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Gastritis staging in clinical practice: The OLGA staging system

Gastritis staging in clinical practice: The OLGA staging system
Atrophy Score		Corpus
Atrophy Score		No Atrophy (Score: 0)	Mild Atrophy (Score: 1)	Moderate Atrophy (Score: 2)	Severe Atrophy (Score: 3)
A N T R U M	No Atrophy (Score: 0) (including incisura angularis)	STAGE 0	STAGE I	STAGE II	STAGE II
	Mild Atrophy (Score: 1) (including incisura angularis)	STAGE I	STAGE I	STAGE II	STAGE III
	Moderate Atrophy (Score: 2) (including incisura angularis)	STAGE II	STAGE II	STAGE III	STAGE IV
	Severe Atrophy (Score: 3) (including incisura angularis)	STAGE III	STAGE III	STAGE IV	STAGE IV

Overview

The H. pylori induced gastritis includes the following stages. They are acute gastritis, active chronic gastritis, atrophy and intestinal metaplasia.

Pathophysiology

The H. pylori induced gastritis includes the following stages: They are

The acute gastritis
Active chronic gastritis
Atrophy
Intestinal metaplasia

The H. pylori induced gastritis is classified based on location into:

Antral predominant gastritis
Corpus predominant gastritis

Acute gastritis

In the majority of patients, the initial acute phase of gastritis is subclinical and is of short duration (about 7 to 10 days).
The organisms are spontaneously cleared in a small minority of people, especially in childhood.
In the majority of cases, the infection is not eliminated and there will be gradual accumulation of chronic inflammatory cells over the next 3 or 4 weeks.^[1]

Pathogenesis

Following transmission, H. pylori penetrates the gastric mucosa and multiplies close to the surface epithelial cells.
Following adhesion to epithelial cells, the bacteria releases lipopolysaccharides (endotoxin) and chemotactic mediators which penetrate the surface epithelial cells.^[2]^[3]
These bacterial factors attract the polymorphonuclear leukocytes to the site of infection and also caused mast cell degranulation, which releases acute inflammatory mediators. Mast cell degranulation leads to:

Increased vascular permeability
Increased polymorphonuclear leukocytes emigration
Increased expression of leukocyte adhesion molecules
The platelet activating factors (PAF) released from mast cells causes microthrombosis in mucosal capillaries resulting in hypoxic injury to the epithelium

The macrophages release IL-1 and tumor necrosis factor alpha (TNF-α) which stimulates gastric epithelium to produce IL-8.
The acute phase is associated with profound hypochlorhydria and a decreased ascorbic acid secretion into the gastric juice.^[4]
The acid output reaches pre-infection levels after several weeks but the ascorbic acid remains lower than normal for the duration of chronic gastritis, indicating that it is due to persisting inflammation rather than hypochlorhydria.^[4]

Microscopic pathology

Surface epithelial degeneration
Increased cell exfoliation
Increased neutrophil polymorphonuclear leucocytes in the superficial lamina propria

Active chronic gastritis

In the majority of cases, the H. pylori infection persists leading to accumulation of large number chronic inflammatory cells leading to active chronic gastritis.

Pathogenesis

The major diagnostic feature of chronic gastritis is an influx of lymphocytes and plasma cells (normally the antral mucosa is devoid of plasma cells and lymphocytes). Hence the presence of these cells is indicative of gastritis.^[5]
H. pylori colonizes more in the antrum than the corpus. Hence there is increased inflammatory cell infiltration in the antrum.
The direct acting antigens of H. pylori like lipopolysaccharides, urease etc along with interleukins 1 and 6, activate T-helper cells which produce the variety of cytokines including IL4, IL5, and IL6.
These interleukins differentiate into plasma cells releasing cytokines and anti-H.pylori infection like IgM-opsonizing and complement-fixing antibodies.
The main role of the mucosa in the immune response is that the IgA prevents bacterial adhesion and IgG causes opsonization and complement activation.
Due to the acidic environment, the antibodies produced quickly lose their adhesive properties and catalase produced by H. pylori protects against polymorphs.
However, this immune response is insufficient to eradicate the organism leading to the development of immune response directed towards preventing the damaging effects of the H. pylori.
Hence the persistent antigenic stimulation leads to the formation of lymphoid follicles, which is the consistent feature of chronic H. pylori infection.
These lymphoid follicles in the gastric mucosa constitutes mucosa-associated lymphoid tissue (MALT) from which gastric marginal zone B-cell lymphoma (MALToma) arises.

Also, these polymorphs accumulate around the pit isthmus, which is a proliferative compartment, causing lethal damage to stem cells resulting in glandular atrophy.

Microscopic pathology

Variable epithelial degeneration
Neutrophil infiltration in the epithelium and the lamina propria
Variable H. pylori colonization
Lymphocytes and plasma cell infiltration
Lymphoid follicles (typical feature of chronic gastritis)

Sydney system of grading of chronic gastritis^[6]

Sydney system for grading of chronic gastritis
Feature	Definition	Grading guidelines
Chronic inflammation	Increased lymphocytes and plasma cells in lamina propria	Mild, moderate or severe increase in density
Activity	Neutrophilic infiltrates of the lamina propria, pits or surface epithelium	Mild: less than one-third of pits and surface inﬁltrated Moderate: one-third to two-thirds Severe: more than two-thirds
Atrophy	Loss of specialized glands from either antrum or corpus	Mild, moderate, or severe loss
Helicobacter pylori	H. pylori density	Mild colonization: scattered organisms covering less than one-third of the surface Moderate colonization: intermediate numbers Severe colonization: large clusters or a continuous layer over two-thirds of surface
Intestinal Metaplasia	Intestinal metaplasia of the epithelium	Mild: less than one-third of mucosa involved Moderate: one-third to two-thirds Severe: more than two-thirds

Atrophy

Atrophy of stomach is defined as loss of glandular tissue due to continuous mucosal injury. This leads to thinning of gastric mucosa.

The prevalence and severity of atrophy of stomach increases with age among the patient's chronic gastritis due to longer duration of H. pylori infection.
Due to glandular atrophy, the prevalence of H. pylori positivity decreases. The main reasons are as follows:

Due to intestinal metaplasia that is usually present in atrophic stomachs, the organisms are absent as they usually colonize only gastric epithelium.
As H. pylori requires partially acidic environment to thrive, hypochlorhydria creats hostile environment to H. pylori to survive.^[7]
The metaplastic epithelium secretes acidic glycoproteins which create the most hostile environment for H. pylori.

Hence, based on above reasons, failure to demonstrate H. pylori does not deny the role of the organism in atrophic gastritis.

Pathogenesis

The continuous mucosal injury due to long-standing H. pylori infection, leads to atrophy of stomach.
This continuous pathological process results in erosion or ulceration of the mucosa leading to the destruction of the glandular layer and followed by fibrous replacement.
The destruction of the glandular basement membrane and the sheath of supporting cells prevents orderly regeneration. This uneven regeneration follows a divergent differentiation pathway producing metaplastic glands (pseudo-pyloric appearance) which are composed of cells of the 'ulcer-associated cell lineage'(UACL).^[8]

Microscopic pathology

Reduced number of oxyntic cells. No intestinal metaplasia
The mucosa is infiltrated with neutrophils
H. pylori is not seen on H&E stain. immunohistochemical stain of H. pylori detects the organisms.

Intestinal metaplasia

The intestinal metaplasia increase in prevalence according to duration of H. pylori infection.^[9]
The damaged epithelium by H. pylori infection will be further eroded by bile reflux and replaced by intestinal type cells during the regenerative process. This metaplasia is transient but with repetitive injury it aggravates and become more permanent.^[10]
Hence H. pylori infection and bile reflux are independent risk factors for intestinal metaplasia of stomach.
Intestinal metaplasia is a protective mechanism as H. pylori does not attach to intestinal-type cells and also intestinal cells are more resistant to damaging effects of bile than gastric mucosa.

Microscopic pathology

Absence of H. pylori
Gastric mucosal cells replaced by epithelium resembling intestinal cells

Updated Sydney classification (Sydney criteria for gastritis)

The updated sydney classification of H. pylori induced classification include:^[6]

Feature	Non-atrophic Helicobacter	Atrophic Helicobacter	Autoimmune
Inflammation pattern	Antral or diffuse	Antrum & corpus, mild inflammation	Corpus only
Atrophy & metaplasia	Nil	Atrophy present, metaplasia at incisura	Corpus only

Antral predominant gastritis	Corpus predominant gastritis
More predominant in antrum in developed countries	Less predominant in developed countries
High acid output	Low acid output
Associated with duodenal ulceration

Classification Gastritis

Classification and grading of Gastritis: Updated Sydney System
Type of Gastritis		Etiology	Gastritis synonyms
Non-atrophic		Helicobacter pylori Other factors	Superficial Diffuse antral gastritis (DAG) Chronic antral gastritis (CAG) Interstitial - follicular Hypersecretory Type B*
Atrophic	Autoimmune	Autoimmunity	Type A* Diffuse corporal Pernicious anemia-associated
	Multifocal atrophic	Helicobacter pylori	Type B, type AB
		Dietary	Environmental
		Environmental factors	Metaplastic
Special forms	Chemical	Chemical irritation	Reactive
		Bile	Reflux
		NSAIDs	NSAID
		Other agents	Type C
	Radiation	Radiation injury
	Lymphocytic	Idiopathic? Immune mechanisms	Varioliform (endoscopic)
		Gluten	Celiac disease-associated
		Drug (ticlopidine)
		H. pylori
	Noninfectious granulomatous	Crohn's disease
		Sarcoidosis
		Granulomatosis with polyangiitis and other vasculitides
		Foreign substances
		Idiopathic	Isolated granulomatous
	Eosinophilic	Food sensitivity	Allergic
	Eosinophilic	Other allergies
	Other infectious gastritides	Bacteria (other than H. pylori)	Phlegmonous
	Other infectious gastritides	Viruses Fungi Parasites


Type of gastritis		Etiologic factors	Gastritis synonyms
Classification and grading of gastritis: Updated Sydney System
Nonatrophic	Helicobacter pylori Other factors	Superficial Diffuse antral gastritis (DAG) Chronic antral gastritis (CAG) Interstitial - follicular Hypersecretory Type B*

Regimens Used to Treat Helicobacter pylori Infection. Standard initial treatment (use one of the following three options) Triple therapy for 7–14 days PPI, healing dose twice/day* Amoxicillin, 1 g twice/day† Clarithromycin, 500 mg twice/day Quadruple therapy for 10–14 days‡ PPI, healing dose twice/day* Tripotassium dicitratobismuthate, 120 mg four times/day Tetracycline, 500 mg four times/day Metronidazole, 250 mg four times/day§ Sequential therapy Days 1–5 PPI, healing dose twice/day* Amoxicillin, 1 g twice/day Days 6–10 PPI, healing dose twice/day* Clarithromycin, 500 mg twice/day Tinidazole, 500 mg twice/day§ Second-line therapy, if triple therapy involving clarithromycin was used initially (use one or the other) Triple therapy for 7–14 days PPI, healing dose once/day* Amoxicillin, 1 g twice/day Metronidazole, 500 mg (or 400 mg) twice/day§ Quadruple therapy, as recommended for initial therapy

Tests for Helicobacter pylori Infection.* Test Advantages Disadvantages Nonendoscopic Serologic test Widely available; the least expensive of available tests Positive result may reflect previous rather than current infection; not recommended for confirming eradication Urea breath test High negative and positive predictive values; useful before and after treatment False negative results possible in the presence of PPIs or with recent use of antibiotics or bismuth preparations; considerable resources and personnel required to perform test Fecal antigen test High negative and positive predictive values with monoclonal-antibody test; useful before and after treatment Process of stool collection may be distasteful to patient; false negative results possible in the presence of PPIs or with recent use of antibiotics or bismuth preparations Endoscopic Urease-based tests Rapid, inexpensive, and accurate in selected patients False negative results possible in the presence of PPIs or with recent use of antibiotics or bismuth preparations Histologic assessment Good sensitivity and specificity Requires trained personnel Culture Excellent specificity; provides opportunity to test for antibiotic sensitivity Variable sensitivity; requires trained staff and properly equipped facilities

