of membrane properties that are useful to differentiate B from T lymphocytes. Many of these techniques utilize antibodies to detect the presence of the marker.

  • Ia is an antigen present in mouse B lymphocyte precursors. It is also found on myeloid cells. An Ia-like antigen is present in human cells.
  • Common ALL antigen (CALLA) is described on ALL cells.
  • Surface immunoglobulins (sIg) are synthesized and carried attached to the membrane of B lymphocytes. Most commonly they belong to the IgM class.
  • Receptors for the Fc fragment of immunoglobulins are also found on the membrane of B and T lymphocytes and monocytes.
  • Complement receptors are present in lymphocytes and peripheral blood monocytes.
  • Mouse rosettes are formed by B lymphocytes in the presence of mouse erythrocytes.

Several tests identify T cells. Sheep erythrocytes attach to the surface of T lymphocytes, forming characteristic rosettes. Monoclonal antibodies able to identify subsets of T cells are now available. For instance, CD4 (Ortho Company) identifies helper T cells, and CD8 identifies cytotoxic and suppressor T cells.

Chemotaxis and phagocytic function of neutrophils can be evaluated in the laboratory. The skin window technique is semiquantitative but has the advantage of simplicity. An abrasion is created in the epidermis and covered for a few hours with a glass coverslide that is then stained and evaluated for attached granulocytes. More complicated in vitro systems have been devised, most of which are based on the ability of neutrophils to traverse a certain obstacle to reach an attracting stimulus.

Phagocytosis and killing abilities can also be evaluated in vitro. These techniques are cumbersome and not universally available. The simplest way to assess the function of the cellular (T cell) immune system is delayed cutaneous hypersensitivity. Several antigens (PPD, mumps, histoplasmin, candida) can be injected intradermally, usually in the forearm. An area of induration appears after 48 hours if the reaction is positive. The ability of the patient to become sensitized to a new substance can also be tested, utilizing a compound to which the patient has had no previous exposure, like dinitrochlorobenzene (DNCB). In vitro techniques rely on stimulating the proliferation of T cells in culture with specific mitogens (concanavalin A, phytohemagglutinin) or antigens.

Humoral immunity can be investigated by measuring the end product of the B system, the immunoglobulins. In electrophoresis, serum proteins are separated in an electric field. Separation is obtained because the electric charge of the protein molecules varies. Protein can be better characterized and quantified by immunoelectrophoresis. Serum proteins are first separated in an electric field and then react with antibodies introduced in the support medium. Each arch of precipitation can then be identified and measured.

Basic Science

WBC are classified into granulocytes, lymphocytes, and monocytes. Granulocytes owe their name to the presence of distinct cytoplasmic granulation. Three varieties are recognized: neutrophils (or polymorphonuclear granulocytes), eosinophils, and basophils.

Myeloid cells originate from a common pluripotent stem cell, colony forming unit (CFU)-S or CFU-GEMM. A more primitive stem cell gives rise to lymphoid cells as well as to the myeloid precursor. Under the influence of poietins and microenvironmental factors, the stem cells evolve through a series of intermediate steps into the mature blood elements. From CFU-S derive burst forming unit (BFU)-E, which will give rise to CFU-E and through it to the erythroid series; CFU-MEGA, which will originate megakaryocytes; and CFU-GM, which will originate monocytes and granulocytes. Stem cells resemble lymphocytes morphologically. They can be recognized by growth characteristics in vitro in semisolid media containing different growth factors.

In the evolution of the neutrophilic granulocyte, the first cell identifiable morphologically is the myeloblast. As maturation progresses, the myeloblast becomes first a promyelocyte and later a myelocyte. These developmental stages constitute predominantly a proliferative compartment, in which the cell number increases geometrically. The next form, the metamyelocyte, is unable to undergo further mitosis but transforms into a band. This cell is either released into circulation (3 to 5% of WBC) where it completes its maturation or enters a storage compartment in the marrow where it becomes a neutrophil and is released later into the circulation.

About half of the intravascular polymorphonuclear cells are circulating, maintaining a dynamic equilibrium with the other half, which are marginated against the vascular endothelium. Only the circulating neutrophils are accounted for in the WBC count. The half-life of mature neutrophils in circulation is about 7 hours. They irreversibly traverse the vascular endothelium into the tissues, where they die after 1 or 2 days.

The main function of neutrophilic granulocytes is phagocytosis of bacteria. This is a complex multistage process that includes engulfment of the organism, incorporation into the cytoplasm, and fusion with a lysosome where enzymes are liberated that will destroy the bacterium while a burst of energy is generated.

Eosinophils and basophils have a similar development. After release from the bone marrow, eosinophils promptly abandon the intravascular compartment (where they constitute up to 5% of WBC), entering the tissues. They are not able to reenter the blood. Heavy concentrations of eosinophils are found in the GI tract, lung, and skin. The precise function of these complex cells is not well known. They possibly play a role in defense against multicellular parasites and in limiting inflammation.

Basophils constitute about 1 to 2% of circulating leukocytes. Their physiologic role is also not known with precision. In their granules they carry heparin and histamine. IgE can be found bound to their surface.

Macrophages and lymphocytes are known collectively as mononuclear leukocytes. Both play important roles in cellular and humoral immunity. These cells are able to exit and reenter circulation, retaining their function. They may spend time in the tissues or in lymph nodes.

The cells of the monocyte–macrophage system have their origin in the bone marrow, deriving from the CFU-GM. They are not stored but are rapidly released into the circulation where they account for 5% of WBC. In tissues, they become macrophages.

Monocyte–macrophages phagocytose bacteria and particulate material, play a role in the inflammatory reaction, and are important in the immune apparatus where they process antigenic material and “communicate” with T lymphocytes through a cell–cell interaction process. Monocytes are able to secrete interleukin, a substance that potentiates B and T lymphocytes. They participate in fibrinolysis by secreting plasminogen activators.

Lymphocytes are immune cells fundamental in cellular and humoral immunity. In the blood they represent 20 to 45% of WBC. They belong to the B (bursa or bone marrow) or T (thymus) systems. Both cells are morphologically indistinguishable. The B system is responsible for synthesis of antibodies. When a B cell is properly stimulated, it proliferates first and transforms later into a plasma cell, the effector limb of the immune arch. Each B lymphocyte is able to synthesize only one species of antibody.

The T system constitutes the cellular immune system and regulates the whole immune apparatus. Several subsets of T cells can be identified with monoclonal antibodies specific against different membrane antigens. For instance, helper T cells favor the function of B cells, whereas suppressor T cells inhibit them. Some T cells are responsible for cell-mediated cytotoxicity; natural killer (NK) lymphocytes are responsible for nonspecific lysis of certain cells.

In the peripheral blood, approximately 15 to 25% of lymphocytes are B cells and 40 to 75% are T cells.

Clinical Significance

Leukocyte Disorders

WBC disorders can be classified as quantitative or qualitative. In quantitative alterations all cells appear normal but are present in abnormal quantities, either in excess or in defect of normal values. In qualitative defects, abnormal appearing cells or extrinsic cells are found in circulation.

Neutrophils

Quantitative abnormalities

Granulocytes can be increased in circulation by four different mechanisms: increased production, decreased egress from the circulation, demargination, and release from storage compartments.

Most instances of neutrophilia are secondary to a pathologic process outside the marrow. It can occur in infectious diseases, especially acute bacterial infections; neoplasia, either affecting the myeloid system (chronic myelogenous leukemia and other myeloproliferative disorders) or secondary to a solid tumor (paraneoplastic syndrome); inflammation secondary to tissue necrosis, metabolic and collagen diseases, hypersensitivity reactions; hemorrhage; hemolysis; and stress.

Neutropenia is due in the great majority of cases to decreased production of granulocytes. Antineoplastic agents and extensive radiation therapy produce neutropenia almost invariably. Drugs such as phenothiazines, phenylbutazone, and allopurinol can induce neutropenia through idiosyncratic reactions. Infections, most often viral but also bacterial or rickettsial, can lower the polymorphonuclear count. Other conditions causing a decrease in WBC production include cyclic neutropenia, congenital disorders, and idiopathic neutropenia.

If peripheral consumption exceeds production, neutropenia and concomitant marrow hypercellularity will result. It can be seen in hypersplenism, Felty’s syndrome, and in the presence of antineutrophil antibodies.

The risk of infection increases when the absolute granulocyte count falls below 1000 per microliter. Gram-negative sepsis is common in this setting.

Qualitative abnormalities of neutrophils include functional defects in chemotaxis, phagocytosis, and bacterial killing. They can be due to extrinsic or intrinsic abnormalities of the granulocyte. Extrinsic abnormalities include treatment with antineoplastic agents and corticosteroids, deficiencies of complement and opsonizing antibody, hypophosphatemia, and sickle cell disease. Intrinsic abnormalities include defects of the killing mechanism of ingested bacteria (chronic granulomatous disease), and defects in lysosomal function (Chédiak-Higashi syndrome with giant lysosomes, premature graying of the hair, a bleeding diathesis, and a terminal phase characterized by adenopathy, hepatosplenomegaly, and marrow failure).

Several abnormalities of cytoplasmic granulation can be found. Toxic granules appear in the cytoplasm of neutrophils during infectious processes and represent probably phagocytic vacuoles. Döhle bodies can be seen in similar circumstances as round, well-delineated structures. The May-Hegglin anomaly is characterized by large inclusion bodies in the cytoplasm of polymorphonuclear cells associated with thrombocytopenia and giant platelets.

The Pelger-Huët anomaly is manifested as a change in the morphology of the nucleus of the polymorphonuclear leukocyte, which has one or two smooth lobes with thick chromatin. The cell is functionally normal.

Monocytosis can follow chronic infectious disorders (tuberculosis, brucellosis), rheumatic diseases (lupus, rheumatoid arthritis), chronic inflammatory bowel disease, and some malignant processes (Hodgkin’s and non-Hodgkin’s lymphoma). Monocytes play an important role in other chronic granulomatous diseases: sarcoidosis, histiocytosis X, and storage diseases (Gaucher’s disease, Niemann–Pick disease).

Eosinophilia occurs in association with hypersensitivity reactions, parasitic infestations, cancers (Hodgkin’s disease, eosinophilic leukemia), connective tissue disorders (rheumatoid arthritis, polyarteritis nodosa), and the syndrome of pulmonary infiltrates with eosinophilia.

Basophilia can be found in chronic myelogenous leukemia and other myeloproliferative disorders, Hodgkin’s disease, and some chronic inflammatory and infectious disorders.

Lymphocytopenia can be seen mainly in association with several congenital diseases of the immune system or following treatment with corticosteroids, antineoplastic agents, or radiation. Lymphocytosis can accompany some infections, both acute and chronic, usually viral, Addison’s disease, and autoimmune diseases.

The Leukemias

Acute leukemia results from the malignant proliferation of cells of the myeloid (acute nonlymphoblastic leukemia or ANLL) or lymphoid (acute lymphoblastic leukemia or ALL) progeny. Untreated it is rapidly fatal. The clinical picture stems predominantly from bone marrow failure but also from infiltration of normal tissues by the leukemic cells. Anemia produces weakness, easy fatigability, dyspnea, palpitations, orthostasis, and pallor. Granulocytopenia results in infection, often with gram-negative organisms, but also with low-grade pathogens. Thrombocytopenia is manifested as purpura: epistaxis, petechiae, easy bruisability, and gum bleeding.

Infiltration of tissues results in lymphadenopathy and hepatosplenomegaly (more common and more marked in ALL than ANLL), chloromas, and, in monocytic leukemia, gum hypertrophy. Bone pain and tenderness are slightly more common in ALL than ANLL. In childhood ALL the long bones of the inferior limbs are predominantly affected. In the peripheral blood a normochromic normocytic anemia is found. Platelets are decreased, often to very low values. The total white cell count may be very elevated, normal, or low. In most cases blasts will be found. These are large, immature-looking cells with a high nucleus to cytoplasm ratio. Myeloblasts have a thin, lacy chromatin and well-defined nucleoli. The cytoplasm is pale and may exhibit Auer rods, pathognomonic of ANLL. Monocytoid or promyelocytic features may be found in AML blasts. Lymphoblasts have a coarser chromatin with less sharply delineated nucleoli and a slightly basophilic cytoplasm with few granules. The bone marrow examination will show hypercellularity, decrease or absence of normal hemopoietic precursors, and infiltrations with blasts.

Sometimes it is difficult to differentiate ALL from ANLL on purely morphologic grounds. Histochemistry and cell surface markers can be helpful in these circumstances. Most patients with ALL have lymphoblasts that mark with neither T nor B cell markers: “null cells”; terminal deoxynucleotidyl transferase, CALLA, and Ia-like antigen are present. It appears that these cells are early B cell precursors. T cell ALL is diagnosed in approximately 20% of ALL patients. Large mediastinal lymphadenopathy is commonly found. B cell ALL is very rare.

Chronic myelogenous leukemia (CML) affects middle-aged patients (median age at diagnosis is 40 to 45 years). A juvenile form of the disease has been recognized. Patients present most often with signs of anemia or after finding a left upper quadrant abdominal mass. As CBC are performed nowadays almost routinely, CML is diagnosed incidentally and asymptomatically in many patients. On physical examination the dominant finding is splenomegaly, which can be enormous, penetrating into the pelvis and extending across the midline. Areas of infarction can result in tenderness on areas of the splenic surface. Palpable lymph nodes are seldom greater than 1 cm in diameter.

Examination of the peripheral smear confirms the diagnosis. The anemia is mild to moderate. Platelet count may be elevated, and counts above 106 per microliter are not uncommon; thrombocytopenia is rare. These platelets may be functionally impaired. The most striking abnormality is found in the white cell series. WBC counts are elevated, sometimes so that leukostasis may occur. Cells of all stages of granulopoiesis (including early progenitor cells) are found in the peripheral blood to the extent that it can resemble a bone marrow aspirate. Basophil and eosinophil counts are increased. The bone marrow appears hypercellular with a very heavy predominance of myeloid elements. Megakaryocytes are increased.

In 90% of patients a characteristic chromosomal abnormality, the Philadelphia chromosome (Ph1), can be found. It results from the translocation of the long arm of chromosome 22 to chromosome 9. The cell primarily affected by the neoplastic process is an early stem cell. As a consequence, the Ph1 chromosome can be found in neutrophils, erythroid precursors, megakaryocytes, and monocytes.

Treatment of CML improves symptoms but not survival. After a median of 3 to 4 years, the disease evolves into a blastic phase that resembles an aggressive acute leukemia on clinical and laboratory grounds. CML is a myeloproliferative disorder together with essential thrombocythemia, polycythemia vera, and agnogenic myeloid metaplasia.

Chronic lymphocytic leukemia (CLL) is a disorder seen usually in older persons (mean age = 60 years). It is not seen in children. In the majority of patients it results from the malignant proliferation of B lymphocytes, although occasionally a T cell CLL is found. Malignant cells resemble mature lymphocytes but have different morphologic features than their normal counterparts. Patients can be diagnosed while asymptomatic when a high lymphocyte count is found incidentally. A count higher than 15,000 lymphocytes per microliter is necessary to make the diagnosis.

After a variable asymptomatic period, lymphadenopathy will develop. It sometimes can be massive. Splenomegaly is common. As the disease progresses, anemia and thrombocytopenia will appear. Examination of the peripheral blood will invariably show an elevated WBC count at the expense of lymphocytosis, which can often be above 90%. Hypogammaglobulinemia develops in almost all patients, increasing the risk of infections, predominantly with encapsulated gram-positive organisms. Autoimmune hemolytic anemia and hypersplenism are common. The natural history of the disease is measured in years.

T cell CLL is a more aggressive disease. The skin is commonly involved and splenomegaly is seen early in the course of the disease.

