Clinical Evaluation and Management of Chronic Kidney Disease

John Feehally DM, FRCP , in Comprehensive Clinical Nephrology , 2019

Establishing Chronicity

When eGFR of less than 60 ml/min/1.73 m2 is detected, careful attention should be paid to previous blood and urine test results and the clinical history to determine if this is a result of AKI; that is, an abrupt decrease in kidney function or CKD that has been present but asymptomatic for some time.

A detailed medical history covering issues, including other medical conditions, family history of kidney disease, prescribed medication, and recreational drug use, may suggest an underlying cause. There may be hints of a history of kidney problems (e.g., hypertension, proteinuria, microhematuria) or symptoms suggestive of prostatic disease. The physical examination findings are not usually helpful, although skin pigmentation, scratch marks, left ventricular hypertrophy, and hypertensive fundal changes favor a chronic presentation (Fig. 80.1). Details of the social and personal circumstances are also crucial, particularly for patients with progressive kidney disease in whom RRT is likely to be required.

Blood tests for other conditions can be helpful because they may indicate evidence of an acute illness that could be the cause of kidney failure, such as systemic vasculitis or multiple myeloma. A normochromic normocytic anemia is usual in CKD, but also may be a feature of acute systemic illnesses and therefore is not discriminatory. Low serum calcium and raised phosphate levels also have little discriminatory value, but normal levels of parathyroid hormone (PTH) are more in keeping with AKI. Patients with grossly abnormal biochemical values—for example, blood urea nitrogen higher than 140 mg/dl, serum creatinine above 13.5 mg/dl (>1200 µmol/l), or blood urea greater than 300 mg/dl (>50 mmol/l)—who appear relatively well and are still passing normal volumes of urine are much more likely to have CKD than AKI.

Dose and Time Determining, and Other Factors Influencing, Toxicity

Karl K. Rozman , ... Wayland J. HayesJr., in Hayes' Handbook of Pesticide Toxicology (Third Edition), 2010

1.3.2.3 Chronicity Index

The chronicity factor introduced independently by Hayes (1967b), is expressed as a quotient rather than a percentage. However, this factor is really an index and ought to be designated as such in the future. Excluding differences in the procedures for measuring the LD 50 values, the chronicity index for a compound is the reciprocal of its C/A LD 50 (0.1L) index expressed as a fraction instead of as a percentage. That is,

Chronicity index = 100 C/A LD50(0 .1 L ) i n d e x

For example, the C/A LD 50 (0.1L) index for sodium chloride (71.7) would correspond to a chronicity index of 1.395.

Because each chronicity index is a ratio, these indices may be used to compare the tendency of different compounds to have cumulative effects without reference to their absolute toxicities. This index is determined on the basis of an observed effect. No distinction is made between effects that depend in part on cumulation of the toxicant (e.g., lead) and those that do not (e.g., alcohol).

The chronicity index for each compound is obtained by dividing its 1-dose LD 50 (expressed as milligrams per kilogram) by its 90-dose LD 50 (expressed as milligrams per kilogram per day). The resulting number is large (2.0 or more) for compounds that are relatively cumulative in their effects and small (less than 2.0) for compounds that show little cumulative effect. The index of 2.0 is recognized as an arbitrary dividing point, but it appears supported by the limited data available and is also plausible on theoretical grounds. In any event, if a compound were absolutely cumulative (in the sense that 1/90 of the 1-dose LD 50 was exactly the 90-dose LD 50), the chronicity index would be 90. A chronicity index of 1.0 associated with oral intake indicates that daily ingestion of the 1-dose LD 50 mixed into the regular diet leads to death of half of a very large population so exposed for 90 days, which is very difficult to verify experimentally, but sodium chloride gets as close to it as experimentally possible.

