Major causes of anemia in IBD and underlying pathophysiology.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"55526",title:"Anemia and IBD: Current Status and Future Prospectives",doi:"10.5772/intechopen.69203",slug:"anemia-and-ibd-current-status-and-future-prospectives",body:'Anemia is the most common systemic complication and extraintestinal manifestation of inflammatory bowel disease (IBD), particularly in Crohn’s disease (CD) patients [1–3]. Although it may be present anytime along the disease course, it is usually recognized at diagnosis and during flare‐ups. However, despite its major clinical relevance and quality of life (QoL) impact in both adult and pediatric IBD patients, it has been for long time neglected in this clinical setting [4].
Following the introduction in the last decade of new intravenous (IV) and oral iron therapies, IBD‐associated anemia (IBD‐A) has been deserving major attention from the scientific community. Furthermore, the increasing focus on extra‐digestive features of IBD, in parallel with the recent emergence of specific management guidelines concerning IBD‐A from the European Crohn’s and Colitis Organisation (ECCO) [5], has also contributed to a paradigm shift in the clinical approach of this clinical entity.
In fact, anemia in IBD is not just a laboratory marker; it is a complication of IBD that requires increased awareness and needs appropriate and timely diagnostic and therapeutic approaches. The impact of anemia on the quality of life of IBD patients is substantial, as it affects several aspects of quality of life, such as physical, emotional, and cognitive functions, work or school absenteeism, hospitalization rate, and health‐care costs [4, 6]. Thus, it seems to be reasonable that both in adult and in pediatric IBD patients, anemia should be recognized, comprehensively evaluated, and treated. Furthermore, not only a disease‐specific treatment has to be administered but in particular iron‐deficiency anemia should be treated, as there is a sound body of evidence demonstrating its beneficial impact in patients’ quality of life [4, 6].
The exact prevalence of IBD‐A is unknown [3, 4, 6]. Reported prevalence rates of anemia in IBD adult patients widely range from 6 to 74%, depending on the definition of anemia, the study design, the patient population considered (e.g., hospitalized patients versus outpatients), and the standards of screening and treatment [4, 6]. In a recent systematic review, the mean prevalence of anemia in adult patients treated in tertiary referral centers with CD was 27% (95% confidence interval 19–35) and 21% (95% confidence interval 15–27) for ulcerative colitis (UC) [6]. Not surprisingly, anemia is reported more frequently in hospitalized patients with IBD and occurs more frequently in CD as compared to UC. In fact, according to recent published studies, the calculated mean prevalence was 20% among outpatients and 68% among hospitalized IBD patients. Furthermore, women with CD are at a higher risk for anemia. It also appears that hemoglobin (Hb) concentrations increase in the years after diagnosis which may be explained by the remission of disease following successful medical or surgical treatment.
The currently used World Health Organization (WHO) definition of anemia (Table 1) applies also to patients with IBD [7–9]. As mentioned in the subsequent text, anemia in IBD is mainly the expression of a mixed pathogenesis with iron deficiency (ID) and anemia of chronic disease (ACD) as the most prominent factors, often coexisting [10]. However, ID is the most frequent cause, with a reported prevalence between 36 and 90% [4, 7]. Recent Scandinavian data in adults indicated the prevalence of iron deficiency anemia (IDA) at 20% and of isolated iron deficiency at 30% (without anemia). After treatment is stopped, IDA has been reported to recur after a 10‐month period and iron deficiency after 19 months after treatment [1–4].
Iron deficiency anemia
|
Anemia of chronic disease
|
Drug‐induced anemia
|
Vitamin B12 e folic acid deficiency anemia |
Major causes of anemia in IBD and underlying pathophysiology.
Recognized limitations concerning most studies on the prevalence of IDA in patients with IBD are their retrospective nature or the fact of being surveys from referral centers. Recently, Ott et al. [10] have prospectively assessed the prevalence of IDA in a population‐based cohort at the time of first diagnosis and during the early course of the disease. A high prevalence of IDA at different points during the early course of disease was reported. At first diagnosis, anemia of chronic disease was predominant, whereas during follow‐up, iron deficiency became the most relevant reason of anemia. These findings are in line with data of other groups [4, 6], also describing a strong association between the severity of anemia and disease activity.
A possible explanation of these findings might be the population‐based character of Ott et al. study [10], as not only outpatients of a tertiary referral center were included in this study but also patients with less severe forms of IBD, which are mainly treated by their family doctors. In this setting, reasons for the insufficient response to the treatment might have been underdosing of iron supplementation, subclinical inflammation of the underlying disease, or lack of adherence of the patient. Surprisingly, only in one‐third of patients with proven anemia, further diagnostic approach was undertaken. Even patients with diagnosed iron‐deficiency anemia were infrequently and inconsequently treated with iron preparations, despite the high impact on quality of life.
Limited previous data suggest that anemia is more prevalent in children than in adults with IBD [7–10], although, to date, there have been no good comparative studies. Although anemia and iron deficiency might be at least as common in pediatric as in adult patients with IBD, the true prevalence in childhood is not known. In fact, IBD‐A has been recently estimated more common (about 70%) in children than in adults (about 30–40%) [10, 11]. In a recent cross‐sectional observational study, including pediatric and adult IBD patients, Goodhand et al. [11] found a prevalence of anemia of 70% (41/59) in children, 42% (24/54) in adolescents, and 40% (49/124) in adults (P < 0.01). Furthermore, children (88% (36/41)) and adolescents (83% (20/24)) were more frequently iron‐deficient than adults (55% (27/49)).
Recent population‐based studies have demonstrated that the phenotype of IBD presenting in the young patient differs from that of adult‐onset disease [5, 6]. Children and adolescents are more likely to be diagnosed with CD than UC, with a more severe and extensive disease distribution at presentation and more frequent extension of disease during the first 2 years [5, 6]. Since they tend to have more severe IBD, it has been hypothesized that the prevalence of anemia would be predictably greater in children and adolescents than in adults attending IBD outpatient clinics. Although in 2007, Gasche et al. have published the first guidelines on the diagnosis and management of iron deficiency and IBD‐IDA [12], only recently the first ECCO guidelines on the management of IDA and ID have emerged. Both guidelines concern IBD‐associated anemia, but no specific considerations on the treatment of pediatric IBD patients have yet been included [5, 13].
In the majority of cases, IBD‐A is mostly multifactorial, being a unique example of the combination of chronic ID and anemia of chronic disease (ACD) (Table 1) [4, 5]. Iron deficiency anemia occurs when iron stores are exhausted and the supply of iron to the bone marrow is compromised. IDA is a severe stage of ID in which hemoglobin (or the hematocrit) declines below the lower limit of normal (biochemical evidence of iron deficiency). The precise biochemical definition agreed on by the experts group is given below [5, 7]. In active disease, inflammatory mediators may alter iron metabolism (by retaining iron in the reticular‐endothelial system), erythropoiesis, and erythrocyte survival. This condition is termed anemia of chronic disease. Anemia due to iron retention in macrophages driven by pro‐inflammatory cytokines and hepcidin is also called functional iron deficiency (FID) [14–16].
Anemia in IBD (an particularly IDA) thus results (a) on the one hand, from low intestinal bioavailability of iron due to chronic intestinal blood loss from inflamed intestinal mucosa; (b) on the other hand, from the combination with impaired iron absorption, either as a consequence of malabsorption and/or short bowel syndrome, or as a consequence of inflammation‐driven blockage of intestinal iron acquisition and macrophage iron reutilization; (c) also, impaired dietary iron uptake might be involved, due to therapeutic or voluntary dietary restrictions and anorexia. Among other possible factors, intake of proton pump inhibitors, persisting H. pylori infection, may be additionally involved.
Other more rare causes of anemia in IBD include vitamin B12 deficiency (particularly after resection of the ileum), folate deficiency, and potential toxic effects of medications (such as proton pump inhibitors, sulfasalazine, methotrexate, and thiopurines; all these may aggravate anemia by negatively affecting iron absorption or erythropoiesis [5–7]. In fact, methotrexate and sulfasalazine interfere with the absorption of folate and may mediate folate deficiency [5–7]; sulfasalazine may also induce hemolysis or bone marrow aplasia; thiopurines and methotrexate can induce bone marrow toxicity in a minority of patients. Finally, other causes may include renal insufficiency, hemolysis, and innate hemoglobinopathies [5–7].