Multiple myeloma results from the monoclonal proliferation of a plasma cell. The malignant population retains its ability to secrete immunoglobulins. As this production continues unchecked, it results in hyperglobulinemia that produces a single (“M”) spike on protein electrophoresis. Most myelomas secrete IgG or IgA. IgE and IgM myelomas are extremely rare.

The clinical presentation includes bone pain and anemia. Symptoms of hypercalcemia, renal failure, and hyperviscosity may be present. On the peripheral smear a normochromic, normocytic anemia is encountered. Rouleaux formation is common. Plasma cells can be found in circulation, and when predominant, a diagnosis of plasma cell leukemia is made.

More than 10% plasma cells are found in the bone marrow. The protein electrophoresis reveals the M spike with greater than 3 g of the immunoglobulin. Immunoelectrophoresis identifies and quantifies the increased immunoglobulin. The hyperglobulinemia is exclusively related to the abnormal antibody; all other immunoglobulins are decreased. Consequently, susceptibility to infection is increased. In the urine, Bence Jones proteins are found. These are filtered light chains that precipitate at 50 to 60°C and redissolve when heated to 100°C. Myeloma cells secrete osteoclast activating factor, which produces hypercalcemia and lytic bone lesions, especially in flat bones. As there is little or no osteoblastic activity, bone scans and alkaline phosphatase often remain negative.

White blood cells (WBC) are a heterogeneous group of nucleated cells that can be found in circulation for at least a period of their life. Their normal concentration in blood varies between 4000 and 10,000 per microliter. They play a most important role in phagocytosis and immunity and therefore in defense against infection.

Technique

Leukocytes can be evaluated through several techniques of varying complexity and sophistication. Both quantitative and qualitative properties can be assessed in the laboratory.

The simplest test is the WBC count and differential. White cells can be counted manually in specially designed chambers (Neubauer) or with automated counters. The latter are widely used, offering the advantage of higher accuracy and speed over manual techniques. To determine the differential, a drop of blood is thinly spread over a glass slide, air dried, and stained with a Romanofsky stain, most commonly the Wright or May-Grunewald-Giemsa technique. Two hundred cells are then counted and classified. Machines have been developed to perform automated differential counts, but they are still inferior to manual techniques as far as reliability and ability to discover morphologic abnormalities.

The absolute number of each type of WBC, often more informative than its proportion, can be calculated if the differential and the total number of leukocytes per volume unit are known.

Many of the conditions affecting the WBC can be diagnosed from studying the peripheral smear, but it may be necessary to evaluate the bone marrow for a better investigation. Bone marrow can be aspirated from the posterior iliac crest or the sternum. A core biopsy can be obtained percutaneously from the iliac crest. Biopsies allow assessment of the architecture of the marrow. Touch preparations can be made at the time the core bone marrow is obtained. Clumps of metastatic epithelial cancer cells can be recognized easily with this technique.

When evaluating a bone marrow specimen, note must be made of the overall cellularity and of the presence and proportion of normal bone marrow elements of abnormal hematopoietic cells or extrinsic cells. Myeloid precursors are two- to fourfold more numerous than erythroid precursors.

Occasionally, the morphologic examination is not sufficient to differentiate among cells of myeloid, monocyte, or lymphoid origin. Histochemistry can be helpful in this regard. In principle it identifies differences in the cellular content of different substances, mainly cytoplasmic enzymes. Among those most commonly used are:

  • Leukocyte peroxidase, which is present in myeloid cells and ANLL (acute nonlymphoblastic leukemia) blasts. It plays a role in the killing of bacteria. It is not found in ALL (acute lymphoblastic leukemia) cells.
  • Leukocyte alkaline phosphatase is found in the more mature cells of the myeloid series, bands and neutrophils. It is useful for the differential diagnosis between CML (chronic myelocytic leukemia) where it is low, from leukemoid reactions, where it is normal.
  • Sudan Black B is a lipid stain positive in the neutrophilic granules of precursors and mature granulocytes. It is also found in ANLL but not ALL blasts.
  • Periodic acid–Schiff (PAS) demonstrates the presence of polysaccharides. Neutrophilic granules stain with this technique. Lymphocytes may have PAS-positive granules. PAS is negative in ANLL blasts, but ALL blasts may show a variable positivity.
  • Acid phosphatase. Macrophages and osteoclasts possess this enzyme. T cell ALL blasts and hairy cells are also positive. Acid phosphatase is tartrate resistant in hairy cell leukemia.
  • Leukocyte esterases are found in monocytes and neutrophils in varying concentrations. Alpha naphtyl esterase is strongly positive in monocytes and weakly positive in neutrophils. The reverse is true for AS-D chloroacetate esterase. These enzymes are useful to differentiate the monocytic from granulocytic precursors in ANLL.
  • Terminal deoxynucleotidyl transferase (TdT) is present in thymocytes and lymphocyte precursors. It is positive in most patients with ALL, except for the rare B-cell ALL. It is absent in ANLL.

Histochemical stains can sometimes be difficult to interpret even in the most experienced hands, especially when leukemic blasts are undifferentiated enough to make a morphologic diagnosis difficult.

Surface markers refer to a group of membrane properties that are useful to differentiate B from T lymphocytes. Many of these techniques utilize antibodies to detect the presence of the marker.

  • Ia is an antigen present in mouse B lymphocyte precursors. It is also found on myeloid cells. An Ia-like antigen is present in human cells.
  • Common ALL antigen (CALLA) is described on ALL cells.
  • Surface immunoglobulins (sIg) are synthesized and carried attached to the membrane of B lymphocytes. Most commonly they belong to the IgM class.
  • Receptors for the Fc fragment of immunoglobulins are also found on the membrane of B and T lymphocytes and monocytes.
  • Complement receptors are present in lymphocytes and peripheral blood monocytes.
  • Mouse rosettes are formed by B lymphocytes in the presence of mouse erythrocytes.

Several tests identify T cells. Sheep erythrocytes attach to the surface of T lymphocytes, forming characteristic rosettes. Monoclonal antibodies able to identify subsets of T cells are now available. For instance, CD4 (Ortho Company) identifies helper T cells, and CD8 identifies cytotoxic and suppressor T cells.

Chemotaxis and phagocytic function of neutrophils can be evaluated in the laboratory. The skin window technique is semiquantitative but has the advantage of simplicity. An abrasion is created in the epidermis and covered for a few hours with a glass coverslide that is then stained and evaluated for attached granulocytes. More complicated in vitro systems have been devised, most of which are based on the ability of neutrophils to traverse a certain obstacle to reach an attracting stimulus.

Phagocytosis and killing abilities can also be evaluated in vitro. These techniques are cumbersome and not universally available. The simplest way to assess the function of the cellular (T cell) immune system is delayed cutaneous hypersensitivity. Several antigens (PPD, mumps, histoplasmin, candida) can be injected intradermally, usually in the forearm. An area of induration appears after 48 hours if the reaction is positive. The ability of the patient to become sensitized to a new substance can also be tested, utilizing a compound to which the patient has had no previous exposure, like dinitrochlorobenzene (DNCB). In vitro techniques rely on stimulating the proliferation of T cells in culture with specific mitogens (concanavalin A, phytohemagglutinin) or antigens.

Humoral immunity can be investigated by measuring the end product of the B system, the immunoglobulins. In electrophoresis, serum proteins are separated in an electric field. Separation is obtained because the electric charge of the protein molecules varies. Protein can be better characterized and quantified by immunoelectrophoresis. Serum proteins are first separated in an electric field and then react with antibodies introduced in the support medium. Each arch of precipitation can then be identified and measured.

Basic Science

WBC are classified into granulocytes, lymphocytes, and monocytes. Granulocytes owe their name to the presence of distinct cytoplasmic granulation. Three varieties are recognized: neutrophils (or polymorphonuclear granulocytes), eosinophils, and basophils.

Myeloid cells originate from a common pluripotent stem cell, colony forming unit (CFU)-S or CFU-GEMM. A more primitive stem cell gives rise to lymphoid cells as well as to the myeloid precursor. Under the influence of poietins and microenvironmental factors, the stem cells evolve through a series of intermediate steps into the mature blood elements. From CFU-S derive burst forming unit (BFU)-E, which will give rise to CFU-E and through it to the erythroid series; CFU-MEGA, which will originate megakaryocytes; and CFU-GM, which will originate monocytes and granulocytes. Stem cells resemble lymphocytes morphologically. They can be recognized by growth characteristics in vitro in semisolid media containing different growth factors.

In the evolution of the neutrophilic granulocyte, the first cell identifiable morphologically is the myeloblast. As maturation progresses, the myeloblast becomes first a promyelocyte and later a myelocyte. These developmental stages constitute predominantly a proliferative compartment, in which the cell number increases geometrically. The next form, the metamyelocyte, is unable to undergo further mitosis but transforms into a band. This cell is either released into circulation (3 to 5% of WBC) where it completes its maturation or enters a storage compartment in the marrow where it becomes a neutrophil and is released later into the circulation.

About half of the intravascular polymorphonuclear cells are circulating, maintaining a dynamic equilibrium with the other half, which are marginated against the vascular endothelium. Only the circulating neutrophils are accounted for in the WBC count. The half-life of mature neutrophils in circulation is about 7 hours. They irreversibly traverse the vascular endothelium into the tissues, where they die after 1 or 2 days.

The main function of neutrophilic granulocytes is phagocytosis of bacteria. This is a complex multistage process that includes engulfment of the organism, incorporation into the cytoplasm, and fusion with a lysosome where enzymes are liberated that will destroy the bacterium while a burst of energy is generated.

Eosinophils and basophils have a similar development. After release from the bone marrow, eosinophils promptly abandon the intravascular compartment (where they constitute up to 5% of WBC), entering the tissues. They are not able to reenter the blood. Heavy concentrations of eosinophils are found in the GI tract, lung, and skin. The precise function of these complex cells is not well known. They possibly play a role in defense against multicellular parasites and in limiting inflammation.

Basophils constitute about 1 to 2% of circulating leukocytes. Their physiologic role is also not known with precision. In their granules they carry heparin and histamine. IgE can be found bound to their surface.

Macrophages and lymphocytes are known collectively as mononuclear leukocytes. Both play important roles in cellular and humoral immunity. These cells are able to exit and reenter circulation, retaining their function. They may spend time in the tissues or in lymph nodes.

The cells of the monocyte–macrophage system have their origin in the bone marrow, deriving from the CFU-GM. They are not stored but are rapidly released into the circulation where they account for 5% of WBC. In tissues, they become macrophages.

Monocyte–macrophages phagocytose bacteria and particulate material, play a role in the inflammatory reaction, and are important in the immune apparatus where they process antigenic material and “communicate” with T lymphocytes through a cell–cell interaction process. Monocytes are able to secrete interleukin, a substance that potentiates B and T lymphocytes. They participate in fibrinolysis by secreting plasminogen activators.

Lymphocytes are immune cells fundamental in cellular and humoral immunity. In the blood they represent 20 to 45% of WBC. They belong to the B (bursa or bone marrow) or T (thymus) systems. Both cells are morphologically indistinguishable. The B system is responsible for synthesis of antibodies. When a B cell is properly stimulated, it proliferates first and transforms later into a plasma cell, the effector limb of the immune arch. Each B lymphocyte is able to synthesize only one species of antibody.

The T system constitutes the cellular immune system and regulates the whole immune apparatus. Several subsets of T cells can be identified with monoclonal antibodies specific against different membrane antigens. For instance, helper T cells favor the function of B cells, whereas suppressor T cells inhibit them. Some T cells are responsible for cell-mediated cytotoxicity; natural killer (NK) lymphocytes are responsible for nonspecific lysis of certain cells.

In the peripheral blood, approximately 15 to 25% of lymphocytes are B cells and 40 to 75% are T cells.

Clinical Significance

Leukocyte Disorders

WBC disorders can be classified as quantitative or qualitative. In quantitative alterations all cells appear normal but are present in abnormal quantities, either in excess or in defect of normal values. In qualitative defects, abnormal appearing cells or extrinsic cells are found in circulation.

Neutrophils

Quantitative abnormalities

Granulocytes can be increased in circulation by four different mechanisms: increased production, decreased egress from the circulation, demargination, and release from storage compartments.

Most instances of neutrophilia are secondary to a pathologic process outside the marrow. It can occur in infectious diseases, especially acute bacterial infections; neoplasia, either affecting the myeloid system (chronic myelogenous leukemia and other myeloproliferative disorders) or secondary to a solid tumor (paraneoplastic syndrome); inflammation secondary to tissue necrosis, metabolic and collagen diseases, hypersensitivity reactions; hemorrhage; hemolysis; and stress.

Neutropenia is due in the great majority of cases to decreased production of granulocytes. Antineoplastic agents and extensive radiation therapy produce neutropenia almost invariably. Drugs such as phenothiazines, phenylbutazone, and allopurinol can induce neutropenia through idiosyncratic reactions. Infections, most often viral but also bacterial or rickettsial, can lower the polymorphonuclear count. Other conditions causing a decrease in WBC production include cyclic neutropenia, congenital disorders, and idiopathic neutropenia.

If peripheral consumption exceeds production, neutropenia and concomitant marrow hypercellularity will result. It can be seen in hypersplenism, Felty’s syndrome, and in the presence of antineutrophil antibodies.

The risk of infection increases when the absolute granulocyte count falls below 1000 per microliter. Gram-negative sepsis is common in this setting.

Qualitative abnormalities of neutrophils include functional defects in chemotaxis, phagocytosis, and bacterial killing. They can be due to extrinsic or intrinsic abnormalities of the granulocyte. Extrinsic abnormalities include treatment with antineoplastic agents and corticosteroids, deficiencies of complement and opsonizing antibody, hypophosphatemia, and sickle cell disease. Intrinsic abnormalities include defects of the killing mechanism of ingested bacteria (chronic granulomatous disease), and defects in lysosomal function (Chédiak-Higashi syndrome with giant lysosomes, premature graying of the hair, a bleeding diathesis, and a terminal phase characterized by adenopathy, hepatosplenomegaly, and marrow failure).

Several abnormalities of cytoplasmic granulation can be found. Toxic granules appear in the cytoplasm of neutrophils during infectious processes and represent probably phagocytic vacuoles. Döhle bodies can be seen in similar circumstances as round, well-delineated structures. The May-Hegglin anomaly is characterized by large inclusion bodies in the cytoplasm of polymorphonuclear cells associated with thrombocytopenia and giant platelets.

The Pelger-Huët anomaly is manifested as a change in the morphology of the nucleus of the polymorphonuclear leukocyte, which has one or two smooth lobes with thick chromatin. The cell is functionally normal.

Monocytosis can follow chronic infectious disorders (tuberculosis, brucellosis), rheumatic diseases (lupus, rheumatoid arthritis), chronic inflammatory bowel disease, and some malignant processes (Hodgkin’s and non-Hodgkin’s lymphoma). Monocytes play an important role in other chronic granulomatous diseases: sarcoidosis, histiocytosis X, and storage diseases (Gaucher’s disease, Niemann–Pick disease).

Eosinophilia occurs in association with hypersensitivity reactions, parasitic infestations, cancers (Hodgkin’s disease, eosinophilic leukemia), connective tissue disorders (rheumatoid arthritis, polyarteritis nodosa), and the syndrome of pulmonary infiltrates with eosinophilia.

Basophilia can be found in chronic myelogenous leukemia and other myeloproliferative disorders, Hodgkin’s disease, and some chronic inflammatory and infectious disorders.

Lymphocytopenia can be seen mainly in association with several congenital diseases of the immune system or following treatment with corticosteroids, antineoplastic agents, or radiation. Lymphocytosis can accompany some infections, both acute and chronic, usually viral, Addison’s disease, and autoimmune diseases.