Table 1.2 summarizes the 1-dose and 90-dose LD 50 values and also the chronicity indices for warfarin and several other compounds. The marked cumulative effect of warfarin and the chemosterilants; the small magnitude of such an effect of table salt, caffeine, and some organic phosphorus compounds; and the essential lack of cumulative effect of potassium cyanide are recorded. The 90-dose LD 50 of warfarin was only about 1/20 of the 1-dose LD 50, indicating a chronicity index of about 20 for that compound. It required daily ingestion of approximately a 1-dose LD 50 of several organic phosphorus insecticides to kill half of the test animals in 90 days, indicating a chronicity index of approximately 1 in each instance. Rats tolerated daily 25 1-dose LD 50s of potassium cyanide mixed with their regular food with no mortality, indicating a chronicity factor of less than 0.04. This tolerance for organic phosphorus compounds and cyanide undoubtedly indicates the ability of the body, and especially the liver, to detoxify moderate dosages of these materials provided there is time in which to accomplish the task. The chronicity index permits comparison of the effects of different classes of compounds of the same class. Whether these smaller intraclass distinctions are really significant or whether they are outweighed by differences caused by species or other factors must be determined by future experience. It is certainly to be hoped that increasing use will be made of 90-dose LD 50 and ED 50 values and of the chronicity index in order that the study of long-term toxicity may be made more quantitative.

Table 1.2. Absolute and Relative, Acute and Subacute Oral Toxicity of Certain Pesticides and Drugs a

Compound Species Sex 1-Dose LD 50 (mg/kg) 90-Dose LD 50 (mg/kg/day) Chronicity index
Mirex Rat F 365 6.0 60.8
Warfarin Rat M 1.6 0.077 20.8
Metepa Rat M 136 7.5 18.1
Dieldrin Rat M 102 8.2 12.8
Atropine Rabbit M 588 b 78 b 7.5
Apholate Rat M 98 17 5.8
Paraquat Rat F 110 20.5 5.4
DDT Rat M 250 46.0 5.4
Benzylpenicillin Rat M 6700 c 4140 c 1.6
Sodium chloride Rat M 3750 d 2690 e 1.4
Caffeine Rat F 192 f 150 g 1.3
Parathion Rat F 3.6 3.1 1.16
3.5 1.03
Azinphosmethyl Rat F 11.0 10.5 1.05
EPN Rat F 7.7 12.0 0.64
Dichlorvos Rat F 56 >70 >0.08
Potassium cyanide Rat M 10 <250 h >0.04
a
From Hayes (1967b) or later U.S. Public Health Service data, except as noted, by permission of Academic Press. The compounds are listed in approximate order by decreasing chronicity index.
b
Boyd and Boyd (1962) (100-intramuscular-dose test).
c
Boyd and Selby (1962 (100-dose test).
d
Boyd and Shanas (1963).
e
Boyd et al. (1966) (100-dose test).
f
Boyd (1959).
g
Boyd et al. (1965) (100-dose test).
h
No mortality occurred at 250   mg/kg/day, the highest dosage administered.

The chronicity index is a measure of cumulative effects. A concentration index has been proposed as a measure of cumulative storage. The effect of a compound cannot be less than that determined by its storage in the body, especially its presence (storage) in sensitive tissues. In this sense, a compound that has a high concentration index will tend to have a high chronicity index. However, some compounds are highly cumulative in their effects even though they show a minimal tendency to storage. Thus, the two indices do not vary in a parallel fashion.

It is generally agreed that what has been called biological magnification is the basis for the injury caused by DDT and a few other compounds to certain large, predatory forms of wildlife. Biological magnification occurs in situations in which a compound shows a high concentration index in each successive species in a food chain.

