The relationship between triglycerides and pancreatic damage has been studied over the years. It is now known that Hypertriglyceridemia (HTG) is the 3rd leading cause of acute pancreatitis (less prevalent only than biliary and alcoholic causes). However, the presence of HTG is common in all etiologies of acute pancreatitis.

How do you know if triglycerides (TG) are the cause or just an epiphenomenon present in an acute pancreatitis of another etiology?

Concept

Hypertriglyceridemia is defined as an increase in serum triglyceride levels above 150 mg/dL. This increase can be categorized into:

• Mild HTG: 150-199 mg/dL
• Moderate HTG: 200-999 mg/dL
• Severe HTG: 1000-1999 mg/dL
• Very severe HTG: > 2000 mg/dL

HTGs are classified into:

• Primary – patients with genetic alterations that do not allow the correct metabolism of triglycerides. These causes were cataloged by Friderickson into types I to V. The types most associated with acute pancreatitis are: types I, IV and V.
• Secondary: some patients raise TG due to: obesity, poorly controlled diabetes, hypercaloric and hyperlipidic diet, pregnancy and alcohol use. In addition, some medications are known to cause HTG and should be researched in this context (eg: retinoids, protease inhibitors, anti-psychotics, calcineurin inhibitors, diuretics and estrogens)

The risk of acute pancreatitis (PA) occurring in individuals with HTG is considered when TG rises > 1000 mg/dL (around 5%) and increases greatly when TG > 2000 mg/dL (risk becomes 10-20%). When analyzing the population with severe hypertriglyceridemia, about 20% reported a previous history of acute pancreatitis, a value much higher than the prevalence found in the population.

Pathophysiology

The pathophysiology of pancreatitis by HTG is complex, and to this day not completely understood. It is known that TG in the microcirculation induces the release of pancreatic lipase, which cleave the molecules into free fatty acids (which are lipotoxic to pancreatic cells). These, in turn, lead to endothelial injury with capillary extravasation. TG also activate substances such as tramboxane, phospholipase A and prostaglandins that lead to vasoconstriction and pancreatic ischemia.

Triglycerides and free fatty acids also tend to group together in the form of micelles, which increases plasma viscosity and leads to gland ischemia.

Added to this we also have the imbalance in intracellular calcium, oxidative stress in organelles, which also precipitate the early activation of trypsin, still within the pancreas.

Diagnosis

The diagnosis of PA by HTG is given in the same way as other etiologies, with the Atlanta criteria, when 2 of the 3 criteria are present (upper abdominal pain, elevation of pancreatic enzymes > 3 the limit of the method and compatible imaging exam) associated with elevation of TG > 1,000 mg/dL.

Here it is important to remember that PAs originating from other causes (biliary, alcoholic and drug) can raise TG in the acute phase, but rarely at levels > 1000 mg/dL. This elevation is seen as an epiphenomenon.

As for severity, in studies conducted, it was observed that PA by HTG tends to be more severe compared to other etiologies. In meta-analyses and systematic reviews, it was observed that these patients evolved with higher severity scores, higher recurrence rates, more ICU admissions, and higher mortality.

Treatment

The initial treatment is based on support, as in any pancreatitis: hydration, analgesia and nutritional support (especially for severe PAs).

Among the specific approaches, the following stand out:

• Heparin pump: heparin can be used in monotherapy or associated with other modalities (such as the insulin pump). The anticoagulant initially increases the degradation of TG into free fatty acids. This effect, however, is temporary and hepatic consumption of plasma lipoprotein lipase causes a rebound increase in TG after discontinuation of the infusion. In addition, heparin infusion increases hemorrhagic events, especially in severe PAs with local complications.
• Insulin pump: continuous insulin infusion also increases the activation of lipoprotein lipase and decreases the release of free fatty acids by adipocytes and promotes the metabolism of these fatty acids by hormone-sensitive cells. It can be used in conjunction with heparin therapy, but the studies that evaluated the results are small. This modality has the potential to reduce TG levels by 50-75% in 3 days.
• Plasmapheresis: this therapy mechanically removes excess chylomicrons from the bloodstream. Similarly, it appears to reduce the levels of pro-inflammatory cytokines, which are determinants for severity in the initial phase of PA. However, the results regarding relevant outcomes (multiple organ dysfunction, mortality) did not favor plasmapheresis over supportive therapy. In addition, these patients had higher ICU admission rates (since it is a procedure performed in an intensive care unit), always need central catheter placement and may present an infusion reaction to plasma. It is a safe therapy to be performed in pregnant women.
• Hemofiltration: this is another controversial therapy, which tends to remove lipids and cytokines from plasma. Although it removes TG quickly and effectively, there was no difference in relevant clinical outcomes, in addition to having a high cost.

Follow-up

Patients who have already had PA by HTG need follow-up after discharge to reduce the risks of recurrence. The use of hypolipidemic agents (such as fibrates) is recommended as soon as the patient is already able to resume the diet orally, still in the hospital. The goal in outpatient treatment is to keep TG levels < 500 mg/dL.

Patients with primary HTGs should be followed by specialists in the lipid area.

In summary, HTG is a relevant cause of PA, especially in patients with primary hypertriglyceridemias. Triglyceride dosage should be done in the first few hours, as levels tend to drop significantly with fasting. The therapeutic approach is similar to that of other pancreatitis, and specific therapies can be associated for short-term TG reduction. Patients should always be referred for follow-up post discharge, to reduce the risk of a new event.

References

1. Yang, AL & McNabb-Blatar, J. Hypertriglyceridemia and acute pancreatitis. Pancreatology 20 (2020) 795-800
2. Qiu, M et al. Comprehensive review on the pathogenesis of hypertriglyceridaemia associated acute pancreatitis. Annals of Medicine 2023, VOL. 55, No. 2, 2265939
3. de Pretis, N et al. Hypertriglyceridemic pancreatitis: Epidemiology, pathophysiology and clinical management. United European Gastroenterology Journal 2018, Vol. 6(5) 649–655
4. Bálint, ER et al. Assessment of the course of acute pancreatitis in the light of aetiology: a systematic review and meta?analysis. Sci Rep 2020 Oct 21;10(1):17936.

How to cite this article

Marzinotto M. Acute Pancreatitis by Hypertriglyceridemia Gastropedia 2024, vol 1. Available at: gastropedia.com.br/gastroenterology/pancreas/acute-pancreatitis-by-hypertriglyceridemia/

The term chronic pancreatitis (CP) is used to define a fibro-inflammatory disease of the pancreas, of a progressive and irreversible nature, which can present with abdominal pain as a symptom and loss of the exocrine and endocrine functions of the gland.

Causes of chronic pancreatitis

What is currently being discussed in the literature are the possible causes for this pathology. Alcohol is already well established as the main environmental risk factor for the onset of CP (42-77% of cases). Patients considered moderate or severe drinkers (35-48 drinks per week) have a relative risk of 2.7 to 3.3 for the development of the disease in a Danish observational study.

Another environmental risk factor is smoking, which is very prevalent in patients with CP, and is currently considered an independent risk factor for the onset of the pathology. It is a potent risk factor, including, for cases of recurrent acute pancreatitis, which sometimes culminate in the appearance of CP. In the case of smoking, the relative risk is 1.93 for current smokers compared to people who have never smoked.

Other causes of CP include autoimmune etiologies (both type I autoimmune pancreatitis – IgG4-related disease – and type II autoimmune pancreatitis are considered etiologies of chronic pancreatitis), obstructive etiologies (as in cases of neoplasms, cysts, scarring stenoses of the main pancreatic duct, oddi sphincter dysfunctions and pancreas divisum), Recurrent Acute Pancreatitis (RAP) and genetic etiologies.