The Leukemias

Acute leukemia results from the malignant proliferation of cells of the myeloid (acute nonlymphoblastic leukemia or ANLL) or lymphoid (acute lymphoblastic leukemia or ALL) progeny. Untreated it is rapidly fatal. The clinical picture stems predominantly from bone marrow failure but also from infiltration of normal tissues by the leukemic cells. Anemia produces weakness, easy fatigability, dyspnea, palpitations, orthostasis, and pallor. Granulocytopenia results in infection, often with gram-negative organisms, but also with low-grade pathogens. Thrombocytopenia is manifested as purpura: epistaxis, petechiae, easy bruisability, and gum bleeding.

Infiltration of tissues results in lymphadenopathy and hepatosplenomegaly (more common and more marked in ALL than ANLL), chloromas, and, in monocytic leukemia, gum hypertrophy. Bone pain and tenderness are slightly more common in ALL than ANLL. In childhood ALL the long bones of the inferior limbs are predominantly affected. In the peripheral blood a normochromic normocytic anemia is found. Platelets are decreased, often to very low values. The total white cell count may be very elevated, normal, or low. In most cases blasts will be found. These are large, immature-looking cells with a high nucleus to cytoplasm ratio. Myeloblasts have a thin, lacy chromatin and well-defined nucleoli. The cytoplasm is pale and may exhibit Auer rods, pathognomonic of ANLL. Monocytoid or promyelocytic features may be found in AML blasts. Lymphoblasts have a coarser chromatin with less sharply delineated nucleoli and a slightly basophilic cytoplasm with few granules. The bone marrow examination will show hypercellularity, decrease or absence of normal hemopoietic precursors, and infiltrations with blasts.

Sometimes it is difficult to differentiate ALL from ANLL on purely morphologic grounds. Histochemistry and cell surface markers can be helpful in these circumstances. Most patients with ALL have lymphoblasts that mark with neither T nor B cell markers: “null cells”; terminal deoxynucleotidyl transferase, CALLA, and Ia-like antigen are present. It appears that these cells are early B cell precursors. T cell ALL is diagnosed in approximately 20% of ALL patients. Large mediastinal lymphadenopathy is commonly found. B cell ALL is very rare.

Chronic myelogenous leukemia (CML) affects middle-aged patients (median age at diagnosis is 40 to 45 years). A juvenile form of the disease has been recognized. Patients present most often with signs of anemia or after finding a left upper quadrant abdominal mass. As CBC are performed nowadays almost routinely, CML is diagnosed incidentally and asymptomatically in many patients. On physical examination the dominant finding is splenomegaly, which can be enormous, penetrating into the pelvis and extending across the midline. Areas of infarction can result in tenderness on areas of the splenic surface. Palpable lymph nodes are seldom greater than 1 cm in diameter.

Examination of the peripheral smear confirms the diagnosis. The anemia is mild to moderate. Platelet count may be elevated, and counts above 106 per microliter are not uncommon; thrombocytopenia is rare. These platelets may be functionally impaired. The most striking abnormality is found in the white cell series. WBC counts are elevated, sometimes so that leukostasis may occur. Cells of all stages of granulopoiesis (including early progenitor cells) are found in the peripheral blood to the extent that it can resemble a bone marrow aspirate. Basophil and eosinophil counts are increased. The bone marrow appears hypercellular with a very heavy predominance of myeloid elements. Megakaryocytes are increased.

In 90% of patients a characteristic chromosomal abnormality, the Philadelphia chromosome (Ph1), can be found. It results from the translocation of the long arm of chromosome 22 to chromosome 9. The cell primarily affected by the neoplastic process is an early stem cell. As a consequence, the Ph1 chromosome can be found in neutrophils, erythroid precursors, megakaryocytes, and monocytes.

Treatment of CML improves symptoms but not survival. After a median of 3 to 4 years, the disease evolves into a blastic phase that resembles an aggressive acute leukemia on clinical and laboratory grounds. CML is a myeloproliferative disorder together with essential thrombocythemia, polycythemia vera, and agnogenic myeloid metaplasia.

Chronic lymphocytic leukemia (CLL) is a disorder seen usually in older persons (mean age = 60 years). It is not seen in children. In the majority of patients it results from the malignant proliferation of B lymphocytes, although occasionally a T cell CLL is found. Malignant cells resemble mature lymphocytes but have different morphologic features than their normal counterparts. Patients can be diagnosed while asymptomatic when a high lymphocyte count is found incidentally. A count higher than 15,000 lymphocytes per microliter is necessary to make the diagnosis.

After a variable asymptomatic period, lymphadenopathy will develop. It sometimes can be massive. Splenomegaly is common. As the disease progresses, anemia and thrombocytopenia will appear. Examination of the peripheral blood will invariably show an elevated WBC count at the expense of lymphocytosis, which can often be above 90%. Hypogammaglobulinemia develops in almost all patients, increasing the risk of infections, predominantly with encapsulated gram-positive organisms. Autoimmune hemolytic anemia and hypersplenism are common. The natural history of the disease is measured in years.

T cell CLL is a more aggressive disease. The skin is commonly involved and splenomegaly is seen early in the course of the disease.

Multiple myeloma results from the monoclonal proliferation of a plasma cell. The malignant population retains its ability to secrete immunoglobulins. As this production continues unchecked, it results in hyperglobulinemia that produces a single (“M”) spike on protein electrophoresis. Most myelomas secrete IgG or IgA. IgE and IgM myelomas are extremely rare.

The clinical presentation includes bone pain and anemia. Symptoms of hypercalcemia, renal failure, and hyperviscosity may be present. On the peripheral smear a normochromic, normocytic anemia is encountered. Rouleaux formation is common. Plasma cells can be found in circulation, and when predominant, a diagnosis of plasma cell leukemia is made.

More than 10% plasma cells are found in the bone marrow. The protein electrophoresis reveals the M spike with greater than 3 g of the immunoglobulin. Immunoelectrophoresis identifies and quantifies the increased immunoglobulin. The hyperglobulinemia is exclusively related to the abnormal antibody; all other immunoglobulins are decreased. Consequently, susceptibility to infection is increased. In the urine, Bence Jones proteins are found. These are filtered light chains that precipitate at 50 to 60°C and redissolve when heated to 100°C. Myeloma cells secrete osteoclast activating factor, which produces hypercalcemia and lytic bone lesions, especially in flat bones. As there is little or no osteoblastic activity, bone scans and alkaline phosphatase often remain negative.

References

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Cholesterol Screening Test – Indications, Procedure, Result

Cholesterol Screening Test/Cholesterol Test is a sterol compound found in most human body tissues. From a physiologic standpoint, cholesterol and its derivatives are vitally crucial for cell membranes and myriad metabolic processes in the body. Also, cholesterol is used to make hormones, fat-soluble vitamins, and bile acids. The primary source of cholesterol is from animal-based foods, such as eggs, dairy, and cheese. Based on density, cholesterol can classify as high-density lipoproteins (HDL), low-density lipoproteins (LDL), or very-low-density lipoproteins (VLDL). Triglycerides are also part of the blood-lipid profile. Of note, LDL, VLDL, and triglycerides have been correlated to increased risk of CHD, while the reverse appears to be true for HDL. Thus, higher HDL levels confer a protective effect on CHD and all-cause mortality.

Framingham Heart Study, a landmark study, is the first to demonstrate unequivocally that higher LDL concentrations were associated with a higher risk of ASCVD.

Specimen Collection of Cholesterol Screening Test

Traditionally, when patients were scheduling for cholesterol testing, they needed to fast for more than eight hours. The reason behind this laboratory routine is to avoid triglyceride elevation postprandially. However, recently, routine fasting is not mandatory for every patient before cholesterol testing. Nevertheless, some circumstances require patients to fast. Thus, the decision to fast or not to fast depends on the clinical question being asked by the respective physician, as outlined below:

  • Non- fasting blood lipid profiles are acceptable in several conditions, i.e. :

    • Initial risk estimation of an untreated primary prevention patient
    • To clarify the diagnosis of metabolic syndrome.
  • Fasting blood lipid profiles are preferred or even mandatory in several conditions, i.e. :

    • For screening and following patients with a family history of genetic hyperlipidemia or premature ASCVD (Fasting is mandatory)
    • Establish the diagnosis of hypertriglyceridemia
    • Residual risk estimation of treated patients
    • Assessment of patients with or at risk for pancreatitis

Then, patients will undergo a venous blood sampling of 0.5 to 1 mL, mostly through their antecubital vein. The container for the specimen must be a gel-barrier transport, green-top (heparin) tube, or lavender-top (EDTA) tube. Then, the serum must be separated from other blood components within 45 minutes of collection. Samples should be stored at room temperature.

Procedures of Cholesterol Screening Test

The LDL cholesterol estimation can proceed with two distinct methods; indirect and direct. The former approach utilizes the Friedewald cholesterol estimation formula. On the other hand, the latter method utilizes homogeneous assays. In unreliable conditions, such as triglyceride >400 mg/dL, the direct methods can be used to supplement the Friedewald calculation, which has shown to able to meet the standard requirements set by National Cholesterol Education Program (NCEP) for LDL-C testing. When used for non-fasting samples, the direct method was precise and accurate (CV <4% and bias <4%).

Nonetheless, there were several limitations to direct methods. A study of comparison between direct and indirect methods with the reference method of the ultracentrifugation in HIV patients, which hypertriglyceridemia are common, found that no adequate agreement between these two tests with the ultracentrifugation. When TG is more than 400 mg/dL, the direct method tends to overestimate the actual LDL, whereas the indirect method tends to underestimate the actual LDL levels.

Indications of Cholesterol Screening Test

There are many major clinical practice guidelines set by several colleges and societies with their subtle differences between them. However, the primary goals of these clinical practice guidelines are all the same, which are cholesterol testing to prevent CAD in healthy populations or primary prevention and to provide early detection and slow down the progression of diseases or secondary prevention.

  • Patient with a family history of premature death due to myocardial infarction in first degree relatives (<55 years [male] and <65 years [female])
  • History of familial hypercholesterolemia or patient with stigmata of familial hypercholesterolemia (xanthoma/ xanthomata or eyelid xanthelasma)
  • Patients with comorbidities that are likely to be benefitted from statins use, i.e., patients with diabetes, chronic kidney disease, HIV, and others.
  • Risk stratification for patients without the disease, which might benefit from cholesterol-lowering treatment.

Potential Diagnosis

Cholesterol screening is an integral part of primary and secondary prevention of ASCVD. It can detect a vulnerable population that may be asymptomatic but with a high risk of ASCVD due to genetic predispositions. Additionally, it can detect cholesterol elevations secondary to other diseases, such as diabetes, chronic kidney disease, and HIV infection, or due to drug usage, such as oral contraceptive drugs and others. Furthermore, abnormally high levels of cholesterol components might indicate familial hypercholesterolemia.

Occasionally, when screening for cardiovascular disease by cholesterol test, the result might reveal low or even untraceable levels of LDL-C. When the LDL is < 80 mg/dL, hypobetalipoproteinemia might be suspected, whereas an undetected level of LDL signifies abetalipoproteinemia.

Normal and Critical Findings of Cholesterol Screening Test

Non-fasting samples*

  • Triglycerides:

    • ≥2 mmol/L (175 mg/dL)
  • Total cholesterol:

    • ≥5 mmol/L (190 mg/dL)
  • LDL cholesterol:

    • ≥3 mmol/L (115 mg/dL)
  • Remnant cholesterol (IDL + VLDL):

    • ≥0.9 mmol/L (35 mg/dL)
  • Non-HDL cholesterol:

    • ≥3.9 mmol/L (150 mg/dL)
  • Lipoprotein (a)

    • ≥0.50 g/L (50 mg/dL)
  • Apolipoprotein B:

    • ≥1.0 g/L (100 mg/dL)
  • HDL cholesterol:

    • ≤1 mmol/L (40 mg/dL)
  • Apolipoprotein A1:

    • ≤1.25 g/L (125 mg/dL)

*When non-fasting triglycerides concentration exceeds 5mmol/L (440 mg/dL), obtaining a fasting plasma sample may be considered.

Fasting samples

  • Triglycerides:

    • ≥1.7 mmol/L (150 mg/dL)
  • Total cholesterol:

    • ≥5 mmol/L (190 mg/dL)
  • LDL cholesterol:

    • ≥3 mmol/L (115 mg/dL)
  • Remnant cholesterol (IDL + VLDL):

    • ≥0.8 mmol/L (30 mg/dL)
  • Non-HDL cholesterol:

    • ≥3.8 mmol/L (145 mg/dL)
  • Lipoprotein (a)

    • ≥0.50 g/L (50 mg/dL)
  • Apolipoprotein B:

    • ≥1.0 g/L (100 mg/dL)
  • HDL cholesterol:

    • ≤1 mmol/L (40 mg/dL)
  • Apolipoprotein A1:

    • ≤1.25 g/L (125 mg/dL)

The NCEP has also set the LDL-C concentrations and their respective labels in adult >18 years old, with <100, 100 – 129, 130 – 159, 160 – 189, and >= 190 mg/dL identified as desirable, above desirable, borderline high, high, and very high, respectively. For children and adolescents, cholesterol concentrations of <110mg/dL, 110 – 129 mg/dL, and >= 130 mg/dL were deemed acceptable, borderline high, and high, respectively.

Interfering Factors

The original Friedewald equation is total cholesterol (TC) = HDL + LDL + Triglycerides( TG)/5, and it is comparable to the ultracentrifuge method of lipoprotein quantification. However, three conditions preclude the use of this equation, explain as follows:

  • The first one is when there is chylomicron in the plasma. Chylomicrons contain triglycerides; thus, it can interfere with the formula for VLDL calculation, which is plasma TG divided by five. Fortunately, normal subjects do not have chylomicrons in their plasma. Furthermore, chylomicrons can be present in the plasma of patients that suffer type I (familial hyperchylomicronemia), type III (familial dysbetalipoproteinemia), and type V (combined hypertriglyceridemia).
  • The second one is in type III familial hypercholesterolemia (FH). In this disorder, VLDL exists in two forms, which are the normal VLDL with the ratio of TG to cholesterol around five,  and the unique VLDL which the cholesterol’s content is abnormally higher with beta mobility on electrophoresis. Therefore, in type III FH, the method of choice is either by centrifugal isolation of the VLDL, checking cholesterol electrophoresis’ mobility, or by finding the TG/cholesterol ratio.
  • Finally, when the plasma triglycerides concentration is higher than 400 mg/dL. Friedewald et al. noticed that when they incorporate type IV FH patient cholesterol values, they notice outlier values and the decreased correlation coefficient between ultracentrifuge and estimated cholesterol measurement. Subsequently, they found that some type IV FH patients had TG levels above 400 mg/dL. Consequently, after they excluded these patients’ values, the correlation coefficient rose.

Therefore, a new estimation method is proposed by Martin et al. Their estimation is more accurate because it does not use fix ratio between TG and VLDL, but it incorporates adjustable factors for the ratios of triglyceride and VLDL. Consequently, when the LDL is very low, or the TG is very high, i.e.,>400 mg/dL, this new estimation gives more accurate results. This equation has also shown to be superior compared to the Friedewald equation for non-fasting samples.

References

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What foods contain pantothenic acid?

What foods contain pantothenic acid?/Pantothenic Acid is a water-soluble vitamin ubiquitously found in plants and animal tissues with antioxidant properties. Vitamin B5 is a component of coenzyme A (CoA) and a part of the vitamin B2 complex. Vitamin B5 is a growth factor and is essential for various metabolic functions, including the metabolism of carbohydrates, proteins, and fatty acids. This vitamin is also involved in the synthesis of cholesterol, lipids, neurotransmitters, steroid hormones, and hemoglobin.