The average adult harbors at least 3–4 g of stored iron that is balanced between physiologic iron loss and dietary intake. Most iron is incorporated into hemoglobin, whereas the remainder is stored as ferritin, myoglobin, or within iron‐containing enzymes. It is estimated that about 20–25 mg of iron is needed daily for heme synthesis; approximately 1–2 mg of this requirement comes from dietary intake and the remainder is acquired from senescent erythrocytes (recycling) [8, 9]. Total iron loss averages about 1–2 mg/day, mostly via fecal losses, skin, and intestine cellular desquamation, as well as through menstruation.
Body iron homeostasis is finely regulated by multiple and sophisticated mechanisms, the interaction of the liver‐derived peptide hepcidin with the major cellular iron exporter ferroportin [15–17] being of major relevance. The synthesis and release of hepcidin are induced by iron loading and inflammatory stimuli such as interleukin 1 (IL‐1) or IL‐6, whereas its synthesis is blocked by ID, hypoxia, and anemia. Hepcidin targets ferroportin on the cell surface (enterocytes and macrophages), resulting in ferroportin internalization and degradation and blockage of cellular iron entry. Low circulating hepcidin levels enable an efficient transfer of iron from enterocytes and macrophages to the circulation, aiming to overcome ID; on the other hand, iron is retained in these cells when hepcidin levels are high and serum iron levels drop [15–17].
Furthermore, inflammatory cytokines can directly inhibit iron absorption and stimulate the uptake and retention of iron in macrophages via hepcidin‐independent pathways. Interestingly, there is clinical evidence that circulating hepcidin levels have an impact on the efficacy of oral iron therapy and can predict its nonresponsiveness; this is consistent with experimental data demonstrating reduced intestinal ferroportin expression and iron absorption in individuals with increased hepcidin levels primarily due to inflammation [17]. As a result, anemia develops and is characterized by low circulating iron levels and an iron‐restricted erythropoiesis in the presence of high iron stores in the reticuloendothelial system, reflected by normal or high levels of ferritin.
Hepcidin expression mediated through cytokine and the direct effects of cytokines on iron trafficking in macrophages play a decisive role in the development of this type of anemia (i.e., ACD or the anemia of inflammation), by retaining iron in the reticuloendothelial system and blocking iron absorption, which results in an iron‐limited erythropoiesis [15,16]. This is reflected clinically by a reduced transferrin saturation (value below 16–20%). In addition, cytokines and chemokines further contribute to anemia by negatively affecting the activity of erythropoietin and an inflammation‐driven impairment of erythroid progenitor cell proliferation [15–17].
As previously mentioned, patients with active IBD may have true ID due to chronic blood loss, as reflected by low ferritin levels. Moreover, true ID and anemia reduce hepcidin expression. These effects drive an iron‐deficiency‐mediated inhibition of SMAD signaling in hepatocytes and erythropoiesis‐driven formation of hepcidin inhibitors such as erythroferron and growth differentiation factor 15 (GDF‐15) [15, 16]. Thus, in the presence of both inflammation and true ID, circulating hepcidin levels decrease because inflammation‐driven hepcidin induction is largely regulated by anemia and ID. Therefore, in truly iron‐deficient patients, despite the presence of systemic inflammation, considerable amounts of iron might still be absorbed from the intestine.
As stated, in IBD patients, anemia is often multifactorial, being IDA, the most common cause. ACD is also an important etiology, and usually is associated with poor disease control or severe disease. Other causes contributing to anemia in IBD include vitamin B12 and folic acid deficiency as well as adverse effects of certain drugs (salazopyrine sulfasalazine and azathioprine). In both adult and pediatric patients with IBD, other chronic conditions should also be considered (i.e., renal insufficiency, hemolysis, and innate hemoglobinopathies).
In pediatric‐IBD setting, other mechanisms of IDA, non‐IBD related, must be considered, as this is a high‐risk group of ID and IDA, namely characterized by high growth periods, insufficient ingestion due to dietetic choices, parasitic infestations, low socioeconomic level, and migrant families. It should also be noticed that ID in the absence of anemia is more common than IDA, as normal Hb levels do not necessarily mean adequate iron stores [5, 7].
World Health Organization anemia definition (Table 2) is considered valid in both adult and pediatric patients with IDA and current ECCO guidelines recommend its application to the establishment of anemia diagnosis.
Age/gender | Hb (g/dL) | Ht (%) |
---|---|---|
6 months to 5 years | 11.0 | 33 |
6–11 years | 11.5 | 34 |
12–13 years | 12.0 | 36 |
Female ≥14 years non‐pregnant | 12.0 | 36 |
Female ≥14 years pregnant | 11.0 | 33 |
Male ≥14 years | 13.0 | 39 |
Minimum Hb and hematocrit (Ht) levels according to age and gender use for anemia definition (WHO) [9].
Hemoglobin levels are influenced by age, gender, pregnancy, ethnicity, altitude, and smoking habits. Interpretation of Hb and hematocrit levels should take these factors into account.
All patients with IBD should be screened regularly for anemia, especially in the presence of active disease, as ACD can coexist with IDA. The initial workup to establish anemia diagnosis (and to differentiate IDA from ACD) should include complete blood count, C‐reactive protein (C‐RP) or erythrocyte sedimentation rate (ERS), serum ferritin, and transferrin saturation. A mean corpuscular volume (MCV) and reticulocytes are also helpful in the classification and differential diagnosis of anemia in IBD setting (Table 3). In some situations, microcytosis and macrocytosis may coexist, neutralizing each other and resulting in a normal MCV. In this case, a wide size range of the red cells (red cell distribution width) (RDW) is an indicator of ID, further contributing to the differential diagnosis. Platelet and white blood cell counts, also available within the complete blood count, are important to distinguish isolated anemia from pancytopenia.
Microcytic anemia with normal or low reticulocytes |
Iron deficiency anemia, anemia of chronic disease, hereditary microcytic anemia, lead poisoning |
Microcytic anemia with elevated reticulocytes |
Hemoglobinopathies |
Normocytic anemia with normal or low reticulocytes |
Anemia of chronic disease, acute hemorrhage, renal disease anemia, aplastic anemia, pure red cell aplasia, primary bone marrow diseases, bone marrow infiltration by cancer, combination of iron deficiency, and B12/folate deficiency |
Normocytic anemia with elevated reticulocytes |
Hemolytic anemia |
Macrocytic anemia with normal or low reticulocytes |
Myelodysplastic syndrome, vitamin B12 deficiency, folate deficiency, long‐term cytostatic medication, hypothyroidism, alcoholism thiamine‐responsive megaloblastic anemia syndrome |
Macrocytic anemia with elevated reticulocytes |
Hemolytic anemia, myelodysplastic syndrome with hemolysis |
By definition, IDA presents as anemia associated with low serum ferritin (referred as the most important laboratory parameter in the definition of IDA), low serum iron, low transferrin saturation, and elevated total iron‐binding capacity. Other hematological parameters, such as RDW, mean corpuscular volume, and mean corpuscular hemoglobin (MCH), might also contribute to IDA diagnosis; high RDW, low MCV, and MCH corroborate IDA. These parameters may be normal in ACD. In the presence of inflammation (such as acute exacerbation or poorly controlled disease), it should be recognized that ferritin levels are usually high. New promising markers, such as a soluble form of transferrin receptor (elevated in iron deficiency despite the presence of inflammation) are particularly helpful in the presence of active disease, being currently available in some centers [17]. Other markers, such as serum hepcidin and red blood cell size factor, may further contribute to differential diagnosis of IDA and ACD [15, 16].
Currently, it has been proposed that, in the absence of inflammation/active disease, serum ferritin levels of <30 μg/L reflect depleted iron stores; during active disease, serum ferritin levels of <100 μg/L should be considered as depleted iron stores. In both settings, transferrin saturation of <16% has been associated with poor iron stores. IDA should be considered in the presence of elevated inflammation parameters and normochromic and normocytic anemia or microcytic and hypochromic anemia with serum ferritin of >100 μg/L.
If, after initial workup, the cause of anemia remains unclear, other tests should be performed according to the most plausible cause of anemia, such as determination of serum B12 vitamin, folic acid, blood smear, haptoglobin, lactate dehydrogenase, urea, creatinine, and electrophoresis of Hb [5].