Even after genetic study, about 10-15% of CPs still remain idiopathic, suggesting that there is much unknown in this field.

Pancreatic genetics and risk of neoplasia

The genetics of pancreatic pathologies is extremely complex, with several genes possibly involved in the phenotypes presented. Many mutations can lead to a RAP picture, which culminates with gland fibrosis, and other mutations or polymorphisms that lead directly to the appearance of CP.

The main genes involved in the pathogenesis of CP are listed below:

• PRRS-1: cationic trypsinogen gene – autosomal dominant inheritance mutation, responsible for Hereditary Chronic Pancreatitis.
• SPINK-1: gene that, in the absence of pathogenic mutations, prevents the activation of trypsinogen.
• CFTR: gene that encodes the chloride channels in the membrane of ductal cells – mutations in this gene can result in the phenotypes of Cystic Fibrosis
• CTRC: gene that promotes the degradation of trypsinogen and that mutated loses this protection mechanism

There are several other genes listed as coadjuvants in the pathological processes of the pancreas, and probably others that we are not yet aware of. The fact is that, in pancreatitis associated with one or more genetic mutations, the risk of Ductal Adenocarcinoma of the Pancreas is higher than other pancreatitis and much higher than the population risk. Patients with PRRS-1 and SPINK-1 mutations have a cumulative risk of 53% of pancreatic neoplasia at 75 years of age, while alcoholic CPs have this same calculated risk of 4%.

However, it was observed that this risk may be even higher in smoking patients. Cigarette smoking is the main risk factor for pancreatic neoplasia not associated with CP, and when the risks of mutated genes are added to smoking

Other mutations (such as CFTR and CTRC) do not seem to contribute to a significant increase in the incidence of pancreatic cancer. Just as other causes of CP, such as autoimmune pancreatitis or rarer causes, also do not confer a significant additional risk of neoplasia.

Although there is a higher incidence of ductal adenocarcinoma of the pancreas in the population with CP, there are no studies suggesting an efficient screening strategy for all patients. For patients with PRSS-1 mutations (or with suspicion of the mutation, in cases with more than two family members affected by CP) the international group recommends annual screening with imaging examination (computed tomography or magnetic resonance imaging). The use of echoendoscopy was not recommended, as it can be falsified by inflammation, fibrosis or calcifications. More studies are needed for recommendations regarding other mutations and other etiologies.

Despite recent advances, there is still a vast unknown field regarding the etiology and risk factors for CP, and more studies are needed so that we can unravel all the mysteries about this topic.

References

1. Singh, VK et al. Diagnosis and Management of Chronic Pancreatitis A Review. JAMA. 2019;322(24):2422-2434.
2. Hart, PA et al. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 January ; 115(1): 49–55.
3. Aune, D et al. Tobacco smoking and the risk of pancreatitis: a systematic review and meta-analysis of prospective studies. Pancreatology, 2019 Dec;19(8):1009-1022.
4. Gardner, TB et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol 2020;115:322–339.
5. Le Cosquer, G et al. Pancreatic Cancer in Chronic Pancreatitis: Pathogenesis and Diagnostic Approach. Cancers 2023, 15, 761.
6. Greenhalf, G et al. International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club. Pancreatology 2020, 20, 910-918

How to cite this article

Marzinotto M. Chronic Pancreatitis – main etiologies and associated risk of Pancreatic Neoplasia Gastropedia 2023, vol 2. Available at: gastropedia.com.br/gastroenterologia/pancreatite-cronica-principais-etiologias-e-risco-associado-de-neoplasia-pancreatica/

Portal hypertension is the most common complication of liver cirrhosis and is considered the key point for the triggering of ascites, encephalopathy and esophageal varices and, in this way, it is considered a milestone for decision making, with its diagnosis being fundamental in the follow-up of cirrhotic patients.

How can we diagnose portal hypertension?