Patterns of H. pylori Gastritis Antral Predominant Gastritis and Local Acid Production In the majority of infected individuals, at least in developed countries, H. pylori gastritis is to some degree more pronounced in the antrum than in the corpus. When there is a substantial difference between the two compartments, such that there is minimal inflammation in the corpus and marked involvement of the antrum, the gastritis is designated "antral predominant." This pattern is found in patients with duodenal (and prepyloric) ulceration and is a marker of the duodenal ulcer diathesis. The relative resistance of the corpus mucosa to H. pylori colonization and inflammation and the susceptibility of the duodenal mucosa to ulceration are best explained by high local acid concentrations in the corpus and increased acid output from stomach to duodenum in subjects at risk of duodenal ulceration. H. pylori has evolved mechanisms that ensure its survival in the acidic environment of the stomach. In the pH range of 3.5 to 5.0 in the presence of urea, the organism can maintain the proton motive force (PMF) across its periplasmic membrane, ensuring a continued supply of energy through ATP synthesis (48). Urea entering the bacterium is acted on by its cytoplasmic urease to produce ammonia, which neutralizes excess hydrogen ions to maintain a pH of 6.2 in the periplasmic space and thereby preserve the PMF (63, 64). However, when there is a high local acid concentration, the protective mechanism fails to keep up with hydrogen ion influx, ATP synthesis declines, and the bacterium dies, or at least loses virulence (19). Thus, in the presence of high acid output, the corpus becomes an even more hostile environment, colonization density is greatly diminished, and infection and inflammation are concentrated in the antrum. Conversely, when the pH in its microenvironment rises above 5.0, the organism produces ammonia in excess of that needed to neutralize the much-diminished influx of hydrogen ions, and the environment becomes increasingly alkaline. Above a pH of 8 the cell ceases to function (6, 27). Thus, in achlorhydric states gastric helicobacters will selfdestruct and infection will be spontaneously eliminated. Corpus Gastritis In a minority of infected subjects in Western populations, a corpus-predominant pattern of gastritis is observed. Such individuals generally have a low acid output. It is thought that the inflammatory infiltrate itself influences parietal cell function by the release of acid-inhibitory cytokines such as IL-1. The influence of local acid production on corpus colonization and virulence is clearly demonstrated by observations in humans and experimental animals. Acid reduction by vagotomy in duodenal ulcer patients resulted in a substantial increase in corpus inflammation over the ensuing 3 months (61), while sustained acid suppression with proton-pump inhibitors in patients with reflux esophagitis led to much-increased H. pylori colonization over the corpus relative to antrum and a swing from antral- to corpus-predominant gastritis (49, 77). Similarly in animals infected with H. felis, acid suppression led to colonization of previously uninfected oxyntic mucosa (10). On the other hand, patients with the Zollinger-Ellison syndrome have a low prevalence of H. pylori infection because their entire gastric mucosa is hostile to colonization (25). Duodenal Ulceration 10/25/2017 Pathology of Gastritis and Peptic Ulceration - Helicobacter pylori - NCBI Bookshelf https://www-ncbi-nlm-nih-gov.ezp-prod1.hul.harvard.edu/books/NBK2461/?report=printable 5/15 Gastric Metaplasia It has long been recognized that patients with duodenal ulcer (DU) have, on average, higher acid secretion than do normal, healthy individuals. We now know that H. pylori-infected individuals with the DU diathesis have hypergastrinemia and increased sensitivity to gastrin. The arrival of unneutralized acid in the first part of the duodenum has certain consequences. Notable among these is gastric metaplasia, the presence of gastric-type mucus-secreting cells in the surface epithelium of the duodenum (81). The pathogenesis of gastric metaplasia is controversial; recent work suggests local goblet-cell transformation to cells of gastric phenotype in response to inflammatory signals (65). However, it is a common observation that gastric metaplasia exists without inflammation. The change probably develops as an adaptive response to acid, a suggestion that is supported by animal experiments with induced hyperchlorhydria (22, 78), and in human subjects by the correlation between the presence and extent of metaplasia and maximal acid output (40). Furthermore, gastric metaplasia is extensive in patients with the Zollinger-Ellison syndrome (59), has a lower prevalence following truncal and proximal selective vagotomy, and is not seen in patients with autoimmune gastritis and achlorhydria (86). Active Chronic Duodenitis While the coexistence of gastric metaplasia and chronic inflammation in duodenitis has been long recognized, it was Marshall et al. (47) who first suggested that H. pylori was responsible for colonizing "antral type" mucosa in the duodenal bulb and giving rise to chronic inflammation. However, these authors considered the presence of gastric epithelium as a primary, presumably congenital, phenomenon rather than accepting its metaplastic origin. Even before Warren and Marshall's rediscovery of bacterial infection of the human stomach (84), Steer (73) had described the migration of polymorphs through gastric epithelium at the sites of bacterial attachment, and later established the presence of a bacterium and the associated polymorph response in gastric metaplasia in the duodenum (74, 75). However, H. pylori is much more difficult to recognize in duodenal than gastric biopsies. The bacteria are usually scanty and may adopt a coccoid form, which then renders recognition based purely on morphology impossible. Thus, prevalence rates for H. pylori in duodenitis are very variable and depend on the number of biopsies examined and the methods of detection used. With the modified Giemsa stain, organisms were observed in 57% of anterior duodenal biopsies with active chronic duodenitis in one study (86), but three methods of microscopy detected H. pylori in 75% in another study (82). Similar prevalence rates for colonization of gastric metaplasia in H. pylori-infected patients with duodenal ulcer and duodenitis have been obtained when multiple tests have been employed (i.e., histology, culture, and rapid urease tests) (81). The conclusion to be drawn from these studies is that intraduodenal infection cannot be demonstrated in a substantial proportion of patients who have all the components of the duodenal ulcer phenotype, namely, gastric metaplasia, chronic duodenitis, and H. pylori gastritis. However, even in histologically H. pylorinegative chronic duodenitis it can be shown that the mucosa contains plasma cells that secrete specific IgA anti-H. pylori antibodies and that this response is restricted to the first part of the duodenum, i.e., the area most likely to exhibit gastric metaplasia and infection (9). Ulceration—pH and Hp The close relationship between acid-induced gastric metaplasia, H. pylori gastritis, and active chronic duodenitis was first emphasized by Wyatt et al. (86). A sequence of events was proposed that embraced acid-induced metaplasia in the first part of the duodenum, spread of H. pylori infection from the stomach, and following colonization of the gastrictype epithelium, the development of an acute and chronic inflammatory cell response. Chronic inflammation and direct bacterial effects on epithelial structure and bicarbonate production render the duodenal mucosa more susceptible to acid/peptic attack and, in a proportion of subjects, frank duodenal ulceration ensues. Thus, in this model two risk factors, acid-induced gastric metaplasia and H. pylori infection, are essential prerequisites for the development of chronic duodenitis and, by extrapolation, duodenal ulceration. Thus the prevalence of gastric metaplasia needs to be taken into account when considering the overall relationship between the incidence of DU and H. pylori infection. It seems likely that in countries where there is a high rate of infection but a low incidence of DU there will also be a low frequency of gastric metaplasia as a consequence of the lower acid output prevailing in these populations. These 10/25/2017 Pathology of Gastritis and Peptic Ulceration - Helicobacter pylori - NCBI Bookshelf https://www-ncbi-nlm-nih-gov.ezp-prod1.hul.harvard.edu/books/NBK2461/?report=printable 6/15 considerations are pertinent in many developing countries and may go some way toward explaining the so-called "African enigma," where there is a low peptic ulcer frequency in populations with high H. pylori infection rates (12). Gastric Ulceration The Antral-Body Transitional Zone Transitional zones are the junctional areas between two contiguous mucosae. The antral-corpus zone is a narrow area in which acid-secreting oxyntic glands give way to simple mucous glands of the antrum. The site of the boundary between antrum and corpus will be governed by the relative size of these compartments. Individuals who have a constitutionally enlarged parietal cell mass will have a relatively large corpus and the transitional zone (TZ) will be shifted caudally. On the other hand, subjects with low acid output will have a relatively larger antrum and proximal shift of the antral-corpus TZ. However, proximal displacement of this zone is usually an acquired change consequent to inflammation, atrophy, and metaplasia encroaching on the corpus mucosa. It has been appreciated for many years that the boundary between nonatrophic corpus and atrophic antral mucosa can be endoscopically visible. The boundary has been called the "atrophic border," and Japanese investigators have demonstrated that it moves proximally with advancing age (36, 37). The dynamics of this migrating border are interesting. Inflammation in the TZ results in glandular atrophy. Loss of corpus glands at the interface with the TZ is followed by mucous cell and pyloric gland metaplasia. Thus, the original corpus-type mucosa close to the boundary takes on the appearance of antrum. Interestingly, the degree of inflammation found in the antral-corpus TZ is often greater than that seen in the adjacent mucosa of either the antrum or corpus proper. The increased inflammation could be a reflection of changes in H. pylori colonization density or the virulence of the organisms. Certainly there is increased colonization immediately proximal to the atrophic border, and there is greater polymorph activity when compared to mucosa immediately distal to the border (88). Conversely, and in keeping with our concepts of causation, the mucosa distal (antral) to the border shows significantly more atrophy and intestinal metaplasia. It is likely that H. pylori colonization and virulence will be affected by the local acid levels prevailing across the transitional zones. H. pylori and the TZ There are two possible explanations for the apparent ability of H. pylori to induce a more intense inflammatory response at the acid-gradient TZs that border the oxyntic (corpus) mucosa (i.e., the antral-corpus and the corpus-cardia zones). The bacteria are either metabolizing and proliferating maximally because the local environment is at their pH optimum, or they are generating more inflammatory products due to induction of stress proteins. Bacteria tend to find their growth optimum when confronted with an environmental gradient. Thus, it is likely that at some point across the gradient of local acid found through the TZs, H. pylori finds optimal conditions and can maximize adhesion, growth, and release of inflammatory products and induce maximal cytokine production via signal transduction at the surface. Alternatively, it is known that bacteria have a series of well-developed physiological mechanisms for dealing with environmental stress, among which is the acid-tolerance response (80). Various genes are switched on that encode proteins that allow the bacterium to survive (57). Examples of such molecules are the acid (heat) shock proteins (24, 38). In the TZ, there will be a "watershed" area where the local acid environment is such that the acid-tolerance response of the bacterium becomes further stressed. It is conceivable that at this site novel proteins could be produced that are more inflammatory than those produced elsewhere. Whatever the explanation, these areas of peak inflammatory response are the sites of maximal development of atrophy and intestinal metaplasia and are at greatest risk of ulceration. Gastric Ulceration—a Moving Experience A distinction is made between distal ulcers occurring within the antrum, i.e., prepyloric ulcers, and more proximal ulcers in the stomach. The former share epidemiological characteristics with duodenal ulcer, and the patients usually have raised acid levels. In such cases, the site of ulceration may be determined by patches of atrophy in the antrum, making the mucosa more susceptible to acid attack. However, the TZs play a pivotal role in the pathogenesis of more proximal gastric ulcers. Oi et al. in 1959 (55, 56) and Stadelmann et al. in 1971 (72) were the first to draw attention to 10/25/2017 Pathology of Gastritis and Peptic Ulceration - Helicobacter pylori - NCBI Bookshelf https://www-ncbi-nlm-nih-gov.ezp-prod1.hul.harvard.edu/books/NBK2461/?report=printable 7/15 the close topographical relationship between gastric ulcers and the TZ, but it required knowledge of the behavior of H. pylori at the TZs to advance a plausible explanation for the finding of peptic ulcers at these sites. Colonization, particularly by the more virulent CagA-positive strains, leads to surface epithelial degeneration and increased exfoliation of surface epithelial cells (83). Accelerated cell exfoliation results in compensatory cell proliferation so that immature cells populate the foveolae and surface. Mucin and bicarbonate production is impaired, and the integrity of the mucous barrier may be compromised. In addition, activation of complement via the alternate pathway and the release of chemical mediators by mast cells and activated polymorphs may lead to microvascular disturbances and focal ischemic damage to the surface epithelium (2, 11). Apart from these inflammatory factors, ulcerogenesis may be promoted by the greater degree of atrophy and intestinal metaplasia found immediately distal to the TZ. Differences in mucus composition and bicarbonate production in metaplastic mucosa may lower the protection afforded by the mucous barrier. Indeed, metaplastic and atrophic mucosa also differs from normal mucosa in the local production of epithelial growth factors and regulatory (trefoil) peptides (28), and there may also be differences in the pattern of receptors for luminal growth factors (e.g., epidermal growth factor) (39). Diminished growth factor or regulatory peptide stimulation will adversely affect mucosal regeneration and exaggerate the effects of injury. However, there may also be bacterial factors at work. H. pylori infection down-regulates E-cadherin expression in gastric epithelial cells (79). E-cadherin is involved in cell-to-cell adhesion and in epithelial cell proliferation so that depressed production could adversely affect the resistance of the mucosa to acid attack. All these consequences of H. pylori infection conspire to make the antrum-corpus TZ peculiarly susceptible to acid-peptic attack and, therefore, the principal site of peptic ulceration. The proximal migration of the TZ with time explains the endoscopic observation that gastric ulcers are found progressively higher up the lesser curve with increasing age. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Synergy with H. pylori Given that NSAIDs (including aspirin) are gastric irritants, it could be predicted that such drugs would act synergistically with H. pylori gastritis to exacerbate mucosal damage. However, a role for H. pylori in increasing the risk of acute gastroduodenal injury has been difficult to establish or refute. Only one study has looked, in a controlled fashion, at the influence of H. pylori status on the frequency and severity of mucosal hemorrhage, erosions, and ulcers after 1 week of treatment with NSAIDs (44). No significant differences between H. pylori-positive and -negative subjects were detected. Although stronger claims have been made for a synergistic link with H. pylori in the causation of chronic gastric and duodenal ulcers, the evidence is controversial. While the point prevalence of ulcers appears higher in H. pylori-positive versus-negative NSAID users, the differences have not achieved statistical significance, even after amalgamation in a meta-analysis (80). Furthermore, two large randomized controlled trials on the prevention of peptic ulcers by prior eradication of H. pylori arrived at opposite conclusions, one (4) claiming that eradication reduced the occurrence of ulcers and another (85) concluding that there was no effect. With regard to bleeding peptic ulcers, it seems quite clear that NSAID use and H. pylori infection are independent risk factors (31, 42, 43). Indeed, one authority on the effects of NSAIDs on the gastrointestinal tract has concluded that under some circumstances patients who are infected are less prone to NSAID-induced ulcers than are uninfected individuals because, at least in part, of opposing effects on mucosal prostaglandin synthesis (30). Conclusion H. pylori infection is now accepted as the cause of the most common form of chronic gastritis. It is also widely accepted that the infection is at least the triggering factor for, if not the direct cause of, atrophy and intestinal metaplasia. These alterations in the gastric mucosa predispose to peptic ulceration. Given that they are maximal in the antrum-corpus TZ, this is the site of predilection for gastric ulcers. Different patterns of H. pylori gastritis are associated with profound alterations in acid output. In antral-predominant gastritis, acid production from the largely unaffected corpus is enhanced whereas corpus inflammation is associated with hypochlorhydria. These changes have an important bearing on peptic ulcer pathogenesis. Eradication of H. pylori infection is followed by resolution of gastritis, and this greatly reduces, if not eliminates, the risk of further peptic ulceration. Whether such intervention can remove the increased risk of progression to gastric cancer has yet to be determined.

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The table below differentiates Gastritis from other conditions


Differential Diagnosis
Disease	Cause	Symptoms									Diagnosis	Other findings
		Pain			Nausea & Vomiting	Heartburn	Belching or Bloating	Weight loss	Loss of Appetite	Stools	Endoscopy findings
		Location	Aggravating Factors	Alleviating Factors	Nausea & Vomiting	Heartburn	Belching or Bloating	Weight loss	Loss of Appetite	Stools	Endoscopy findings
Acute gastritis	H. pylori NSAIDS Corticosteroids Alcohol Spicy food Viral infections Crohn's disease Autoimmune diseases Bile reflux Cocaine use Breathing machine or ventilator Ingestion of corrosives	Epigastric pain	Food	Antacids	✔	✔	✔	-	✔	Black stools	Pangastritis or antral gastritis Erosive (Superficial, deep, hemorrhagic) Nonerosive (H. pylori)	-
Chronic gastritis	H. pylori Alcohol Medications Autoimmune diseases Chronic stress	Epigastric pain	Food	Antacids	✔	✔	✔	✔	✔	-	H. pylori gastritis Atrophy Intestinal metaplasia Lymphocytic gastritis Enlarged folds Aphthoid erosions	-
Atrophic gastritis	H. pylori Autoimmune disease	Epigastric pain	-	-	✔	-		✔	✔	-	H. pylori Mucosal atrophy Autoimmune Mucosal atrophy	Iron deficiency anemia Autoimmune gastritis diagnosis includes: Antiparietal and anti-IF antibodies Achlorhydria and hypergastrinemia Low serum cobalamine
Crohn's disease	Autoimmune disease	Abdominal pain	-	-	-	-	-	✔	✔	Chronic diarrhea often bloody with pus or mucus Rectal bleeding	Mucosal nodularity with cobblestoning Multiple aphthous ulcers Linier or serpiginous ulcerations Thickened antral folds Antral narrowing Hypoperistalsis Duodenal strictures	Fever Fatigue Anemia (pernicious anemia)
GERD	Lower esophageal sphincter abnormalities Hiatal hernia Abnormal esophageal contractions Prolonged emptying of stomach Gastrinomas	Epigastric pain	Spicy food Tight fitting clothing	Antacids Head elevation during sleep	✔ (Suspect delayed gastric emptying)	✔	-	-	-	-	Esophagitis Barrette esophagus Strictures	Other symptoms: Dysphagia Regurgitation Nocturnal cough Hoarseness Complications Esophagitis Strictures Barrette esophagus
Peptic ulcer disease	H. pylori Smoking Alcohol Radiation therapy Medications Zollinger-ellison syndrome	Epigastric pain sometimes extending to back Right upper quadrant pain	Duodenal ulcer Pain aggravates with empty stomach Gastric ulcer Pain aggravates with food	Antacids Duodenal ulcer Pain alleviates with food	✔	✔	-	-	-	Black stools	Gastric ulcers Discrete mucosal lesions with a punched-out smooth ulcer base with whitish fibrinoid base Most ulcers are at the junction of fundus and antrum 0.5-2.5cm Duodenal ulcers Well-demarcated break in the mucosa that may extend into the muscularis propria of the duodenum Found in the first part of duodenum <1cm	Other diagnostic tests Serum gastrin levels Secretin stimulation test Biopsy
Gastrinoma	Associated with MEN type 1	Abdominal pain	-	-	✔ (suspect gastric outlet obstruction)	✔	-	-	-	Black stools	Useful in collecting the tissue for biopsy	May present with symptoms of GERD or peptic ulcer disease Associated with MEN type 1 Diagnostic tests Serum gastrin levels Somatostatin receptor scintigraphy CT and MRI
Gastric Adenocarcinoma	H. pylori infection Smoked and salted food	Abdominal pain	-	-	✔	✔	✔	✔	✔	Black stools, or blood in stools	Esophagogastroduodenoscopy Multiple biopsies are taken to establish the diagnosis	Other symptoms Dysphagia Early satiety Frequent burping
Primary gastric lymphoma	H. pylori infection	Abdominal pain Chest pain	-	-	-	-	-	✔	-	-	Useful in collecting the tissue for biopsy	Other symptoms Painless swollen lymph nodes in neck and armpit Night sweats Fatigue Fever Cough or trouble breathing


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Chronology of Yersinia pestis infection Outbreaks("WHO \| Plague".)
Date	Region Affected	Suspected, Probable & Confirmed Cases	Deaths	Details
15 October 2017	Seychelles - Suspected Plague (Ex- Madagascar)	1	0	On 10 October 2017, the Seychellois Ministry of Health notified WHO of a probable case of pneumonic plague The probable case is a 34-year-old man who had visited Madagascar and returned to Seychelles on 6 October 2017. He developed symptoms on 9 October 2017 and presented to a local health centre(pneumonic plague infection suspected, isolated and treated) 11 October, rapid diagnostic test (RDT) preformed, sputum sample was weakly positive. October 9 to 11 2017, eight of his contacts developed mild symptoms and have been isolated October 13 was the last day of monitoring of over 320 contact persons of the probable case Contact tracing is done thoroughly and 577 children and 63 teachers in potential contact with one of the individual identified by contact tracing were given antibiotics.
2 October 2017	Madagascar	73	17	The outbreak started following the death of a 31-year-old male from Ankazobe District in the Central Highlands (Hauts-Plateaux), a plague-endemic area. Since then, the Ministry of Public Health of Madagascar enhanced field investigations, contact tracing, surveillance, and monitoring all close contacts As of 30 September, 10 cities have reported pneumonic plague cases and the three most affected districts include: the capital city and suburbs of Antananarivo (27 cases, 7 deaths), Toamasina (18 cases, 5 deaths), and Faratshio (13 cases, 1 death) In addition to the 73 cases of pneumonic plague, from 1 August to 30 September, 58 cases of bubonic plague including seven deaths have been reported. One additional case of septicaemic plague has also been reported, and one case where the type is not specified
29 September 2017	Madagascar	51	12	On 23 August 2017, a 31-year-old male from Tamatave, visiting Ankazobe District in central highlands, developed malaria-like symptoms. On 27 August, he developed respiratory symptoms during his journey in a shared public taxi from Ankazobe District to Tamatave (via Antananarivo). His condition worsened and he died. In addition to the 51 suspected, probable and confirmed cases of pneumonic plague, and during the same period another 53 cases of bubonic plague including seven deaths have been reported throughout the country. One case of septicaemic plague has also been identified and they were not directly linked to the outbreak. Additionally, 31 people who came into contact with this case either through direct contact with the primary case or had other epidemiological links, became ill, and four cases of them died The outbreak was detected on 11 September, following the death of a 47-year-old woman from Antananarivo, who was admitted to a hospital with respiratory failure caused by pneumonic plague
9 January 2017	Madagascar	62 cases (6 confirmed, 5 probable, 51 suspected)	26 (case fatality rate of 42%)	Of the 11 samples tested, 5 were positive for plague on rapid diagnostic test and 6 are now confirmed at Institut Pasteur laboratory. Of the total reported cases, 5 are classified as pneumonic plague cases and the remaining as bubonic plague Retrospective investigations carried out in those two districts showed that it is possible that the outbreak might have started in mid-August 2016. The investigation in neighbouring villages is still ongoing. On 29 December, an investigation carried out within 25 km of the initial foci in Befotaka district has reported three deaths and is being investigated further for possible linkage to the outbreak
6 September 2015	Madagascar	14	10	The Ministry of Health of Madagascar has notified WHO of an outbreak of plague. The first case was identified on 17 August in a rural township in Moramanga district. The case passed away on 19 August All confirmed cases are of the pneumonic form. Since 27 August, no new cases have been reported from the affected or neighbouring districts
21 November 2014	Madagascar	119	40	On 4 November 2014, WHO was notified by the Ministry of Health of Madagascar of an outbreak of plague. The first case, a male from Soamahatamana village in the district of Tsiroanomandidy, was identified on 31 August. The patient died on 3 September Only 2% of reported cases are of the pneumonic form Cases have been reported in 16 districts of seven regions. Antananarivo, the capital and largest city in Madagascar, has also been affected with 2 recorded cases of plague, including 1 death. There is now a risk of a rapid spread of the disease due to the city’s high population density and the weakness of the healthcare system. The situation is further complicated by the high level of resistance to deltamethrin (an insecticide used to control fleas) that has been observed in the country
10 August 2010	Peru	17	-	As of 30 July 2010, the Ministry of Health in Peru confirmed a total of 17 cases of plague in Ascope province of Department La Libertad. Of these, four are pneumonic plague, 12 are bubonic plague and one was septicemic plague. The onset of symptoms for the last reported case of pneumonic plague was on 11 July 2010. During the investigations, 10 strains of Y. pestis were isolated from humans, rodents and domestic cats
11 August 2009	China	12	3	On 1 August 2009, a cluster outbreak of pulmonary plague cases in the remote town of Ziketan, Qinghai province was reported by the Ministry of Health (MoH), China. On 26th July 2009, the first case was a 32 year old male herdsman, who developed fever and hemoptysis was reported. He died enroute to hospital. On 30 July, 11 people who had close contact with the case (mainly relatives who attended the funeral) were all hospitalized as they developed fever and cough. They were all tested positive for plague. On 2 August 2009, 2 people who helped to bury the corpse, 64 year old father-in-law of the first case and a 37 year old male neighbour of the first case also died. On August 6 2009, the local health authority isolated 332 close contacts for further medical observation, and implemented traffic control around affected area. Preventive measures were taken to stop teh spread. Epidemiological investigation showed that the source of this outbreak was a wild marmot, which had contact with the dog of the index case.
7 November 2006	Democratic Republic of the Congo	1174	50	As of 29 September 2006, WHO received reports of a suspected pneumonic plague outbreak in 4 health zones in Haut-Uele district, Oriental province in the north-eastern part of the country. More than 50 samples have been collected and analysed; however, the diagnosis of plague has not been finally laboratory confirmed.
13 October 2006	Democratic Republic of the Congo	626	42	WHO has received reports of a suspected pneumonic plague outbreak in 2 health zones in Haut-Uele district, the majority reported from Wamba health zone in Oriental province in the northern part of the country However, the low case fatality ratio is unusual for pneumonic plague which suggests that the number of suspected cases may be an overestimation Preliminary results from a rapid diagnosis test in the field found three samples positive, out of eight
14 June 2006	Democratic Republic of the Congo	100	19	Suspected cases of bubonic plague have also been reported but the total number is not known at this time. Preliminary results from rapid diagnostic tests in the area confirm pneumonic plague. Ituri is known to be the most active focus of human plague worldwide, reporting around 1000 cases a year. The first cases in this outbreak occurred in a rural area, in the Zone de Santé of Linga, in mid-May
15 March 2005	Plague in the Democratic Republic of the Congo - update 4	130	57	Reported in Zobia, Bas-Uélé district, Oriental province No cases of bubonic plague have been detected
9 March 2005	Plague in the Democratic Republic of the Congo - update 3	114 cases (110 suspect cases, 4 probable cases)	54	Reported in Zobia, Bas-Uélé district, Oriental province
4 March 2005	Plague in the Democratic Republic of the Congo - update 2	57 cases (54 suspect cases, 3 probable cases)	16	Reported in Zobia, Bas-Uélé district, Oriental province
1 March 2005	Plague in the Democratic Republic of the Congo - update	4 probable cases and 4 suspect cases	1	Reported in Zobia, Bas-Uélé district, Oriental province
18 February 2005	Plague in the Democratic Republic of the Congo	-	61	Reported in Bas-Uele district, Oriental province Preliminary results from rapid diagnostic tests in the area confirm pneumonic plague, and the cases had clinical features compatible with this disease Cases have occurred in workers in a diamond mine in Zobia where c. 7000 people work. The mine was re-opened on 16 December 2004 and the first case occurred on 20 December
10 July 2003	Plague in Algeria - Update 2	10 laboratory confirmed cases and 1 probable case	-	Reported in oran district
3 July 2003	Plague in Algeria - Update	10 cases of which 8 have been laboratory confirmed	-	Reported by Ministry of Health, Algeria 8 cases of bubonic plague and 2 of septicemic plague, of which one was fatal
24 June 2003	Plague in Algeria	10 cases, 8 cases of bubonic plague and 2 of septicemic plague	one fatal case reported	Reported by the Ministry of Health, Algeria in Tafraoui, on the outskirts of Oran
5 June 2002	2002 - Plague in Malawi	71	-	Reported by the Malawian Ministry of Health 71 cases of bubonic plague in the district of Nsanje since the onset of the outbreak on 16 April 2002 Outbreak has so far affected 26 villages, 23 in the Ndamera area, 2 in Chimombo and 1 village in neighbouring Mozambique
20 February 2002	2002 - Plague in India	16 cases of pneumonic plague	4 deaths in Hat Koti village	Reported by the Ministry of Health, India
26 March 2001	2001 - Plague in Zambia	23 hospitalized cases	3 deaths in Petauke district, Eastern Province	The last case reported was 15 March 2001