The treatment strategies of IDA in IBD both in adult and in pediatric patients are evolving from an expectant approach, which is no longer acceptable, to a more interventive approach. A pediatric retrospective study [13] including 80 children with active IBD and IDA evaluated the hematological recovery associated with an expectant management (for a median period of 12 weeks, in parallel with induction therapy). The authors concluded that this approach caused only a modest increase in hemoglobin levels, and that the proportion of children with exclusive IDA had increased within the follow‐up period.
In adult IBD setting, the available evidence also supports an interventive attitude as having better outcomes. In one retrospective population‐based cohort study [11] (with 279 both adult and pediatric IBD patients: 183 CD, 90 UC, and six indeterminate colitis) that aimed to assess the prevalence of anemia at first diagnosis and during the early course of the disease (during the 5 years of study period), anemia was found at any time during the study time in 90/279 patients (32.2%). At the time of initial IBD diagnosis, 68 patients were anemic (75.5% of all patients with anemia) and 44 patients develop anemia at the first year. IDA was found in 63 (70%) of 90 patients (all anemic patients) and 26 (38.2%) of 68 anemic patients with anemia at diagnosis and in 27/44 patients at 1 year after diagnosis. Considering IDA treatment, only nine patients with IDA at diagnosis (35%) received iron therapy and 18 patients with anemia at 1 year after diagnosis. Overall, considering the study period, only 32 patients with IDA at any time of the study received iron treatment (IV iron was only prescribed in five patients) and 38 remaining patients with IDA did not receive any treatment. The authors concluded that despite the high prevalence of IDA during the early course of disease and the potential highly negative impact on the quality of life, the treatment was infrequent and inconsequent.
IDA and ID without IDA are associated with poor quality of life that is independent of IBD clinical activity [5, 7, 18]. Several studies document that IDA treatment is associated with better outcomes in quality live assessment [5, 7, 18]. Thus, currently, IDA treatment is a formal recommendation in IBD patients, reflected by the recent ECCO guidelines [5]. The goal of iron supplementation is to normalize hemoglobin levels and iron stores. Current treatment options, in IBD‐associated IDA, include both oral and IV iron formulas [5, 19–21] (Table 4).
Products | ||||||
---|---|---|---|---|---|---|
IV formulations | Low Mw* iron dextran (CosmoFer®) | Iron gluconate (Ferrlecit®) hemodialysis patients | Iron sucrose (Venofer) | Iron carboxymaltose (Ferinject®) | Ferumoxytol (Feraheme®)** | Iron isomaltoside 1000 (Monofer®) |
Carbohydrate molecule | Dextran (branched polysaccharides) | Gluconate (monosaccharides) | Sucrose (disaccharides) | Carboxymaltose (branched polysaccharides) | Carboxymethyl dextran (branched polysaccharides) | Isomaltoside 1000 (unbranched linear oligosaccharides) |
Complex stability | High | Low | Moderate | High | High | High |
Maximum single dose | 20 mg/kg | 125 mg | 200 mg | 20 mg/kg | 510 mg | 20 mg/kg |
Single dose; limit 200 mg | Single dose; limit: 1000 mg | |||||
Infusion within 1 h | No | NA | NA | Yes | Yes | Yes |
Test dose required | Yes | No | Yes/no | No | No | No |
Iron concentration (mg/mL) | 50 | 12.5 | 20 | 50 | 30 | 100 |
Vial volume (mL) | 2 | 5 | 5 | 2 and 10 | 17 | |
Pediatric use/data available | No | Yes (in chronic renal disease) | Yes (maximum dose per administration 5–7 mg/kg) | Yes (approved > 14 years old) | No | No |
Dosage in 0.12 mL/kg. (maximum dosages 125 mg per dose) | ||||||
Oral formulations | ||||||
Ferric hydroxide‐polymaltose, iron sulfate (oral solutions 100 mg/5 ml and tablets 50 mg; 100 mg; 200 mg) approved in pediatric patients (3–5 mg/kg/day up to 100 mg/day) | ||||||
Ferric maltol (30 mg hard capsules): dosage 30 mg bid, no data available in pediatric population, 12‐weeks treatment required, it should not be used in patients with IBD flare or in IBD‐patients with Hb <9.5 g/dL [22]. |
The ECCO guidelines recommend IV iron as first‐line treatment in patients with clinically active IBD, with previous intolerance to oral iron and Hb below 10 g/dL, as well as in patients who need erythropoiesis‐stimulating agents [5]. These guidelines consider that IV iron is a good treatment option in IDA‐IBD patients, as it has demonstrated to be more effective, better tolerated, and to improve quality of life to a greater extent than oral iron supplements. Recently published ECCO guidelines, however, do not take into consideration the pediatric age group and no specific considerations are made considering this age group [5].
Oral iron is available as inorganic ferrous salts, the daily dose ranging between 50 and 200 mg, in adults and 3–5 mg/kg/day up to 100 mg/day in pediatric patients (Table 4). Although oral iron supplementation has been traditionally used in IBD patients (adult and pediatrics) in the presence of IDA, IV iron, however, is rapidly becoming the first line of treatment in this setting, mainly based on efficacy data, convenience of administration (especially with the most recent formulations—Table 4), and good safety profile [23–28]. At present time, there are several available formulations for this purpose, as previously mentioned [5, 19–22]. At pediatric age, IV formulas currently approved by Food and Drug Administration (FDA) and by European Medicines Agency (EMA) are expressed in Table 4.
Regarding dosage of IV iron, Ganzoni’s formula [29] [(body weight in kg × [target Hb‐actual Hb in g/dL] × 0.24 + 500)], has been used to calculate iron dosage, both in adult and in pediatric patients. However, the formula is complex, difficult to use in clinical practice, and appears to underestimate iron requirements. Alternatively, a simple scheme (Table 5) has been proposed in the FERGIcor study (Note:FERGIcor has no additional definition, as it is the specific name/designation of a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in IBD) [25], in which the estimation of IV iron need is based according to pretreatment Hb level and body weight. Although initially used only to calculate FCM dosage, it has currently been used in other IV iron formulations, and is recommended in the ECCO guidelines. Limitations of this scheme include lack of validation in pediatric patients with bodyweight of <35 kg and patients with Hb below 7.0 g/dL, who may require an additional 500 mg. Also, the estimation of iron needs in ID without anemia is not taken into account.
The efficacy and safety of IV iron for the treatment of IDA in IBD adult patients is well established and demonstrated by several studies [23–28]. However, evidence regarding the superiority of IV iron versus oral formulas is yet to be proven [30–33]. In fact, there are several studies and systematic reviews comparing oral and different IV formulas, with variable results considering efficacy in improving Hb levels, tolerance, and safety (related to common severe adverse effects) [4, 6]. Particularly in adult IBD patients, data from large published trials are available, concerning iron sucrose (IO), ferric carboxymaltose (FCM), and iron isomaltoside (IS) [6, 23, 24, 26–28].
The first IV formulas (high‐molecular‐weight iron dextran (HMW ID) were associated with more frequent and severe side effects (anaphylactic reactions), as a consequence of IV iron. It has been initially used in specific settings, such as chronic kidney disease, neoplastic, and gynecologic diseases. In gastroenterological disease, IV iron was traditionally reserved for patients with intolerance or inadequate response to oral iron and/or in whom a rapid increase in iron stores was desired. As new IV iron formulas developed, composed by strongly bound iron carbohydrate complex (an iron core is wrapped in a carbohydrate shell), in order to minimize the potential risk of free iron reactions and the high immunogenicity leading to severe adverse reactions of the oldest IV iron formulas, IV iron is becoming a more frequent treatment option in IBD setting. These new formulas largely replaced the use of iron dextrans, as they have better safety profiles (allowing the administration without the need of a test dose), and also allowing a more time‐efficient fashion in a single high‐dose infusion. Nevertheless, iron reactions may occur with all IV iron preparations, but they are generally not thought to be immune mediated [30–33].
Each IV formula has a different profile of side effects, being the most common hypotension, tachycardia, stridor, nausea, dyspepsia, diarrhea, and skin flushing. Other described side effects include itching, dyspnea, wheezing, and myalgias (especially in the infusion of large‐molecule iron complexes); however, it should be referred that an acute myalgia at the first administration of IV (without any other symptoms) that alleviates spontaneously within minutes (i.e., the so‐called Fishbane reaction) usually does not recur, and rechallenge is unnecessary. Serious side effects are rare and include severe allergic reactions, anaphylactic shock, and cardiac arrest, but such problems are more common with the older IV formulas mostly dextran‐containing preparations [30–33].