Vitamin B5  or Pantothenic acid is a water-soluble vitamin. Pantothenic acid is an essential nutrient. Animals require pantothenic acid in order to synthesize coenzyme-A (CoA), as well as to synthesize and metabolize proteins, carbohydrates, and fats. The anion is called pantothenate. Pantothenic acid is the amide between pantoic acid and β-alanine. Its name derives from the Greek pantothen, meaning from everywhere, and small quantities of pantothenic acid are found in nearly every food, with high amounts in fortified whole-grain cereals, egg yolks, liver, and dried mushrooms whole-grain cereals, and dried mushrooms. It is commonly found as its alcohol analog, the provitamin panthenol (pantothenol), and calcium pantothenate. It is commonly found as its alcohol analog, the provitamin panthenol (pantothenol), and calcium pantothenate.

Deficiency Symptoms of Pantothenic Acid / Vitamin B5

Pantothenic acid deficiency has only been observed in individuals who were fed diets virtually devoid of pantothenic acid or who were given a pantothenic acid metabolic antagonist, omega-methyl pantothenic acid. The subjects exhibited various degrees of signs and symptoms, including irritability and restlessness; fatigue; apathy; malaise; sleep disturbances; gastrointestinal complaints such as nausea, vomiting, and abdominal cramps; neurobiological symptoms such as numbness, paresthesias, muscle cramps, and staggering gait; and hypoglycemia and increased sensitivity to insulin.

Symptoms of a vitamin B5 deficiency may include

Recommended Intakes of Vitamin B5

Intake recommendations for pantothenic acid and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the National Academies of Sciences, Engineering, and Medicine. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include:

  • Recommended Dietary Allowance (RDA) – Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
  • Adequate Intake (AI) – Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.
  • Estimated Average Requirement (EAR) – Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.
  • Tolerable Upper Intake Level (UL) – Maximum daily intake unlikely to cause adverse health effects.

When the FNB evaluated the available data, it found the data insufficient to derive an EAR for pantothenic acid. Consequently, the FNB established AIs for all ages based on usual pantothenic acid intakes in healthy populations.

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Adequate Intakes (AIs) for Pantothenic Acid 
Age Male Female Pregnancy Lactation
Birth to 6 months 1.7 mg 1.7 mg
7–12 months 1.8 mg 1.8 mg
1–3 years 2 mg 2 mg
4–8 years 3 mg 3 mg
9–13 years 4 mg 4 mg
14–18 years 5 mg 5 mg 6 mg 7 mg
19+ years 5 mg 5 mg 6 mg 7 mg

Dietary Reference Intakes for Pantothenic Acid by Life Stage Group (mg/day)

Adequate Intake
Life Stage Group
0-6 mo 1.7
7-12 mo 1.8
1-3 yr 2
4-8 yr 3
9-13 yr 4
14-18 yr 5
19-30 yr 5
31-50 yr 5
51-70 yr 5
> 70 yr 5
Pregnancy
< or = 18 yr 6
19-50 yr 6
Lactation
< or = 18 yr 7
19-50 yr 7

 

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Food Source of Pantothenic Acid / Vitamin B5

Several food sources of pantothenic acid are listed bellow

 Selected Food Sources of Pantothenic Acid 
Food Milligrams
(mg) per
serving		 Percent
DV*
Breakfast cereals, fortified with 100% of the DV 10 100
Beef liver, boiled, 3 ounces 8.3 83
Shitake mushrooms, cooked, ½ cup pieces 2.6 26
Sunflower seeds, ¼ cup 2.4 24
Chicken, breast meat, skinless, roasted, 3 ounces 1.3 13
Tuna, fresh, bluefin, cooked, 3 ounces 1.2 12
Avocados, raw, ½ avocado 1.0 10
Milk, 2% milkfat, 1 cup 0.9 9
Mushrooms, white, stir-fried, ½ cup sliced 0.8 8
Potatoes, russet, flesh, and skin, baked, 1 medium 0.7 7
Egg, hard-boiled, 1 large 0.7 7
Greek yogurt, vanilla, nonfat, 5.3-ounce container 0.6 6
Ground beef, 85% lean meat, broiled, 3 ounces 0.6 6
Peanuts, roasted in oil, ¼ cup 0.5 5
Broccoli, boiled, ½ cup 0.5 5
Whole-wheat pita, 1 large 0.5 5
Chickpeas, canned, ½ cup 0.4 4
Rice, brown, medium-grain, cooked, ½ cup 0.4 4
Oats, regular and quick, cooked with water, ½ cup 0.4 4
Cheese, cheddar, 1.5 ounces 0.2 2
Carrots, chopped, raw, ½ cup 0.2 2
Cabbage, boiled, ½ cup 0.1 1
Clementine, raw, 1 clementine 0.1 1
Tomatoes, raw, chopped or sliced, ½ cup 0.1 1
Cherry tomatoes, raw, ½ cup 0 0
Apple, raw, slices, ½ cup 0 0

*DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for the values in Table 2 is 10 mg for adults and children age 4 years and older. This value, however, decreases to 5 mg when the updated Nutrition and Supplement Facts labels are implemented. The updated labels must appear on food products and dietary supplements beginning in January 2020, but they can be used now. The FDA does not require food labels to list pantothenic acid content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

The U.S. Department of Agriculture’s (USDA’s) National Nutrient Database for Standard Reference website lists the nutrient content of many foods and provides a comprehensive list of foods containing pantothenic acid arranged by pantothenic acid content and by food name.

Health Benefit of Pantothenic Acid / Vitamin B5

  • Pantothenic acid – has been used for a wide range of disorders such as acne, alopecia, allergies, burning feet, asthma, grey hair, dandruff, cholesterol-lowering, improving exercise performance, depression, osteoarthritis, rheumatoid arthritis, multiple sclerosis, stress, shingles, aging and Parkinson’s disease. It has been investigated in clinical trials for arthritis, cholesterol-lowering and exercise performance.[Mason P; Dietary Supplements,
  • The topical application of pantothenate –  is widely used in clinical practice for wound healing.
  • Pantothenic acid deficiency –  Taking pantothenic acid by mouth prevents and treats pantothenic acid deficiency.
  • Skin reactions from radiation therapy – Applying dexpanthenol, a chemical similar to pantothenic acid, to areas of irritated skin does not seem to help treat skin reactions from radiation therapy.
  • Some research suggests that taking pantothenic acid in combination with pantethine and thiamine does not improve muscular strength or endurance in well-trained athletes.
  • There is conflicting evidence regarding the usefulness of pantothenic acid in combination with large doses of other vitamins for the treatment of ADHD.
  • Early research suggests that taking dexpanthenol, a chemical similar to pantothenic acid, by mouth daily or receiving dexpanthenol shots can help treat constipation.
  • Early research suggests that using specific eye drops (Siccaprotect) containing dexpanthenol, a chemical similar to pantothenic acid, does not improve most symptoms of dry eyes.
  • Some evidence suggests that applying gel or drops containing dexpanthenol, a chemical similar to pantothenic acid, reduces some symptoms of eye trauma. However, not all research is consistent.
  • Early research suggests that pantothenic acid (given as calcium pantothenate) does not reduce symptoms of osteoarthritis.
  • There is inconsistent evidence on the potential benefits of taking pantothenic acid after surgery. Taking pantothenic acid or dexpanthenol, a chemical similar to pantothenic acid, does not seem to improve bowel function after stomach surgery. However, taking dexpanthenol by mouth might reduce other symptoms after surgery, such as sore throat.
  • Developing research suggests that pantothenic acid (given as calcium pantothenate) does not reduce the symptoms of arthritis in people with rheumatoid arthritis.
  • Early research suggests that using a specific spray (Nasicur) that contains dexpanthenol, a chemical similar to pantothenic acid, helps relieve nasal dryness.
  • Early research suggests that using a nasal spray containing dexpanthenol, a chemical similar to pantothenic acid, after sinus surgery reduces discharge from the nose, but not other symptoms.
  • Research on the effects of pantothenic acid for preventing skin irritations is not consistent. Some early research suggests that a specific product (Bepanthol Handbalsam) containing dexpanthenol, a chemical similar to pantothenic acid, does not prevent skin irritation when applied to the skin. However, other research suggests that dexpanthenol ointment can prevent skin irritation.
  • Early research suggests that using a specific ointment (Hepathrombin-50,000-Salbe Adenylchemie) containing dexpanthenol, a chemical similar to pantothenic acid, as well as heparin and allantoin reduces swelling related to ankle sprains.
  • Alcoholism.
  • Allergies.
  • Hair loss.
  • Asthma.
  • Heart problems.
  • Carpal tunnel syndrome.
  • Lung disorders.
  • Colitis.
  • Eye infections (conjunctivitis).
  • Convulsions.
  • Kidney disorders.
  • Dandruff.
  • Depression.
  • Diabetic problems.
  • Enhancing immune function.
  • Headache.
  • Hyperactivity.
  • Low blood pressure.
  • Inability to sleep (insomnia).
  • Irritability.
  • Multiple sclerosis.
  • Muscular dystrophy.
  • Muscle cramps.

References

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Dosage and Daily Allowance for Riboflavin

Dosage and Daily Allowance for Riboflavin

Dosage and Daily Allowance for Riboflavin/Riboflavin vitamin B2, is a water-soluble and heat-stable vitamin that the body uses to metabolize fats, protein, and carbohydrates into glucose for energy. In addition to boosting energy, riboflavin is used as an antioxidant for proper function of the immune system, healthy skin and hair. This is done with the help of two main coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Without an adequate amount of riboflavin, macros like carbohydrates, fats, and proteins cannot be digested and maintain the body. With a healthy digestive system, the body can absorb most of the nutrients from the diet, so it is important to get most of the riboflavin from dietary sources. Riboflavin has a yellow-green fluorescent pigment, which causes urine to turn yellow and that means the body is absorbing riboflavin. Riboflavin also helps convert tryptophan to niacin, which activates vitamin B-6. Some diseases that can be prevented with adequate riboflavin are anemia, cataracts, migraines, and thyroid dysfunction. Riboflavin is necessary for normal development, lactation, physical performance, and reproduction.

Deficiency Symptoms of Riboflavin

  • Pregnant/lactating women and infants – Pregnancy demands higher riboflavin intake as it crosses the placenta. If the maternal status is poor during gestation, the infant is likely to be born riboflavin deficient. Breast milk riboflavin content may reflect maternal intake and can be moderately increased by riboflavin concentration of the mother when maternal intake is low.
  • Schoolchildren – Riboflavin deficiency among children is demonstrated in many regions of the world where they are deprived of adequate milk and meat in their diet. Riboflavin deficiency among children in the Western world seems to be largely confined to adolescents, especially girls, because of increased metabolic demand.
  • The elderly – There is an increasing requirement of riboflavin with advancing age as a result of decreased efficiency of its absorption by the enterocytes.
  • Athletes – Some studies report that vigorous exercise may deplete riboflavin due to its consumption in the metabolic pathways.
  • Eating disorders – Young women practicing unorthodox eating habits accompanied by excessive exercise in order to lose weight have been shown to have low levels of riboflavin.
  • Migraine prophylaxis – Riboflavin may be effective for the prophylaxis of migraine (not FDA-approved) to minimize the frequency of attacks.
  • Neonates undergoing phototherapy – Hyperbilirubinemia in the neonatal period is often managed with phototherapy. But it has been shown to degrade riboflavin and cause a deficiency in the newborns. A prophylactic daily oral dose of riboflavin prevents the development of the deficiency.
  • Antiretroviral induced lactic acidosis – This rare syndrome is caused by a group of antiretroviral drugs used to treat HIV infection called nonnucleoside reverse transcriptase inhibitors (NNRTI). Discontinuation of the drug along with treatment with riboflavin causes its reversal.
  • Corneal ectasia – This is gradual corneal narrowing caused by an alteration in the collagen matrix in the stroma, resulting in protrusion of the cornea in an irregular pattern. Therapy was aimed at correcting the refractory error until 1990; however, now a radical approach targeting the pathophysiology of the disease by cross-linking the corneal fibers is undertaken where the superficial epithelium is removed, 0.1% riboflavin is applied for 30 minutes, and the cornea is treated with UVA for another 30 minutes. 

Prominent Features of Riboflavin Deficiency

Although clinical features of some vitamin deficiencies are similar and often coexist, the following are more common features of riboflavin deficiency are as follows:

  • Lips become red, dry, fissured or ulcerated.
  • Angular cheilitis is often noted
  • The tongue gets dry, atrophic, magenta red or sometimes blackish
  • Seborrheic dermatitis may be present on the face
  • Scrotum or vulva may get hyperpigmented resembling zinc deficiency
  • Conjunctivitis can occur
  • Sore throat
  • Fatigue

Recommended Daily Allowance for Riboflavin

  • Adults (Age 19-70 years): Women: 0.9 – 1.1 mg/dl and Men: 1.1 – 1.3 mg/d. [These values are based on observing clinical evidence of deficiency in intake less than 0.6 mg/d]
  • Adolescents (Age 10-18 years): 0.9 – 1.3 mg/dl
  • Children (Age 1-9 years): 0.5 – 0.6 mg/d
  • Infants (Age: 0-12 mo): 0.3 – 0.4 mg/d

Apart from supplementation in deficiency, it is also prescribed in some clinical situations as follows:


Dosage of Riboflavin

Riboflavin supplements come in 25 mg, 50 mg, and 100 mg tablets. According to the National Institutes of Health, the recommended daily nutrient intake of riboflavin is 1.3 mg for men, 1.1 mg for women, 1.3 mg for male adolescents (age 14 to 18), and 1.0 mg for female adolescents (age 14-18). It is recommended that pregnant women take 1.4 mg and breastfeeding women take 1.6 mg. For infants age of 0 to 6 months old is 0.3 mg, 7 to 12 months is 0.4 mg, 1 to 3 years old is 0.5 mg, 4 to 8 years old is 0.6 mg, and 9 to 13 years old is 0.9 mg. It is important to take riboflavin supplements between meals because absorption levels increase with food. If supplements cannot be taken orally, then injections can also be used.

[stextbox id=’warning’]

Drug Warnings

Riboflavin may cause urine to have a more yellow color than normal, especially if large doses are taken. This is to be expected and is no cause for alarm. Usually, however, riboflavin does not cause any side effects.

[/stextbox]

References

Dosage and Daily Allowance for Riboflavin


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Prominent Features of Riboflavin Deficiency

Prominent Features of Riboflavin Deficiency/Riboflavin vitamin B2, is a water-soluble and heat-stable vitamin that the body uses to metabolize fats, protein, and carbohydrates into glucose for energy. In addition to boosting energy, riboflavin is used as an antioxidant for proper function of the immune system, healthy skin and hair. This is done with the help of two main coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Without an adequate amount of riboflavin, macros like carbohydrates, fats, and proteins cannot be digested and maintain the body. With a healthy digestive system, the body can absorb most of the nutrients from the diet, so it is important to get most of the riboflavin from dietary sources. Riboflavin has a yellow-green fluorescent pigment, which causes urine to turn yellow and that means the body is absorbing riboflavin. Riboflavin also helps convert tryptophan to niacin, which activates vitamin B-6. Some diseases that can be prevented with adequate riboflavin are anemia, cataracts, migraines, and thyroid dysfunction. Riboflavin is necessary for normal development, lactation, physical performance, and reproduction.