**Chronology of Marburg Hemorrhagic Fever Outbreaks** ("Marburg Hemorrhagic Fever". *Center for Disease Control and Prevention*. Center for Disease Control and Prevention (CDC).)
Years	Country	Apparent or suspected origin	Reported number of human cases	Reported number (%) of deaths among cases	Situation
2014	Uganda	Uganda	1	1 (100%)	Ninety-nine individuals were quarantined after a 30-year-old male health-worker died of Marburg hemorrhagic fever on the 28th of September.
2012	Uganda	Kabale	15	4 (27%)	Testing at CDC/UVRI identified a Marburg virus disease outbreak in the districts of Kabale, Ibanda, Mbarara, and Kampala over a 3 week time period^[11]
2008	Netherlands ex Uganda	Cave in Maramagambo forest in Uganda, at the southern edge of Queen Elizabeth National Park	1	1 (100%)	A 40-year-old Dutch woman with a recent history of travel to Uganda was admitted to hospital in the Netherlands. Three days prior to hospitalization, the first symptoms (fever, chills) occurred, followed by rapid clinical deterioration. The woman died on the 10th day of the illness.
2007	Uganda	Lead and gold mine in Kamwenge District, Uganda	4	1 (25%)	Small outbreak, with 4 cases in young males working in a mine. To date, there have been no additional cases identified^[12]
2004-2005	Angola	Uige Province, Angola	252	227 (90%)	Outbreak believed to have begun in Uige Province in October 2004. Most cases detected in other provinces have been linked directly to the outbreak in Uige^[13]
1998-2000	Democratic Republic of Congo (DRC)	Durba, DRC	154	128 (83%)	Most cases occurred in young male workers at a gold mine in Durba, in the north-eastern part of the country, which proved to be the epicenter of the outbreak. Cases were subsequently detected in the neighboring village of Watsa.^[12]
1990	Russia	Russia	1	1 (100%)	Laboratory contamination.^[12]
1987	Kenya	Kenya	1	1 (100%)	A 15-year-old Danish boy was hospitalized with a 3-day history of headache, malaise, fever, and vomiting. Nine days prior to symptom onset, he had visited Kitum Cave in Mount Elgon National Park. Despite aggressive supportive therapy, the patient died on the 11th day of illness. No further cases were detected^[14]
1980	Kenya	Kenya	2	1 (50%)	A man with a recent travel history to Kitum Cave in Kenya's Mount Elgon National Park. Despite specialized care in Nairobi, the male patient died. A doctor who attempted resuscitation developed symptoms 9 days later but recovered^[15]
1975	Johannesburg, South Africa	Zimbabwe	3	1 (33%)	A man with a recent travel history to Zimbabwe was admitted to hospital in South Africa. Infection spread from the man to his traveling companion and a nurse at the hospital. The man died, but both women were given vigorous supportive treatment and eventually recovered.^[16]
1967	Germany and Yugoslavia	Uganda	31	7 (23%)	Simultaneous outbreaks occurred in laboratory workers handling African green monkeys imported from Uganda. In addition to the 31 reported cases, an additional primary case was retrospectively diagnosed by serology. ^[17]

https://www-ncbi-nlm-nih-gov.ezp-prod1.hul.harvard.edu/pubmed/28901578 Irritable bowel syndrome in Asia: pathogenesis, natural history, epidemiology and management.

https://www-ncbi-nlm-nih-gov.ezp-prod1.hul.harvard.edu/pubmed/29026591 Irritable bowel syndrome diagnosis and management: A simplified algorithm for clinical practice


Marburg hemorrhagic fever: Symptoms and Disease Progression
Generalisation Phase (Day 1 to Day 5)	Fever Headache Chills Myalgia Malaise Fatigue Nausea Vomiting Diarrhoea Abdominal Pain Conjunctivitis Rash Pharyngitis
Early Organ Phase (Day 6 to Day 13)	Fever Bloody Diarrhoea(Malena) Hematemesis Exanthema Petechiae?Ecchymoses Muscosal hemorrhage Visceral hemorrhage Dyspnea Conjunctival injection Edema Apathy/Depression Irritability/aggression
Late Organ or Convalescence Phase (Day 14 to Day 21)	Fever Obtundation Dementia Coma Convulsions Diffuse coagulopathy Metabolic disturbances Shock Myalgia Arthralgia Hepatitis Asthenia Ocular disease Psychosis Social separation


Disease	Gene	Chromosome	Differentiating Features	Components of MEN			Diagnosis
Disease	Gene	Chromosome	Differentiating Features	Parathyroid	Pitutary	Pancreas	Diagnosis
von Hippel-Lindau syndrome	Von Hippel–Lindau tumor suppressor	3p25.3	Angiomatosis, Hemangioblastomas, Pheochromocytoma, Renal cell carcinoma, Pancreatic cysts (pancreatic serous cystadenoma) Endolymphatic sac tumor, Bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women)	-	-	+	Clinical diagnosis In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations.
Carney complex	PRKAR1A	17q23-q24	Myxomas of the heart Hyperpigmentation of the skin (lentiginosis) Endocrine (ACTH-independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease)	-	-	-	Clinical diagnosis
Neurofibromatosis type 1	RAS	17	Scoliosis Learning disabilities Vision disorders Cutaneous lesions Epilepsy.	-	-	-	Prenatal Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus. Postnatal Cardinal Clinical Features" are required for positive diagnosis. Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals. Two or more neurofibromas of any type or 1 plexiform neurofibroma Freckling in the axillary (Crowe sign) or inguinal regions Optic glioma Two or more Lisch nodules (pigmented iris hamartomas) A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
Li-Fraumeni syndrome	TP53	17	Early onset of diverse amount of cancers such as Sarcoma Cancers of Breast Brain Adrenal glands	-	-	-	Criteria Sarcoma at a young age (below 45) A first-degree relative diagnosed with any cancer at a young age (below 45) A first or second degree relative with any cancer diagnosed before age 60.
Gardner's syndrome	APC	5q21	Multiple polyps in the colon Osteomas of the skull Thyroid cancer, Epidermoid cysts, Fibromas Desmoid tumors	-	-	-	Clinical diagnosis Colonoscopy
Multiple endocrine neoplasia type 2	RET	-	Medullary thyroid carcinoma (MTC) Pheochromocytoma Primary hyperparathyroidism	+	-	-	Hypercalcemia Hypophosphatemia, Elevated parathyroid hormone, Elevated norepinephrine Criteria Two or more specific endocrine tumors Medullary thyroid carcinoma Pheochromocytoma Parathyroid hyperplasia
Cowden syndrome	PTEN	-	Hamartomas	-	-	-	PTEN mutation probability risk calculator
Acromegaly/gigantism	-	-	Enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin Hypertrichosis Hyperpigmentation Hyperhidrosis Carpal tunnel syndrome.	-	+	-	An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly.
Pituitary adenoma	-	-	Visual field defects classically bitemporal hemianopsia Increased intracranial pressure Migraine Lateral rectus palsy	-	+	-	Elevated serum level of prolactin Elevated or decreased serum level of adrenocorticotropic hormone (ACTH) Elevated or decreased serum level of growth hormone (GH) Elevated or decreased serum level of thyroid-stimulating hormone (TSH) Elevated or decreased serum level of follicle-stimulating hormone (FSH) Elevated or decreased serum level of luteinizing hormone (LH)
Hyperparathyroidism	-	-	- Kidney stones Hypercalcemia, Constipation Peptic ulcers Depression	+	-	-	An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyroidism. Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium. An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism.
Pheochromocytoma/paraganglioma	VHL RET NF1 SDHB SDHD	-	Characterized by Episodic hypertension Palpitations Anxiety Diaphoresis Weight loss	-	-	-	Increased catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection.
Adrenocortical carcinoma	p53 Retinoblastoma h19 Insulin-like growth factor II (IGF-II) p57^kip2	17p, 13q	Cushing syndrome (cortisol hypersecretion) Conn syndrome (aldosterone hypersecretion) virilization (testosterone hypersecretion)	-	-	-	Increased serum glucose Increased urine cortisol Serum androstenedione and dehydroepiandrosterone Low serum potassium Low plasma renin activity High serum aldosterone. Excess serum estrogen.
Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013^[18]


Disease	Definition

von Hippel-Lindau syndrome	An autosomal dominant genetic disorder causing abnormal growth of blood vessels in different parts of the body.
Tuberous sclerosis	A rare multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin.
Carney complex	An autosomal dominant condition comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity.
Neurofibromatosis type 1	An autosomal dominant tumor disorder of central nervous system due to germline mutations in neurofibromin manifesting as scoliosis (curvature of the spine), learning disabilities, vision disorders, cutaneous lesions and epilepsy.
Li-Fraumeni syndrome	An autosomal dominant rare disorder due to germline mutations of the TP53 tumor suppressor gene characterized by early onset of diverse amount of cancers such as sarcoma, cancers of the breast, brain and adrenal glands.
Gardner's syndrome	Familial colorectal polyposis is an autosomal dominant form of polyposis characterized by the presence of multiple polyps in the colon together with tumors outside the colon .
Multiple endocrine neoplasia type 2	An autosomal dominant disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary hyperparathyroidism.
Cowden syndrome	A rare autosomal dominant disorder due to germline mutation of PTEN, a tumor suppressor gene characterized by multiple tumor-like growths called hamartomas.
Cushing's syndrome	A disorder due to prolonged exposure to cortisol characterized by hypertension, abdominal obesity but with thin arms and legs, purple abdominal striae, moon facies, buffalo lump, weak muscles, weak bones, acne, and fragile skin that heals poorly.
Acromegaly/gigantism	A rare syndrome due to excess growth hormone characterized by enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin, hypertrichosis, hyperpigmentation and hyperhidrosis and carpal tunnel syndrome.
Hyperaldosteronism	A disorder due to excess production of the aldosterone by the adrenal glands characterized by hypertension, muscular weakness, muscle spasms, tingling sensations and excessive urination.
Pituitary adenoma	A tumor in pituitary gland characterized by visual field defects, classically bitemporal hemianopsia, increased intracranial pressure, migraine and lateral rectus palsy.
Hyperparathyroidism	A disorder due to excess production of parathyroid hormone characterized by kidney stones, hypercalcemia, constipation, peptic ulcers and depression.
Thyroid carcinoma	A tumor of the thyroid gland characterized by signs and symptoms of hyperthryroidism or hypothyroidism.
Pheochromocytoma/paraganglioma	A neuroendocrine tumor of the medulla of the adrenal glands characterized by episodic hypertension, palpitations, anxiety, diaphoresis and weight loss.
Adrenocortical carcinoma	An aggressive cancer originating in the cortex of the adrenal gland that may either by non-secretory (asymptomatic) or secretory with signs and symptoms of Cushing syndrome (cortisol hypersecretion), Conn syndrome (aldosterone hypersecretion), virilization (testosterone hypersecretion)
Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013^[18]

Risk factors of VTE may be categorized in to modifiable, non-modifiable, temporary and other risk factors.

Modifiable Risk Factors

Non-Modifiable Risk Factors

Temporary Risk Factors

Other Risk Factors

❑ Modifiable risk factors are reversible based upon lifestyle/behavior modification.
❑ Obesity is defined as a body-mass index (BMI) above 30 kg/m2.^[19] ^[20] ^[21]
❑ Smoking:^[19] Smoking significantly increases the risk of DVT, particularly among women who are taking oral contraceptive pills as well as among obese people.
❑ Use of oral contraceptives^[22]
❑ Hyperhomocysteinemia:^[23] Hyperhomocysteinemia can be reduced with vitamin B supplementation.

❑ Advanced age
❑ Heart failure
❑ Thrombophilia or hypercoagulable state
❑ Polycythemia vera

❑ Factor V Leiden

❑ Prothrombin G20210A mutation

❑ Protein C deficiency

❑ Protein S deficiency

❑ Activated protein C resistance

❑ Antithrombin III deficiency

❑ Factor VIII mutation

❑ Antiphospholipid syndrome

❑ Heparin induced thrombocytopenia

❑ Nephrotic syndrome

❑ Paroxysmal nocturnal hemoglobinuria

❑ Pregnancy and the peri-partum period
❑ Active cancer
❑ Central venous catheter

❑ Other possible factors associated with VTE include:^[24]

❑ Nutrition low in fish

❑ Psychological stress

❑ Cardiovascular risk factors such as diabetes and hypercholesterolemia


Diagnosis	Degree of Thyrotoxicosis	Radioactive iodine Uptake	Scintigraphy Image
Functional (Nuclear) Imaging for Thyrotoxicosis
Toxic multinodular goiter	+/++	Normal or +/++	Enlarged gland with multiple "hot" or "cold" nodules
Grave's disease	++++	++++	Enlarged gland with homogenous uptake
Thyrotoxic phase of subacute thyroiditis	++++	<1% at 4 or 24 hr.	Absent isotope uptake
Toxic adenoma	+/++	Normal or +/++	Dominant "hot" nodule with low or absent uptake in the surrounding normal gland.


Multiple Endocrine Neoplasia-1 (MEN-1) Syndrome Tumors
Enteropancreatic tumor	Gastrinoma Insulinoma Glucagonoma Nonfunctioning and PPoma VIPoma
Pituitary adenoma	Prolactinoma Somatotrophinoma Corticotropinoma Nonfunctioning
Associated tumors	Adrenal cortical tumor Pheochromocytoma Bronchopulmonary NET Thymic NET Gastric NET Lipomas Angiofibromas Collagenomas Meningiomas
Parathyroid adenoma	-

|- ! colspan="1" style="background: #4479BA; padding: 5px 5px;" | Parathyroid adenoma | style="padding: 5px 5px; background: #F5F5F5;" | Parathyroid adenoma


Condition	PTH	Serum Calcium	Serum phosphate	Urine Calcium	Urine Calcium/Serum Creatinine Ratio
Laboratory Findings of Familial Hypocalciuric Hypercalcemia
Familial Hypocalciuric Hypercalcemia	Normal	Normal or ↑	Normal	↓	↓
Primary Hyperparathyroidism	↑	↑	↓	Normal	↑


Cause of dementia	Characteristics and clinical and cognitive features

Alzheimer's disease	Brain disease that encompasses predementia and dementia phases. Memory changes and AD biomarker evidence required for diagnosis of probable AD. Slow cognitive and functional decline with early loss of awareness. Amnestic and nonamnestic phenotypes
Lewy body dementia	Spectrum of disorders with movement, cognitive, autonomic changes. Includes dementia with Lewy bodies and Parkinson's disease dementia. Early visual hallucinations, muscle rigidity, sleep disturbance. α-synuclein deposits present in neurons
Frontotemporal lobar degeneration	Focal atrophy of frontal and temporal lobes; knife-edge atrophy noted on MRI. Younger onset, changes in personality and behavior, language impairment, strong familial component.
Vascular dementia	Stepwise progression and focal neurologic signs (also known as multi-infarct dementia or poststroke dementia). Dysexecutive syndrome, slowed processing speed, retrieval difficulties, depression, mild motor signs in subcortical vascular dementia. Symptoms overlap with alzheimer's disease.