This section demonstrates that Hayes (1991) was fully aware of the importance of time in the manifestation of toxicity without generalizing time as an equivalent and fully quantifiable variable of toxicity along with the dose. Perhaps for this reason, he made no reference to measuring time accurately in toxicological experiments. There are additional issues to be considered when viewing time as a variable of toxicity: the timescale on which the effect is occurring and the frequency of observation, which are related to each other as well as to the half-lives of compound or effect and exposure frequency. A clear distinction must also be made whether dose-time or effect-time relationships are being considered because the former requires the study to be conducted at constant effect, whereas the latter necessitates an experiment at constant dose (steady state). Routine daily observation of experimental animals in chronic experiments arises out of practicality and is (e.g., cancer studies) without scientific rationale. In fact, in two-year or longer lasting cancer studies weekly observation would yield satisfactory time resolution of the cancer latency period (but not for harvesting tissues). However, the daily observation of animals in acute experiments often provides worthless information on that timescale if all the animals die within 2–3 days or even sooner. Automated cameras could provide hourly or continuous monitoring, which would result in the necessary accuracy for quantitative time relationships. Toxicant-induced reduced sea urchin sperm motility occurring on a timescale of hours is only meaningfully measured on a timescale of minutes and nobody in his right mind would want to study pungency on a timescale of minutes when it requires time resolution on a scale of seconds. This all sounds simple and straightforward, yet cookbook-type toxicology is devoid of these simple considerations. The timescale on which an effect is occurring is important for several reasons. The length of the observation period for any experiment should be the time required by a LOAEL to cause the effect. The relationship between the time to an effect and the dynamic or kinetic half-life of an effect are other critical variables which often confuse toxicological experiments, because the respective rate-determining time ratios will introduce different ratios of intoxication/recovery as discussed in Section 1.3.1.1 with dieldrin and toxaphene as examples. It must be recognized that our understanding of time is perhaps more limited than mankind's understanding of matter was during the era of Paracelsus and yet toxicology is one of the few fields that can open the gate to the structure of time.

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Secondary Glomerular Disease

Alan S.L. Yu MB, BChir , in Brenner and Rector's The Kidney , 2020

Activity and Chronicity

Current guidelines advocate that renal biopsies should be accorded an activity and chronicity score, as modified from the NIH system. 50 The purpose is to identify and quantify active (potentially reversible) lesions and chronic (irreversible) lesions. In the newly modified NIH system, activity index is calculated by grading the biopsy on a scale of 0 to 3+ for each of six histologic features; these features are endocapillary hypercellularity, glomerular neutrophil infiltration and/or karyorrhexis, wire loop deposits, fibrinoid necrosis, cellular and/or fibrocellular crescents, and interstitial inflammation. The severe lesions of crescents and fibrinoid necrosis are assigned double weight. The sum of the individual components yields a total histologic activity index score from 0 to 24. Likewise, a chronicity index of 0 to 12 is derived from the sum of global and/or segmental glomerulosclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis, each graded on a scale of 0 to 3+. Studies at the NIH correlated both a high activity index (>12) and especially a high chronicity index (>4) with a poor 10-year renal survival rate. However, in several other large studies, neither the activity index nor the chronicity index correlated well with long-term prognosis. Other NIH studies concluded that a combination of an elevated activity index (>7) and chronicity index (>3) predicts a poor long-term outcome. 60 A major value of calculating the activity and chronicity indices is in the comparison of sequential biopsies in individual patients. This provides useful information about the efficacy of therapy and the relative degree of reversible versus irreversible lesions. 4,5,16,36,61,62

Immunity to Pathogens and Tumors

Paul M. Kaye , in Encyclopedia of Immunobiology, 2016

Response Exhaustion

The chronicity of many parasitic and bacterial infections (and indeed some viral infections) may manifest in various states of immune exhaustion. Lack of immune function may then precipitate disease and drive pathogenesis through multiple downstream pathways, including increased pathogen multiplication, and/or loss of containment ( Pauken and Wherry, 2015). Evidence of T cells with an exhausted phenotype is now emerging from clinical studies of bacterial and protozoal disease, for example, leishmaniasis (Gautam et al., 2014). To date, there have been no examples of exhaustion where this is a direct consequence of a pathogen-derived virulence factor; rather this appears a generic consequence of the long-term struggle established between host and pathogen. An understanding of the mechanisms of exhaustion is important, as it may provide a potential approach to reactivating immunity in chronic infection for therapeutic benefit.

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Irritable Bowel Syndrome

Mark Feldman MD , in Sleisenger and Fordtran's Gastrointestinal and Liver Disease , 2021

Chronicity

For a confident diagnosis of IBS, symptoms should have been present for at least 6 months 7 ; IBS may accompany other chronic disorders. For example, IBS is present in up to one-third of patients with celiac disease, even after institution of a gluten-free diet. 26 Up to 40% of patients with IBD may also report IBS-type symptoms. 27 This does not seem to reflect occult inflammation at the time symptoms are reported, 28 , 29 or to lead to adverse outcomes reflecting evolving disease activity during extended follow-up, but it is associated with increased healthcare utilization and poor psychologic health. 30 A number of different conditions can cause transient bowel symptoms in healthy persons, as well as those with preexisting IBS including pregnancy, dietary indiscretion, food poisoning, travelers' diarrhea, bed rest, weight loss, and acute stress (nervous diarrhea); these must be distinguished from the chronic, recurrent symptoms of IBS.