The new IV iron compounds FCM and IS are currently approved for use in IBD setting in Europe and ferumoxytol in the United States. All three compounds have showed high stability, favorable safety profile, and complete replacement of total doses of iron in 15 min [24–27]. FCM was the first of the new agents to be approved for more rapid administration of large doses. FCM can be administered as an infusion of 500–1500 mg in 15 min; however, it allows only doses up to 1000 mg per single dose. This IV iron formula is approved in both adult and pediatric patients (age >14 years old). IS is a particularly promising IV iron formulation, as it can be administered in high doses with a maximum single dosage of 20 mg/kg body weight, allowing single administration of iron doses exceeding 1000 mg. However, it is only approved in adult patients. In younger pediatric patients (<14 years old), IS is the only approved formula.
In 2013, Gasche et al. [7] recommended that oral iron should be considered a possible treatment options in patients with mild to moderate anemia (Hb ≥10 g/dL, ferritin <30 μg/L), as oral iron formulations have low cost and are administered at home. Current published ECCO guidelines reinforce this recommendation, as they suggest that oral iron is effective in patients with IBD and may be used in patients with mild anemia, whose disease is clinically inactive and who have not been previously intolerant to oral iron.
Nevertheless, though several studies (including adult and pediatric patients) have demonstrated the effectiveness of oral iron formulas in reestablishing normal hemoglobin levels, these compounds have a slow response in Hb levels (as it may take until at least 2 months to achieve the desirable Hb level, and up to 6 months to reestablish adequate iron stores), poor gastrointestinal tolerance (especially if high doses are required), poor absorption (in active disease and in the presence of inflammation iron absorption is further limited due to inflammation‐driven blockade as referred before), and low compliance (compromising the treatment goal). Intolerance to oral iron therapy leading to discontinuation has been reported to be as high as 20% [7, 23, 24].
Additionally, there is some evidence in animal model [34] that oral iron might contribute to deterioration of mucosal injury. Furthermore, as absorption of iron from the gastrointestinal tract is limited, the unabsorbed iron is exposed to the ulcerated intestinal surface. One animal model study [35] compared the effect of oral versus IV formulas on inflammatory and oxidative stress markers in colitis induced in rats. The animals were divided in four groups (one healthy control, one colitis‐induced control), two of the three colitis rats received 5 mg iron/kg of body weight a day (as oral or IV iron) for 7 days. Histologic and laboratory inflammatory markers were assessed. The authors found that the oral iron‐treated group had a significant worsening of histologic and inflammatory markers, as compared with the IV iron treatment group and the two control groups. They proposed that IV iron should be considered in IBD patients, as it has shown negligible effects on systemic oxidative stress and local or systemic inflammation.
Other feature that has negatively influenced the option of treatment with oral iron is the putative reported increased prevalence of intestinal adenomas associated to prolonged oral iron treatment, in murine colitis model [30, 32, 33]. However, the true impact of oral iron on mucosal injury in IBD patients is not well established and the potential risk of colorectal carcinoma in humans remains controversial [36]. So far, these potential adverse effects of oral iron could not be confirmed in several published trials [30, 32, 33]. Only one human study specifically assessed this question [37]. In a small study including 10 CD patients with active disease and 10 healthy controls treated with ferrous fumarate for 7 days, the Crohn’s Disease Activity Index (CDAI), gastrointestinal complaints and blood samples for antioxidant status, anemia, inflammation, and iron absorption were evaluated (on days 1 and 8). The authors found an increase in CDAI, and patients reported an increase in diarrhea, abdominal pain, and nausea at day 8; moreover, a deteriorated plasma antioxidant status in CD patients as compared with controls was observed, thus suggesting that oral iron treatment deteriorated plasma antioxidant status and increased specific clinical symptoms in patients with active Crohn disease. However, these data should be interpreted with caution, as it was a small sample, referring to a group of patients in which oral iron was not recommended, according to past and current guidelines.
Another potential negative effect of oral iron is the modification of the gut microbiome. In one recent open‐labeled clinical trial, the effects of oral (iron sulfate) versus IV iron (Iron sucrose) over a 3‐month period, in adult patients with IBD (CD: 31; UC: 22) versus control subjects with IDA without inflammation and its impact in clinical parameters, gut microbioma, and metabolome [38] were compared. The authors concluded that both oral and IV iron were effective in the correction of Hb levels, and moreover they found that oral iron distinctively affected bacterial phylotypes and fecal metabolites, as compared to IV iron. Although these data should take into consideration that IBD patients have already a disturbed gut microbioma, they highlight the potential additional gut damage of oral iron.
A recently published prospective controlled open‐label 6‐week non‐inferiority trial, including 45 adolescents (aged 13–18 years) and 43 adults (>18 years) with IBD, aimed to assess the effects of oral iron (ferrous sulfate) on Hb level, disease activity (clinical scores and inflammatory parameters—fecal calprotectin and CRP) and also the relationship between baseline serum hepcidin and Hb response [39]. Quality of life was also evaluated. Rampton et al. [39] found that the effectiveness (improvement in Hb level) and tolerance of oral iron were similar in both age groups, and an inverse relationship between Hb response and baseline Hb, CRP, and hepcidin was observed. Also, the disease activity was not affected by oral iron and patients reported an improved quality of life—short IBD questionnaire (IBDQ) and perceived stress questionnaire scores in adults. The authors concluded that oral iron was effective in IDA treatment and that CRP and that hepcidin levels at baseline could be used as additional markers to better decide whether iron should be given orally or IV.
Ferric maltol is a novel oral ferric iron compound, associated with a lower rate of gastrointestinal effects, with potential use to treat iron deficiency anemia in mild‐to‐moderate IBD, even in those who are intolerant to oral ferrous products [40]. This clinical benefit has the potential to change treatment pathways and increase treatment options. Currently, this compound is only approved in adult patients.
In the last decade, numerous studies aimed to compare oral and IV iron treatment options, regarding safety, tolerance and efficacy, as well as impact in the quality of life [23–28, 41]. There are several published systematic reviews in this subject, as well as single and multicenter studies. All the main IV iron formulations have been compared with oral compounds. However, studies comparing different new IV iron formulas among each other and comparing traditional oral iron with the new formulations are lacking. Also, most data refer to adult IBD population; pediatric evidence, although scare, is emerging.
Considering the studies comparing oral iron sulfate to most used IV formulas (IS, FCM, and II) in IBD adult patients, the published data highlight that all IV formulas are safe, well tolerated, and effective in achieving desirable Hb levels. The superiority of IV versus oral iron in treating IDA‐IBD remains unclear, as different results have been published. Studies have found, however, that treatment discontinuation due to adverse events was lower in patients treated with IV iron, as compared to patients treated with oral iron. These data are reflected in the current ECCO recommendations (mentioned previously), as oral iron is still a treatment option.
In the IS versus oral iron trial [23], a randomized 20‐week, controlled, evaluator‐blind, multicenter study with 91 adult patients with IBD and anemia (Hb <115 g/L), the authors reported that IV iron was more effective in correcting hemoglobin and iron stores, when compared to oral iron. In the oral iron group, only 48% tolerated the prescribed dose (which might had influence in the final result in terms of achieving normal Hb levels).
The FCM versus oral iron multicenter study trial [24] (including 200 adult IBD; follow‐up of 12 weeks) attested the safety and effectiveness of FCM IDA‐IBD. Although in this study, FCM allowed fast Hb increase and adequate iron stores, it could only demonstrate the non‐inferiority of this IV iron formulation in terms of Hb change over the study time. Also, the rate of adverse effects was similar in both iron formulas.
Finally, the IV versus oral iron study, published by Reinisch et al. [28], was a randomized, open‐label trial with a total of 338 adult IBD patients in clinical remission or with mild disease and an Hb of <12 g/dL. They aimed to prove the non‐inferiority of IV iron when compared to oral iron regarding the correction of IDA, as well as to document the number of patients who discontinued the study because of lack of response or intolerance of investigational drugs, change in total quality of life, and safety. This study could not demonstrate the non‐inferiority in changing Hb at week 8 post treatment. Indeed, there was a trend for oral iron sulfate being more effective in increasing Hb than IV. The authors suggested that the results might have been influenced by the underestimation of true iron needs by the Ganzoni formula.