Causes of Hypergastrinemia
Appropriate hypergastrinemia	Atrophic gastritis with or without pernicious anemia Antisecretory therapy (PPIs or high-dose histamine H2-receptor antagonist) Chronic renal failure H pylori pangastritis Vagotomy
Inappropriate hypergastrinemia	ZES (sporadic or associated with MEN-1) Antral-predominant H pylori infection Retained-antrum syndrome Gastric-outlet obstruction Small-bowel resection
Spurious hypergastrinemia	Nonfasting patient Inaccurate assay

Cause of dementia	Characteristics and clinical and cognitive features
AD	Brain disease that encompasses predementia and dementia phases. Memory changes and AD biomarker evidence required for diagnosis of probable AD. Slow cognitive and functional decline with early loss of awareness. Amnestic and nonamnestic phenotypes

Lewy body dementia	Spectrum of disorders with movement, cognitive, autonomic changes. Includes dementia with Lewy bodies and Parkinson's disease dementia. Early visual hallucinations, muscle rigidity, sleep disturbance. α-synuclein deposits present in neurons

Frontotemporal lobar degeneration	Focal atrophy of frontal and temporal lobes; knife-edge atrophy noted on MRI. Younger onset, changes in personality and behavior, language impairment, strong familial component

VaD	Stepwise progression and focal neurologic signs (also known as multi-infarct dementia or poststroke dementia). Dysexecutive syndrome, slowed processing speed, retrieval difficulties, depression, mild motor signs in subcortical VaD. Symptoms overlap with AD

Cause of dementia	Characteristics and clinical and cognitive features
AD	Brain disease that encompasses predementia and dementia phases. Memory changes and AD biomarker evidence required for diagnosis of probable AD. Slow cognitive and functional decline with early loss of awareness. Amnestic and nonamnestic phenotypes

Lewy body dementia	Spectrum of disorders with movement, cognitive, autonomic changes. Includes dementia with Lewy bodies and Parkinson's disease dementia. Early visual hallucinations, muscle rigidity, sleep disturbance. α-synuclein deposits present in neurons

Frontotemporal lobar degeneration	Focal atrophy of frontal and temporal lobes; knife-edge atrophy noted on MRI. Younger onset, changes in personality and behavior, language impairment, strong familial component

VaD	Stepwise progression and focal neurologic signs (also known as multi-infarct dementia or poststroke dementia). Dysexecutive syndrome, slowed processing speed, retrieval difficulties, depression, mild motor signs in subcortical VaD. Symptoms overlap with AD


Criteria	Minimal	Questionable	Mild	Moderate	Severe
Clinical Dementia Rating
Based on the severity of Impairment
Memory	No memory loss or slight inconsistent forgetfulness	Consistent slight forgetfulness; partial recollection of events; “benign” forgetfulness	Moderate memory loss; more marked for recent events; defect interferes with everyday activities	Severe memory loss; only highly learned material retained; new material rapidly lost	Severe memory loss; only fragments remain
Orientation	Fully oriented	Fully oriented except for slight difficulty with time relationships	Moderate difficulty with time relationships; oriented for place at examination; may have geographic disorientation elsewhere	Severe difficulty with time relationships; usually disoriented to time, often to place	Oriented to person only
Judgment and problem solving	Solves everyday problems and handles business and financial affairs well; judgment good in relation to past performance	Slight impairment in solving problems, determining similarities and differences	Moderate difficulty in solving problems, determining similarities and differences; social judgment usually maintained	Severely impaired in solving problems, determining similarities and differences; social judgment usually impaired	Unable to make judgments or solve problems
Community affairs	Independent function at usual level in job, shopping, and volunteer and social groups	Slight impairment in these activities	Unable to function independently at these activities, although may still be engaged in some; appears normal to casual inspection	No pretense of independent function outside of home; appears well enough to be taken to functions outside a family home	No pretense of independent function outside of home; appears too ill to be taken to functions outside a family home
Home and hobbies	Life at home, hobbies, and intellectual interests well maintained	Life at home, hobbies, and intellectual interests slightly impaired	Mild but definite impairment of function at home; more difficult chores abandoned; more complicated hobbies and interests abandoned	Only simple chores preserved; interests very restricted and poorly maintained	No significant function in home
Personal care	Fully capable of self-care	Fully capable of self-care	Needs prompting	Requires assistance in dressing, hygiene, keeping of personal effects	Requires much help with personal care; frequent incontinence

{| class="wikitable"

!Condition !T3 !T4 !TSH |- |Thyrotoxicosis |Increased |Increased |Supressed |- |T3 Toxicosis |2X (Increased Twice) |Normal |Supressed |- |Hypothyroidism |Low/Normal |Low |Increased |} ↓ β

Differentiating Thyroid adenoma from other Diseases

The table below summarizes the findings that differentiate thyroid adenoma from other conditions that cause neck swelling.^[25]


Disease	Findings

Multinodular goiter	Multinodular goiter is the multinodular enlargement of the thyroid gland. They are large nodules of more than 1 cm that produces symptoms of hyperthyroidism.
Grave's disease	Grave's disease is an autoimmune disease that affects the thyroid. It frequently results in hyperthyroidism and an enlarged thyroid. Pretibial myxedema and ophthalmopathy are some of the findings of grave's disease.
Hashimoto's disease	Hashimoto's disease is an autoimmune disease in which the thyroid gland is attacked by a variety of cell-mediated and antibody-mediated immune processes, causing primary hypothyroidism.
Medullary thyroid carcinoma	Medullary thyroid carcinoma is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.
Thyroid lymphoma	Thyroid lymphoma is a rare malignant tumor which manifests as rapidly enlarging neck mass causing respiratory difficulty.
De Quervain's thyroiditis	De Quervain's thyroiditis is a subacute granulomatous thyroiditis preceded by an upper respiratory tract infection.
Acute suppurative thyroiditis	Acute suppurative thyroiditis is an uncommon thyroid disorder usually caused by bacterial infection.

Thyroid adenoma must be differentiated from other causes of hyperthyroidism such as Grave's disease and toxic nodular goiter.

Cause of thyrotoxicosis	TSH receptor antibodies	Thyroid US	Color flow Doppler	Radioactive iodine uptake/Scan	Other features
Graves' disease	+	Hypoechoic pattern	?	?	Ophthalmopathy, dermopathy, acropachy
Toxic nodular goiter	-	Multiple nodules	-	Hot nodules at thyroid scan	-
Toxic adenoma	-	Single nodule	-	Hot nodule	-
Subacute thyroiditis	-	Heterogeneous hypoechoic areas	Reduced/absent flow	?	Neck pain, fever, and elevated inflammatory index
Painless thyroiditis	-	Hypoechoic pattern	Reduced/absent flow	?	-
Amiodarone induced thyroiditis-Type 1	-	Diffuse or nodular goiter	?/Normal/?	? but higher than in Type 2	High urinary iodine
Amiodarone induced thyroiditis-Type 2	-	Normal	Absent	?/absent	High urinary iodine
Central hyperthyroidism	-	Diffuse or nodular goiter	Normal/?	?	Inappropriately normal or high TSH
Trophoblastic disease	-	Diffuse or nodular goiter	Normal/?	?	-
Factitious thyrotoxicosis	-	Variable	Reduced/absent flow	?	? Serum thyroglobulin
Struma ovarii	-	Variable	Reduced/absent flow	?	Abdominal RAIU

Disease		Findings
Thyroiditis	Direct chemical toxicity with inflammation	Amiodarone, sunitinib, pazopanib, axitinib, and other tyrosine kinase inhibitors may also be associated with a destructive thyroiditis.^[26]^[27]
	Radiation thyroiditis	Patients treated with radioiodine may develop thyroid pain and tenderness 5 to 10 days later, due to radiation-induced injury and necrosis of thyroid follicular cells and associated inflammation.
	Drugs that interfere with the immune system	Interferon-alfa is a well-known cause of thyroid abnormality. It mostly leads to the development of de novo antithyroid antibodies.^[28]
	Lithium	Patients treated with lithium are at a high risk of developing painless thyroiditis and Graves' disease.
	Palpation thyroiditis	Manipulation of the thyroid gland during thyroid biopsy or neck surgery and vigorous palpation during the physical examination may cause transient hyperthyroidism.
Exogenous and ectopic hyperthyroidism	Factitious ingestion of thyroid hormone	The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.^[29]
	Acute hyperthyroidism from a levothyroxine overdose	The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.^[30]
	Struma ovarii	Functioning thyroid tissue is present in an ovarian neoplasm.
	Functional thyroid cancer metastases	Large bony metastases from widely metastatic follicular thyroid cancer cause symptomatic hyperthyroidism.
Hashitoxicosis		It is an autoimmune thyroid disease that initially presents with hyperthyroidism and a high radioiodine uptake caused by TSH-receptor antibodies similar to Graves' disease. It is then followed by the development of hypothyroidism due to the infiltration of the thyroid gland with lymphocytes and the resultant autoimmune-mediated destruction of thyroid tissue, similar to chronic lymphocytic thyroiditis.^[31]
Toxic adenoma and toxic multinodular goiter		Toxic adenoma and toxic multinodular goiter are results of focal/diffuse hyperplasia of thyroid follicular cells independent of TSH regulation. Findings of single or multiple nodules are seen on physical examination or thyroid scan.^[32]
Iodine-induced hyperthyroidism		It is uncommon but can develop after an iodine load, such as administration of contrast agents used for angiography or computed tomography (CT), or iodine-rich drugs such as amiodarone.
Trophoblastic disease and germ cell tumors		Thyroid-stimulating hormone and HCG have a common alpha-subunit and a beta-subunit with considerable homology. As a result, HCG has weak thyroid-stimulating activity and high titer HCG may mimic hyperthyroidism.^[33]

Chickenpox:

Classification :

https://www.ncbi.nlm.nih.gov/pubmed/7800783/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754837/

ascites, hydrothorax, elevated CA125, and hyperthyroidism. This rare condition should be considered in the differential diagnosis in patients with ascites and pleural effusions

teratoma and fibrothecoma ^[34]

Overview

Struma ovarii, the tumor was first described in 1889 by Boettlin. By observing the ovaries, he discovered the presence of thyroid follicular tissue in them. Further reports thereafter were published by Gottschalk in 1899.

Historical Perspective

In 1889 by Boettlin, who observed the presence of thyroid follicular tissue in ovaries first described the tumor. ^[35]
In 1895, Von Klden and Gottschalk in 1899 described Struma ovarii as the most common type of monodermal teratoma. ^[36]

Laboratory Studies

Fasting serum gastrin levels Fasting serum gastrin is the best single screening test for Zollinger-Ellison syndrome (ZES). Preferably, patients should not be taking gastric antisecretory medications at the time of the test, but this is not essential for the initial screen. Because fasting gastrin levels can fluctuate from day to day and can appear to be normal, serial measurements on different days should be performed. Normal levels of serum gastrin in untreated ZES are extremely rare (<1%). Serum calcium levels Elevated serum calcium levels should prompt a search for multiple endocrine neoplasia-type 1 (MEN 1) syndrome. Gastric acid secretory tests Basal acid output (BAO) greater than 15 mEq/h or greater than 5 mEq/h in patients with a prior vagotomy and partial gastrectomy is suggestive of ZES. Basal gastric secretory volume greater than 140 mL in patients with no prior gastric acid–reducing surgery has a high sensitivity and specificity. Gastric pH less than 2.0 in the presence of a large gastric volume (>140 mL over 1 h in patients without prior gastric acid–reducing surgery) is highly suggestive of ZES. Currently, maximal acid output measurement is rarely performed. Provocative tests Various provocative diagnostic tests for ZES have been proposed, including the secretin stimulation test, calcium stimulation test, secretin-plus-calcium stimulation tests, bombesin test, and protein meal test. The secretin stimulation test is the provocative test of choice because of its higher sensitivity. In this test, a 2-U/kg bolus of secretin is administered intravenously after an overnight fast, and serum levels of gastrin are determined at 0, 2, 5, 10, and 15 minutes. An increase in serum gastrin of greater than 200 pg/mL is diagnostic. Potential algorithm for suspected gastrinoma A suggested algorithm for the evaluation of a patient with suspected gastrinoma is as follows: Step 1: Check the fasting gastrin level. Measure at least 3 fasting levels of gastrin on different days. Step 2: Perform gastric acid secretory studies. A BAO value of greater than 15 mEq/h or a gastric volume of greater than 140 mL and pH of less than 2.0 are highly suggestive of gastrinoma. Step 3: Perform a provocative test. The secretin stimulation test is the preferred test. Step 4: Perform somatostatin receptor scintigraphy (SRS). Step 5: Perform imaging studies to stage and localize the gastrinoma. Step 6: Determine if patient is a surgical candidate for tumor resection.

Pathophysiology

The gastrinoma tumor cells secrete excessive amounts of gastrin which leads to hyperplasia of the fundic parietal cells and increased basal gastric acid output. The excessive gastric acid output breaches the mucosal defenses of the gastric as well as the duodenal wall, causes ulceration, and inactivates pancreatic digestive enzymes with resultant fat malabsorption and diarrhea. Inhibition of absorption of sodium and water by the small intestine results in a secretory component of the diarrhea.

Histologically, well-differentiated neuroendocrine tumor (NET) has a typical organoid arrangement of cells with nesting, trabecular, or gyriform patterns. The tumor cells are round with regular bland nuclei and produce large amounts of secretory granules with diffuse immunoexpression of neuroendocrine markers. In contrast, the poorly differentiated NET has atypical, sheet-like, diffuse and irregular nuclei, less cytoplasmic secretory granules, and limited biomarker immunoexpression. An important feature for the diagnosis of neuroendocrine tumors is immunostaining for chromogranin A and synaptophysin. Gastrin immunostaining can be used to differentiate from other neuroendocrine tumors. Gastrinomas express a high density of somatostatin receptors, thus making somatostatin scintigraphy an effective localizing tool.

The WHO (2010) classified all neuroendocrine tumors, including gastrinomas into three grades based on the mitotic rate, or Ki-67 index: (1) Low grade, well-differentiated endocrine tumors with benign or uncertain behavior at the time of diagnosis with a mitotic rate of < 2 and Ki-67 index of < 3% (10% to 30%); (2) well-differentiated endocrine carcinomas with low-grade malignant behavior with a mitotic rate of 2 to 20 and Ki-67 index of 3% to 20% (50% to 80%), and (3) High grade, poorly differentiated endocrine carcinomas with high-grade malignant behavior with a mitotic rate of > 20 and Ki-67 index of > 20% (1% to 3%).

PMID: 28722872

Natural history and experience with diagnosis and treatment of the Zollinger-Ellison syndrome.

Thompson JC, Reeder DD, Villar HV, Fender HR. Abstract With better methods of diagnosis, patients will be identified earlier in the course of their disease and will often have atypical and borderline manifestations of the syndrome. Serum gastrin measurements with calcium and especially with secretin challenge will be the most important method of diagnosis. Any patient with acid hypersecretion who has a high serum gastrin level that does higher on secretin infusion should be considered to have the Zollinger-Ellison syndrome. A firm diagnosis of the Zollinger-Ellison syndrome should be made, if at all possible, prior to operation. At operation, a thorough search of the pancreas, duodenum, stomach, greater and lesser omentum and liver should be made for primary and secondary gastrinomas. If the preoperative data firmly establish the diagnosis of the Zollinger-Ellison syndrome, a total gastrectomy should be carried out even if no primary tumor is found. Similarly, a total gastrectomy should be done even if there are massive hepatic metastases. If total gastrectomy is not performed, the patient is apt to die of complications of acid hypersecretion. The only possible exceptions to the rule of always performing a total gastrectomy are in asymptomatic patients with easily excisable tumors or patients with tumors of the duodenum that are easily excisable, providing that in both instances after the excision of the tumor the output of gastric acid as measured at operation is immediately halted. All possible metastatic tumor tissue should be removed. The more tumor tissue removed, the longer the patient will survive. Metastases should be treated aggressively. They do not disappear after total gastrectomy in our experience, and they may kill patients. Patients should be followed after operation with serial measurements of serum gastrin concentrations and by hepatic scintillation scans and hepatic angiography. If hepatic metastases develop, intrahepatic artery infusions of 5-fluorouracil may slow tumor growth.

PMID: 1145407

Zollinger-Ellison syndrome (ZES) is an endocrinopathy characterized by gastrin-secreting tumors, responsible for causing the formation of multiple, refractory, and recurrent peptic ulcers in the distal duodenum and proximal jejunum. Two main variants have been described, sporadic and those found in association with parathyroid and pituitary tumors, a genetic disorder known as multiple endocrine neoplasia-1 (MEN-1). Biochemical serum evaluation for elevated gastrin, followed by radiological or nuclear localization of the primary lesion, is mandated for establishing diagnosis. The mainstays of treatment include management of hypersecretory state with medical suppression of gastric acid production and surgical resection of primary tumor for the prevention of malignant transformation and metastatic complications. Medical therapy with proton pump inhibitors has virtually eliminated the need for acid-reducing surgical procedures. Surgical approach to sporadic and MEN-1-associated ZES varies based on our understanding of the natural history of the condition and the probability of cure; however, resection to a negative microscopic margin is indicated in both cases. Postoperative surveillance involves measurement of gastrin level, followed by imaging if elevation is detected. Re-excision of recurrent or resection of metastatic disease is a subject of controversy; however, at the present time aggressive cytoreductive approach is favored.

In the 1960s, gastrin was discovered as the key hormone in the pathogenesis of the gastric hypersecretion [2]. With further advances in biochemical detection techniques, as well as improved understanding of the gastrointestinal hormone interactions, specifically the identification of the role of secretin stimulation on the serum gastrin levels [3], the diagnosis of ZES could now be conclusively established. It was observed that some cases of ZES were decidedly sporadic, whereas others occurred in constellation with other clinical features that comprised what we now understand to be a genetic syndrome that later became known as MEN-1 [4]. Advances in radiological imaging, angiography, and endoscopic techniques allowed for more precise tumor localization. Finally, understanding the natural history of the tumors responsible for ZES has allowed us to make evidence-based recommendations about their ultimate management.

It is the purpose of the current review to present a historically based overview of the diagnosis and treatment of Zollinger-Ellison syndrome and to discuss some of the controversies that exist today with regard to its management.

Diagnostic accuracy of imaging for localization of gastrinoma
CT	50%	Tumors enhance on early arterial phase because of high vascularity; sensitivity decreases for tumors <2cm
MRI


Modality	Sensitivity	Comments
Diagnostic accuracy of imaging for localization of gastrinoma
CT MRI SRS EUS Angiography / Arterial Stimulation	50% 25-50% 80% 70% 40-60%	Tumors enhance on early arterial phase because of high vascularity; sensitivity decreases for tumors <2cm Low T1 and high T2 signal intensity. Additional ability to detect extra abdominal metastatic lesions; enhanced sensitivity when combined with single photon emission computed tomography (SPECT) Much higher sensitivity for pancreatic compared with duodenal lesions; can guide needle biopsy to obtain tissue diagnosis. Contrast administered into GDA and inferior pancreaticoduodenal artery; may be performed intraoperatively


Factors	Sopradic ZES	MEN-1 ZES
Sporadic and MEN-1-associated ZES
Prevalence Family History Other Endocrinopathies Gastrinoma Size Number of tumors Most Common Tumor Location Lymph Node Primary Surgical Cure Rate Malignant Potential	80% No No >2cm Single Pancreas 10% 60% High	20% Yes Yes <2cm Multiple Duodenum No Rare Low


Causes of Hypergastrinemia
Appropriate hypergastrinemia	Atrophic gastritis with or without pernicious anemia Antisecretory therapy (PPIs or high-dose histamine H2-receptor antagonist) Chronic renal failure H pylori pangastritis Vagotomy
Inappropriate hypergastrinemia	ZES (sporadic or associated with MEN-1) Antral-predominant H pylori infection Retained-antrum syndrome Gastric-outlet obstruction Small-bowel resection
Spurious hypergastrinemia	Nonfasting patient Inaccurate assay

Current Management of the ZollingerEllison Syndrome

doi /10.1016/j.yasu.2013.02.004

Zollinger-Ellison Syndrome (ZES) should be considered in patients with upper gastrointestinal tract symptoms (gastroesophageal reflux disease, peptic ulcer disease) with or without secretory diarrhea, or in those with peptic ulcer disease and primary hyperparathyroidism or family history suspicious for multiple endocrine neoplasia type 1 (MEN1). � The initial workup should include a measurement of serum gastrin, serum calcium, gastric pH, and/or basal acid output when off antacid medications. � Gastric acid hypersecretion should be controlled with proton-pump inhibitors. � Localization studies including positron emission tomography, somatostatin receptor scintigraphy, computed tomography, magnetic resonance imaging, and endoscopic ultrasonography should be performed initially to evaluate for metastases and identify surgically resectable disease. � In patients with MEN1, surgical correction of hyperparathyroidism (3½-gland parathyroidectomy) should precede surgical resection of the primary tumor, as patients have multiple tumors and are seldom cured; however, surgical resection is recommended for pancreatic neuroendocrine tumors larger than 2.5 cm because of malignant potential. � All patients with localized sporadic gastrinoma should undergo surgical exploration for tumor resection, regardless of the results of imaging studies.