Molecular and Cell Biology of Pain

Andrew Michael Tan , in Progress in Molecular Biology and Translational Science, 2015

5 Dendritic Spines in Neuropathic Pain

The chronicity of neuropathic pain underscores the importance of understanding the contribution of dendritic spines. Multiple factors contribute to hyperexcitability of nociceptive neurons associated with neuropathic pain. These factors include chronic nerve damage, e.g., amputation or diabetic neuropathy, CNS inflammation, dysregulation of potassium-chloride cotransporter 2 (KCC2) activity, loss of inhibitory inputs, e.g., reduced GABAergic signaling, and altered growth factor and sodium channel expression in dorsal root ganglia (DRG) or spinal cord neurons. 65–72 A synaptic model similar to that involved in long-term memory storage has also been proposed to explain the persistent, intractable nature of neuropathic pain. 65 Previous studies in multiple pain models, i.e., spinal cord injury, peripheral nerve injury, diabetic neuropathy, and burn injury, demonstrate that dendritic spine dysgenesis can abnormally change the electrical properties of dorsal horn neurons in a manner that reflects nociceptive hyperexcitability associated with neuropathic pain 73 (Fig. 4). Because of the link between dendritic spine structure and neuronal function, 74 a thorough investigation of dendritic spine behavior in the spinal cord is a unique opportunity to better understand the mechanisms of sensory dysfunction after injury or disease.

Figure 4. Dendritic branches from a dorsal horn neuron in a normal condition (top panel) and 10 days after peripheral nerve injury (bottom panel) demonstrate qualitative differences in dendritic spine morphology, including changes in dendritic spine size, shape, and number. Scale bar   =   10   μm.

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Neurotic, stress-related and somatoform disorders

Michael Sharpe , ... Jane Walker , in Companion to Psychiatric Studies (Eighth Edition), 2010

Diagnosis

The chronicity and multiplicity of the symptoms and medical help-seeking are the hallmarks of the condition. These patients histories of lifetime symptoms have been found to be unreliable ( Simon & Gureje 1999) and a review of case notes is desirable. Clearly a major differential diagnosis is that of a medical condition that can produce multiple symptoms (such as systemic lupus erythematosus). However, as these patients have been extensively – indeed, often excessively – investigated, this differential is often less of an issue than it may first appear to be. The other condition associated with a high level of medical help seeking is hypochondriasis. In hypochondriasis the patient's predominant concern is with the fear or belief that they have a serious medical condition; in somatisation disorder it is with relief of the symptoms. It is also likely that hypochondriasis and somatisation disorder represent opposite ends of a spectrum, rather than being clearly distinct conditions.

The distinction from factitious disorder and malingering is based on the requirement that symptoms are intentionally feigned in these conditions. This distinction can be hard to make.

Any psychiatric disorder can present with somatic symptoms and must be considered in the differential diagnosis. Anxiety and depressive disorders can have prominent somatic symptoms. Occasionally the concern with symptoms is delusional and part of a psychotic disorder.

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Theranostic drug delivery systems for targeted therapy of lung diseases

Haliza Katas , in Targeting Chronic Inflammatory Lung Diseases Using Advanced Drug Delivery Systems, 2020

3 Challenges in lung delivery

The chronicity of lung diseases is the main challenge to the effective treatment because of the adverse effects associated with current treatments. For example, the chronic use of corticosteroids may cause systemic side effects that lead to noncompliance to medication and subsequently poor therapeutic outcomes [40]. In the case of COPD, the sustained delivery of drugs such as bronchodilators, corticosteroids, and antibiotics to the pulmonary tissues with current treatments is still a great challenge [41]. Additionally, multidrug resistance of pathogens and certain types of cancer further complicate the management of these diseases [40].