Deficiency Symptoms of Riboflavin

  • Pregnant/lactating women and infants – Pregnancy demands higher riboflavin intake as it crosses the placenta. If the maternal status is poor during gestation, the infant is likely to be born riboflavin deficient. Breast milk riboflavin content may reflect maternal intake and can be moderately increased by riboflavin concentration of the mother when maternal intake is low.
  • Schoolchildren – Riboflavin deficiency among children is demonstrated in many regions of the world where they are deprived of adequate milk and meat in their diet. Riboflavin deficiency among children in the Western world seems to be largely confined to adolescents, especially girls, because of increased metabolic demand.
  • The elderly – There is an increasing requirement of riboflavin with advancing age as a result of decreased efficiency of its absorption by the enterocytes.
  • Athletes – Some studies report that vigorous exercise may deplete riboflavin due to its consumption in the metabolic pathways.
  • Eating disorders – Young women practicing unorthodox eating habits accompanied by excessive exercise in order to lose weight have been shown to have low levels of riboflavin.
  • Migraine prophylaxis – Riboflavin may be effective for the prophylaxis of migraine (not FDA-approved) to minimize the frequency of attacks.
  • Neonates undergoing phototherapy – Hyperbilirubinemia in the neonatal period is often managed with phototherapy. But it has been shown to degrade riboflavin and cause a deficiency in the newborns. A prophylactic daily oral dose of riboflavin prevents the development of the deficiency.
  • Antiretroviral induced lactic acidosis – This rare syndrome is caused by a group of antiretroviral drugs used to treat HIV infection called nonnucleoside reverse transcriptase inhibitors (NNRTI). Discontinuation of the drug along with treatment with riboflavin causes its reversal.
  • Corneal ectasia – This is gradual corneal narrowing caused by an alteration in the collagen matrix in the stroma, resulting in protrusion of the cornea in an irregular pattern. Therapy was aimed at correcting the refractory error until 1990; however, now a radical approach targeting the pathophysiology of the disease by cross-linking the corneal fibers is undertaken where the superficial epithelium is removed, 0.1% riboflavin is applied for 30 minutes, and the cornea is treated with UVA for another 30 minutes. 

Prominent Features of Riboflavin Deficiency

Although clinical features of some vitamin deficiencies are similar and often coexist, the following are more common features of riboflavin deficiency are as follows:

  • Lips become red, dry, fissured or ulcerated.
  • Angular cheilitis is often noted
  • The tongue gets dry, atrophic, magenta red or sometimes blackish
  • Seborrheic dermatitis may be present on the face
  • Scrotum or vulva may get hyperpigmented resembling zinc deficiency
  • Conjunctivitis can occur
  • Sore throat
  • Fatigue

Recommended Daily Allowance for Riboflavin

  • Adults (Age 19-70 years): Women: 0.9 – 1.1 mg/dl and Men: 1.1 – 1.3 mg/d. [These values are based on observing clinical evidence of deficiency in intake less than 0.6 mg/d]
  • Adolescents (Age 10-18 years): 0.9 – 1.3 mg/dl
  • Children (Age 1-9 years): 0.5 – 0.6 mg/d
  • Infants (Age: 0-12 mo): 0.3 – 0.4 mg/d

Apart from supplementation in deficiency, it is also prescribed in some clinical situations as follows:


Dosage of Riboflavin

Riboflavin supplements come in 25 mg, 50 mg, and 100 mg tablets. According to the National Institutes of Health, the recommended daily nutrient intake of riboflavin is 1.3 mg for men, 1.1 mg for women, 1.3 mg for male adolescents (age 14 to 18), and 1.0 mg for female adolescents (age 14-18). It is recommended that pregnant women take 1.4 mg and breastfeeding women take 1.6 mg. For infants age of 0 to 6 months old is 0.3 mg, 7 to 12 months is 0.4 mg, 1 to 3 years old is 0.5 mg, 4 to 8 years old is 0.6 mg, and 9 to 13 years old is 0.9 mg. It is important to take riboflavin supplements between meals because absorption levels increase with food. If supplements cannot be taken orally, then injections can also be used.

[stextbox id=’warning’]

Drug Warnings

Riboflavin may cause urine to have a more yellow color than normal, especially if large doses are taken. This is to be expected and is no cause for alarm. Usually, however, riboflavin does not cause any side effects.

[/stextbox]

References

 

Prominent Features of Riboflavin Deficiency


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Deficiency Symptoms of Riboflavin

Deficiency Symptoms of Riboflavin

Deficiency Symptoms of Riboflavin/Riboflavin vitamin B2, is a water-soluble and heat-stable vitamin that the body uses to metabolize fats, protein, and carbohydrates into glucose for energy. In addition to boosting energy, riboflavin is used as an antioxidant for proper function of the immune system, healthy skin and hair. This is done with the help of two main coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Without an adequate amount of riboflavin, macros like carbohydrates, fats, and proteins cannot be digested and maintain the body. With a healthy digestive system, the body can absorb most of the nutrients from the diet, so it is important to get most of the riboflavin from dietary sources. Riboflavin has a yellow-green fluorescent pigment, which causes urine to turn yellow and that means the body is absorbing riboflavin. Riboflavin also helps convert tryptophan to niacin, which activates vitamin B-6. Some diseases that can be prevented with adequate riboflavin are anemia, cataracts, migraines, and thyroid dysfunction. Riboflavin is necessary for normal development, lactation, physical performance, and reproduction.

Deficiency Symptoms of Riboflavin

  • Pregnant/lactating women and infants – Pregnancy demands higher riboflavin intake as it crosses the placenta. If the maternal status is poor during gestation, the infant is likely to be born riboflavin deficient. Breast milk riboflavin content may reflect maternal intake and can be moderately increased by riboflavin concentration of the mother when maternal intake is low.
  • Schoolchildren – Riboflavin deficiency among children is demonstrated in many regions of the world where they are deprived of adequate milk and meat in their diet. Riboflavin deficiency among children in the Western world seems to be largely confined to adolescents, especially girls, because of increased metabolic demand.
  • The elderly – There is an increasing requirement of riboflavin with advancing age as a result of decreased efficiency of its absorption by the enterocytes.
  • Athletes – Some studies report that vigorous exercise may deplete riboflavin due to its consumption in the metabolic pathways.
  • Eating disorders – Young women practicing unorthodox eating habits accompanied by excessive exercise in order to lose weight have been shown to have low levels of riboflavin.
  • Migraine prophylaxis – Riboflavin may be effective for the prophylaxis of migraine (not FDA-approved) to minimize the frequency of attacks.
  • Neonates undergoing phototherapy – Hyperbilirubinemia in the neonatal period is often managed with phototherapy. But it has been shown to degrade riboflavin and cause a deficiency in the newborns. A prophylactic daily oral dose of riboflavin prevents the development of the deficiency.
  • Antiretroviral induced lactic acidosis – This rare syndrome is caused by a group of antiretroviral drugs used to treat HIV infection called nonnucleoside reverse transcriptase inhibitors (NNRTI). Discontinuation of the drug along with treatment with riboflavin causes its reversal.
  • Corneal ectasia – This is gradual corneal narrowing caused by an alteration in the collagen matrix in the stroma, resulting in protrusion of the cornea in an irregular pattern. Therapy was aimed at correcting the refractory error until 1990; however, now a radical approach targeting the pathophysiology of the disease by cross-linking the corneal fibers is undertaken where the superficial epithelium is removed, 0.1% riboflavin is applied for 30 minutes, and the cornea is treated with UVA for another 30 minutes. 

Prominent Features of Riboflavin Deficiency

Although clinical features of some vitamin deficiencies are similar and often coexist, the following are more common features of riboflavin deficiency are as follows:

  • Lips become red, dry, fissured or ulcerated.
  • Angular cheilitis is often noted
  • The tongue gets dry, atrophic, magenta red or sometimes blackish
  • Seborrheic dermatitis may be present on the face
  • Scrotum or vulva may get hyperpigmented resembling zinc deficiency
  • Conjunctivitis can occur
  • Sore throat
  • Fatigue

Recommended Daily Allowance for Riboflavin

  • Adults (Age 19-70 years): Women: 0.9 – 1.1 mg/dl and Men: 1.1 – 1.3 mg/d. [These values are based on observing clinical evidence of deficiency in intake less than 0.6 mg/d]
  • Adolescents (Age 10-18 years): 0.9 – 1.3 mg/dl
  • Children (Age 1-9 years): 0.5 – 0.6 mg/d
  • Infants (Age: 0-12 mo): 0.3 – 0.4 mg/d

Apart from supplementation in deficiency, it is also prescribed in some clinical situations as follows:


Dosage of Riboflavin

Riboflavin supplements come in 25 mg, 50 mg, and 100 mg tablets. According to the National Institutes of Health, the recommended daily nutrient intake of riboflavin is 1.3 mg for men, 1.1 mg for women, 1.3 mg for male adolescents (age 14 to 18), and 1.0 mg for female adolescents (age 14-18). It is recommended that pregnant women take 1.4 mg and breastfeeding women take 1.6 mg. For infants age of 0 to 6 months old is 0.3 mg, 7 to 12 months is 0.4 mg, 1 to 3 years old is 0.5 mg, 4 to 8 years old is 0.6 mg, and 9 to 13 years old is 0.9 mg. It is important to take riboflavin supplements between meals because absorption levels increase with food. If supplements cannot be taken orally, then injections can also be used.

[stextbox id=’warning’]

Drug Warnings

Riboflavin may cause urine to have a more yellow color than normal, especially if large doses are taken. This is to be expected and is no cause for alarm. Usually, however, riboflavin does not cause any side effects.

[/stextbox]

References

 

Deficiency Symptoms of Riboflavin


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Health Benefit Dosage of Riboflavin

Health Benefit Dosage of Riboflavin

Health Benefit Dosage of Riboflavin /Riboflavin vitamin B2, is a water-soluble and heat-stable vitamin that the body uses to metabolize fats, protein, and carbohydrates into glucose for energy. In addition to boosting energy, riboflavin is used as an antioxidant for proper function of the immune system, healthy skin and hair. This is done with the help of two main coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Without an adequate amount of riboflavin, macros like carbohydrates, fats, and proteins cannot be digested and maintain the body. With a healthy digestive system, the body can absorb most of the nutrients from the diet, so it is important to get most of the riboflavin from dietary sources. Riboflavin has a yellow-green fluorescent pigment, which causes urine to turn yellow and that means the body is absorbing riboflavin. Riboflavin also helps convert tryptophan to niacin, which activates vitamin B-6. Some diseases that can be prevented with adequate riboflavin are anemia, cataracts, migraines, and thyroid dysfunction. Riboflavin is necessary for normal development, lactation, physical performance, and reproduction.

Deficiency Symptoms of Riboflavin

  • Pregnant/lactating women and infants – Pregnancy demands higher riboflavin intake as it crosses the placenta. If the maternal status is poor during gestation, the infant is likely to be born riboflavin deficient. Breast milk riboflavin content may reflect maternal intake and can be moderately increased by riboflavin concentration of the mother when maternal intake is low.
  • Schoolchildren – Riboflavin deficiency among children is demonstrated in many regions of the world where they are deprived of adequate milk and meat in their diet. Riboflavin deficiency among children in the Western world seems to be largely confined to adolescents, especially girls, because of increased metabolic demand.
  • The elderly – There is an increasing requirement of riboflavin with advancing age as a result of decreased efficiency of its absorption by the enterocytes.
  • Athletes – Some studies report that vigorous exercise may deplete riboflavin due to its consumption in the metabolic pathways.
  • Eating disorders – Young women practicing unorthodox eating habits accompanied by excessive exercise in order to lose weight have been shown to have low levels of riboflavin.
  • Migraine prophylaxis – Riboflavin may be effective for the prophylaxis of migraine (not FDA-approved) to minimize the frequency of attacks.
  • Neonates undergoing phototherapy – Hyperbilirubinemia in the neonatal period is often managed with phototherapy. But it has been shown to degrade riboflavin and cause a deficiency in the newborns. A prophylactic daily oral dose of riboflavin prevents the development of the deficiency.
  • Antiretroviral induced lactic acidosis – This rare syndrome is caused by a group of antiretroviral drugs used to treat HIV infection called nonnucleoside reverse transcriptase inhibitors (NNRTI). Discontinuation of the drug along with treatment with riboflavin causes its reversal.
  • Corneal ectasia – This is gradual corneal narrowing caused by an alteration in the collagen matrix in the stroma, resulting in protrusion of the cornea in an irregular pattern. Therapy was aimed at correcting the refractory error until 1990; however, now a radical approach targeting the pathophysiology of the disease by cross-linking the corneal fibers is undertaken where the superficial epithelium is removed, 0.1% riboflavin is applied for 30 minutes, and the cornea is treated with UVA for another 30 minutes. 

Prominent Features of Riboflavin Deficiency

Although clinical features of some vitamin deficiencies are similar and often coexist, the following are more common features of riboflavin deficiency are as follows:

  • Lips become red, dry, fissured or ulcerated.
  • Angular cheilitis is often noted
  • The tongue gets dry, atrophic, magenta red or sometimes blackish
  • Seborrheic dermatitis may be present on the face
  • Scrotum or vulva may get hyperpigmented resembling zinc deficiency
  • Conjunctivitis can occur
  • Sore throat
  • Fatigue

Recommended Daily Allowance for Riboflavin

  • Adults (Age 19-70 years): Women: 0.9 – 1.1 mg/dl and Men: 1.1 – 1.3 mg/d. [These values are based on observing clinical evidence of deficiency in intake less than 0.6 mg/d]
  • Adolescents (Age 10-18 years): 0.9 – 1.3 mg/dl
  • Children (Age 1-9 years): 0.5 – 0.6 mg/d
  • Infants (Age: 0-12 mo): 0.3 – 0.4 mg/d

Apart from supplementation in deficiency, it is also prescribed in some clinical situations as follows:


Dosage of Riboflavin

Riboflavin supplements come in 25 mg, 50 mg, and 100 mg tablets. According to the National Institutes of Health, the recommended daily nutrient intake of riboflavin is 1.3 mg for men, 1.1 mg for women, 1.3 mg for male adolescents (age 14 to 18), and 1.0 mg for female adolescents (age 14-18). It is recommended that pregnant women take 1.4 mg and breastfeeding women take 1.6 mg. For infants age of 0 to 6 months old is 0.3 mg, 7 to 12 months is 0.4 mg, 1 to 3 years old is 0.5 mg, 4 to 8 years old is 0.6 mg, and 9 to 13 years old is 0.9 mg. It is important to take riboflavin supplements between meals because absorption levels increase with food. If supplements cannot be taken orally, then injections can also be used.

[stextbox id=’warning’]

Drug Warnings

Riboflavin may cause urine to have a more yellow color than normal, especially if large doses are taken. This is to be expected and is no cause for alarm. Usually, however, riboflavin does not cause any side effects.

[/stextbox]

References

 

Health Benefit Dosage of Riboflavin


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Amygdalin; Food Source, Health Benefits

Amygdalin is found in almond. Bitter glycoside of the Rosaceae, found especially in kernels of cherries, peaches and apricots. Amygdalin is present in cold-pressed bitter almond oil from the above sources prior to enzymic hydrolysis and steam distillation for food use Amygdalin , C20H27NO11, is a glycoside initially isolated from the seeds of the tree Prunus dulcis, also known as bitter almonds, by Pierre-Jean Robiquet and A. F. Boutron-Charlard in 1803, and subsequently investigated by Liebig and Wohler in 1830, and others. Several other related species in the genus of Prunus, including apricot (Prunus armeniaca) and black cherry (Prunus serotina), also contain amygdalin. It was promoted as a cancer cure by Ernst T. Krebs under the name “Vitamin B17“, but studies have found it to be ineffective. Amygdalin is sometimes confounded with laevomandelonitrile, also called laetrile for short; however, amygdalin and laetrile are different chemical compounds.