Two systematic reviews and meta‐analysis of iron replacement therapy in IBD patients with IDA recently published compared the efficacy of oral versus iron therapy in the treatment of IDA in adult IBD patients [21, 30]. One review identified 757 articles. The total sample size included 333 patients, with 203 patients receiving IV iron treatment. The primary outcome was the mean change in the hemoglobin and secondary outcomes included the mean change in ferritin, clinical disease activity index, quality of life score, and the adverse reaction rate. The authors concluded that IV iron is better tolerated and more effective than oral iron treatment in improving ferritin levels. Another systematic review published in 2013 [30], including again only adult IBD patients, also highlighted that IV iron was the best option to the treatment for IDA‐IBD, due to improved Hb response, no added toxicity, and no negative effect on disease activity, when compared with oral iron replacement.
The most recently published systematic review, including only evidence from randomized controlled trials [33] (five studies including 694 adults with IBD), and comparing IV versus oral iron, also concluded that IV iron appears to be more effective and better tolerated than oral iron for the treatment of IBD‐associated anemia, as IV iron presented higher efficacy in achieving a hemoglobin rise of ≥2.0 g/dL, lower treatment discontinuation rates due to intolerance or adverse effects (including lower gastrointestinal adverse events).
In pediatric patients with IBD‐associated IDA, the evidence concerning the different treatment strategies, namely the use of IV iron formulas, is still scare. Also, as previously mentioned, only IS and FCM IV iron formulations are currently approved, wherein FCM is only recommended in pediatric patients of >14 years old (Table 4). In the pediatric IDA‐IBD setting, so far three published studies support the efficacy of available IV iron formulas [11, 41, 42]. In these studies, both IS and FCM were used and showed to be equally effective in the treatment of IBD‐IDA, achieving both the desirable Hb level and adequate iron stores in most patients.
In a small single‐center prospective study, including 19 pediatric CD patients (median age: 15.5 years) with remissive/mild disease, with a follow‐up of 40 months, Azevedo et al. [41] evaluated the safety and efficacy (short and long term) of IV iron, as well as the need of re‐treatment. The median Hb before and after IV iron was 10.5 and 12.7 g/dL, respectively. No major adverse reactions were documented. This prospective study thus emphasized the efficacy and safety of IV iron in pediatric IBD patients. In a retrospective study, Laass et al. [42] reported the treatment of pediatric patients with IDA associated to several gastrointestinal disorders, including a subset of 52 IBD patients (29 CD patients) with a mean age of 11.8 years. In this pediatric study, all patients were treated with FCM, and the mean Hb level after treatment of 11.9 g/dL was achieved, with good tolerance and minor side effects. In this study, FCM showed efficacy and a good safety profile, although data concerning the disease activity and long‐term follow‐up of the patients were not reported.
The safety and effectiveness of IV iron (IS) in the pediatric setting were also recently reported in another prospective single‐center study (conducted in 24 children with IBD treated with infliximab) [43]. In this study, IS was administered after infliximab and no adverse reactions were documented.
The recurrence of IDA in IBD is well recognized, occurring in about 50% of the adult patients within 10 months after IV iron treatment [5, 7, 44, 45].
Recurrence of IDA is directly related with iron replenishment at the end of IV iron treatment [5, 44–46]. It is admitted that ferritin levels over 400 µg/L might prevent recurrence of IDA in the subsequent 1–5 years.
ECCO guidelines state that IBD patients should be monitored for recurrent iron deficiency every 3 months for at least 1 year after correction, and between 6 and 12 months thereafter [5]. Furthermore, they highlight that recurrence might be associated to persistent intestinal disease activity even if there is clinical remission and remission in inflammatory parameters. An important message is that recurrence of anemia, especially in the setting of ACD, should lead to the evaluation of disease activity and an optimized treatment strategy would be required, as disease control is usually sufficient to correct anemia.
Data concerning recurrence of IDA in pediatric patients are scarce; however, considering the high prevalence of pediatric IBD‐IDA anemia, a recurrence rate similar to that reported in adult patients should be expected. So far, these data were only described in one study [41], in which six of 19 (30%) patients needed re‐treatment within the 40 months of follow‐up (median period of 15.5 months). Re‐treatment was proposed when Hb levels fell under the baseline level according to WHO criteria and after excluding other factors than IDA contributing to anemia. This study reinforces the importance of long‐term follow‐up of the iron status, also in pediatric CD patients.
The most recent ECCO guidelines suggest that after IV iron treatment, re‐treatment should be initiated as soon as serum ferritin drops below 100 μg/L or Hb drops below cutoff level according to WHO criteria [5]. However, the benefit evidence of treating iron deficiency in the absence of anemia in IBD patients and particularly in pediatric IBD patients is yet unavailable. Currently, there are no guidelines concerning the management of ID without anemia in both adult and pediatric IBD patients. However, ID without anemia and IDA should be closely monitored.
The rational of preventing IDA by treating ID relies on the fact that iron is important to cell function and that ID can cause symptoms with a negative impact on the quality of life [5, 18]. Several symptoms have been associated to ID, such as reduced physical performance and cognitive function, fatigue, headache, sleeping disorders, loss of libido, or restless‐legs syndrome among others [47].
The evidence concerning the treatment of ID without anemia in the IBD setting, however, is not yet available. ECCO guidelines recommend that the choice of treating ID without anemia should be considered on an individual basis (according to patients’ past medical history and comorbidities, age group, symptoms, and individual/parental preferences) [5]. Data on the effectiveness of periodic IV iron administration as a prevention of IDA in IBD patients are available for FCM and II (in adult patients) [44–46]. In the adult studies, after IDA treatment with IV iron, patients received regular doses of IV iron (300–500 mg of FCM or II) during a 12‐month period allowing to maintain stable Hb levels without IDA recurrence and with good tolerance regarding side effects.
In refractory cases of ACD with an insufficient response to intravenous iron and despite optimized IBD, therapy ECCO guidelines propose that these patients may be considered for erythropoiesis‐stimulating agent treatment. The recommendation is supported by studies demonstrating the improvement of Hb levels; follow‐up data, however, are lacking and these agents should be used with caution [5]. There are no pediatric data on the use of erythropoiesis‐stimulating agents in IBD patients.
Red blood cell transfusion may be considered when Hb concentration is below 7 g/dL, or above if symptoms or particular risk factors are present. ECCO guidelines also recommend that blood transfusions should be followed by subsequent intravenous iron supplementation [5].
In conclusion, the current management of IBD‐A represents a paradigm shift in clinical practice, involving several specific challenges. A pro‐active approach is recommended, and both adult and pediatric IBD patients should be regularly assessed for the presence of anemia, because of its high prevalence, impact on quality of life, and comorbidity.
Although both oral and IV formulations have demonstrated efficacy in IBD‐A, oral iron might not be an ideal treatment for active IBD‐A, with gastrointestinal intolerance occurring in many patients and a long course needed to resolve anemia and replenish stores. Nonadherence to a prescribed course of oral iron is common, and even in adherent patients, poor intestinal absorption fails to compensate for iron need in the presence of ongoing blood losses. In addition, studies in animal models do not exclude the possibility that oral iron formulations might increase disease activity in IBD and even the risk of development of colorectal cancer.
IV iron treatment has shown to be safe and well tolerated in IBD patients with good clinical response in different formulations (prolonged response). However, although the safety of IV iron has been demonstrated in studies comprising thousands of patients with numerous clinical entities associated with ID, safety concerns still exist. All iron products can cause hypersensitivity or other reactions and the comparative frequencies of reactions remain unknown. All involved clinicians should acquaint with the incidence, clinical nature, and significance of reactions to the existing preparations, systematically reporting to a central agency.
Although any IV iron can cause acute severe reactions, the incidence and severity of reactions seem quite low, with the doses commonly administered in clinical practice and currently available dextran‐free formulations of intravenous iron (as iron gluconate, IO, and FCM). Similarly, concerns about IV iron therapy potentially increasing the risks for infections and cardiovascular disease have not been confirmed in prospective studies or clinical trials and remain largely unproven hypothesis. There remain, however, some concerns about the potential for long‐term harm from repeated iron administration.