In lung diseases that involve severe inflammation, the reaction causes mucus hypersecretion, for example, in the case of asthma, COPD, and CF. Mucus hypersecretion is the hallmark of these diseases, and it could be induced by infection or components in cigarette smoke [41]. The mucus is viscous, elastic, and sticky in the lung upper airway and bronchi that restrict the penetrability of drug carriers, including theranostics [14]. Besides airway narrowing and mucus hypersecretion, airway defense mechanisms are the other obstacles to successful theranostic delivery that have yet to be overcome, including rapid drug clearance by mucociliary and phagocytic cells such as macrophages and neutrophils.

Despite pulmonary delivery (inhalation) is a great strategy to target the lung tissues, the deposition of inhaled drug particles in the lung is primarily dictated by the particle size. Different ranges of particle size are designed to target different regions of the lung. Large particles in the range of 1–5   μm are used to deposit drug particles in bronchioles and smaller airways, while small particles (0.5–1   μm) are designed to target alveolar regions. Fine particles of less than 500   nm should be avoided as the drug may not be effective due to exhalation [42]. The barriers to successful pulmonary drug delivery are summarized in Table 2. The combined effects of these barriers may lead to more difficult challenges to be overcome [43]. To get access to the target site, for example, underlying epithelia or inflammatory cells, drug and carriers should be able to escape the airway defense and penetrate through the mucus [14].

Table 2. Barriers to successful pulmonary drug delivery.

Mechanical
1. Deposition of inhaled drug particles and droplets in mouth and nose due to impaction and restrict delivery to peripheral lung regions
2. Progressive branching and narrowing of the pulmonary airways caused impaction of inhaled particles
3. Disease conditions such as bronchoconstriction, mucus hypersecretion and accumulation, and airway narrowing alter drug deposition in the lung
4. Lung clearance mechanism:
•

Inhaled drug particles deposited in the airway are mostly eradicated by mucociliary clearance

•

Mucociliary clearance is impaired in the presence of tenacious mucus, for example, cystic fibrosis
Chemical
1. Drug degradation via drug metabolism or inactivation by proteolytic enzymes
2. Effects of other chemicals that may affect the ability of drug particles to adhere to the lung surfaces and clearance, for example, surfactant
Immunological
1. Clearance of drug deposited in the alveolar region by alveolar macrophages engulfment. Macrophages are the main phagocytic cells in the lung
Behavioral
1. Poor therapy adherence due to factors such as the belief that medication is no longer needed as the symptoms improved, forgetfulness, and social embarrassment in using inhalers
2. Problems with inhaler technique, for example, poor coordination and breathing technique

Modified from Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 2003;56:588–99; Newman SP. Drug delivery to the lungs: challenges and opportunities. Ther Deliv 2017;8:647–61.

Despite increasing numbers of theranostic approach have been studied over the years, however, not many are used clinically because significant hurdles remain, which are yet to be overcome. Due to the advances in nanobased technology, both diagnostic and therapy could be achieved simultaneously. Nanotechnology is the engineering of matter at an atomic and molecular scale [44]. Nanoparticles have shown many capabilities including in vivo imaging, phototherapy, and thermostimulation, delivering more than one drug and specific targeting to tissues or cells [40], making them a promising agent for theranostic purpose. Therefore theranostic nanoparticles are expected to improve diagnosis and treatment including lung diseases, leading to more effective disease management.

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SLE in Children

Rina Mina , Hermine I. Brunner , in Systemic Lupus Erythematosus (Fifth Edition), 2011

Special therapeutic considerations

The chronicity of illness and uncertainty of prognosis is a source of apprehension for patients with cSLE and their parents alike. Growth, development, long residual lifespan, incomplete brain development, and reproductive potential all need to be considered in the treatment of any pediatric disease, including cSLE. The most commonly used medications including the doses suggested are summarized in Table 32.2. More detailed information on drug dosing and monitoring for cSLE is provided elsewhere [220].