Amygdalin is a cyanogenic glucoside isolated from almonds and seeds of other plants of the family Rosaceae. Amygdalin is converted by plant emulsion (a combination of a-glucosidase and a nitrilase) or hydrochloric acid into benzaldehyde, D-glucose, and hydrocyanic acid. (NCI04)

Food Source of Amygdalin

Amygdalin is found in almond. Bitter glycoside of the Rosaceae, found especially in kernels of cherries, peaches and apricots. Amygdalin is present in cold-pressed bitter almond oil from the above sources prior to enzymic hydrolysis and steam distillation for food use Amygdalin , C20H27NO11, is a glycoside initially isolated from the seeds of the tree Prunus dulcis, also known as bitter almonds, by Pierre-Jean Robiquet and A. F. Boutron-Charlard in 1803, and subsequently investigated by Liebig and Wohler in 1830, and others. Several other related species in the genus of Prunus, including apricot (Prunus armeniaca) and black cherry (Prunus serotina), also contain amygdalin. It was promoted as a cancer cure by Ernst T. Krebs under the name “Vitamin B17“, but studies have found it to be ineffective. Amygdalin is sometimes confounded with laevomandelonitrile, also called laetrile for short; however, amygdalin and laetrile are different chemical compounds.

References

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Vitamin B18

Vitamin B18 (Choline), Functions, Food Source, Benefits

Vitamin B18 (Choline) is a water-soluble nutrient and a new member of the vitamin B family.  Since all the numbers of the vitamin B family have been already taken, we, at the Canadian Academy of Sports Nutrition, have named choline as the “vitamin B18” for the first time. Being referred to as a “lipotropic agent”, choline is considered a “conditionally essential” nutrient in that de novo synthesis occurs in the liver.

Functions of Choline Vitamin B18 (Choline)

  • It is a precursor for acetylcholine, phospholipids, and betaine.
  • It is required for the metabolism of fat and cholesterol.
  • It is necessary for the integrity of cell membranes and transmembrane signaling.
  • It helps with the utilization of fats in the body (lipotropic).
  • It has an important role in the detoxification system.
  • It is vital for the myelin sheaths of the nerves and normal function of the liver and gallbladder.

Food Sources and Absorption Vitamin B18 (Choline)

  • The highest amount of choline is found in phosphatidylcholine (lecithin), which is usually extracted from soybeans. Other food sources are brewer`s yeast, wheat germ, egg yolk, organ meats, flaxseeds, sesame seeds, and peanuts. Small amounts can be found in potatoes, lentils, cauliflowers, and oats. This vitamin is manufactured by the liver as well.
  • Choline is absorbed well from the small intestine and can easily cross the blood-brain barrier into the spinal fluid and brain wherein it is used to produce the neurotransmitter acetylcholine.

Athletic Benefits of Choline

Heavy exercise and intense training lower the levels of choline in the body. Being claimed as a sport ergogenic aid, choline may demonstrate the following athletic benefits:

  • It may improve exercise recovery.
  • It may enhance mental acuity.
  • It may increase endurance performance.
  • It may prevent post-exercise muscle damage (rhabdomyolysis).under the section of “Athletic Disorders”.
  • It may diminish exercise-induced fatigue.

Non-Athletic Benefits of Choline

Choline may be beneficial in the following conditions:

Choline Deficiency

Choline deficiency results in a wide range of health concerns, such as fatty liver, elevated liver enzymes, skeletal muscle damage with elevated levels of creatine phosphokinase, and fatigue. It has been also linked to insomnia, high levels of homocysteine, and heart diseases.

Dosage and Side Effects:

The recommended adequate intakes of choline for men and women are 550 mg per day and 425 mg per day, respectively. The PDI (performance daily intake) of choline for athletes and physically active men and women is 600 – 1200 mg a day. The upper limit for choline has been set at 3500 mg a day.

Choline is available either as 250 mg, 500 mg, and 1000 mg and usually combined with inositol (vitamin B8) or as lecithin at 1200 mg. One pill of lecithin provides about 50 mg of choline.

Larger doses of choline may cause stomach upset, nausea, vomiting, diarrhea, sweating, and fishy body odor (due to breakdown of choline to trimethylamine in the GI tract).

People with fish odor syndrome (trimethylaminuria) should avoid taking choline supplements.

References

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Why is WordPress site so slow? Lets Go For Speedup

Why is WordPress site so slow? Lets Go For Speedup/Improving your website’s speed is something you should worry about the most during a technical audit. Generally, users prefer to browse sites that have better page loading speed and there are numerous online tools that offer detailed insights on your website speed performance.

Increasing the speed of a site starts with your WordPress web hosting. It is not much different than the process used for optimizing a website hosted on a shared or a dedicated server. For that reason, you might find some of the tools like Breeze mentioned below as being similar to what you were doing to your shared website.

How To Improving Your Website’s Speed

Why is WordPress site so slow?

Use a Good Web Hosting Plan

  • It really all starts with choosing the right WordPress hosting plan with the right hosting company. Even before talking about speed, you must have a reliable company with solid and reliable hardware to host your website. If your site is unreliable, it doesn’t matter how fast it performs. Visitors will run away and never come back. Do your homework and check out user reviews for hosting companies.
  • Getting back to speed up your website, most hosting companies, such as Bluehost, offer a range of hosting plans, starting with inexpensive shared hosting and moving up through virtual servers, dedicated servers, and cloud servers. The prices increase as you move up through the different types of hosting, but the number of resources dedicated to your website also increases.
  • While it is OK, to begin with, shared hosting when you are just starting your site, be sure to regularly track your traffic volume and resource usage so that you can upgrade to a better hosting plan before visitors start noticing your site is sluggish.

Enable Caching

  • Simply put, caching is the technical term for storing data in a temporary storage area. This improves a site’s performance since a lot of a page’s content is already prepared and available and does not need to be fetched and processed in order to be displayed for a user. It also reduces the load of various system resources on your server.
  • We recommend you use the caching plugins provided by Bluehost, that are built to work best in that environment. You can find these cache settings on the performance page of the Bluehost plugin or WordPress section of the control panel.
  • If your site is not a WordPress site, enabling caching is more complex and beyond the scope of this article. In either case, you should discuss caching options with your hosting provider, since they will often have recommendations based on the optimizations they have implemented on their end.

Use Light Weight Theme

  • There are many shiny and beautiful themes in the WordPress market. But don’t forget, themes with a lot of dynamic content, widgets, slider, sidebar, etc., can cause your hosting server to respond slowly.
  • Always optimize the WordPress theme or use a lightweight WordPress theme. The default WordPress themes can be enough if you want to run a blogging website. For more features, you can use themes that are built on Bootstrap and Foundation.
  • The best option here is to use lightweight themes, like WordPress’ default themes. The new Twenty Fifteen theme is always a good way to start off a blog. For a feature-rich website, you can also opt for a theme that uses a good framework like Bootstrap or Foundation. For instance, all themes at ThemeIsle are built on top of Bootstrap, which provides a great way to speed up WordPress.

Control Post Revisions

  • No doubt, post revision is a great feature in WordPress. But, not every feature is feasible for everyone. There are few users with low disk and database space.
  • In post revisions, every time you change the content, a new copy of the post is saved in the database rather than deleting the previous one. So that you can always have a chance to revert. It increases the database size, and a large size database can cause many problems.
  • You can limit the frequency to autosave a post. From the root folder of your WordPress installation, open wp-config file with any file editor and write any of the below code before the code requirements.

Optimize Your WordPress site’s Homepage

  • Another thing you can do to speed up a WordPress site is to optimize your homepage. Make it look simpler, without clustered content and useless widgets or tools.
  • Also, don’t show the posts at their full length. You can show only the first paragraph or a specific excerpt from the text. Displaying too many posts on the same page could cause a longer loading time as well.

Things that you can do include

  • Show excerpts instead of full posts
  • Reduce the number of posts on the page (I like showing between 5-7)
  • Remove unnecessary sharing widgets from the home page (include them only in posts)
  • Remove inactive plugins and widgets that you don’t need
  • Keep in minimal! Readers are here for content, not 8,000 widgets on the homepage

Reduce Image Sizes

Images are the major contributors to the size increment of a given webpage. The trick is to reduce the size of the images without compromising on the quality.

  • If you manually optimize the images using Chrome PageSpeed Insights extension or Photoshop or any other tools, the process will take a long time. Fortunately, there are plugins available for just about everything you can think of, including image optimization.
  • Using any of the above-mentioned plugins on your WordPress site will drastically reduce image sizes, thus improving the speed of your website.
  • Images bring life to your content and help boost engagement. Researchers have found that using colored visuals makes people 80% more likely to read your content.
  • However, if your images aren’t optimized, then they could be hurting more than helping. In fact, non-optimized images are one of the most common speed issues that we see on beginner websites.
  • Before you upload a photo directly from your phone or camera, we recommend that you use photo editing software to optimize your images for the web.
  • Well, the PNG image format is uncompressed. When you compress an image it loses some information, so an uncompressed image will be higher quality with more detail. The downside is that it’s larger file size, so it takes longer to load.

JPEG, on the other hand, is a compressed file format that slightly reduces image quality, but it’s significantly smaller in size.

So how do we decide which image format to choose?

  • If our photo or image has a lot of different colors, then we use JPEG.
  • If it’s a simpler image or we need a transparent image, then we use PNG.

The majority of our images are JPEGs.

Minify JS and CSS files

  • If you run your website through the Google PageSpeed Insights tool, you will probably be notified about minimizing the size of your CSS and JS files. What this means is that by reducing the number of CSS and JS calls and the size of those files, you can improve the site loading speed.
  • Also, if you know your way around WordPress themes, you can study the guides provided by Google and do some manual fixing. If not, then there are plugins that will help you achieve this goal; the most popular being the Autoptimize that can help in optimizing CSS, JS and even HTML of your WordPress website.
  • If you test your WordPress website with Google PageSpeed Insights or slow, you’ll be prompt up with a warning to minify JavaScript and CSS files. That means you need to reduce JS and CSS calls to reduce server response time and minify file sizes. By reducing them, you’ll observe site-loading speed becomes much faster than before. This will eventually help you to save bandwidth usage.

Use a CDN

  • The people who visit your website belong to various locations in the world, and needless to say, the site-loading speed will differ if the visitors are located far away from where your site is hosted. There are many CDN (Content Delivery Networks) that help in keeping the site-loading speed to a minimum for visitors from various countries. A CDN keeps a copy of your website in various data centers located in different places. The primary function of a CDN is to serve the webpage to a visitor from the nearest possible location. Cloudflare and MaxCDN are among the most popular CDN services.
  • For example, let’s say your web hosting company has its servers in the United States. A visitor who’s also in the United States will generally see faster loading times than a visitor in India.
  • Using a Content Delivery Network (CDN) can help to speed up loading times for all of your visitors. A CDN is a network made up of servers all around the world. Each server will store “static” files used to make up your website. These static files include unchanging files such as images, CSS, and JavaScript, unlike your WordPress pages which are “dynamic” as explained above.
  • When you use a CDN, every time a user visits your website they are served those static files from whichever server is closest to them. Your own web hosting server will also be faster since the CDN is doing a lot of the work


Enable GZIP compression

  • Compressing files on your local computer can save a lot of disk space. Similarly, for the web, we can use GZIP compression. This maneuver will dramatically reduce the bandwidth usage and the time it takes to gain access to your website. GZIP compresses various files so that whenever a visitor tries to access your website; their browser will first have to unzip the website. This process brings down the bandwidth usage to a considerable extent.

You can use either a plugin like the PageSpeed Ninja, which enables GZIP compression or add the following codes in your .htaccess file.

AddOutputFilterByType DEFLATE text/plain
AddOutputFilterByType DEFLATE text/html
AddOutputFilterByType DEFLATE text/xml
AddOutputFilterByType DEFLATE text/css
AddOutputFilterByType DEFLATE application/xml
AddOutputFilterByType DEFLATE application/xhtml+xml
AddOutputFilterByType DEFLATE application/rss+xml
AddOutputFilterByType DEFLATE application/javascript
AddOutputFilterByType DEFLATE application/x-javascript

Cleanup WordPress Database

  • Deleting unwanted data from your database will keep its size to a minimum and also helps in reducing the size of your backups. It is also necessary to delete spam comments, fake users, old drafts of your content and maybe even unwanted plugins as well as themes. All of this will reduce the size of your databases and web files, and thus speed up WordPress – your WordPress.

Deactivate or Uninstall Plugins

  • Keeping unwanted plugins on your WordPress websites will add a tremendous amount of junk to your web files. Moreover, it will also increase the size of your backup and put an overwhelming amount of load on your server resources while backup files are being generated. It is better to get rid of the plugins that you don’t use and also look for alternate methods to use third-party services for automating or scheduling tasks (like sharing of your latest posts to social media).
  • IFTTT or Zapier are two web services that help in automating such tasks and reduce the burden on your website and server resources.

Keep External Scripts to a Minimum

  • The usage of external scripts on your web pages adds a big chunk of data to your total loading time. Thus, it is best to use a low number of scripts, including only the essentials such as tracking tools (like Google Analytics) or commenting systems (like Disqus).

Disable Pingbacks and Trackbacks

  • Pingbacks and trackbacks are two core WordPress components that alert you whenever your blog or page receives a link. It might sound useful, but you also have things such as Google Webmaster Tools and other services to check the links of your website.
  • Keeping pingbacks and trackbacks on can also put an undesirable amount of strain on your server resources. This is so because whenever anyone tries to link up to your site, it generates requests from WordPress back and forth. This functionality is also widely abused when targeting a website with DDoS attacks.

Use Latest PHP Version

  • WordPress is mainly written in the PHP programming language. It is a server-side language, which means it is installed and runs on your hosting server.
  • All good WordPress hosting companies use the most stable PHP version on their servers. However, it is possible that your hosting company is running a slightly older PHP version.
  • The newer PHP 7 is two times faster than its predecessors. That’s a huge performance boost that your website must take advantage of.

Upon activation, the plugin will show your PHP version in the footer area of your WordPress admin dashboard.

How To Improving Your Website’s Speed

  • If your website is using a version lower than PHP 7, then ask your hosting provider to update it for you. If they are unable to do so, then it is time to find a new WordPress hosting company. That’s it! We hope this article helped you learn how to improve WordPress speed and performance.
  • Go ahead and try out these techniques. Don’t forget to test your website speed before and after implementing these best practices. You’ll be surprised these changes will boost your WordPress performance.

Decrease Server Requests

A server request happens every time your browser asks some type of resource from your server. This can be a file like a style sheet, a script or an image.

The more server requests necessary to complete loading your site, the longer it will take. As a consequence, requests should be as few as possible. Here are a few things you can do to reduce them to a minimum:

  • Lower the number of posts shown on a page
  • Only show post excerpts, no full posts on your archive pages (find the option under Settings > Reading)
  • Split longer posts into pages it’s easy
  • If you get a lot of comments, break them up into several pages (Settings > Discussion)
  • Reduce the number of images and other elements on your page
  • Uninstall unnecessary plugins, especially slower ones (find them with this plugin)
  • Deactivate plugins you are not using permanently
  • Enable lazy loading to delay loading images until they are actually visible on the page
  • Reduce external resources such as fonts if they aren’t necessary

Turn off Pingbacks and Trackbacks

  • By default, WordPress interacts with other blogs that are equipped with pingbacks and trackbacks.
  • Every time another blog mentions you, it notifies your site, which in turn updates data on the post. Turning this off will not destroy the backlinks to your site, just the setting that generates a lot of work for your site.
  • For more detail, read this explanation of WordPress Pingbacks, Trackbacks and Linkbacks.