The gold standard for defining portal hypertension is the measurement of the hepatic venous pressure gradient (HPVG). Values above 5mmHG define portal hypertension. When this gradient exceeds 10mmHg, we consider that portal hypertension is clinically significant (HPCS), with the patient prone to the appearance of decompensations. The presence of esophageal varices in patients diagnosed with cirrhosis also implies the presence of clinically significant portal hypertension regardless of the venous gradient measurement.

As the measurement of the hepatic venous pressure gradient is not a routine practice, in addition to being an invasive examination, it is admitted that, liver stiffness values ? 25 kPa obtained through transient hepatic elastography, are defining of HPCS, with specificity and positive predictive value > 90%. As it is a non-invasive examination, capable of providing such information, transient hepatic elastography has been increasingly used in the follow-up of compensated cirrhotic patients in order to provide data so that the pharmacological treatment of portal hypertension can be instituted early, without the need for serial endoscopies or even the measurement of the hepatic venous pressure gradient.

And what is the role of beta-blockers in the treatment of patients with liver cirrhosis?

Non-selective beta-blockers (propranolol, nadolol and carvedilol), have been used routinely, with proven benefits in the primary prophylaxis of bleeding from risk varices and as an adjunct in the secondary prophylaxis of varicose bleeding.

Patients at high risk for bleeding are those with thin-caliber esophageal varices with red color signs, medium and large caliber varices, gastric varices and decompensated patients in ascites with varices of any size.

Carvedilol is a non-selective beta-blocker, with alpha-1 blocking activity and appears to be more effective than traditional beta-blockers in reducing portal hypertension, having been recommended in the last Baveno VII consensus, as the beta-blocker of choice in the treatment of portal hypertension. Its currently recommended dose is 12.5mg/day, divided into two doses and patients should be monitored for their main adverse effects such as asthenia, dyspnea and low blood pressure (SBP< 90mmHG).

The PREDESCI study showed that the use of beta-blockers, especially carvedilol, in cirrhotic patients with clinically significant portal hypertension (HPVG> 10mmHG) reduced the chance of decompensation in ascites by up to 40% in a subgroup of patients with thin-caliber varices without red color signs, implying an improvement in survival.

The use of beta-blockers in patients with portal hypertension without varices has no clearly proven benefits. Pre-primary prophylaxis, that is, the use of this medication in compensated cirrhotic patients, did not show benefit in the appearance of varices, however, the use in patients with HPCS, even in the absence of varices, has been an increasingly routine practice, suggested in the latest consensuses, with the aim of reducing long-term decompensation.

In summary…

In patients diagnosed with liver cirrhosis, the use of beta-blockers, preferably carvedilol, is indicated in:

• patients without ascites with thin-caliber esophageal varices without red color signs – for prevention of decompensation in ascites;
• decompensated patients in ascites with thin-caliber esophageal varices without red color signs – for primary prophylaxis of bleeding;
• thin-caliber varices with red color signs, medium and large caliber varices and gastric varices– as primary prophylaxis;
• thin-caliber varices with red color signs, medium and large caliber varices and gastric varices – as secondary prophylaxis associated with elastic ligation;
• recurrent bleeding from portal hypertensive gastropathy;
• patients with clinically significant portal hypertension ( LMS ? 25 kPa).