Zollinger-Ellison syndrome remains a challenging condition more than 50 years after its discovery. Diagnosis should be prompted by high index of suspicion based on clinical presentation, and confirmatory biochemical testing should be performed. Sporadic and MEN-1-associated variants should be distinguished. All patients without contraindication to surgery should undergo surgical exploration following radiological and nuclear localization studies. The optimal approach, open versus minimally invasive, remains the subject of debate; however, it is clear that gastrinoma triangle should be carefully and meticulously explored at the time of surgery, with inclusion of intraluminal duodenal evaluation. Extent of surgical resection, vis-à-vis prophylactic pancreaticoduodenectomy, is controversial; however, current recommendation remains to aim for R0/R1 outcome. Postoperative surveillance should center on biochemical serum testing, and cases of recurrence should be carefully considered for possible reoperation. Further studies with longer follow-up are necessary to conclusively describe the natural history of this condition, identify factors predictive of recurrence and survival, and make categorical recommendations regarding treatment.

Conclusions:

These results demonstrate that routine surgical exploration increases survival in patients with ZES by increasing disease-related survival and decreasing the development of advanced disease. Routine surgical exploration should be performed in ZES patients.

The role of routine surgical exploration for gastrinoma resection has remained controversial since almost the initial description of this syndrome in 1955 by Zollinger and Ellison.1 Initially, the controversy was between whether to only perform a total gastrectomy or whether attempted tumor resection was an alternative either alone or combined with a total gastrectomy or a lesser acid-reducing procedure.2–4 With the development of effective gastric antisecretory drugs first with histamine H2 antagonists in the 1970s and 1980s and later proton pump inhibitors (PPIs) the nature of the debate has changed; however, the controversy has only increased.5–9 The nature of the debate changed to whether medical treatment alone should be carried out or whether surgery for gastrinoma resection should be considered in patients with potentially resectable disease for all such patients or a subset.5–8 The controversy not only continued but increased because medical therapy is highly effective,7,9,10 in many patients over the short-term the tumor pursues a benign course,7,11 and until recently the long-term natural history of gastrinomas or the ability to cure these patients was largely unclear.12 Even though recently the natural history has been better defined, and it clearly established that an increasing proportion of these patients are dying from the malignant nature of the gastrinoma,13,14 as well as that up to 40% of patients can be cured long-term,8,12,15–17 the place of routine surgical resection for possible cure still remains controversial.7,18 This has occurred in large part because no study has demonstrated that routine surgical exploration with gastrinoma resection leads to increased survival. A previous study by us in 199419 showed that routine surgery decreased the rate of development of liver metastases, the most important prognostic factor for survival in most studies;13,14 however, the follow-up duration and number of patients were not sufficient to show an effect on survival. We now report our experience with a larger group of patients (n = 160) who were followed for a mean of 12 years after surgery. These patients' survival is compared with a nonsurgical group (n = 35) who had potentially resectable disease but did not undergo surgery for a variety of reasons; however, they did not differ from the surgical group in clinical, laboratory features or imaging results in initial evaluations.


	sporadic ZES	MEN-1 ZES
Surgical approach to gastrinoma in sporadic ZES and ZES associated with MEN-1
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Well-known

Can be previewed/debugged with any HTML editor
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	sporadic ZES	MEN-1 ZES
Surgical approach to gastrinoma in sporadic ZES and ZES associated with MEN-1
ABCD	abcd	1234

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Wiki-pipe

Table

{|
|}

Caption

<caption>caption</caption>

|+ caption

Row

<tr>

|-

Data cell

<td>cell1
<td>cell2

| cell1
| cell2

Data cell

<td>cell1 <td>cell2 <td>cell3

| cell1 || cell2 || cell3

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<th>heading</th>

<th>heading

! heading

Sample table

1	2
3	4

<table>
   <tr>
      <td>1</td>
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   </tr> 
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      <td>3</td> 
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1	2
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5	6

<table>
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Pros

Can be previewed/debugged with any XHTML editor
Can be formatted for easier reading
Well-known

Can be previewed/debugged with any HTML editor
Can be formatted for easier reading
Well-known
Takes less space than XHTML

Easy to write
Easy to read
Takes little space

Cons

Tedious
Takes a lot of space
Difficult to read quickly

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Poorly formed
Poorly delimited
Generally odd looking
May not have browser support in future

Unfamiliar syntax

XHTML

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Pathogenesis

Pathogenesis is the mechanism by which a certain factor causes disease (pathos = disease, genesis = development). The term can also be used to describe the development of the disease, whether it is acute, chronic, or recurrent. It can also be used to describe whether the disease causes inflammation, malignancy,necrosis etc.
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Genetics

Approximately 80% of the time, the primary causative lesion is thought to arise sporadically; in the remainder of recorded cases, this entity exists as part of MEN-1, an autosomal dominant disorder characterized by tumors of the pituitary, the parathyroid, and the pancreas.

Associated Conditions

Conditions associated with the disease can be detailed in this section.
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Gross Pathology

Gross pathology refers to macroscopic or larger scale manifestations of disease in organs, tissues and body cavities. The term is commonly used by pathologist to refer to diagnostically useful findings made during the gross examination portion of surgical specimen processing or an autopsy.
This section is a good place to include pictures. Search for copyleft images on The Pathology Wiki [1] and Ask Dr. Wiki [2].
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Microscopic Pathology

Microscopic pathology is the disease process as it occurs at the microscopic level.
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References

2. Pharmacotherapy and suspect ZES For ZES to be diagnosed it has to be first suspected. The diagnosis is very frequently missed early in the disease course with a mean delay in diagnosis in various studies of 5–8 years[3] and even in patients with MEN1, in which ZES is the most common functional PET syndrome[19,21], the diagnosis is frequently delayed a mean of 5 years[22]. Pharmacotherapy can contribute to this delay in diagnosis and in fact, studies provides evidence that it is increasingly contributing to a delay as well as increasing the difficult in making the diagnosis[4,29–31,51,52]. The latter aspect will be discussed in the next paragraph. One study[51] demonstrates that since the widespread use of proton pump inhibitors (PPIs)(omeprazole, lansoprazole, esopmeprazole, pantoprazole, rabeprazole) the number of possible ZES cases referred to well two established centers, one in the United States[NIH] and the other in Rome, has decreased. This decrease was ascribed[51] largely to the fact that the disease was less often suspected since the widespread use of PPIs. PPIs, because of their long duration of action (lasting>3–4 days) cause potent, prolonged inhibition of gastric acid secretion in almost all normals and patients with various diseases, including those with ZES[4,10,11,27,28, 29,53–59]. Prior to PPIs, histamine H2- receptor antagonists (primarily cimetidine, ranitidine, famotidine) were widely used to treat gastroesophageal reflux(GERD) and peptic ulcer disease (PUD) in both patients with[11,58,60–63] or without ZES[64]. Histamine H2-receptor antagonists have a significantly shorter duration of action than PPIs (<8–15 hours) and cause less potent inhibition of acid secretion than PPIs[62,64,65]. Consistent with their lower potency, subsequent studies demonstrated that the acid hypersecretion in most patients with ZES was not controlled long-term with the conventional doses of histamine H2-receptor antagonists used in patients without ZES[60–62,65], whereas this was not the case with PPIs[10,27,56,66,67]. The result of this was that many patients were suspected as having ZES when their symptoms/ GERD/PUD were not controlled by conventional doses of histamine H2-receptor antagonists, while this occurred much less frequently with PPIs[10,27,56,66,67]. This delay in diagnosis by the use of PPIs can result in a delay in treatment which is likely to prove particularly important to patients with advanced disease who are increasing dying from tumor progression [7,8,12,18,37,51]. At present in this era of PPIs, ZES should be suspected in any patient with a history of severe PUD/GERD disease; PUD in unusual locations; with prominent gastric folds on endoscopy because these occur in 92% of ZES patients[3]; with a history of endocrinopathies; H. pylori negative PUD[68]; family history of PUD; PUD with diarrhea or the presence of hypergastrinemia while not taking PPIs[4,10,62].

Go to: 3. Pharmacotherapy and diagnosis of ZES Pharmacotherapy is involved in two aspects in the diagnosis of ZES. First, as mentioned above the widespread use of PPIs has greatly complicated the diagnosis of ZES, not only because PPIs control acid hypersecretion in most patients with ZES with conventional doses [56], but also because their use leads to hypergastrinemia in up to 80–100% of normal subjects as well as patients with idiopathic GERD or PUD in a number of series[4,29,31,34,69–72]. Therefore, while the patient is taking PPIs, hypergastrinemia could be due to the presence of underlying ZES (uncommonly) or to the use of the PPI itself resulting in physiological hypergastrinemia due to the hypo-/achlorhydria induced by its long-term use. Second, secretin provocation tests are needed in some patients to make the diagnosis of ZES[32]. In the past calcium infusions were used or meal testing but these are rarely used at present[32,62,73]. In some countries where secretin is not available, it has been proposed a glucagon stimulation test could be used[74].

Assessment of fasting serum gastrin levels is the initial study usually performed when ZES is suspected[8,27,31,33,75]. This approach is taken, because except in special, uncommon circumstances (postgastrinoma resection[75], MEN1/ZES patients postparathyroidectomy[76]), >98% of ZES patients have an elevated fasting serum gastrin when initially diagnosed[33]. Therefore, because PPIs so frequently can cause hypergastrinemia themselves in ranges that overlap with that seen in ZES and are so widely used, the only way to be certain the hypergastrinemia is not due to the PPI, is to stop the PPI, however, this can lead to severe PUD/GERD complications if not done carefully[29,30,34]. Because of these risks, one recent study[30] has proposed that the diagnosis of ZES should be made by not stopping the PPI and instead an attempt be made to establish the diagnosis by identifying other manifestations of ZES (i.e., PET, prominent gastric folds, etc) that would support the diagnosis. Unfortunately, as pointed out in two recent papers[29,34], this latter approach is frequently not possible in many patients with ZES, especially early in their disease course. Furthermore, as discussed below, PPIs can also lead to a false positive secretin provocative test[77], so this approach cannot be used to diagnose ZES on PPIs. The above study [30] also proposes that if the diagnosis can not be made by not stopping the PPI then an attempt should be made by titrating the PPI dose downward and retesting. This approach has not been systematically studied, however it may not be possible not to achieve an acidic pH (<2) in many patients because they are well controlled on even the lowest omeprazole dose [56]. It is therefore recommended that when ZES is suspected the patient should be referred to a center with expertise in making the diagnosis and with familiarity with the potential risks of stopping PPIs[29,34].

Whereas 40% of ZES patients initially have a fasting serum gastrin level off of PPIs >10 fold elevated and their diagnosis can be established by demonstrating the presence of a gastric pH<2[2,4,10,33], however 60% have fasting gastrin levels elevated<10-fold and the presence of a gastric pH<2[2,4,8,10,12,31,33,78], findings which overlap with a number of other diagnoses (H. pylori infections, antral G cell syndromes, gastric obstruction, etc)[4,32] and thus are not specific for ZES. Therefore the secretin provocative test is recommended in this group to establish the diagnosis[4,8,12,78]. In the US at present the secretin test is performed using synthetic human secretin (ChiRhoStim, Inc., Burtonsville, MD) with a recommended bolus intravenous dose of 0.4 mcg/Kg-body weight[79]. A recent detailed review of secretin testing in ZES demonstrates the best criterion for a positive response is an increase in fasting serum gastrin postsecretin injection of ≥120 pg/mL which has a sensitivity of 94% and specificity of 100%[32] when the test is performed off of PPIs. Most studies support the conclusion that the exaggerated increase in fasting gastrin levels in patients with ZES postsecretin injection is due to the direct interaction with secretin receptors on the gastrinomas[32,80]. This conclusion is supported by results from a number of studies which demonstrate secretin receptor mRNA/receptor and /or receptors on gastrinoma cells, as well as the ability of secretin to stimulate gastrin release from dispersed gastrinoma cells in vitro[32,80].

Go to: 4. Pharmacotherapy and control of acid hypersecretion or other hormone-excess states in ZES 4A. Pharmacotherapy and control of acid hypersecretion-General

Gastric acid hypersecretion is a hallmark of ZES with mean basal secretory rates >4-times normal (41.7 mEq/hr)[2] and with basal secretory rates up to 12 times normal in individual patients[2,5]. A large number of studies have demonstrated that the gastric acid hypersecretion must be controlled both acutely and long-term in ZES patients and if it is not, severe complications of GERD/PUD almost invariably developed which were very frequently fatal[1,4,5,62].

Initially only total gastrectomy was effective at controlling the gastric acid hypersecretion[1,5,62], however with the development of histamine H2-receptor antagonists and later, PPIs, medical control is now possible in almost every patient[4,10,28,59,62,66,67,81], except for the rare patient who cannot or will not take oral antisecretory drugs, hence total gastrectomy is now rarely needed[18,62,82]. Histamine H2-receptor antagonists including cimetidine, ranitidine and famotidine have all been used to successful control the gastric acid hypersecretion in ZES patients[4,11,61,65,81,83]. Comparative studies show that cimetidine; ranitidine; famotidine have a relative potency of 1:3:32 on a milligram basis for inhibiting acid secretion in ZES patients and that ranitidine and cimetidine have the same duration of action, whereas famotidine has a 30% longer duration of action, allowing in some patients less frequent dosing[65]. To control the acid in ZES patients, high, frequent (q4–6 hourly) doses are frequently required with all histamine H2-receptor antagonists with mean daily doses of 4.9,2.2, and 0.33 grams for cimetidine, ranitidine and famotidine, respectively in the long-term NIH studies[62]. Despite these high, frequent histamine H2-receptor antagonist doses, these drugs were generally free of dose- related side-effects except for anti-androgen side-effects with cimetidine (gynecomastia, impotence)[61,62,65,81,83] and were effective long-term, although on the average at least one dosage increase was required per year[61,62,65,81,84]. Vagotomy (complete or selective) can also reduce acid hypersecretion and could result in lower doses of histamine H2-receptor antagonists [5,58,62, ], however with the availability of PPIs it is rarely used at present.

PPIs because of their long duration of action and potency, which allow once a day dosing in most patients, are now the drugs of choice for treating the acid hypersecretion in ZES patients[4,11,12,27,28]. Each of the PPIs has been shown to be effective in ZES patients including omeprazole[27,56,66,81], lansoprazole[11,27,59,67], esomeprazole[27,55,85,86], rabeprazole[27,53,87], and pantoprazole[27,88,89]. PPI’s have remained effective in long-term studies for up to 10 years with no evidence of tachyphylaxis[66,67,81].

Long-term PPI treatment in ZES has proven safe with very few patients (<0.1%) having to stop treatment because of any side effect. The long-term effects of PPI-induced hypo-/achlorhydria have been a potential concern especially related to the possible malabsorption of nutrients requiring gastric acid secretion (vitamin B12, iron, calcium), as well as the possible effect of enhanced hypergastrinemia, resulting in a possible increased development of gastric carcinoid tumors or other neoplasms[57,90,91]. Low vitamin B12 levels are not infrequent in ZES patients[92,93] and one study[92]demonstrated that it was more frequent in patients treated with PPIs as well as demonstrating that low vitamin B12 levels correlated with the presence of PPI-induced hypochlorhydria, whereas a second study[93] did not show this association. No deficiency in body iron with long-term PPI in ZES patients was found[94]. Recently evidence has been provided from correlative studies or epidemiological studies, that long-term PPI treatment results in an increased incidence of bone fractures, particularly of the hip or spine[91,95], but there are no specific studies on ZES patients demonstrating such an occurrence. There are a number of reports of lansoprazole-included colitis in patients with various diseases in the literature[96], but none in any patients with ZES. Similarly chronic PPI treatment is reported to be associated with the development of community-acquired pneumonias, hypomagnesemia, enteric infections, and interstitial nephritis[91,97,98], however there are no reports in ZES patients treated long-term with PPIs, even though in many cases the patients were treated with higher than conventional doses. Prolonged hypergastrinemia in animals and in man results in proliferation of the enterochromaffin-like cells (ECL-cells) of the gastric mucosa and in numerous animal models in which chronic hypergastrinemia is induced, gastric carcinoid tumors (ECLomas) develop, some of which are malignant[90,99]. In patients with ZES, >90% of patients demonstrate ECL-cell proliferation, however those with the sporadic form of ZES (non-MEN1) rarely develop gastric carcinoid tumors[99,100], however they occur with >70 higher frequency in patients with MEN1/ZES with 23% having gastric carcinoids in one study and in 10–30% they can be malignant[23]. There are no reports that the treatment with PPI’s accelerates the development of these gastric carcinoid tumors, perhaps related to the fact that ZES patients have hypergastrinemia already due to the gastrinoma and if the acid treatment is appropriately monitored in many cases the fasting gastrin levels do not change. Some studies propose that hypergastrinemia is associated with increased development of colonic cancer[90,101], but in one study of ZES patients no increase in the occurrence of colonic neoplasms was found[90].

There is no general agreement on the best protocol to start the use of PPIs. In the center with the largest experience (NIH) it is recommended in uncomplicated disease (see next paragraph for definition) that patients be started on a dose equivalent to ompreprazole 60 mg/day and that it can be decreased with time [4,5,7,8,12,27,57,58,66, 84 ]. The ideal is to titrate the dose using acid output but few now have this capability. Symptom control (particularly diarrhea, pain) can be used and if mucosal disease is present repeat examination should be performed after 4–6 weeks. In patients with complicated disease higher doses are required as outlined in the next paragraph [21,56,60,66,76,103].