Sound data are still lacking, on when to stop iron supplementation therapy in order to avoid iron overloading, which may cause side effects, because of the potential of the metal to catalyze the formation of toxic radicals. Recent guidelines on the management of anemia in dialysis patients suggest that ferritin levels of up to 500 ng/mL appear to be safe and this limit might be a useful upper threshold in the management of patients with IBD‐A. Interestingly, in a recently published prospective single‐center study, iron supplementation in chronic kidney disease patients was associated with a significant reduction in overall mortality.
Certainly, the control of inflammation is a key objective in the treatment of IBD. Because IDA has a considerable impact on patient quality of life, a thorough and complete diagnostic and therapeutic strategy should be followed to help patients attain as normal a life as possible. Given the novel intravenous iron‐replacement regimens introduced within the last 10 years, physicians may have some doubts concerning the optimal iron‐replacement regimen to be prescribed. Based on the current evidence and guidelines, oral iron therapy should be preferred for patients with mild IDA in quiescent disease stages unless they are intolerant or have an inadequate response, whereas IV iron supplementation may be advantageous in patients with more severe IDA or flaring IBD, because inflammation compromises intestinal iron absorption.
Further well‐designed clinical trials, including well‐selected patients and clearly detailing primary and secondary outcomes, are warranted, to optimize the treatment schedule in these patients. In particular, considering the small number of published randomized controlled studies in this important area, prospective studies will be necessary to establish the optimal dose for correction and maintenance of target Hb levels and iron stores (definition of clinical end point) and to clarify the impact of anemia correction and iron supplementation on the course of IBD‐A and patient outcomes. Ideally, these clinical trials should integrate new surrogate biomarkers, reflecting more precisely the true systemic iron pathways.
Also, prospective clinical trials are needed to better define the clinical and hematological long‐term outcomes in patients with IBD‐A. In fact, good‐quality data are required both in adults and in children, demonstrating the efficacy, safety, and tolerance profile of different available iron formulas (oral and IV) in IBD‐IDA, as well as to determine their cost‐efficacy ratio.
The importance of long‐term follow‐up of the iron status in IBD patients, including in those in remission and/or with mild disease, should also be emphasized, as well as the inclusion of quality of life impact as a relevant specific intervention outcome. Finally, the future acquisition of larger pediatric experience in the field will drive the emergence of evidence‐based‐specific pediatric guidelines.
In summary, all clinicians (particularly gastroenterologists) treating patients with IBD will need to be increasingly aware of the importance of the screening, diagnosis, and management specificities of anemia and IBD, for improvement in their general well‐being, a matter which frequently does not yet gain the required attention. With the new generation of available iron compounds and existent guidelines, the ultimate goal will be the improvement of the patients’ quality of life.
Petroleum is a complex mixture of hydrocarbons of varying nature and small fractions of nitrogen, oxygen, sulfur, and metal compounds. At room temperature, petroleum can be gas, liquid, and/or solid, being considered as gases and solids dispersing in a liquid phase [1]. Under high temperature and pressure, as encountered at reservoirs (e.g., 8000–15,000 psi and 70–150°C), Newtonian rheological behavior prevails, whereas at low temperatures the pseudoplastic behavior is commonly found [2].
A large portion of the Brazilian oil production comes from offshore fields, from the pre-salt layer. These oils have high levels of waxes, which are alkanes (linear or branched) encompassing carbonic chains of 15–75 carbons [3, 4]. This class of compounds has a high precipitation potential, due to the low sea temperatures (about 4–5°C) [5, 6, 7]. In temperatures below the wax appearance temperature (WAT), the wax crystallization takes place with subsequent deposition [2]. The wax deposition is dominated by the molecular diffusion mechanism [8] in which the waxes initially precipitate at the cold pipeline walls and subsequently generate a radial gradient of precipitation causing deposit [9, 10]. This can lead to a strong waxy crystal interlocking network, which causes pipeline clogs and dramatically affects the rheological fluid behavior [9, 11, 12, 13].
Gelation and deposition problems, leading to increases in yield stress and losses in production, are probably connected to wax morphology. This chapter aims to show some techniques to characterize the structure and morphology of wax crystals based on four pre-salt Brazilian crude oils, all provided by Petrobras, under different shear conditions, aging times, and temperatures. In addition, some physicochemical characterization techniques are discussed as density, viscosity, and SAP (saturated, aromatic, and polar). The wax quantification is the harder part of the study of crude oils, due to the petroleum complex matrix, which can cause complications related to the wax crude oil separation; however, through differential scanning calorimeter (DSC) measurements, it is possible to obtain a precipitated wax content as well as through some American Society for Testing and Materials (ASTM), Universal Oil Products Collection (UOP), gas chromatography (GC), and others.
Due to the petroleum multicomponent nature, the wax precipitation occurs heterogeneously, and resins and asphaltene molecules, inorganic solids, and corrosion products, among others, can behave as nuclei for the phenomenon, enhancing the flow assurance issue [14].
Waxes crystallize into basically orthorhombic and hexagonal shapes. The orthorhombic form is needle-shaped, and it is found in crudes with high waxy content [15, 16]. Crystallization kinetics and crystal morphology can be highly affected by some recognized factors, such as cooling rate [13, 17, 18, 19, 20, 21, 22, 23], carbonic chain nature (branched or linear and average length) [21], resins and asphaltene content [2, 7, 24, 25], and shear rate [16, 26, 27, 28].
The polarized light (PL) optical microscopy is the fundamental technique for wax crystal examination [24]. According to [29] it allows verifying the anisotropic optical behavior of crystalline materials, named birefringence. This technique uses two cross polarizers. When the light beam passes through crystalline structures, as wax crystals, the polarized light plane is altered generating a visible image pattern. On the other hand, isotropic structures, which do not exhibit the same level of organization, are not able to modify the light plane. Apart from PL microscopy, the bright-field (BF) microscopy regards another important technique for wax crystal visualization. The procedure is very simple, and no artifacts are employed in the optical path.
Figure 1 shows BF and PL micrographs of P1 Brazilian crude oil, for the same point of the coverslip, at 25°C, as received, i.e., without any thermal treatment. All the aliquots of crude oil in this chapter were observed on optical microscope Axio Vert 40 MAT (Carl Zeiss).
(A) BF and (B) PL micrograph of P1, for the same point of cover slip at 25°C, as received.
The BF technique (Figure 1a) provides lower contrast than PL technique (Figure 1b); however, it can be seen that in BF micrographs the wax crystal is continuous, i.e., the structure appears and integrates, without rupture. On the other hand, PL micrographs show “dark cracks,” i.e., the wax crystals do not appear entirely. These “dark cracks” can be attributed to two factors: first, amorphous or low crystallinity regions due to the presence of impurities and second, due to light extinction positions, related to the parallel orientation of polarizers and the crystal organization, i.e., no light is deflected by the sample [30]. Therefore, much attention should be taken to make length measurements in crystals observed by PL technique. According to these results, to determine the size and crystal shape (as verified by BF) can be critical to avoid erroneous measurements. In this work, the length measurements were performed on images obtained by BF, but the PL images are shown due to easy observation.
Another characteristic of wax crystals that can be seen in Figure 1a is a roughened surface. The roughness, as well as the tortuosity of wax crystals, can be attributed to a heterogeneous nucleation and growth, by the presence of asphaltenes, resins, and different wax chain lengths or the presence of isocycle [24, 31].
In order to characterize the wax morphology and crystals length in dependence of temperature and shear, a continuous cooling protocol was performed (Figure 2). Initially, the thermal history removal of 100 mL of each oil was carried out by heating the samples for 2 h at 80°C in a circulating oven model 400-3ND (Ethik Technology). This condition is sufficient to dissolve all wax present in the crude oil and prevent that the wax crystal formation was not influenced by pre-existing nuclei [32, 33]. Secondly, the samples were transferred to a jacketed Becker coupled to a circulation bath (Haake Phoenix II-C25P - Thermo Scientific). Then, the cooling step was carried out quiescently or in presence of shear (mechanical agitation 250 rpm on RW20 Digital IKA) for 80–5°C. The cooling rate was 0.5°C/min. Figure 2 shows the influence of shear on waxy crystal growth of P1–P4 paraffinic oil comparing the PL micrographs of tests carried out at 5°C, on quiescent and shear cooling conditions.
PL micrographs of test performed at 5°C on quiescent (A–D) and shear (E–H) conditions of waxy crude oils P1–P4.