Look for Inactive Plugins or for Plugins that Don’t Work Properly

  • Another solution to speed up a WordPress site is by verifying if your current plugins are working correctly. Everyone uses various plugins and tools for various needs. They sometimes cause lag in your website, rendering it slow to load. You might give it a try and see how fast they are working.
  • To do the tests, you can get another plugin. It’s called the Query Monitor. This plugin is free and once installed, it will report any performance problems with your website. If there are plugins that slow down your website, remove them or try to find alternatives. Also, keeping a large number of active plugins will affect your WordPress site speed as well.

Testing and Digging Deeper

  • There is really a lot more to site optimization than what we’ve discussed here. However, these are five steps that will give you the most bang for the buck. For those of you who want to learn more and/or further optimize your website, I’d like to leave you with a list of three popular performance analysis sites (all with very useful free versions). These tools will run a series of tests on your site to identify performance issues and direct you as to how to correct them.

Disable Hotlinking and Leaching of Your Content

  • If you’re creating quality content on your WordPress site, then the sad truth is that it’ll probably get stolen sooner or later.
  • One way this happens is when other websites serve your images directly from their URLs on your website, instead of uploading them to their own servers. In effect, they’re stealing your web hosting bandwidth, and you don’t get any traffic to show for it.

Simply add this code to your .htaccess file to block hotlinking of images from your WordPress site.

[stextbox id=’grey’]

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#disable hotlinking of images with forbidden or custom image option
RewriteEngine on
RewriteCond %{HTTP_REFERER} !^$
RewriteCond %{HTTP_REFERER} !^http(s)?://(www\.)?wpbeginner.com [NC]
RewriteCond %{HTTP_REFERER} !^http(s)?://(www\.)?google.com [NC]
RewriteRule \.(jpg|jpeg|png|gif)$ – [NC,F,L]

[/stextbox]

Note: Don’t forget to change wpbeginner.com with your own domain.

  • You may also want to check our article showing 4 ways to prevent image theft in WordPress. Some content scraping websites automatically create posts by stealing your content from your RSS feed. You can check out our guide on preventing blog content scraping in WordPress for ways to deal with automated content theft.

What Slows Down Your WordPress Website?

Your speed test report will likely have multiple recommendations for improvement. However, most of that is technical jargon which is hard for beginners to understand.

  • Learning what slows down your website is the key to improving performance and making smarter long-term decisions.

The primary causes of a slow WordPress website are:

  • Web Hosting – When your web hosting server is not properly configured it can hurt your website speed.
  • WordPress Configuration – If your WordPress site is not serving cached pages, then it will overload your server thus causing your website to be slow or crash entirely.
  • Page Size – Mainly images that aren’t optimized for the web.
  • Bad Plugins – If you’re using a poorly coded plugin, then it can significantly slow down your website.
  • External scripts – External scripts such as ads, font loaders, etc can also have a huge impact on your website performance.

Now that you know what slows down your WordPress website, let’s take a look at how to speed up your WordPress website.

Server and Hosting Technology

At the very bottom of how quickly a page load is a server it is hosted on, it’s location and your WordPress hosting plan. Let’s start with the latter.

Generally, there are three different types of hosting:

  • Shared hosting — That means your site lies on the same server as a number of other websites and needs to share its resources (processing power, RAM) with everyone else. This can lead to “bad neighbor” effects where one site is hogging the majority of resources and downtimes due to overload.
  • Virtual private server (VPS) — With this type of hosting, you usually have fewer sites on the same server. In addition, resources are allocated evenly across all sites present without the option to exceed them.
  • Dedicated server — You have one server just for you. There are no resources to share, everything is at the disposal of just your site.

In addition to the type of hosting, the technology used in the servers (both hardware and software) is also important. For example, does your server use the latest versions of PHP, HTML and other web techs? How about SSD hard drives? How much memory does it have? All that factors into how quickly it can serve up your website files.


References

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Dosage of Probiotics

Dosage of Probiotics, Mechanism, Contraindications

Dosage of Probiotics/Probiotics mean live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. These microorganisms, which consist mainly of bacteria but also include yeasts, are naturally present in fermented foods, may be added to other food products, and are available as dietary supplements. However, not all foods and dietary supplements labeled as probiotics on the market have proven health benefits.[rx]

Probiotics should not be confused with prebiotics, which is typically complex carbohydrates (such as inulin and other fructooligosaccharides) that microorganisms in the gastrointestinal tract used as metabolic fuel [rx]. Commercial products containing both prebiotic sugars and probiotic organisms are often called synbiotics. In addition, products containing dead microorganisms and those made by microorganisms (such as proteins, polysaccharides, nucleotides, and peptides) are, by definition, not probiotics.

Probiotics may be defined as selected viable microorganisms that, following consumption in a food or feed, have the potential for improving the health or nutrition of man or animal. Bacteria in this group may be used to ferment food or are added to food as dietary supplements. Foods for human consumption containing these organisms are sometimes referred to as functional foods. A number of different bacterial species have been suggested as probiotics (Table 1). The major species that have been considered over the years, however, are Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium species, and Bifidobacterium longum [].

Types of Probiotics

Many types of bacteria are classified as probiotics. They all have different benefits, but most come from two groups. Ask your doctor about which might best help you.

  • Lactobacillus – This may be the most common probiotic. It’s the one you’ll find in yogurt and other fermented foods. Different strains can help with diarrhea and may help people who can’t digest lactose, the sugar in milk.
  • Bifidobacterium – You can find it in some dairy products. It may help ease the symptoms of irritable bowel syndrome (IBS) and some other conditions.
  • Saccharomyces boulardii – is a yeast found in probiotics. It appears to help fight diarrhea and other digestive problems.

Food Source of Probiotics

  • Ingredients – Lactobacillus casei (Lc-11), Lactobacillus acidophilus (La-14), Lactobacillus paracasei (LPC-37), Lactobacillus Salivarius (Ls-33), Lactobacillus Plantarum (Lp-115), Bifidobacterium lactis (Bl-04), Bifidobacterium bifidum (Bb-02), Bifidobacterium longum (Bl-05), Bifidobacterium breve, Lactobacillus Bulgaricus (Lb-87), Jerusalem Artichoke Root (Organic), Gum Arabic tree exudate from stem and branches (Organic), Fibergum Bio Chicory Root powder (Cichorium intybus) (Organic), Vegetable capsule (Hydroxypropylmethylcellulose and water), Maltodextrin (Rice), L-Leucine (natural)
  • Probiotics that are naturally found in your intestines include – Saccharomyces boulardii (a yeast) and bacteria in the Lactobacillus and Bifidobacterium families of microorganisms. (Outside of the body, Lactobacillus acidophilus is the probiotic that is found in some yogurts.)
  • Foods that contain probiotics include – some juices and soy drinks; fermented and unfermented milk; buttermilk; some soft cheeses; miso; tempeh; kefir; kimchi; sauerkraut; many pickles; and yogurt (probably the most well-known food product that contains probiotics).
  • Supplements – Dietary probiotic supplements — which are available in capsules, tablets, powders and liquid extracts — each contain a specific type of probiotic. These products are available at health food and natural food stores, vitamin shops, and other stores. As an example, one commonly used supplement is Acidophilus, which is available from several supplement manufacturers.

Fruit, vegetables, cereals, and other edible plants are sources of carbohydrates constituting potential prebiotics. The following may be mentioned as such potential sources:

  • Tomatoes
  • Artichokes
  • Bananas
  • Asparagus
  • Berries
  • Garlic
  • Onions
  • Chicory
  • Green vegetables
  • Legumes, as well as oats
  • Linseed
  • Barley, and wheat [].

Some artificially produced prebiotics are, among others

  • Lactulose
  • Galactooligosaccharides
  • Fructooligosaccharides
  • Maltooligosaccharides
  • Cyclodextrins, and
  • Lactosaccharose.
  • Lactulose constitutes a significant part of produced oligosaccharides (as much as 40%).
  • Fructans, such as inulin and oligofructose, are believed to be the most used and effective in relation to many species of probiotics [].

[stextbox id=’custom’]

Bacteria used as probiotics

Major bacteria
 Lactobacillus acidophilus
 Lactobacillus casei
 Bifidobacterium longum
 Bifidobacterium bifidum
Others
 Lactobacillus ruterii
 Lactobacillus johnsonii
 Bifidobacterium lactis
 Lactobacillus Plantarum

 

[/stextbox]

Probiotics contain three potent prebiotics

  • Organic Jerusalem Artichoke Root – Loaded with inulin, a dietary fiber that probiotics devour to push out harmful molecules in your gut. Jerusalem artichoke root is one of the top inulin-rich foods. 76% of its fiber comes from inulin.
  • Organic Fibregum Bio – A patented, GMO-free prebiotic that restores the tight spaces between the cells lining.
  • Organic Chicory Root – The most inulin-rich food on earth! In conjunction with probiotics it Chicory Root has been shown to help support digestive health, reduce gas, bloating, and stomach discomfort.


Mechanisms of Action of Probiotics

The human gastrointestinal tract is colonized by many microorganisms, including bacteria, archaea, viruses, fungi, and protozoa. The activity and composition of these microorganisms (collectively known as the gut microbiota, microbiome, or intestinal microflora) can affect human health and disease.

Probiotics exert their effects usually in the gastrointestinal tract, where they may influence the intestinal microbiota. Probiotics can transiently colonize the human gut mucosa is highly individualized patterns, depending on the baseline microbiota, probiotic strain, and gastrointestinal tract region [rx].

Probiotics also exert health effects by nonspecific, species-specific, and strain-specific mechanisms [rx]. The nonspecific mechanisms vary widely among strains, species, or even genera of commonly used probiotic supplements. These mechanisms include inhibition of the growth of pathogenic microorganisms in the gastrointestinal tract (by fostering colonization resistance, improving intestinal transit, or helping normalize a perturbed microbiota), production of bioactive metabolites (e.g., short-chain fatty acids), and reduction of luminal pH in the colon. Species-specific mechanisms can include vitamin synthesis, gut barrier reinforcement, bile salt metabolism, enzymatic activity, and toxin neutralization. Strain-specific mechanisms, which are rare and are used by only a few strains of a given species, including cytokine production, immunomodulation, and effects on the endocrine and nervous systems. Through all of these mechanisms, probiotics might have wide-ranging impacts on human health and disease.

Because the effects of probiotics can be specific to certain probiotic species and strains, recommendations for their use in the clinic or in research studies need to be species and strain-specific [rx,rx,rx]. Furthermore, pooling data from studies of different types of probiotics can result in misleading conclusions about their efficacy and safety.

Dietary Supplements of Probiotics

Probiotics are also available as dietary supplements (in capsules, powders, liquids, and other forms) containing a wide variety of strains and doses [rx]. These products often contain mixed cultures of live microorganisms rather than single strains. The effects of many commercial products containing probiotics have not been examined in research studies, and it is difficult for people not familiar with probiotic research to determine which products are backed by evidence. However, some organizations have systematically reviewed the available evidence and developed recommendations on specific probiotics—including appropriate product, dose, and formulation—to use for preventing or treating various health conditions [rx,rx].

Probiotics are measured in colony-forming units (CFU), which indicate the number of viable cells. Amounts may be written on product labels as, for example, 1 x 109 for 1 billion CFU or 1 x 1010 for 10 billion CFU. Many probiotic supplements contain 1 to 10 billion CFU per dose, but some products contain up to 50 billion CFU or more. However, higher CFU counts do not necessarily improve the product’s health effects.

Indications of Probiotics

As food products or dietary supplements, probiotics are under preliminary research to evaluate if they provide any effect on health.[rx][rx] In all cases proposed as health claims to the European Food Safety Authority, the scientific evidence remains insufficient to prove a cause-and-effect relationship between consumption of probiotic products and any health benefit.[rx][rx] There is no scientific basis for extrapolating an effect from a tested strain to an untested strain.[rx][rx] Improved health through gut flora modulation appears to be directly related to long-term dietary changes.[rx] According to the National Center for Complementary and Integrative Health: “Although some probiotics have shown promise in research studies, strong scientific evidence to support specific uses of probiotics for most health conditions is lacking.”[rx] Claims that some lactobacilli may contribute to weight gain in some humans[rx][rx] remain controversial.

  • Allergies – No good evidence shows that probiotics are effective in preventing or treating allergies.[rx]
  • Antibiotic-associated diarrhea – Antibiotics are a common treatment for children, with 11% to 40% of antibiotic-treated children developing diarrhea. Antibiotic-associated diarrhea (AAD) results from an imbalance in the colonic microbiota caused by antibiotic therapy.[rx] These microbial community alterations result in changes in carbohydrate metabolism, with decreased short-chain fatty acid absorption and osmotic diarrhea as a result. A 2015 Cochrane review concluded that a protective effect of some probiotics existed for AAD in children.[rx] In adults, some probiotics showed a beneficial role in reducing the occurrence of AAD and treating Clostridium difficile disease.[rx]
  • Blood pressure – As of 2017, only limited evidence indicated any direct link between high blood pressure and gut microbiota.[rx]
  • Cholesterol – A 2002 meta-analysis that included five double-blind trials examining the short-term (2–8 weeks) effects of a yogurt with probiotic strains on serum cholesterol levels found little effect of 8.5 mg/dl (0.22 mmol/l) (4% decrease) in total cholesterol concentration, and a decrease of 7.7 mg/dl (0.2 mmol/l) (5% decrease) in serum LDL concentration.[rx]
  • Eczema – Probiotics are commonly given to breast-feeding mothers and their young children to prevent eczema, but no good evidence shows they are effective for this purpose.[rx][rx]
  • Helicobacter pylori – Some strains of lactic acid bacteria (LAB) may affect Helicobacter pylori infections (which may cause peptic ulcers) in adults when used in combination with standard medical treatments, but no standard in medical practice or regulatory approval exists for such treatment.[rx] The only peer-reviewed treatments for H. pylori to date all include various Antibiotic Regimes.[rx]
  • Immune function and infections – Some strains of LAB may affect pathogens by means of competitive inhibition (i.e., by competing for growth) and some evidence suggests they may improve immune function by increasing the number of IgA-producing plasma cells and increasing or improving phagocytosis, as well as increasing the proportion of T lymphocytes and natural killer cells.[rx][rx]
  • Inflammatory bowel disease – Probiotics are being studied for their potential to influence inflammatory bowel disease. Some evidence supports their use in conjunction with standard medications in treating ulcerative colitis and no evidence shows their efficacy in treating Crohn’s disease.
  • Irritable bowel syndrome – Probiotics are under study for their potential to affect irritable bowel syndrome, although uncertainty remains around which type of probiotic works best, and around the size of possible effect.[rx][rx]
  • Necrotizing enterocolitis – Several clinical studies provide evidence for the potential of probiotics to lower the risk of necrotizing enterocolitis and mortality in premature infants. One meta-analysis indicated that probiotics reduce these risks by more than 50% compared with controls.[rx]
  • Recurrent abdominal pain – A 2017 review based on moderate to low-quality evidence suggests that probiotics may be helpful in relieving pain in the short term in children with recurrent abdominal pain, but the proper strain and dosage are not known.[rx]
  • Urinary tract – Research has been promising for these friendly critters. Potential benefits of probiotics have been seen in the treatment or prevention of

Gastrointestinal Conditions

Conditions in Infants

  • Infant Colic
  • Necrotizing Enterocolitis
  • Sepsis in Infants

Dental Disorders

  • Dental Caries (Tooth Decay)
  • Periodontal Diseases (Gum Disease)

Conditions Related to Allergy

  • Allergic Rhinitis (Hay Fever)
  • Asthma
  • Atopic Dermatitis
  • Prevention of Allergies

Other Conditions

  • Acne
  • Hepatic Encephalopathy
  • Upper Respiratory Infections
  • Urinary Tract Infections


Can Probiotics Be Harmful?