TABLE 32.2. Anti-inflammatory Medications for Children with cSLE

Drug(s) Suggested doses Usual maximum dose Useful for Remarks
NSAIDS
Naproxen 10–25 mg/kg/day 1000 mg orally divided in b.i.d. Mild disease Musculoskeletal disease; needs monitoring for effect on NPSLE and kidneys
Ibuprofen 20–40 mg/kg/day 2400 ma orally divided in t.i.d.
Diclofenac 1–3 mg/kg/day 150 mg orally divided in b.i.d.
CORTICOSTEROIDS
Prednisone 1–2 mg/kg/day 80 mg orally per day Rapid control of acute disease symptoms of moderate to severe degree Rarely exceed 60 mg daily; may be divided in quid dosing, if necessary. Some patients will require low-dose oral corticosteroids for maintenance therapy.
Oral methylprednisolone 1–2 mg/kg/day 60 mg orally per day Use for patients with liver involvement.
Intravenous methylprednisolone 10–30 mg/dose 1000 mg per dose Acute manifestations of NPSLE, kidney, and hematological disease.
IMMUNOSUPPRESSIVES
Azathioprine 0.5–2.5 mg/kg/day 200 mg orally once daily Moderate or severe disease Vasculitis, NPSLE, glomerulonephritis Steroid sparing medications; use is associated with improved outcome of NPSLE and kidney disease
Oral cyclophosphamide 0.5–2 mg/kg/day 2000 mg orally divided in b.i.d.
Intravenous cyclophosphamide 500–1000 mg/m2 2500 mg per dose
Mycophenolate mofetil 60 mg/kg/day 3000 mg orally divided in b.i.d.
OTHERS
Hydroxychloroquine 5–7 mg/kg/day 400 mg orally once daily Mucocutaneous disease, arthritis
Dapsone 2 mg/kg/day 100 mg orally once daily Skin disease and skin vasculitis
Immunoglobulins 1–2 mg/kg/dose 25 mg orally or subcutaneously once every week Hematological disease
Methotrexate 15–20 mg/m2/week Arthritis; not in patients with kidney disease

As with aSLE, the therapeutic approaches to cSLE are nonstandardized at present and are influenced by organ involvement, severity of global disease, availability of drug, and concomitant damage. Antimalarials are taken by about two-thirds of all cSLE patients [6], and in some centers virtually all cSLE patients are prescribed hydroxychloroquine. Patients with SLE of all ages older than 6 years are equally likely to be prescribed antimalarials [14, 87]. Adults and children with SLE are comparable in their use of nonsteroidal anti-inflammatory medications [5, 87], except for cyclooxygenase 2 inhibitors, which appear to be less commonly prescribed to children and adolescents [87].

In comparing medication choice in cSLE and aSLE, a larger proportion of children and adolescents are treated with high-dose corticosteroids and immunosuppressive medications than patients with aSLE [14]. Currently azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, and leflunomide are most often used in cSLE.

Based on several observational studies, virtually all cSLE patients will be exposed to oral corticosteroids during the course of their disease [87]. In a study of patients followed at Canadian tertiary centers, 97% of the 67 cSLE patients compared to only 70% of the 131 aSLE patients were prescribed oral corticosteroids [14]. Patients with cSLE in this study received high-dose intravenous methylprednisolone therapy more frequently than aSLE patients, 30% vs. 11%, respectively. Similarly, immunosuppressive medications were more often prescribed to children as compared to patients with aSLE (66% vs. 37%), while the choice of specific immunosuppressive medications appears quite similar in both groups [14]. An exception may be the more common use of methotrexate in aSLE than cSLE patients (31% vs. 9%) [14].

The most common indication for cyclophosphamide treatment in cSLE is cNPSLE and LN [6]. How the more common use of mycophenolate mofetil and CD20-depleting therapies in recent years influences the overall medication profiles of cSLE is unknown at present. Infection rates with immunosuppression in cSLE vary considerably, likely reflecting differences in health milieu and local practices. Fatal infections with fungus or Gram-negative bacilli occur more commonly in patients treated with immunosuppressive medications for active LN.

At this point, there are no data on the life-long risk of malignancy in cSLE patients exposed to immunosuppressive drugs. There are no reports of pediatric malignancy in cSLE patients treated with cyclophosphamide [91].

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Molecular Basis of Diseases of the Gastrointestinal Tract

Antonia R. Sepulveda MD, PhD , Armando J. Del Portillo MD, PhD , in Molecular Pathology (Second Edition), 2018

Stepwise Progression of H. pylori Gastritis to Gastric Carcinoma: Histologic Changes of the Gastric Mucosa

The chronicity associated with H. pylori gastritis is critical to the carcinogenic potential of H. pylori infection. H. pylori is generally acquired during childhood and persists throughout life unless the patient undergoes eradication treatment [34–37]. Gastric cancer develops several decades after acquisition of the infection, in a sequence of mucosal damage with development of specific histological alterations [38].