It was verified that experiments performed with quiescent condition (Figure 2A–D) were characterized by large crystals and cluster of crystals when compared with experiments carried out with shear condition (Figure 2E–H). The researchers carried out by [2, 16, 34] show that under quiescent conditions, the waxy crystals were characterized by extended and continuous particles. The formation of extended and continuous particles allowed a colloidal network that embodies the oil itself. Probably, the gel would have a high shear modulus, in order to the side-by-side interactions between particles. Under the shear condition, the lateral growth of the individual crystals is constricted. However, extended particles are not observed, and consequently, these particles lost their interconnectivity.
The wax crystals presented in waxy crude oils (Figure 2) are elongated. According to [16], waxes precipitated in crude oil tend to crystallize in an orthorhombic structure, which is characterized by an elongated structure. Evidently, the crystals of Figure 2 (and in detail in Figure 1) are not linear (needle-like). The sinuosity and tortuosity are probably due to the presence of impurities during nucleation and crystal growth processes [2, 21]. [2] analyzed the aspect ratio, which is the ratio between the length and the width of a crystal. Based on aspect ratio value, it is possible to verify how the structure is elongated. The values of average aspect ratio, at 5°C, of samples P1, P2, and P3, are 5.5, 6.2, and 5.0, respectively, legitimizing the elongated characteristic. P4 sample has a 4.0 aspect ratio value, which indicates that the crystals are less elongated than other samples.
Table 1 shows the average length and width of crystals to waxy crude oils P1–P4 in function of temperature for 30, 10, and 5°C, for quiescent and shear conditions, and shows the average percentage of crystal growth between both cooling conditions.
Length and width of crystal’s average and growth percentage.
For quiescent conditions, it is possible to note the crystal length increases between 10 and 5°C; however, for shear conditions, the length becomes basically stationary at these temperatures. This behavior could be attributed to a possible crystal breakage by the shear, which prevents the crystals from becoming large. The average percentage of growth between quiescent and shear conditions increases with the temperature decrease. For 30°C the crystals obtained in quiescent cooling are about 12.4% higher than that obtained by shear conditions. At 5°C this difference reaches 25.1%. On the other hand, the crystal width underwent an effective action of the shear, being about 22.3% less wide than those obtained in quiescent conditions.
To illustrate the Table 1, Figure 3 shows PL micrographs of P3 obtained at 30, 10, and 5°C during quiescent cooling. This condition resembles the operational shutdowns when crude oil is cooled. As expected and discussed above, the concentration and size of wax crystals increase with the decrease in temperature. Since the solubility of high molecular weight waxes decreases sharply with the decrease in temperature, they precipitate out and crystallize. This result indicates that in low temperatures, it is more probably to have problems of flow assurance due to pipeline blockage occasioned by wax crystal depositions and to the formation of a high-strength gel, characterized by yield stress [35, 36, 37].
PL micrographs of P3 obtained at (A) 30°C, (B) 10°C, (C) 5°C and during quiescent cooling.
Another common factor studied on precipitation and morphology of waxy crystals is the aging time, which represents the influence of the time at a certainly constant temperature on the crystal wax. PL micrographs in Figure 4 show the influence of 1 h aging time at temperatures 40, 20, and 5°C, for P4. To study the aging time influence, first, the thermal history was removed. The samples were transferred to the jacketed Becker coupled to a circulation bath at 80°C and then started the cooling steps (80–40°C; 80–20°C or 80–5°C). When the temperature arrives 40, 20, or 5°C, the samples were kept cool for 1 h at this temperature. The cooling rate was 0.5°C/min.
PL micrographs of tests carried out with P4, at t = 0 h for 40°C (A), 20°C (B) and 5°C (C); and after 1 h at 40°C (D), 20°C (E) and 5°C (F).
It was verified that the aging time favored the increase of crystal length and appearance of large clusters. This result can be attributed to the Ostwald ripening of wax crystals, a mechanism by which the large crystals grew at the expenses of smaller crystals of higher energy. Furthermore, oil uptake can also change the wax crystal distribution, leading to larger and softer wax crystals that can interpenetrate increasing intermolecular interactions between crystals [11, 37, 38].
Table 2 shows the wax crystal’s average length at t = 0 h and after 1 h (t = 1 h) at temperatures 40, 20, and 5°C, as well as the crystal growth percentage in function of aging time.
Average wax crystal length at t = 0 h and t = 1 h at 40, 20, and 5°C and crystal’s growth percentage.
Analyzing Table 2, at 40°C the oils P1 and P3 show an increase of about 26.3% in the length of the crystal after 1 h in an isothermal condition. Under these same conditions, P2 shows a growth of almost 80.0%. P2 has the WAT at 42.1°C (see 4. Wax quantification), and consequently, there is no visible crystal on microscope when the temperature just arrives at 40°C. For this reason, the crystal size, in this case, was considered 1.0 μm, the microscope detection limit. However, after 1 h at 40°C, this sample presents small crystals of about 4.8 μm. Evaluating a percentage of growth at 20 and 5°C, a reduction is noticed. The wax crystals seem to grow more significantly at elevated temperatures. In t = 0 at 5°C, the wax crystal has a large size due to the temperature decrease, and after 1 h in an isothermal condition, the wax crystal grows little, i.e., its sizes do not “double” as at 40°C. A smaller variation was noted between the sample growth percentages at 5°C. This temperature is close to that observed in the production fields. After 1 h at 5°C, the wax crystals are 10.3 ± 2.8% higher than when the temperature just arrives 5°C. Generalizing this information and transferring it to offshore production fields, after a 1-h stop with the oil at 5°C, the crystals can grow about 10%. Of course, this is a hypothetical condition because it is impossible to happen, since the cooling rate in the fields is smaller than that used in this study, which can result in greater wax crystals.
Due to the complex matrix that is the petroleum itself, the physicochemical characterization is very relevant in order to address a proper comparison between the microscopic images, which is a very useful tool in the wax crystal morphology study. The most common physicochemical characterization techniques are:
Density: measured mainly by ASTM-D7042. By density (at 60°F = 15.6°C) it is possible to obtain the °API following Eq. (1). °API is the most general classification at petroleum industry:
Viscosity: can be also determined by ASTM-D7042 on a viscometer or by rheological tests.
Saturated, aromatic, resin, and asphaltene (SARA): can be determined mainly by Clay-Gel, according to ASTM D2007, thin layer chromatography with flame ionization detection (TLC-FID) according to IP-469, or by high-performance liquid chromatography (HPLC) according to IP-368. In this work, SARA content was obtained by TLC-FID using the IATROSCAN MK-6 (NTS International), for all paraffinic crude oils.
SAP: this characterization is less specific than SARA because resins and asphaltenes are considered together as polars. The SAP contents were determined by a liquid chromatography separation composed by silica gel column 60 (2.5 g silica, 0.063–0.200 mm) from Merck, which was used to determine the SAP content. The column was heated for 10 hrs at 120°C for activation. Fractions were eluted with 10 mL n-hexane for saturated, 10 mL of n-hexane/dichloromethane (8:2) for aromatic, and dichloromethane/methanol (9:1) for polar fractions. Residual solvents were submitted to a rotary evaporation. This technique was employed only for non-paraffinic (NP).
WAT: this is one of the main characterizations when working with waxy crudes, because it gives an idea of the precipitation potential of the oil and ideas about the wax type. A wide range of techniques can be used to determine WAT, as microscopy, rheology, and near-infrared spectroscopy (NIR), but the most used is DSC. In this work, measurements were performed using Nano DSC differential scanning calorimeter (TA Instruments). The samples were heated from room temperature to 80°C, at 2°C/min. Then they were held for 15 min at 80°C, following by a cooling step from 80–4°C, at 0.5°C/min. Kerosene was used as the reference. Before measurements, samples were homogenized and kept under vacuum for degasification for at least 30 min. A volume of 300.0 μL of crude was used.
Gas chromatography: this technique is employed to characterize the carbon number distribution of petroleum waxes and the normal and non-normal hydrocarbons. It is oriented by ASTM D5442-17. In this work the GC evaluated the carbon distribution up to C36.
Table 3 presents some physicochemical characterization of the four paraffinic P1–P4 and NP oils used as reference of wax absence, also provided by Petrobras. All crude oils have relatively similar values of density. The paraffinic samples are considered medium oils, while NP is classified as heavy oil according to the °API scale. The viscosity varies greatly between samples, with P1 and P3 being the less viscous. P4 exhibits the highest viscosity at 20°C, being 100 times greater than the lower one (P3). Non-paraffinic petroleum classified as heavy oil also has high viscosity (896.8 mPa.s).