  • Probiotics have an extensive history of apparently safe use, particularly in healthy people. However, few studies have looked at the safety of probiotics in detail, so there’s a lack of solid information on the frequency and severity of side effects.
  • The risk of harmful effects of probiotics is greater in people with severe illnesses or compromised immune systems. When probiotics are being considered for high-risk individuals, such as premature infants or seriously ill hospital patients, the potential risks of probiotics should be carefully weighed against their benefits.
  • Possible harmful effects of probiotics include infections, production of harmful substances by the probiotic microorganisms, and transfer of antibiotic resistance genes from probiotic microorganisms to other microorganisms in the digestive tract.
  • Some probiotic products have been reported to contain microorganisms other than those listed on the label. In some instances, these contaminants may pose serious health risks.

Are Probiotics Safe?

  • Most probiotics are like what is already in a person’s digestive system. Some probiotics have been used for a very long time throughout history, such as in fermented foods and cultured milk products. These don’t appear to cause illness.
  • But more study is needed on the safety of probiotics in young children, the elderly, and people who have weak immune systems. As with any natural health product, be aware that probiotic supplements are regulated as foods, not drugs. Tell your doctor about everything you are taking, including the specific bacteria in your probiotic supplement.

Dosage of Probiotics

  • As a dietary supplement, take one (1) veggie probiotic capsule once daily. Because our probiotic uses delayed-release capsules, do not chew or crush. Our capsules help ensure the active probiotic strains reach your intestinal tract.


References

Dosage of Probiotics


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Side Effects and Contraindications of Probiotics

Side Effects and Contraindications of Probiotics/Probiotics mean live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. These microorganisms, which consist mainly of bacteria but also include yeasts, are naturally present in fermented foods, may be added to other food products, and are available as dietary supplements. However, not all foods and dietary supplements labeled as probiotics on the market have proven health benefits.[rx]

Probiotics should not be confused with prebiotics, which is typically complex carbohydrates (such as inulin and other fructooligosaccharides) that microorganisms in the gastrointestinal tract used as metabolic fuel [rx]. Commercial products containing both prebiotic sugars and probiotic organisms are often called synbiotics. In addition, products containing dead microorganisms and those made by microorganisms (such as proteins, polysaccharides, nucleotides, and peptides) are, by definition, not probiotics.

Probiotics may be defined as selected viable microorganisms that, following consumption in a food or feed, have the potential for improving the health or nutrition of man or animal. Bacteria in this group may be used to ferment food or are added to food as dietary supplements. Foods for human consumption containing these organisms are sometimes referred to as functional foods. A number of different bacterial species have been suggested as probiotics (Table 1). The major species that have been considered over the years, however, are Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium species, and Bifidobacterium longum [].

Types of Probiotics

Many types of bacteria are classified as probiotics. They all have different benefits, but most come from two groups. Ask your doctor about which might best help you.

  • Lactobacillus – This may be the most common probiotic. It’s the one you’ll find in yogurt and other fermented foods. Different strains can help with diarrhea and may help people who can’t digest lactose, the sugar in milk.
  • Bifidobacterium – You can find it in some dairy products. It may help ease the symptoms of irritable bowel syndrome (IBS) and some other conditions.
  • Saccharomyces boulardii – is a yeast found in probiotics. It appears to help fight diarrhea and other digestive problems.

Food Source of Probiotics

  • Ingredients – Lactobacillus casei (Lc-11), Lactobacillus acidophilus (La-14), Lactobacillus paracasei (LPC-37), Lactobacillus Salivarius (Ls-33), Lactobacillus Plantarum (Lp-115), Bifidobacterium lactis (Bl-04), Bifidobacterium bifidum (Bb-02), Bifidobacterium longum (Bl-05), Bifidobacterium breve, Lactobacillus Bulgaricus (Lb-87), Jerusalem Artichoke Root (Organic), Gum Arabic tree exudate from stem and branches (Organic), Fibergum Bio Chicory Root powder (Cichorium intybus) (Organic), Vegetable capsule (Hydroxypropylmethylcellulose and water), Maltodextrin (Rice), L-Leucine (natural)
  • Probiotics that are naturally found in your intestines include – Saccharomyces boulardii (a yeast) and bacteria in the Lactobacillus and Bifidobacterium families of microorganisms. (Outside of the body, Lactobacillus acidophilus is the probiotic that is found in some yogurts.)
  • Foods that contain probiotics include – some juices and soy drinks; fermented and unfermented milk; buttermilk; some soft cheeses; miso; tempeh; kefir; kimchi; sauerkraut; many pickles; and yogurt (probably the most well-known food product that contains probiotics).
  • Supplements – Dietary probiotic supplements — which are available in capsules, tablets, powders and liquid extracts — each contain a specific type of probiotic. These products are available at health food and natural food stores, vitamin shops, and other stores. As an example, one commonly used supplement is Acidophilus, which is available from several supplement manufacturers.

Fruit, vegetables, cereals, and other edible plants are sources of carbohydrates constituting potential prebiotics. The following may be mentioned as such potential sources:

  • Tomatoes
  • Artichokes
  • Bananas
  • Asparagus
  • Berries
  • Garlic
  • Onions
  • Chicory
  • Green vegetables
  • Legumes, as well as oats
  • Linseed
  • Barley, and wheat [].

Some artificially produced prebiotics are, among others

  • Lactulose
  • Galactooligosaccharides
  • Fructooligosaccharides
  • Maltooligosaccharides
  • Cyclodextrins, and
  • Lactosaccharose.
  • Lactulose constitutes a significant part of produced oligosaccharides (as much as 40%).
  • Fructans, such as inulin and oligofructose, are believed to be the most used and effective in relation to many species of probiotics [].

[stextbox id=’custom’]

Bacteria used as probiotics

Major bacteria
 Lactobacillus acidophilus
 Lactobacillus casei
 Bifidobacterium longum
 Bifidobacterium bifidum
Others
 Lactobacillus ruterii
 Lactobacillus johnsonii
 Bifidobacterium lactis
 Lactobacillus Plantarum

 

[/stextbox]

Probiotics contain three potent prebiotics

  • Organic Jerusalem Artichoke Root – Loaded with inulin, a dietary fiber that probiotics devour to push out harmful molecules in your gut. Jerusalem artichoke root is one of the top inulin-rich foods. 76% of its fiber comes from inulin.
  • Organic Fibregum Bio – A patented, GMO-free prebiotic that restores the tight spaces between the cells lining.
  • Organic Chicory Root – The most inulin-rich food on earth! In conjunction with probiotics it Chicory Root has been shown to help support digestive health, reduce gas, bloating, and stomach discomfort.


Mechanisms of Action of Probiotics

The human gastrointestinal tract is colonized by many microorganisms, including bacteria, archaea, viruses, fungi, and protozoa. The activity and composition of these microorganisms (collectively known as the gut microbiota, microbiome, or intestinal microflora) can affect human health and disease.

Probiotics exert their effects usually in the gastrointestinal tract, where they may influence the intestinal microbiota. Probiotics can transiently colonize the human gut mucosa is highly individualized patterns, depending on the baseline microbiota, probiotic strain, and gastrointestinal tract region [rx].

Probiotics also exert health effects by nonspecific, species-specific, and strain-specific mechanisms [rx]. The nonspecific mechanisms vary widely among strains, species, or even genera of commonly used probiotic supplements. These mechanisms include inhibition of the growth of pathogenic microorganisms in the gastrointestinal tract (by fostering colonization resistance, improving intestinal transit, or helping normalize a perturbed microbiota), production of bioactive metabolites (e.g., short-chain fatty acids), and reduction of luminal pH in the colon. Species-specific mechanisms can include vitamin synthesis, gut barrier reinforcement, bile salt metabolism, enzymatic activity, and toxin neutralization. Strain-specific mechanisms, which are rare and are used by only a few strains of a given species, including cytokine production, immunomodulation, and effects on the endocrine and nervous systems. Through all of these mechanisms, probiotics might have wide-ranging impacts on human health and disease.

Because the effects of probiotics can be specific to certain probiotic species and strains, recommendations for their use in the clinic or in research studies need to be species and strain-specific [rx,rx,rx]. Furthermore, pooling data from studies of different types of probiotics can result in misleading conclusions about their efficacy and safety.

Dietary Supplements of Probiotics

Probiotics are also available as dietary supplements (in capsules, powders, liquids, and other forms) containing a wide variety of strains and doses [rx]. These products often contain mixed cultures of live microorganisms rather than single strains. The effects of many commercial products containing probiotics have not been examined in research studies, and it is difficult for people not familiar with probiotic research to determine which products are backed by evidence. However, some organizations have systematically reviewed the available evidence and developed recommendations on specific probiotics—including appropriate product, dose, and formulation—to use for preventing or treating various health conditions [rx,rx].

Probiotics are measured in colony-forming units (CFU), which indicate the number of viable cells. Amounts may be written on product labels as, for example, 1 x 109 for 1 billion CFU or 1 x 1010 for 10 billion CFU. Many probiotic supplements contain 1 to 10 billion CFU per dose, but some products contain up to 50 billion CFU or more. However, higher CFU counts do not necessarily improve the product’s health effects.

Indications of Probiotics

As food products or dietary supplements, probiotics are under preliminary research to evaluate if they provide any effect on health.[rx][rx] In all cases proposed as health claims to the European Food Safety Authority, the scientific evidence remains insufficient to prove a cause-and-effect relationship between consumption of probiotic products and any health benefit.[rx][rx] There is no scientific basis for extrapolating an effect from a tested strain to an untested strain.[rx][rx] Improved health through gut flora modulation appears to be directly related to long-term dietary changes.[rx] According to the National Center for Complementary and Integrative Health: “Although some probiotics have shown promise in research studies, strong scientific evidence to support specific uses of probiotics for most health conditions is lacking.”[rx] Claims that some lactobacilli may contribute to weight gain in some humans[rx][rx] remain controversial.

  • Allergies – No good evidence shows that probiotics are effective in preventing or treating allergies.[rx]
  • Antibiotic-associated diarrhea – Antibiotics are a common treatment for children, with 11% to 40% of antibiotic-treated children developing diarrhea. Antibiotic-associated diarrhea (AAD) results from an imbalance in the colonic microbiota caused by antibiotic therapy.[rx] These microbial community alterations result in changes in carbohydrate metabolism, with decreased short-chain fatty acid absorption and osmotic diarrhea as a result. A 2015 Cochrane review concluded that a protective effect of some probiotics existed for AAD in children.[rx] In adults, some probiotics showed a beneficial role in reducing the occurrence of AAD and treating Clostridium difficile disease.[rx]
  • Blood pressure – As of 2017, only limited evidence indicated any direct link between high blood pressure and gut microbiota.[rx]
  • Cholesterol – A 2002 meta-analysis that included five double-blind trials examining the short-term (2–8 weeks) effects of a yogurt with probiotic strains on serum cholesterol levels found little effect of 8.5 mg/dl (0.22 mmol/l) (4% decrease) in total cholesterol concentration, and a decrease of 7.7 mg/dl (0.2 mmol/l) (5% decrease) in serum LDL concentration.[rx]
  • Eczema – Probiotics are commonly given to breast-feeding mothers and their young children to prevent eczema, but no good evidence shows they are effective for this purpose.[rx][rx]
  • Helicobacter pylori – Some strains of lactic acid bacteria (LAB) may affect Helicobacter pylori infections (which may cause peptic ulcers) in adults when used in combination with standard medical treatments, but no standard in medical practice or regulatory approval exists for such treatment.[rx] The only peer-reviewed treatments for H. pylori to date all include various Antibiotic Regimes.[rx]
  • Immune function and infections – Some strains of LAB may affect pathogens by means of competitive inhibition (i.e., by competing for growth) and some evidence suggests they may improve immune function by increasing the number of IgA-producing plasma cells and increasing or improving phagocytosis, as well as increasing the proportion of T lymphocytes and natural killer cells.[rx][rx]
  • Inflammatory bowel disease – Probiotics are being studied for their potential to influence inflammatory bowel disease. Some evidence supports their use in conjunction with standard medications in treating ulcerative colitis and no evidence shows their efficacy in treating Crohn’s disease.
  • Irritable bowel syndrome – Probiotics are under study for their potential to affect irritable bowel syndrome, although uncertainty remains around which type of probiotic works best, and around the size of possible effect.[rx][rx]
  • Necrotizing enterocolitis – Several clinical studies provide evidence for the potential of probiotics to lower the risk of necrotizing enterocolitis and mortality in premature infants. One meta-analysis indicated that probiotics reduce these risks by more than 50% compared with controls.[rx]
  • Recurrent abdominal pain – A 2017 review based on moderate to low-quality evidence suggests that probiotics may be helpful in relieving pain in the short term in children with recurrent abdominal pain, but the proper strain and dosage are not known.[rx]
  • Urinary tract – Research has been promising for these friendly critters. Potential benefits of probiotics have been seen in the treatment or prevention of

Gastrointestinal Conditions

Conditions in Infants

  • Infant Colic
  • Necrotizing Enterocolitis
  • Sepsis in Infants

Dental Disorders

  • Dental Caries (Tooth Decay)
  • Periodontal Diseases (Gum Disease)

Conditions Related to Allergy

  • Allergic Rhinitis (Hay Fever)
  • Asthma
  • Atopic Dermatitis
  • Prevention of Allergies

Other Conditions

  • Acne
  • Hepatic Encephalopathy
  • Upper Respiratory Infections
  • Urinary Tract Infections


Can Probiotics Be Harmful?

  • Probiotics have an extensive history of apparently safe use, particularly in healthy people. However, few studies have looked at the safety of probiotics in detail, so there’s a lack of solid information on the frequency and severity of side effects.
  • The risk of harmful effects of probiotics is greater in people with severe illnesses or compromised immune systems. When probiotics are being considered for high-risk individuals, such as premature infants or seriously ill hospital patients, the potential risks of probiotics should be carefully weighed against their benefits.
  • Possible harmful effects of probiotics include infections, production of harmful substances by the probiotic microorganisms, and transfer of antibiotic resistance genes from probiotic microorganisms to other microorganisms in the digestive tract.
  • Some probiotic products have been reported to contain microorganisms other than those listed on the label. In some instances, these contaminants may pose serious health risks.

Are Probiotics Safe?

  • Most probiotics are like what is already in a person’s digestive system. Some probiotics have been used for a very long time throughout history, such as in fermented foods and cultured milk products. These don’t appear to cause illness.
  • But more study is needed on the safety of probiotics in young children, the elderly, and people who have weak immune systems. As with any natural health product, be aware that probiotic supplements are regulated as foods, not drugs. Tell your doctor about everything you are taking, including the specific bacteria in your probiotic supplement.

Dosage of Probiotics

  • As a dietary supplement, take one (1) veggie probiotic capsule once daily. Because our probiotic uses delayed-release capsules, do not chew or crush. Our capsules help ensure the active probiotic strains reach your intestinal tract.


References

Side Effects and Contraindications of Probiotics


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What are the side effects of too much probiotics?What are the side effects of too much probiotics? Dosage of ProbioticsDosage of Probiotics, Mechanism, Contraindications Can you take probiotics every day?Can you take probiotics every day? Dietary Supplements of ProbioticsDietary Supplements of Probiotics What Are The Food Source Of ProbioticsWhat Are The Food Source Of Probiotics Uses Indications of ProbioticsUses Indications of Probiotics, Dosages ProbioticsProbiotics; Uses, Indications, Health Benefits http://rxharun.com/crohns-disease-types-causes-symptoms-treatment/How Probiotics Can Help You Lose Weight and Belly Fat Default ThumbnailBest Natural Probiotics Devil's claw ContraindicationsDevil’s claw Contraindications, Indications, Side Effects Bisacodyl ContraindicationsBisacodyl Contraindications, Dosage, Side Effects Default ThumbnailUlipristal Side Effects – Indication, Contraindications
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