Somatostatin analogues (Octreotide, Lanreotide) inhibit the release of gastrin from the gastrinoma and can also control gastric acid hypersecretion[28]. However, because parenteral administration is required, and because the oral PPIs are so effective, somatostatin analogues are rarely used in ZES to control the acid hypersecretion[28]. Somatostatin analogues are increasingly used for their anti-tumor growth effects in patients with advanced disease and this will be discussed in a later section[36,37,39,44,45,102].

4B. Pharmacotherapy and control of acid hypersecretion in ZES-Specific situations:(complicated disease, pregnancy with ZES, use of parenteral therapy)

Gastric acid hypersecretion in ZES patients with complicated disease defined as those with moderate-severe GERD with or without esophageal strictures, previous acid-reducing surgery (particularly Billroth-2 operations) or with MEN1, especially with hyperparathyroidism that is not well-controlled, has been shown in number of studies to be more difficult to control[21,56,60,66,76,103]. In each case either higher doses or more frequent doses of histamine H2-receptor antagonists are required and even with PPI’s, higher doses and more frequent use of twice a day or rarely three times a day administration is required[21,56,60,66,103]. Studies demonstrate that if sufficient antisecretory drug is given to reduce gastric acid hypersecretion before the next drug dose to <10 mEq/hr (<5 mEq/hr if previous gastric acid-reducing surgery), PUD will heal, PUD complications averted, and new disease prevented, as well as the patient becoming asymptomatic[56,104]. However, patients with moderate-severe GERD or with previous Billroth-2 resections frequently require greater acid inhibition for mucosal healing with acid reduced to <1 mEq/hr before the next dose if still symptomatic and repeat endoscopy to assess healing[56,60,66,76,103]. The hypercalcemia due to the hyperparathyroidism results in an increased resistance to antisecretory drugs and therefore higher doses of PPIs and usually BID dosing is required until the it is adequately controlled[21,56,66,76]. This is usually accomplished by performing a 3.5 or 4-gland parathyroid resection with implant[76], although in some special cases, medical therapy with the calcium sensing receptor allosteric modulator, cincalcet is being used[105,106].

Until recently there was very little data to plan management of the gastric acid hypersecretion in pregnant females with ZES[107]. Various strategies were proposed[107] including attempted curative resection of gastrinoma prior to pregnancy; performing a parietal cell vagotomy prior to pregnancy to reduce the antisecretory drug dose and perhaps need for antisecretory drug administration; if the patient has MEN1/ZES with hyperparathyroidism then correcting the hyperparathyroidism can markedly reduce the dose of antisecretory drug needed; the use of low dose ranitidine instead of cimetidine, because of cimetidine’s anti-androgen effects and possibly the use of PPI’s, for which there was little data available, until recently, to assess there possible safely in this situation[107]. Recently meta-analyses have concluded that the use of either oral histamine H2-receptor antagonists[108,109] or PPIs[110,111] is safe during pregnancy. Their use during pregnancy was not associated an increased occurrence of congenital malformations, spontaneous abortions or preterm delivery, with the authors concluding that they can be used for the treatment of diseases such as ZES during pregnancy. Furthermore, two case studies report the delivery of normal babies in two patients with ZES treated with PPIs[112,113], one patient treated with omeprazole and the other with lansoprazole.

If patients can not take oral antisecretory drugs, it is important to control the acid hypersecretion rapidly and until they can be resumed because PUD complications can develop rapidly. During these periods, parenteral administration of gastric antisecretory drugs is often required in the course of treating patients with ZES[4,10,27,114–116]. Even though PPIs can have a long duration of action in an individual patient (>3 days), is not possible without careful previous studies to know the exact duration it is effective for a given patient, therefore for most major surgical procedures, parenteral antisecretory drug administration to control the gastric hypersecretion is required, as well as during other illness when oral intake can not be maintained for a number of days. Studies show that parenteral histamine H2- receptor antagonists can control acid hypersecretion in ZES for prolonged periods of time, however relative higher doses are required and a continuous intravenous administration is needed[58,114–116]. Studies show that parenteral PPI’s (omeprazole, pantoprazole) can also control acid hypersecretion in ZES[54,88,117–119] and that because of their long duration of action; intermittent parenteral administration (every 8–12 hours) is effective and can control acid hypersecretion for extended periods without tachyphlaxis. At present in the US, intravenous preparations of PPI’s that could be used in ZES include intravenous pantoprazole, esomeprazole and lansoprazole[119]. In one study [118] a starting dose of 80 mg of pantoprazole given by 15 min infusion every 8 hours was recommended because it controlled gastric acid hypersecretion in all ZES patients studied both acutely and up to 7 days.

4C. Pharmacotherapy and control of other hormone-excess states in patients with ZES[carcinoid syndrome, Cushing’s syndrome, other functional PETs]

Patients with ZES, particularly those with MEN1/ZES, not infrequently develop another functional hormonal syndrome during their disease course[19,22,120–124]. The functional syndromes most commonly seen include Cushing’s syndrome[121,122,125]; other functional PETs (insulinomas, glucagonomas, etc) especially in patients with MEN1[22,126]; tumor-mediated hypercalcemia[124] and rarely carcinoid syndrome[123,127]. These are in additional to the development of hyperparathyroidism in almost all patients with MEN1 (discussed above)[22,128] and the development of functional pituitary syndromes (prolactinomas, acromegaly, Cushing’s disease) in MEN1 patients[22]. These additional functional PET syndromes frequently require specific treatments, because in many cases the PETs may be advanced and unresectable. This is particularly true in the case of Cushing’s syndrome, which when it occurs in ZES patients without MEN1, it is almost always associated with advanced metastatic disease and has a very poor prognosis[121,122,125]. In some cases surgical excision is effective at controlling the additional hormone excess state (insulinomas, especially in MEN1 patients)[14,129] and should be performed whenever possible. In most of the cases the appropriate pharmacotherapy is used to control these additional functional syndromes or in the case of advanced metastatic disease, anti-tumor treatments are used (discussed in a later section). This pharmacotherapy includes treatment of prolactinomas in patients with MEN1(dopamine agonists, surgery)[129]; the treatment of Cushing’s syndrome (surgical or medical [ketoconazole, metyrapone, mitotane, etomidate, mifepristone, adrenalectomy]) [130]; treatment of functional PET syndromes or carcinoid syndrome with advanced disease with long-acting somatostatin analogues (octreotide-LAR, lanreotide-autogel)[36,37,39,44,45]; treatment of metastatic insulinomas with the mTor inhibitor, everolimus[8,131] and treatment of insulinomas with frequent feedings, diazoxide and occasionally somatostatin analogues prior to surgery[8,131].

Go to: 5. Pharmacotherapy and tumor localization in ZES Tumor localization is needed in all steps in the management of ZES including the need to assess tumor location, size, changes with time, tumor extent and changes with treatment during the course of the disease[7,8,78,132,133]. Pharmacotherapy contributes in some fashion in the performance of almost every tumor imaging modality used; in many cases functioning as a contrast agent. A large number of different imaging modalities are used for gastrinoma localization including cross-sectional imaging studies)[computed tomography (CT), ultrasound, magnetic resonance imaging (MRI)][132,134], selective angiography[132], somostatin receptor scintigraphy (SRS) using radiolabeled somostatin analogues [In the US principally 111Indium-penetreotide (Octreoscan)][132,135]; endoscopic ultrasound (EUS)[12,18], assessment of gastrin gradients either basally in the portal venous circulation or in the hepatic veins after secretin-provocation[136–138] and increasingly in many parts of the world, positron emission tomography using various somostatin labeled analogues [primarily 68Ga-DOTA0, Tyr3-octreotide][8,49]. At surgery additional localization methods are used primarily aimed at localizing duodenal gastrinomas which are frequently small and difficult to find[8,16,139,140]. These include transillumination of the duodenum, intraoperative ultrasound, and full mobilization of the duodenum (Kocher maneuver)[13,16,140,141].

Gastrinomas, as are other PETs and NETs, are generally highly vascular tumors and thus are frequently best seen with contrast agents. During the triphasic CT scan various contrast agents are used with pre-contrast, contrast and post contrast assessment and during MRI, various gadolinium contrast agents are used[132,142,143]. Unfortunately, detection of gastrinomas, as with other PETs, is size dependent to a large degree and small lesions (< 1 cm), especially duodenal gastrinomas, are frequently missed on cross-sectional imaging studies[132,135,139,140]. Gastrinomas, as other NETs, frequently overexpress somatostatin receptors and this overexpression is now widely used to image these tumors as well as increasingly to treatment them by coupling various somostatin analogues to various radiolabeled compounds[49,132,135](see section below). In the US localization is primarily performed using [111In-DTPA0]-octreotide (Octreoscan) which has been shown in a number of studies to be more sensitive than cross-sectional imaging when combined with SPECT imaging for detection of both the primary tumor and their metastases, as well as also to have the advantage of allowing whole body imaging at one time[49,132,135,144,145]. Although not yet available in the US, recent studies demonstrate that positron emission tomography using various radiolabeled somatostatin analogues (primarily 68Ga-DOTA0, tyr3]octreotide/octreotate) are even more sensitive and that their use will change management in a significant number of patients[49].

Go to: 6. Pharmacotherapy and treatment of advanced disease in patients with gastrinomas 6A. Pharmacotherapy and treatment of advanced disease in patients with gastrinomas: General

Patients with advanced metastatic gastrinomas, similar to with other PETs, have a significant decreased survival with the survival depending to a large degree on the extent of the metastatic disease as well as its rate of growth[121,133,146]. In patients with gastrinomas 10 year survival is 96% with no liver metastases, with development of any liver metastases is 85%, with liver metastases when first seen is 26%, with limited liver metastases at any time with one lobe involved is 78%, limited liver metastases with both lobes involved (<5 metastases/lobe) is 80% and with diffuse liver metastases at any time is 16%[121,146]. Furthermore, 30% of patients with liver metastases develop bone metastases at some point and this is a very poor prognostic factor with the mean time of death of 1.9 years and a 10-year survival rate of 15%[121]. Because gastrinomas are malignant in 60–90% of patients[5,146], if not cured surgically[147], a significant proportion of patients will require treatment directed at the gastrinoma itself with time now that the acid hypersecretion can be satisfactorily treated. There are a large number of different treatments proposed, and as mentioned earlier, many have been recently reviewed and thus will not be covered in detail in this review on pharmacotherapy. These include articles dealing generally with the treatment of advanced disease in patients with ZES and other PETs or gastrointestinal NETs[36–41]. The latter include reviews of targeted therapies with mTor inhibitors[36,37,39,42,43], tyrosine kinase inhibitors[36,37,39,42], somatostatin analogues[36,37,39,44,45]; liver-directed therapies; peptide radio-receptor therapy (PRRT)[36,37,39,46–48]; surgical debulking/cytoreduction[35–37] and chemotherapy[36,37,39].

6B. Pharmacotherapy and treatment of advanced disease in patients with gastrinomas: chemotherapy

In contrast to treatment of patients with advanced carcinoid tumors, chemotherapy continues to have a role in the treatment of advanced gastrinomas and other PETs[7,9,36,37,78,141,148]. In patients with well-differentiated metastatic PET/gastrinomas chemotherapy with streptozotocin in combination with 5-fluorouracil alone or with doxorubicin results in objective response rates of 20–40%, however complete response rates are uncommon, and the responses are generally not long-term (mean 5–20 months)[7,37,141,148]. Pharmacotherapy with streptozotocin combinations is associated with considerable morbidity (especially nausea/vomiting, renal toxicity). Recently[149], it is reported that the combination of capecitabine/temozolomide show promise with a partial response rate of 70% in 30 patients with advanced PETs, and this has lead to this regimen now being investigated in larger studies. Poorly differentiated gastrinomas/PETs (grade 3 with high proliferative indices[Ki67>20%, presence of nuclear atypia, necrosis]), characteristically show rapid growth with a poor prognosis[37,150,151]. The recommended treatment is cisplatin-based therapy combined with either etoposide alone or in combination with other drugs (paclitaxel, vincristine). This regimen result in remissions in 14–80% with a mean duration of <12 months.

6C. Pharmacotherapy and treatment of advanced disease in patients with gastrinomas: Biotherapy (Somatostatin analogues, Interferon)

Numerous basic studies and various clinical studies support the conclusion that both somatostatin analogues and interferon can have anti-growth effects on PETs and carcinoid tumors, as well as their antisecretory effects on ectopically secreted hormones/amines[7,36,37,44,45,152]. In patients with metastatic midgut carcinoid tumors in a prospective, double-blind, placebo controlled study; octreotide LAR[153] extended the time to progression (14.3 vs 6 mos, p<0.00008) resulting in a 67% of patients treated developing stable disease compared to 37% in controls (p=0.0079). A similar study[The CLARINET study](Controlled study of Lanreotide antiproliferative response in NETS) is being carried out in patients with PETs using Lanreotide autogel[36,37]. In various nonrandomized studies reporting the effects of either somatostatin analogues or interferon (principally alpha-interferon) tumoricidal responses with decrease in tumor size are rare (<10%), however tumoristatic responses with a stabilization of tumor size are frequent (40–80%[7,36,37,45,152,154]. In some cases the tumoristatic effect is reported to be longstanding[102,154,155]. Whether this tumor-stabilizing effect will result in enhanced survival in patients with advanced PETs remains unproven at present. Long-term somatostatin treatment is generally well-tolerated with few patients stopping treatment because of side-effects, although potentially important side-effects could be a problem in some patients, including development of glucose intolerance/diabetes, steatorrhea (usually mild) and cholelithiases (10–80% develop gallbladder sludge,1%-symptomatic)[37,152]. With interferon, side-effects are more frequent with 80–97% developing a flu-like syndrome, however in most these improve with continued treatment[152]. More serious side-effect can develop including bone-marrow toxicity, hepatotoxicity, hyperlipidemia, autoimmune disorders and rarely CNS side-effects[7,37,152]. At present the exact role or sequence for use in patients with advanced PETs for somatostatin or interferon is unclear[37]. In the recent ENET guidelines it is concluded that in patients with advanced PETs with low proliferative rates (G1) that are slowly progressive, somatostatin analogues or if the tumor is somatostatin receptor negative, interferon treatment should be considered[36,37].

6D. Pharmacotherapy and treatment of advanced disease in patients with gastrinomas: liver-directed therapies

Treatments involving pharmacotherapy specifically directed at metastatic disease in the liver in patients with advanced PETs include: embolization, chemoembolization, radio-embolization or selected internal radiation therapy (SIRT) and are frequently used when diffuse, symptomatic or progressive metastatic disease is present which can not be treated surgically or by radiofrequency ablation[7,36,37,148,156–158]. Because the normal liver derives most of its blood supply from the portal vein, whereas PET liver metastases derive 70–80% of their blood supply from the hepatic artery, occlusion of hepatic arterial radicals affects tumoral deposits much more than normal liver[7,36,37,148,156–158].

Embolization is performed either alone or frequently with administration of various chemotherapeutic agents (most commonly used include: doxorubicin,5-fluorouracil, cisplatin, mitomycin C, streptozotocin)[7,36,37,148,156–158]. In various studies 50–100% of patients have a symptomatic response to embolization/chemoembolization and 25–85% an objective tumor response with a mean duration of 6–45 months[7,36,37,148,156–158]. Both embolization and chemoembolization can be associated with serious side-effects with a complication rate of 10–80% including: a post-embolization syndrome of abdominal pain, fever and nausea/vomiting, as well as rarely, liver abscesses, gallbladder necrosis, hepatic and renal failure[7,36,37,148,156–158]. The mortality rate is <6%. In both the recent NANTES[78] and ENETs[36] treatment guidelines, it was concluded that either embolization/chemoembolization should be considered for palliative treatment in patients with hepatic-predominant metastatic PETs that is not surgically resectable, especially if symptomatic.

Radio-embolization or selected internal radiation therapy (SIRT) with 90Yttrium (90Y) microspheres is a newer therapy with relatively few patients systematically studied and followed long-term, resulting in the recommendation in the 2012 ENETs treatment guidelines that it be still considered investigational[36,37,159–161]. Two types of microspheres are currently used: 90Y resin microspheres (SIR-spheres, Sirtex Medical, Inc, Australia) with a 20–60 um diameter and approximately 50Bq/sphere and glass microspheres (TheraSpheres, Nordion (Canada) with a 20-to 30um diameter with a radioactive content to 2500 Bq/sphere[36,37,159–161]. The mean overall objective tumor response rate from 12 studies with different types of unresectable metastatic NETs was 55% and stable disease was seen in 32%[37,161]. In general the side-effects are reported to be less than seen with embolization or chemoembolization with grade 2 or 3 side-effects including constitutional side-effects (fever, fatigue, weight loss) in 43% and 1% respectively, gastrointestinal side-effects (nausea, vomiting, pain) in 25 and 5% and radiation induced liver disease in >1%[37,159].

6E. Pharmacotherapy and treatment of advanced disease in patients with gastrinomas: Peptide radioreceptor therapy (PRRT)

As discussed above a high percentage (>90%) of well differentiated PETs including gastrinomas overexpress or ectopically express at least one of the five types of somostatin receptors (sst1–5) which can be targeted to deliver cytotoxic agents to the tumor[7,37,48,162]. To accomplish this, a number of different synthetic agonist analogues of somatostatin have been coupled to different cytotoxic radiochemical (primarily 111Indium,90Yttrium,177Lutetium) using various chelators (primarily DTPA, DOTA)[7,37,48,162,163]. The most commonly used combinations are 90Y-[DOTA0, Tyr3]octreotide/octreotate,90Y-[DOTA]lanreotide or 177[DOTA0, Tyr3] octreotate[7,37,48,162]. Of 10 studies (400 patients-malignant NETs) reporting results with 90Y-labeled somostatin analogues[37] and one study with 177Lu[DOTA0, Tyr3] octreotate (510 patients), complete tumor responses were seen in 0–6% and 2%, respectively; partial/minor tumor regression in 7–37% and 43%; and tumor stabilization in 42–86% and 35%, respectively[37,162]. With 177Lu[DOTA0, Tyr3]octreotate[162] the mean duration of the objective response was not reached (>48 months). In a recent study specifically in patients with metastatic gastrinomas (11 cases)[163] with PRRT treatment with either 90Y- or 177Lu-somatostatin analogues, 9% showed a complete response, 45% a partial response and 45% tumor stabilization. Most side-effects with PRRT in the various studies were mild and with 177Lu[DOTA0, Tyr3] octreotate[162] mild symptoms (pain, vomiting, nausea) occurred in 30%. More severe side-effects included hematological toxicity (15% transient, 0.8% developed a myelodysplastic disorder) and liver toxicity (0.6%). Renal toxicity was seen primarily in patients receiving 90Y-somatostatin analogues and this side-effect could be limited by co-administering an amino acid solution with treatment[7,37,48,162]. Although PRRT from these different reports appears to hold much promise, there are not controlled studies and only at present is a prospective study underway in patients with advanced NETs. The initial study which will start early next year (2013) will also include centers in the US but will be restricted to patients with metastatic ileal carcinoid disease. Therefore, at present in both the NANETs[78] and ENETs[36]guidelines for treatment of advanced NETs/PETs, PRRT is listed as an experimental/investigational treatment.