Physicochemical characterizations.
WAT is defined as the onset temperature, that is, the intersection point of the baseline and the tangent line of the inflection point of the exothermic peak [4, 39, 40]. In crude oils, it is common to observe two exothermic events (peaks). WAT depends on the concentration and molecular weight of waxes and the chemical characterization of hydrocarbon matrix [41]. Due to the oil complexity, the values of the peaks are around 50°C for the first exothermic event and 25°C for the second; [16, 42] assign the first peak to a liquid-liquid transition and the second to liquid-solid transition. However, in this paper, the authors believe that each exothermic event refers to a different group of waxes according to the chain length. [43, 44] declare that n-alkanes with similar carbon numbers can co-crystallize with the longer n-alkane chains.
Figure 5 shows the thermal curves for all samples obtained by Nano DSC. All oils have at least two well-defined exothermic peaks. It is possible to note a great similarity between the WAT values and the intensity of the exothermic peaks in the curves of the oils P1 and P3. However, the saturated values are quite different (Table 3). P1 has the 54.0 wt% and P3 has the 63.1 wt%, the highest values between the samples. Nevertheless, we must keep in mind that not all saturated content refers to wax; thus, these differences between saturated content among the oils do not represent the real wax content.
P1-P4 and NP thermal curves behavior.
Continuing the analysis of Figure 5, it is noted that P2 was characterized by the lower WAT values and P4 shows the higher (Table 3), which may be an evidence that the P2 is composed by short waxy chains and P4 has the longest. According to [36] the larger the carbon chain size, the higher the crystallization temperature. Moreover, the first peak of P2 is barely evident which can be a sign of less wax content. P4 has a second peak very evident, that is, this oil may contain the higher wax content. However, P4 has the smallest crystals, as discussed before, being on average 35% smaller than the others are. According to the P4 higher WAT value, large crystals were expected. Senra et al. [45] suggest a co-crystallization between chains with different carbon numbers and with other compounds, affecting the crystal morphology. According to [46] the co-crystallization weakens the crystal structure and disfavors large crystal formation. This is a plausible hypothesis, since according to SARA, P4 has 42.7 wt% of resins and the higher content of asphaltenes (0.65 wt%).
Another curious fact is a possible third peak at temperatures just below the second, especially for P2 and P4. This peak may represent a third population of waxes, and as far as we know, it was never reported in conventional DSC analyses. Possibly this third peak is related to a group of very-short-chain waxes. Based on this observation, it is verified that the Nano DSC technique presents greater sensitivity to enthalpy variations. In the conventional DSC technique, this third peak may be masked with the second. According to [19] the conventional DSC is not sufficiently sensitive to identify WAT for samples with low wax contents; however, the Nano DSC shows two slight baseline variations for NP sample, even in a low cooling rate (0.5°C/min). These peaks are very low if compared to other oils due to the non-paraffinic characteristic of NP, but their presence confirms the sensitivity of the equipment.
Figure 6 shows the GC graphs of the crude oils P1–P4 and their respective extracted waxes through the UOP46–85 method (see Section 4). It is possible to note that the values obtained for the GC of the crude oil (white bars) are dispersed and have a tendency of decrease after around C30. This behavior can be attributed to the complex matrix of the oil itself. However, the carbon distribution number obtained from the extracted wax fraction from each oil (dark bars) has a more plausible chain distribution. For all oils, there is a chain predominance around C30.
Carbon number distribution for P1-P4 crude oil.
Figure 7 shows the crystal length versus temperature for P1–P4. The first experimental point of the curves is the respective WAT values. This graph is presented in order to analyze the growth tendency of the wax crystals as a function of the temperature reduction, as a way to summarize the information previously discussed.
P1-P4 crystal length versus temperature.
The wax quantification is more difficult to develop than the other characterizations. However, some techniques are available:
GC: as mentioned on 3. Physicochemical characterization, this technique is employed to characterize the carbon number distribution. In this work the GC evaluated the carbon distribution up to C36.
Nuclear magnetic resonance (NMR) correlation: presented by [47], estimates the wax content of crude oil and their fractions by H NMR spectroscopy. The method shows good fit for oils with boiling range from 340 to 550°C.
UOP 46–85 method: estimates the wax content of the crude oil and is defined as the mass percentage of precipitated material when an asphaltene-free sample solution is cooled to −30°C.
DSC integration baseline: is possible to obtain the total thermal effect of the wax precipitation (
By means of simple math, it is possible to calculate the mass content of precipitated waxes (
The percentages by mass of precipitated wax obtained by the DSC integration baseline show 3.1 and 2.9 wt% for P1 and P3, respectively. As cited before these oils have many similarities. P2 has the lowest value (2.2 wt%) and P4 has 4.7 wt% of precipitated waxes. However, by the UOP 46–85 method, the wax contents in mass percentage obtained were 3.7 ± 0.3 for P1, 5.7 ± 0.4 for P2, 5.0 ± 0.1 for P3, and 3.6 ± 0.2 for P4. In general, these values are at the same range of the values obtained by DSC integration baseline, but they are not in agreement with the values obtained by this same technique. The UOP 46‒85 method is a traditional way of wax estimation by very steps extractions, as well as time-consuming, lots of chemicals and solvents. These many delicate steps have great chances to produce erroneous results if not done properly [47].
Figure 8 shows the carbon number distribution, obtained through GC, only for the extracted waxes by means of UOP method. As determined by DSC integration baseline, P2 has the lowest percentage of waxes, and P4 has the highest. This can be observed again on the GC graph. According to [50] the GC and DSC analyses can be used to quantify wax content of crude oils showing reasonable agreement, but wax precipitation technique, as UOP method, must be corrected due to the presence of trapped crude oil in the precipitated solid wax crystal.
Carbon number distribution for P1-P4 crude oil.
The polarized light microscope is the most used technique to visualize wax crystals; however, bright-field microscopy shows crystal details that are not seen on the polarized light. The wax crystals observed have elongated structure, but they are not linear, i.e., not needle-shaped. They have superficial roughness attributed to the presence of crystallization interferers such as asphaltenes, resins, organic solids, and different carbon chain sizes. The gradual temperature decrease favors the length crystal increases, as well as the increase in the quantity and size of the agglomerates. Under shear conditions, crystals were observed around 25% smaller and in less quantity than under quiescent conditions. In addition, shearing promotes crystal breakage at very low temperatures. The aging time of the oil favors the crystal growth more drastically at higher temperatures (around 45% after 1 h at 40°C) than in low temperatures (around 10% after 1 h at 5°C), as well as the formation of agglomerates. P4 shows the higher content of precipitated waxes by means of DSC integration baseline and GC analysis, but their crystals were smaller, possibly due to the higher polar content. The DSC integration baseline is in accordance to the GC result to wax content determination; however, the UOP method is in disagreement. Another characteristic observed about Nano DSC was the great sensitivity to obtain WAT values. This technique can identify a possibly third peak precipitation and two peaks for the NP sample.
This chapter looks at some techniques of wax characterization and quantification; however, there are many other techniques that can be used and that present satisfactory results. The use of combined techniques may assist in the more accurate analysis of sample characteristics.
The authors thank Conselho Nacional de Pesquisa e Desenvolvimento (CNPq), Fundação Carlos Chagas de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), and Petrobras for supporting this work.
The authors declare no competing financial interest.
API | American Petroleum Institute |
ASTM | American Society for Testing and Materials |
BF | brightfield |
DSC | differential scanning calorimeter |
GC | gas chromatography |
HPLC | high performance liquid chromatography |
NIR | near-infrared spectroscopy |
NMR | nuclear magnetic resonance |
NP | non-paraffinic |
P1–4 | paraffinic petroleum |
PL | polarized light |
SAP | saturated, aromatic and polar |
SARA | saturated, aromatic, resins and asphaltenes |
TLC-FID | thin layer chromatography with flame ionization detection |
UOP | universal oil products collection |
WAT | wax appearance temperature |
Q | total thermal effect of wax precipitation |
cw | wax precipitated concentration |
Q¯ | constant thermal value of wax precipitation |
Tf | final DSC temperature |
w | mass content of precipitated waxes |
ρ | specific mass |
Ve | experimental volume used to the DSC measurement |
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