H. pylori infection of the stomach activates both humoral and cellular inflammatory responses within the gastric mucosa involving dendritic cells, macrophages, mast cells, recruitment and expansion of T-lymphocytes and B-lymphocytes, and neutrophils [39,40]. Despite a continuous inflammatory response, H. pylori organisms are able to evade the host immune mechanisms and persist in the mucosa, causing chronic gastritis.

Histologically, the progression of H. pylori-associated chronic gastritis to gastric cancer starts with chronic gastritis, which leads to progressive damage of gastric glands resulting in atrophy (atrophic gastritis). There is patchy replacement of normal gastric glands by intestinal metaplasia over the entire stomach, but usually it is more severe in the antrum than in the body/fundus. Later, dysplasia and carcinoma may develop in some patients (Fig. 19.1) [5,19,41,42].

Figure 19.1. Gastric carcinogenesis: stepwise progression of H. pylori-associated gastric cancer (Panels A1–A4), and hereditary diffuse gastric cancer (Panels B1 and B2).

Panel A1: Chronic active gastritis involving the mucosa of the gastric antrum (H&E stain, original magnification 10×); Panel A2: Immunohistochemical stain highlights H. pylori organisms with typical S and comma shapes, seen at higher magnification in the inset. H. pylori organisms typically appear attached or adjacent to the gastric surface and foveolar epithelium (original magnification 40×); Panel A3: Gastric mucosa with intestinal metaplasia and low-grade dysplasia/adenoma (H&E stain, original magnification 10×); Panel A4: Gastric carcinoma of intestinal type (moderately differentiated adenocarcinoma) (H&E stain, original magnification 10×). Gastric mucosa of patient with hereditary diffuse gastric cancer with in situ signet ring cell carcinoma (arrow) (B1) and invasive signet ring cell carcinoma expanding the lamina propria between the gastric glands (H&E stain, original magnification 20×).

 Panels B1 and B2 Courtesy of Dr. Adrian Gologan, Jewish General Hospital, McGill University.

The potential role of bone marrow–derived stem cells in chronic gastritis and H. pylori-associated neoplastic progression has been proposed based on studies in animal models [30,43]. The current hypothesis is that H. pylori-associated inflammation and glandular atrophy create an abnormal microenvironment in the gastric mucosa that favors engraftment of bone marrow–derived stem cells into the inflamed gastric epithelium. It is postulated that engrafted bone marrow–derived stem cells do not follow a normal differentiation pathway and undergo uncontrolled replication, progressive loss of differentiation, and neoplastic behavior [30,43–45]. However, the potential role of bone marrow–derived stem cells in human disease remains unclear.

Stomach cancers are classified according to the World Health Organization guidelines based on their grade of differentiation into well-differentiated, moderately differentiated, and poorly differentiated adenocarcinomas [46]. In addition, gastric adenocarcinomas can be categorized into intestinal and diffuse types (Lauren classification), based on the morphologic features on hematoxylin and eosin (H&E)-stained tissue sections [47].

Gastric cancers arising on the inflammatory background of H. pylori-associated chronic gastritis are most commonly intestinal-type adenocarcinoma, which are predominantly well-differentiated to moderately differentiated adenocarcinomas, but diffuse-type cancers, which are poorly differentiated or are signet ring cell carcinomas, also occur in the sequence of H. pylori gastritis [20,23,48] (Fig. 19.1).

Progression to gastric cancer is higher in patients with extensive forms of atrophic gastritis with intestinal metaplasia involving large areas of the stomach, including the gastric body and fundus. This pattern of gastritis has been described as pangastritis or multifocal atrophic gastritis [7,8,22,49,50]. Extensive gastritis involving the gastric body and fundus results in hypochlorhydria, allowing for bacterial overgrowth and increased carcinogenic activity in the stomach through the conversion of nitrites to carcinogenic nitroso-N compounds [51,52]. H. pylori-associated pangastritis is frequently seen in the family relatives of gastric cancer patients, which may contribute to gastric cancer clustering in some families [53].

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