References

1. Turco L, Reiberger T, Vitale G, La Mura V. Carvedilol as the new non-selective beta-blocker of choice in patients with cirrhosis and portal hypertension. Liver Int. 2023 Jun;43(6):1183-1194. doi: 10.1111/liv.15559. Epub 2023 Apr 17. PMID: 36897563.
2. Wong YJ, Zhaojin C, Tosetti G, Degasperi E, Sharma S, Agarwal S, Chuan L, Huak CY, Jia L, Xiaolong Q, Saraya A, Primignani M. Baveno-VII criteria to predict decompensation and initiate non-selective beta-blocker in compensated advanced chronic liver disease patients. Clin Mol Hepatol. 2023 Jan;29(1):135-145. doi: 10.3350/cmh.2022.0181. Epub 2022 Sep 5. PMID: 36064306; PMCID: PMC9845679.
3. Gralnek IM, Camus Duboc M, Garcia-Pagan JC, Fuccio L, Karstensen JG, Hucl T, Jovanovic I, Awadie H, Hernandez-Gea V, Tantau M, Ebigbo A, Ibrahim M, Vlachogiannakos J, Burgmans MC, Rosasco R, Triantafyllou K. Endoscopic diagnosis and management of esophagogastric variceal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2022 Nov;54(11):1094-1120. doi: 10.1055/a-1939-4887. Epub 2022 Sep 29. PMID: 36174643.
4. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-974. doi: 10.1016/j.jhep.2021.12.022. Epub 2021 Dec 30. Erratum in: J Hepatol. 2022 Apr 14;: PMID: 35120736.
5. Katarey D, Jalan R. Non-selective beta blockers in cirrhosis: time to extend the indications? Ann Transl Med. 2019 Dec;7(Suppl 8):S355. doi: 10.21037/atm.2019.09.56. PMID: 32016073; PMCID: PMC6976476.
6. Villanueva C, Albillos A, Genescà J, Garcia-Pagan JC, Calleja JL, Aracil C, Bañares R, Morillas RM, Poca M, Peñas B, Augustin S, Abraldes JG, Alvarado E, Torres F, Bosch J. ? blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2019 Apr 20;393(10181):1597-1608. doi: 10.1016/S0140-6736(18)31875-0. Epub 2019 Mar 22. Erratum in: Lancet. 2019 Jun 22;393(10190):2492. PMID: 30910320.
7. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017 Jan;65(1):310-335. doi: 10.1002/hep.28906. Epub 2016 Dec 1. Erratum in: Hepatology. 2017 Jul;66(1):304. PMID: 27786365

How to cite this article

Ramos JSD, When is the use of beta-blockers recommended in patients with liver cirrhosis? Gastropedia 2023 Vol 2. Available at: gastropedia.com.br/gastroenterology/when-is-the-use-of-beta-blockers-recommended-in-patients-with-liver-cirrhosis/

Patients with a IBD (Inflammatory Bowel Disease) moderate to severe phenotype and/or with risk factors for a worse prognosis, once elected for advanced therapy with biologics, should undergo preparation for the start of treatment safely.

This stage involves the evaluation of 3 pillars:

• Check if there is a relative or absolute contraindication to the use of such medications;
• Screening for active or latent infections;
• Updating vaccination status

Regarding contraindications or signs of greater attention to the use of biologics, we have:

• Severe ongoing infection, including perianal abscess;
• Untreated latent tuberculosis (a period from the start of treatment should be awaited to start the biologic, preferably a non-anti-TNF);
• Decompensated CHF or EF ? 35% (absolute contraindication to anti-TNF);
• History of severe previous infusion reaction to biologics;
• Multiple sclerosis or other demyelinating diseases; optic neuritis; previous lymphoma (in these conditions anti-TNF has an absolute contraindication, the others weigh risk x benefit);
• Current malignancy;
• Decompensated liver disease (cirrhosis Child B or C);
• Untreated chronic infection by the hepatitis B virus;
• Uncontrolled HIV infection;
• History of melanoma (absolute contraindication to anti-TNF) or recurrent cervical dysplasia (relative contraindication to anti-TNF)

The next step is to carry out the infectious screening, which includes:

• Chest X-ray;
• PPD and/or IGRA (interferon gamma release test);
• Serologies for hepatitis B, C and HIV (also consider adding screening for measles, CMV, varicella zoster and Epstein-Barr – note that primary EBV infection in immunosuppressed patients increases the risk of lymphoproliferative diseases, in this scenario caution should be exercised when prescribing associated thiopurines);
• In the presence of diarrhea, exclude the presence of Clostridium difficile as a mimicking agent;
• In the female population, colpocytology is also recommended for HPV infection screening.