6F. Pharmacotherapy and treatment of advanced disease in patients with gastrinomas: Targeted medical therapy (mTor inhibitors (everolimus); tyrosine kinase inhibitors (sunitinib)

6F.1. Pharmacotherapy and treatment of advanced disease in patients with gastrinomas: Targeted medical therapy with mTor inhibitors (everolimus) Numerous experimental, molecular, clinical and pathological studies have provided evidence that mTOR serine-threonine kinase, plays an important role in regulation of the growth of NETs and particularly in PETs[9,37,37,42,164–166]. Everolimus[RAD001, Affinitor, Novartis AG, Basel, Switzerland] is an orally active mTOR inhibitor reported to have anti-growth effects on PETs in a number of studies[37,39,42,165]. Recently, the results of a double-blind, placebo-controlled, trial[RADIANT-3] of everolimus (10 mg/day) in 410 patients with advanced, progressive PETs has been reported[165]. In this study everolimus demonstrated a significant extension of progressive-free survival (11 vs 4.6 months, p<0.0001) and an increase by a factor of almost 4-fold the proportion of patients with progressive-free survival at 18 months of followup[165]. Overall survival between placebo/everolimus-treated groups did not differ; however, due to crossover from placebo to everolimus at the end of the study, the ability to calculate this was limited[42,165]. In the RADIANT-3 study everolimus treatment was associated with side-effects in some patients causing a two-fold overall increase in side-effects with most being grade 1 or 2, however grade 3 or 4 adverse events did occur. The most series grade 3/4 events were: diarrhea, stomatitis, hyperglycemia and hematological (occurring in 3–7%)[165]. These side-effects could generally be managed by dose-reduction. Subsequently, in the US and Europe everolimus was approved for use in patients with unresectable, metastatic, well-differentiated PETs.

6F.1. Pharmacotherapy and treatment of advanced disease in patients with gastrinomas: Targeted medical therapy with tyrosine kinase inhibitors (sunitinib) Numerous studies demonstrate that PETs as well as other NETs, frequently possess tyrosine kinase receptors, including those of the epidermal growth factor family, insulin-like growth factor, hepatocyte growth factor[c-Met], platelet-derived-growth factor[PDGFR], stem cell factor[c-KIT], vascular-endothelial growth factors[VEGFR] and a number of others and that there activation can effect cell growth[7,37,166–168].

A number of small molecule inhibitors of these various tyrosine kinases activation have been developed, show antigrowth effects in PETs/NETs and are now undergoing studies in patients with advanced PETs/NETs[37,38,166–168]. At present the best studied and only one approved for use in patients with advanced, well-differentiated PETs is Sunitinib(Sutent, Pfizer, New York)[37,42,167,169]. Sunitinib is an orally active inhibitor of the tyrosine kinase activity of PDGFRs, VEGFR-1, VEGFR-2, c-KIT and FLT-3[167,169] PETs and has been shown to have anti-growth effects in patients with advanced PETs in an international, double-blind, randomized study[169]. In that study[169] 171 patients with progressive, advanced PETS were treated with sunitinib(37.5 mg/day) or placebo. Sunitinib treatment caused a doubling in the progression-free survival rate (11.4 vs 5.5 months, p<0.001), an increase in objective tumor response (9 vs 0%, p=0.007) and an increase in overall survival[169]. Sunitinib treatment was associated with a three-fold increase in side-effects of which most were grade 1 or 2. However some grade 3 or 4 adverse side-effects developed, with the most common being neutropenia (12%) and hypertension (9.6%) which could often be managed by dose-reduction[169]. Despite these side-effects there was no difference in a quality of life-index in the two groups of patients[169]. Subsequently, in the US and Europe sunitinib was approved for use in patients with unresectable, metastatic, well-differentiated PETs.

Go to: 7. Pharmacotherapy of patients with gastrinomas-Conclusions Since its original description, pharmacotherapy has played an increasing role in the management of patients with ZES, with the result that ZES has progressed from entirely a surgical disorder, to a disorder in which pharmacotherapy plays a role in all management aspects.

Go to: 8. Pharmacotherapy of patients with gastrinomas-Expert Opinion Pharmacotherapy, in one form or the other, is involved in all stages of the management of patients with ZES. It is involved in both a positive manner in many aspects of the management of ZES (control of hormonal hypersecretion, tumor localization studies, medical/other anti-tumor treatments) and in the case of the diagnosis of ZES, in a negative manner. The negative effect occurs because of the widespread use of PPIs in patients with various gastrointestinal complaints and even their increased over-the counter use which can both complicate and delay the diagnosis of ZES. It complicates the diagnosis because PPIs can increase fasting gastrin levels, frequently in ranges that overlap with that seen in most ZES patients. Although an attempt can be made to decrease the PPI dose to achieve an acidic pH<2 while still taking a low dose of PPI, studies suggest in most patients the PPIs will have to be stopped to establish the diagnosis. This is time consuming because of the PPI’s long duration-of-action and in a patient with ZES can be hazardous if not properly performed. The PPI’s delay the diagnosis because, in contrast to histamine H2-receptor antagonists, they control symptoms in most ZES patients with conventional doses and thus obscure the diagnosis. Pharmacotherapy has had a profoundly beneficial effect on allowing acid hypersecretion to be controlled medically in almost every patient with ZES as well as allowing effective treatments of other hormonal hypersecretory states that may develop. Pharmacotherapy has greatly enhanced the ability to localize gastrinomas and their extent by the use of various contrast agents with cross sectional imaging (CT, MRI) and angiography; the use of stimulants for hormonal gradient localization, and recently the use of radiolabeled somatostatin analogues for localization utilizing the ectopic, overexpression of somatostatin receptors by most gastrinomas. Lastly, pharmacotherapy is playing an increasing role in the treatment of patients with advanced, metastatic disease both in the form of different chemotherapy regimens, also with liver-directed therapies, biotherapy with somatostatin analogues or interferon, peptide radioreceptor therapy and most recently with effective molecular targeted therapies with the mTOR inhibitor, everolimus or the tyrosine kinase inhibitor, sunitinib. Many of these therapies are not specific to gastrinomas but also used in similar or related forms in the treatment of other PETs and NETS.

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Genetics

Associated Conditions

Gross Pathology

Microscopic Pathology

References

Epidemiology and Demographics

Prevalence

Incidence

Case Fatality Rate

Age

Gender

Race

Developed Countries

Developing Countries

References

↑ Sobala GM, Crabtree JE, Dixon MF, Schorah CJ, Taylor JD, Rathbone BJ; et al. (1991). "Acute Helicobacter pylori infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations". Gut. 32 (11): 1415–8. PMC 1379180. PMID 1752479.
↑ Slomiany BL, Piotrowski J, Slomiany A (1998). "Induction of caspase-3 and nitric oxide synthase-2 during gastric mucosal inflammatory reaction to Helicobacter pylori lipopolysaccharide". Biochem Mol Biol Int. 46 (5): 1063–70. PMID 9861460.
↑ Crabtree JE (1996). "Gastric mucosal inflammatory responses to Helicobacter pylori". Aliment Pharmacol Ther. 10 Suppl 1: 29–37. PMID 8730257.
↑ ^4.0 ^4.1 Sobala GM, Schorah CJ, Shires S, Lynch DA, Gallacher B, Dixon MF; et al. (1993). "Effect of eradication of Helicobacter pylori on gastric juice ascorbic acid concentrations". Gut. 34 (8): 1038–41. PMC 1374349. PMID 8174949.
↑ Genta RM, Hamner HW, Graham DY (1993). "Gastric lymphoid follicles in Helicobacter pylori infection: frequency, distribution, and response to triple therapy". Hum Pathol. 24 (6): 577–83. PMID 8505036.
↑ ^6.0 ^6.1 Dixon MF, Genta RM, Yardley JH, Correa P (1996). "Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994". Am J Surg Pathol. 20 (10): 1161–81. PMID 8827022.
↑ Neithercut WD, Milne A, Chittajallu RS, el Nujumi AM, McColl KE (1991). "Detection of Helicobacter pylori infection of the gastric mucosa by measurement of gastric aspirate ammonium and urea concentrations". Gut. 32 (9): 973–6. PMC 1379031. PMID 1916500.
↑ Pera M, Heppell J, Poulsom R, Teixeira FV, Williams J (2001). "Ulcer associated cell lineage glands expressing trefoil peptide genes are induced by chronic ulceration in ileal pouch mucosa". Gut. 48 (6): 792–6. PMC 1728308. PMID 11358897.
↑ Craanen ME, Blok P, Dekker W, Ferwerda J, Tytgat GN (1992). "Subtypes of intestinal metaplasia and Helicobacter pylori". Gut. 33 (5): 597–600. PMC 1379284. PMID 1612473.
↑ Walker MM (2003). "Is intestinal metaplasia of the stomach reversible?". Gut. 52 (1): 1–4. PMC 1773527. PMID 12477745.
↑ Kuhn JH, Bao Y, Bavari S, Becker S, Bradfute S, Brister JR; et al. (2013). "Virus nomenclature below the species level: a standardized nomenclature for natural variants of viruses assigned to the family Filoviridae". Arch Virol. 158 (1): 301–11. doi:10.1007/s00705-012-1454-0. PMC 3535543. PMID 23001720.
↑ ^12.0 ^12.1 ^12.2 "Outbreak of Marburg Hemorrhagic Fever Among Miners in Kamwenge and Ibanda Districts, Uganda, 2007". Missing or empty |url= (help)
↑ Towner JS, Khristova ML, Sealy TK, Vincent MJ, Erickson BR, Bawiec DA; et al. (2006). "Marburgvirus genomics and association with a large hemorrhagic fever outbreak in Angola". J Virol. 80 (13): 6497–516. doi:10.1128/JVI.00069-06. PMC 1488971. PMID 16775337.
↑ Mehedi M, Groseth A, Feldmann H, Ebihara H (2011). "Clinical aspects of Marburg hemorrhagic fever". Future Virol. 6 (9): 1091–1106. doi:10.2217/fvl.11.79. PMC 3201746. PMID 22046196.
↑ Smith DH, Johnson BK, Isaacson M, Swanapoel R, Johnson KM, Killey M; et al. (1982). "Marburg-virus disease in Kenya". Lancet. 1 (8276): 816–20. PMID 6122054.
↑ "WHO". Missing or empty |url= (help)
↑ Feldmann H, Slenczka W, Klenk HD (1996). "Emerging and reemerging of filoviruses". Arch Virol Suppl. 11: 77–100. PMID 8800808.
↑ ^18.0 ^18.1 Toledo SP, Lourenço DM, Toledo RA (2013). "A differential diagnosis of inherited endocrine tumors and their tumor counterparts". Clinics (Sao Paulo). 68 (7): 1039–56. doi:10.6061/clinics/2013(07)24. PMC 3715026. PMID 23917672.
↑ ^19.0 ^19.1 Holst AG, Jensen G, Prescott E (2010). "Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study". Circulation. 121 (17): 1896–903. doi:10.1161/CIRCULATIONAHA.109.921460. PMID 20404252.
↑ Vayá A, Martínez-Triguero ML, España F, Todolí JA, Bonet E, Corella D (2011). "The metabolic syndrome and its individual components: its association with venous thromboembolism in a Mediterranean population". Metab Syndr Relat Disord. 9 (3): 197–201. doi:10.1089/met.2010.0117. PMID 21352080.
↑ Eichinger S, Hron G, Bialonczyk C, Hirschl M, Minar E, Wagner O; et al. (2008). "Overweight, obesity, and the risk of recurrent venous thromboembolism". Arch Intern Med. 168 (15): 1678–83. doi:10.1001/archinte.168.15.1678. PMID 18695082.
↑ Pomp ER, Rosendaal FR, Doggen CJ (2008). "Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use". Am J Hematol. 83 (2): 97–102. doi:10.1002/ajh.21059. PMID 17726684.
↑ den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH; et al. (1996). "Hyperhomocysteinemia as a risk factor for deep-vein thrombosis". N Engl J Med. 334 (12): 759–62. doi:10.1056/NEJM199603213341203. PMID 8592549.
↑ Konofal E, Lecendreux M, Cortese S (2010). "Sleep and ADHD". Sleep Med. 11 (7): 652–8. doi:10.1016/j.sleep.2010.02.012. PMID 20620109.
↑ Thyroid adenoma. Wikipedia. https://en.wikipedia.org/wiki/Thyroid_adenoma Accessed on October 11, 2015
↑ Lambert M, Unger J, De Nayer P, Brohet C, Gangji D (1990). "Amiodarone-induced thyrotoxicosis suggestive of thyroid damage". J. Endocrinol. Invest. 13 (6): 527–30. PMID 2258582.
↑ Ahmadieh H, Salti I (2013). "Tyrosine kinase inhibitors induced thyroid dysfunction: a review of its incidence, pathophysiology, clinical relevance, and treatment". Biomed Res Int. 2013: 725410. doi:10.1155/2013/725410. PMC 3824811. PMID 24282820.
↑ Vialettes B, Guillerand MA, Viens P, Stoppa AM, Baume D, Sauvan R, Pasquier J, San Marco M, Olive D, Maraninchi D (1993). "Incidence rate and risk factors for thyroid dysfunction during recombinant interleukin-2 therapy in advanced malignancies". Acta Endocrinol. 129 (1): 31–8. PMID 8351956.
↑ Cohen JH, Ingbar SH, Braverman LE (1989). "Thyrotoxicosis due to ingestion of excess thyroid hormone". Endocr. Rev. 10 (2): 113–24. doi:10.1210/edrv-10-2-113. PMID 2666114.
↑ Jha S, Waghdhare S, Reddi R, Bhattacharya P (2012). "Thyroid storm due to inappropriate administration of a compounded thyroid hormone preparation successfully treated with plasmapheresis". Thyroid. 22 (12): 1283–6. doi:10.1089/thy.2011.0353. PMID 23067331.
↑ Fatourechi V, McConahey WM, Woolner LB (1971). "Hyperthyroidism associated with histologic Hashimoto's thyroiditis". Mayo Clin. Proc. 46 (10): 682–9. PMID 5171000.
↑ Laurberg P, Pedersen KM, Vestergaard H, Sigurdsson G (1991). "High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves' disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland". J. Intern. Med. 229 (5): 415–20. PMID 2040867.
↑ Oosting SF, de Haas EC, Links TP, de Bruin D, Sluiter WJ, de Jong IJ, Hoekstra HJ, Sleijfer DT, Gietema JA (2010). "Prevalence of paraneoplastic hyperthyroidism in patients with metastatic non-seminomatous germ-cell tumors". Ann. Oncol. 21 (1): 104–8. doi:10.1093/annonc/mdp265. PMID 19605510.
↑ Morrissey K, Winkel C, Hild S, Premkumar A, Stratton P (2007). "Struma ovarii coincident with Hashimoto's thyroiditis: an unusual cause of hyperthyroidism". Fertil. Steril. 88 (2): 497.e15–7. doi:10.1016/j.fertnstert.2006.11.095. PMC 2753978. PMID 17276434.
↑ Yoo SC, Chang KH, Lyu MO, Chang SJ, Ryu HS, Kim HS (2008). "Clinical characteristics of struma ovarii". J Gynecol Oncol. 19 (2): 135–8. doi:10.3802/jgo.2008.19.2.135. PMC 2676458. PMID 19471561.
↑ Wee JY, Li X, Chern BS, Chua IS (2015). "Struma ovarii: management and follow-up of a rare ovarian tumour". Singapore Med J. 56 (1): 35–9. PMC 4325564. PMID 25640097.

Template:WH Template:WS

Laboratory Findings

Supportive laboratory findings

Normal 46,XY karyotype Evidence of normal or increased synthesis of testosterone (T) by the testes Evidence of normal conversion of testosterone to dihydrotestosterone (DHT) Evidence of normal or increased luteinizing hormone (LH) production by the pituitary gland In CAIS, but not in PAIS: possible reduction in postnatal (0-3 months) surge in serum LH and serum T concentrations [Bouvattier et al 2002] In the “predominantly male” phenotype: Less than normal decline of sex hormone-binding globulin in response to a standard dose of the anabolic androgen, stanozolol. Higher than normal levels of anti-müllerian hormone during the first year of life or after puberty has begun


Type	External Genitalia	Findings
Classification of Androgen Insensitivity Syndrome Phenotypes
CAIS - (Complete androgen insensitivity syndrome)	Female (“testicular feminization”)	Absent OR rudimentary wolffian duct derivatives. Absence or presence of epididymides and/or vas deferens. Inguinal, labial, or abdominal testes. Short blind-ending vagina. Scant OR absent pubic AND/OR axillary hair.
Predominantly female (“incomplete AIS”)	Inguinal OR labial testes. Clitoromegaly and labial fusion. Distinct urethral and vaginal openings OR a urogenital sinus.
PAIS - (Partial androgen insensitivity syndrome)	Ambiguous	Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum. Descended OR undescended testes. Perineoscrotal hypospadias OR urogenital sinus. Gynecomastia (development of breasts) in puberty.
Predominantly male	Simple (glandular or penile) OR severe (perineal) “isolated” hypospadias with a normal-sized penis and descended testes OR severe hypospadias with micropenis, bifid scrotum, and either descended OR undescended testes. Gynecomastia in puberty.
MAIS - (Mild androgen insensitivity syndrome)	Male (“undervirilized male syndrome”)	Impaired spermatogenesis AND/OR impaired pubertal virilization. Gynecomastia in puberty.

In the early 1990s, an average of 4 million people got varicella, 10,500 to 13,000 were hospitalized (range, 8,000 to 18,000), and 100 to 150 died each year. In the 1990s, the highest rate of varicella was reported in preschool-aged children. ^[1]

Since the chickenpox vaccine was developed in 1995, the major data of chickenpox in the environment is before 1995. In the prevaccine era, varicella was endemic in the United States, and virtually all persons acquired varicella by adulthood. As a result, the number of cases occurring annually was estimated to approximate the birth cohort, or approximately 4 million per year. Varicella was removed from the list of nationally notifiable conditions in 1981, but some states continued to report cases to CDC. The majority of cases (approximately 85%) occurred among children younger than 15 years of age.

In 2004, varicella vaccination coverage among children 19–35 months in two of the active surveillance areas was estimated to be 89% and 90%. Compared with 1995, varicella cases declined 83%–93% by 2004. Cases declined most among children aged 1–4 and 5–9 years, but a decline occurred in all age groups including infants and adults, indicating reduced transmission of the virus in 308 Varicella 21 these groups. The reduction of varicella cases is the result of the increasing use of varicella vaccine. Varicella vaccine coverage among 19–35-month-old children was estimated by the National Immunization Survey to be 90% in 2007.

Despite high one-dose vaccination coverage and success of the vaccination program in reducing varicella morbidity and mortality, varicella surveillance indicates that the number of reported varicella cases appears to have plateaued. An increasing proportion of cases represent breakthrough infection (chickenpox occurring in a previously vaccinated person). In 2001–2005, outbreaks were reported in schools with high varicella vaccination coverage (96%–100%). These outbreaks had many similarities: all occurred in elementary schools; vaccine effectiveness was within the expected range (72%–85%); the highest attack rates occurred among the younger students; each outbreak lasted about 2 months; and persons with breakthrough infection transmitted the virus although the breakthrough disease was mild.Overall attack rates among vaccinated children were 11%–17%, with attack rates in some classrooms as high as 40%. These data indicate that even in settings where almost everyone was vaccinated and vaccine performed as expected, varicella outbreaks could not be prevented with the current one-dose vaccination policy.

These observations led to the recommendation in 2006 for a second routine dose of varicella vaccine. Chickenpox used to be very common in the United States. In the early 1990s, an average of 4 million people got varicella, 10,500 to 13,000 were hospitalized (range, 8,000 to 18,000), and 100 to 150 died each year. In the 1990s, the highest rate of varicella was reported in preschool-aged children.

Chickenpox vaccine became available in the United States in 1995. In 2014, 91% of children 19 to 35 months old in the United States had received one dose of varicella vaccine, varying from 83% to 95% by state. Among adolescents 13 to 17 years of age without a prior history of disease, 95% had received 1 dose of varicella vaccine, and 81% had received 2 doses of the vaccine. Eighty-five percent of adolescents had either a history of varicella disease or received 2 doses of varicella vaccine. Each year, more than 3.5 million cases of varicella, 9,000 hospitalizations, and 100 deaths are prevented by varicella vaccination in the United States.

−

Each year, more than 3.5 million cases of varicella, 9,000 hospitalizations, and 100 deaths are prevented by varicella vaccination in the United States.

In the early 1990s, an average of 4 million people got varicella, 10,500 to 13,000 were hospitalized (range, 8,000 to 18,000), and 100 to 150 died each year. In the 1990s, the highest rate of varicella was reported in preschool-aged children. ^[1]

Template:Topic Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]; Associate Editor(s)-in-Chief:

Overview

Topic

References

↑ ^1.0 ^1.1 "Chickenpox | Monitoring Vaccine Impact | Varicella | CDC".

Template:WH Template:WS

| style="background: #DCDCDC; padding: 5px;"|Chickenpox |

It commonly starts with conjunctival and catarrhal symptoms and then characteristic spots appearing in two or three waves, mainly on the body and head, rather than the hands, becoming itchy raw pox (small open sores which heal mostly without scarring). Touching the fluid from a chickenpox blister can also spread the disease.

|-

Vaccine is recommended for children as well as adults who haven't been vaccinated previously to prevent chickenpox. Two doses of chickenpox vaccine are recommended for children who never have contracted chickenpox at the following intervals. First dose is recommended between 12-15 months of age. Second dose is recommended around 4-6 years of age and also it may be given earlier if the gap between the doses is at least three months from the first dose. In adults, vaccine is recommended in people who are of 13 years of age or older. There should be a gap of atleast 28 days between the two doses.

Primary varicella is a common childhood disease in Western countries, which presents as pruritic macules, papules, vesicles, pustules, and crusts, usually on the back, chest, face, and abdomen.
The vesicles progress to pustules, then to crusts that eventually are lost. Scarring and changes in pigmentation can result, but the most frequent sequela of zoster is postherpetic neuralgia, which is usually most severe in the elderly.
Primary varicella or herpes zoster in immunocompromised patients can sometimes involve internal organs (eg, lungs, liver, brain) resulting in high rates of morbidity and mortality.
Chickenpox typically requires no medical treatment in otherwise healthy individuals. Only symptomatic treatment is advised to ease the discomfort.

VZV can be spread by varicella or herpes zoster carrying:
- Patients
- Health care providers
- Visitors
Individuals susceptible to the be infected by VZV include:
- Patients and health care providers in hospitals
- Long-term-care facilities
- Other healthcare settings
These transmissions have been attributed to
- Delays in the diagnosis of varicella and zoster
- Delay in the reporting of varicella and zoster
- Failures to promptly implement control measures

Immunocompromised Patients

Immunocompromised persons who get varicella are at risk of developing visceral dissemination (VZV infection of internal organs) leading to pneumonia, hepatitis, encephalitis, and disseminated intravascular coagulopathy. They can have an atypical varicella rash with more lesions, and they can be sick longer than immunocompetent persons who get varicella. The lesions may continue to erupt for as long as 10 days, may appear on the palms and soles, and may be hemorrhagic.

People with HIV or AIDS

Children with HIV infection tend to have atypical rash with new crops of lesions presenting for weeks or months. HIV-infected children may develop chronic infection in which new lesions appear for more than one month. The lesions may initially be typical maculopapular vesicular lesions but can later develop into non-healing ulcers that become necrotic, crusted, and hyperkeratotic. This is more likely to occur in HIV-infected children with low CD4 counts.

In adults, the disease can be more severe, though the incidence is much less common. Infection in adults is associated with greater morbidity and mortality due to pneumonia, hepatitis and encephalitis. In particular, up to 10% of pregnant women with chickenpox develop pneumonia, the severity of which increases with onset later in gestation. In England and Wales, 75% of deaths due to chickenpox are in adults. Inflammation of the brain, or encephalitis, can occur in immunocompromised individuals, although the risk is higher with herpes zoster.Necrotizing fasciitis

Secondary bacterial infection of skin lesions, manifesting as impetigo, cellulitis, and erysipelas, is the most common complication in healthy children. Disseminated primary varicella infection, usually seen in the immunocompromised or adult populations, may have high morbidity. Ninety percent of cases of varicella pneumonia occur in the adult population. Rarer complications of disseminated chickenpox also include myocarditis, hepatitis, and glomerulonephritis.

Primary varicella (chickenpox)

Primary varicella is a common childhood disease in Western countries, which presents as pruritic macules, papules, vesicles, pustules, and crusts, usually on the back, chest, face, and abdomen.
In immunocompetent children, chickenpox is generally a mild disease with little morbidity and rare mortality.
Primary varicella is associated with more morbidity in adults. Following resolution of primary varicella, VZV persists in a latent form in dorsal ganglion cells for what is usually an extended period of time. For reasons that are still poorly understood, VZV can later start replicating in the ganglion, producing severe neuralgia and spread of the virus down the sensory nerve. Vesicles then appear on the skin in the distribution of this nerve, producing the characteristic dermatomal rash of shingles. The vesicles progress to pustules, then to crusts that eventually are lost. Scarring and changes in pigmentation can result, but the most frequent sequela of zoster is postherpetic neuralgia, which is usually most severe in the elderly.
In immunocompromised patients can sometimes involve internal organs (eg, lungs, liver, brain) resulting in high rates of morbidity and mortality.
Primary varicella or herpes zoster Congenital VZV infection is uncommon but can result in severe congenital malformations.
A Tzanck smear can be useful to demonstrate a herpesvirus infection, but confirmation of VZV as the cause of the infection requires at least one of the following tests: culture, serology, direct immunofluorescence staining, or molecular techniques.

Zoster (shingles)

Anyone who has recovered from chickenpox may develop shingles; even children can get shingles. The risk of shingles increases as one gets older. About 50% all cases occur in men and women 60 years old or older. One in every three people develop shingles in their lifetime which is estimated at 1 million cases every year.

Certain cancers like leukemia and lymphoma, human immunodeficiency virus (HIV) positive individuals, and people on immunosuppressive drugs such as steroids and drugs given after organ transplantation have a greater risk of getting shingles.

Shingles typically occurs only once in a person's lifetime. However, a person can have a second or even a third episode.

Some studies have found that VZV dissemination to the visceral organs is less common in children with HIV than in other immunocompromised patients with VZV infection. The rate of complications may also be lower in HIV-infected children on antiretroviral therapy or HIV-infected persons with higher CD4 counts at the time of varicella infection. Retinitis can occur among HIV-infected children and adolescents.

Most adults, including those who are HIV-positive have already had varicella disease and are VZV seropositive. As a result, varicella is relatively uncommon among HIV-infected adults.

Neonates

Varicella infection in pregnant women can lead to viral transmission via the placenta and infection of the fetus. If infection occurs during the first 28 weeks of gestation, this can lead to fetal varicella syndrome (also known as congenital varicella syndrome). Effects on the fetus can range in severity from underdeveloped toes and fingers to severe anal and bladder malformation. Possible problems include:

- Damage to brain: encephalitis, microcephaly, hydrocephaly, aplasia of brain
- Damage to the eye (optic stalk, optic cap, and lens vesicles), microphthalmia, cataracts, chorioretinitis, optic atrophy
- Other neurological disorder: damage to cervical and lumbosacral spinal cord, motor/sensory deficits, absent deep tendon reflexes, anisocoria/Horner's syndrome
- Damage to body: hypoplasia of upper/lower extremities, anal and bladder sphincter dysfunction
- Skin disorders: (cicatricial) skin lesions, hypopigmentation

Infection late in gestation or immediately post-partum is referred to as neonatal varicella. Maternal infection is associated with premature delivery. The risk of the baby developing the disease is greatest following exposure to infection in the period 7 days prior to delivery and up to 7 days post-partum. The neonate may also be exposed to the virus via infectious siblings or other contacts, but this is of less concern if the mother is immune. Newborns who develop symptoms are at a high risk of pneumonia and other serious complications of the disease.

Pregnant Women

Pregnant women who get varicella are at risk for serious complications; they are at increased risk for developing pneumonia, and in some cases, may die as a result of varicella.

If a pregnant woman gets varicella in her 1st or early 2nd trimester, her baby has a small risk (0.4 – 2.0 percent) of being born with congenital varicella syndrome. The baby may have scarring on the skin, abnormalities in limbs, brain, and eyes, and low birth weight.

If a woman develops varicella rash from 5 days before to 2 days after delivery, the newborn will be at risk for neonatal varicella. In the absence of treatment, up to 30% of these newborns may develop severe neonatal varicella infection.

Infants without Passive Immunity

Children under one year of age whose mothers have had chickenpox are not very likely to catch it. If they do, they often have mild cases because they retain partial immunity from their mothers' blood. Children under one year of age whose mothers have not had chickenpox, or whose inborn immunity has already waned, can get severe chickenpox.

Chickenpox in Unvaccinated People

The rash is generalized and pruritic (itchy). It progresses rapidly from macules to papules to vesicular lesions before crusting. The rash usually appears first on the head, chest, and back then spreads to the rest of the body. The lesions are usually most concentrated on the chest and back.

In healthy children, varicella is generally mild, with an itchy rash, malaise, and temperature up to 102°F for 2 to 3 days. Adults are at risk for more severe disease and have a higher incidence of complications. Recovery from primary varicella infection usually provides immunity for life. In otherwise healthy people, a second occurrence of varicella is uncommon and usually occurs in people who are immunocompromised. As with other viral infections, re-exposure to natural (wild-type) varicella may lead to re-infection that boosts antibody] titers without causing illness or detectable viremia.

Chickenpox in Vaccinated People

Chickenpox in people who are vaccinated is referred to as breakthrough varicella. Breakthrough varicella is infection with wild-type VZV occurring in a vaccinated person more than 42 days after varicella vaccination. Breakthrough varicella is usually mild. Patients typically are afebrile or have low fever and develop fewer than 50 skin lesions. They usually have a shorter illness compared to unvaccinated people who get varicella. The rash is more likely to be predominantly maculopapular rather than vesicular. However, 25%-30% of persons vaccinated with 1 dose with breakthrough varicella have clinical features typical of varicella in unvaccinated people.

Since the clinical features of breakthrough varicella are often mild, it can be difficult to make a diagnosis on clinical presentation alone. Laboratory testing is increasingly important for confirming varicella and appropriately managing cases and their contacts. There is limited information about breakthrough varicella in persons who have received two doses of varicella vaccine, though it appears to occur less frequently among people vaccinated with two doses of varicella vaccine compared to persons who have received a single dose of varicella vaccine.

Race

he female-to-male ratio is 4:1.

Age

The frequency of goiters decreases with advancing age.

Race

No racial predilection exists.

References

[pmid1752479-1] Sobala GM, Crabtree JE, Dixon MF, Schorah CJ, Taylor JD, Rathbone BJ; et al. (1991). "Acute Helicobacter pylori infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations". Gut. 32 (11): 1415–8. PMC 1379180. PMID 1752479.

[pmid9861460-2] Slomiany BL, Piotrowski J, Slomiany A (1998). "Induction of caspase-3 and nitric oxide synthase-2 during gastric mucosal inflammatory reaction to Helicobacter pylori lipopolysaccharide". Biochem Mol Biol Int. 46 (5): 1063–70. PMID 9861460.

[pmid8730257-3] Crabtree JE (1996). "Gastric mucosal inflammatory responses to Helicobacter pylori". Aliment Pharmacol Ther. 10 Suppl 1: 29–37. PMID 8730257.

[pmid8174949-4] 4.0 ^4.1 Sobala GM, Schorah CJ, Shires S, Lynch DA, Gallacher B, Dixon MF; et al. (1993). "Effect of eradication of Helicobacter pylori on gastric juice ascorbic acid concentrations". Gut. 34 (8): 1038–41. PMC 1374349. PMID 8174949.

[pmid8505036-5] Genta RM, Hamner HW, Graham DY (1993). "Gastric lymphoid follicles in Helicobacter pylori infection: frequency, distribution, and response to triple therapy". Hum Pathol. 24 (6): 577–83. PMID 8505036.

[pmid8827022-6] 6.0 ^6.1 Dixon MF, Genta RM, Yardley JH, Correa P (1996). "Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994". Am J Surg Pathol. 20 (10): 1161–81. PMID 8827022.

[pmid1916500-7] Neithercut WD, Milne A, Chittajallu RS, el Nujumi AM, McColl KE (1991). "Detection of Helicobacter pylori infection of the gastric mucosa by measurement of gastric aspirate ammonium and urea concentrations". Gut. 32 (9): 973–6. PMC 1379031. PMID 1916500.

[pmid11358897-8] Pera M, Heppell J, Poulsom R, Teixeira FV, Williams J (2001). "Ulcer associated cell lineage glands expressing trefoil peptide genes are induced by chronic ulceration in ileal pouch mucosa". Gut. 48 (6): 792–6. PMC 1728308. PMID 11358897.

[pmid1612473-9] Craanen ME, Blok P, Dekker W, Ferwerda J, Tytgat GN (1992). "Subtypes of intestinal metaplasia and Helicobacter pylori". Gut. 33 (5): 597–600. PMC 1379284. PMID 1612473.

[pmid12477745-10] Walker MM (2003). "Is intestinal metaplasia of the stomach reversible?". Gut. 52 (1): 1–4. PMC 1773527. PMID 12477745.

[pmid23001720-11] Kuhn JH, Bao Y, Bavari S, Becker S, Bradfute S, Brister JR; et al. (2013). "Virus nomenclature below the species level: a standardized nomenclature for natural variants of viruses assigned to the family Filoviridae". Arch Virol. 158 (1): 301–11. doi:10.1007/s00705-012-1454-0. PMC 3535543. PMID 23001720.

[Marburg-12] 12.0 ^12.1 ^12.2 "Outbreak of Marburg Hemorrhagic Fever Among Miners in Kamwenge and Ibanda Districts, Uganda, 2007". Missing or empty |url= (help)

[pmid16775337-13] Towner JS, Khristova ML, Sealy TK, Vincent MJ, Erickson BR, Bawiec DA; et al. (2006). "Marburgvirus genomics and association with a large hemorrhagic fever outbreak in Angola". J Virol. 80 (13): 6497–516. doi:10.1128/JVI.00069-06. PMC 1488971. PMID 16775337.

[pmid22046196-14] Mehedi M, Groseth A, Feldmann H, Ebihara H (2011). "Clinical aspects of Marburg hemorrhagic fever". Future Virol. 6 (9): 1091–1106. doi:10.2217/fvl.11.79. PMC 3201746. PMID 22046196.

[pmid6122054-15] Smith DH, Johnson BK, Isaacson M, Swanapoel R, Johnson KM, Killey M; et al. (1982). "Marburg-virus disease in Kenya". Lancet. 1 (8276): 816–20. PMID 6122054.

[AO-16] "WHO". Missing or empty |url= (help)

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[urlChickenpox_|_Monitoring_Vaccine_Impact_|_Varicella_|_CDC-37] 1.0 ^1.1 "Chickenpox | Monitoring Vaccine Impact | Varicella | CDC".

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 ==Updated Sydney classification (Sydney criteria for gastritis)==
-The updated sydney classification of ''[[H. pylori]]'' induced classification include:<ref name="pmid8827022">{{cite journal| author=Dixon MF, Genta RM, Yardley JH, Correa P| title=Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. | journal=Am J Surg Pathol | year= 1996 | volume= 20 | issue= 10 | pages= 1161-81 | pmid=8827022 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8827022  }} </ref>
+*The updated sydney classification of ''[[H. pylori]]'' induced classification include:<ref name="pmid8827022">{{cite journal| author=Dixon MF, Genta RM, Yardley JH, Correa P| title=Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. | journal=Am J Surg Pathol | year= 1996 | volume= 20 | issue= 10 | pages= 1161-81 | pmid=8827022 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8827022  }} </ref>
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Sandbox: Dr.Reddy
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Sandbox: Dr.Reddy: Difference between revisions

Revision as of 20:47, 7 November 2017

Overview

Pathophysiology

Acute gastritis

Pathogenesis

Microscopic pathology

Active chronic gastritis

Pathogenesis

Microscopic pathology

Atrophy

Pathogenesis

Microscopic pathology

Intestinal metaplasia

Microscopic pathology

Updated Sydney classification (Sydney criteria for gastritis)

Classification Gastritis

Differentiating Thyroid adenoma from other Diseases

Chickenpox:

Classification :

https://www.ncbi.nlm.nih.gov/pubmed/7800783/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754837/

Overview

Historical Perspective

Pathogenesis

Genetics

Associated Conditions

Gross Pathology

Microscopic Pathology

References

Causes

Life-Threatening Causes

Common Causes

Risk Factors

Common Risk Factors

Less Common Risk Factors

Screening

Natural History

Complications

Prognosis

Pathophysiology

Pathogenesis

Genetics

Associated Conditions

Gross Pathology

Microscopic Pathology

References

Epidemiology and Demographics

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Incidence

Case Fatality Rate

Age

Gender

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Developed Countries

Developing Countries

References

Laboratory Findings

Overview

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Immunocompromised Patients

People with HIV or AIDS

Primary varicella (chickenpox)

Zoster (shingles)

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Chickenpox in Unvaccinated People

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