The screening for latent TB should be renewed annually while the patient is using the biologic, especially if it is of the anti-TNF class, as we know how much TNF-alpha is crucial for granuloma stability.

In the case of patients with PPD ? 5mm, or IGRA + or sequelae on chest X-ray suggestive, first the treatment of latent TB should be started and only start the biologic after 30 days from the start of treatment.

Patients with HBsAg + or with isolated anti-HBc + should receive antiviral therapy during the use of biologics or oral immunosuppressants. In the first case, the treatment time will be guided by liver disease. In the second case (hidden infection), for at least 6 months after the end of treatment (if applicable).

Vaccination status

Regarding the vaccination schedule, inactivated vaccines are extremely safe and indicated for all patients with IBD, and ideally should be administered at least 2 weeks before the biologic, so as not to compromise the vaccine response. The attenuated vaccines are contraindicated for patients who are already using immunosuppressants or biologics, or who are planning to start such medications in the next 4 to 6 weeks. They can only use attenuated vaccines after 3 months of suspension of such medications (if applicable).

The inactivated vaccines to be considered in patients with IBD are: Influenza, Pneumococcal, Tetanus/Diphtheria (Adult Double), Meningococcal, Hepatitis A, Hepatitis B (including possibly making 4 double doses aiming for anti-HBs >10), HPV, COVID-19. Recently, the recombinant inactivated herpes zoster vaccine was also launched, allowing use to patients in immunosuppression or planning to start biologics, unlike the vaccine available until then which was attenuated virus.

Reinforcing, the attenuated vaccines that should not be done in the scenario of immunosuppressed patients are: MMR (measles, mumps and rubella), varicella, yellow fever and the older version of the herpes zoster vaccine composed of live attenuated virus.

References:

1. T. Kucharzik et al. ECCO Guidelines on the Prevention, Diagnosis, and Management of Infections in Inflammatory Bowel Disease. Journal of Crohn’s and Colitis, 2021, 879–913
2. Chebli JMF et al. Preparing Patients With Inflammatory Bowel Diseases For Biological Therapies In Clinical Practice. Journal of Gastroenterology and Hepatology Research 2018; 7(2): 2535-2554
3. Beaugerie et al. Predicting, Preventing, and Managing Treatment-Related Complications in Patients With Inflammatory Bowel Diseases. Clinical Gastroenterology and Hepatology 2020;18:1324–1335
4. S. Riestra et al. Recommendations of the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) on screening and treatment of tuberculosis infection in patients with inflammatory bowel disease. Gastroenterología y Hepatología 44 2021 51—66
5. R. Ferreiro-Iglesias et al. Recommendations of the Spanish Group on Crohn’s Disease and Ulcerative Colitis on the importance, screening and vaccination in inflammatory bowel disease patients. Gastroenterología y Hepatología 45 (2022) 805—818

How to cite this article

Vilela PBM, Check-list to start biological therapy in IBD Gastropedia 2023, Vol 2. Available at: gastropedia.com.br/sem-categoria/check-list-para-iniciar-terapia-biologica-na-dii/

When we think of Exocrine Pancreatic Insufficiency – EPI (decrease in the activity of pancreatic enzymes in the intestinal lumen, below the values for normal digestion) we automatically relate it to primary pancreas problems, such as chronic pancreatitis or pancreatic neoplasia. And that’s correct, these pathologies are indeed a cause of EPI. However, we have several other causes that should be remembered by the gastroenterologist.

To understand correctly, let’s turn to pancreatic physiology. The production of digestive enzymes by the pancreas is not only dependent on the morphology of the gland. Initially, the pancreas is stimulated by neural pathways derived from the vagus nerve, and later has its main stimulation pathway through the passage of chyme through the duodenum. At this stage, the release of secretin and cholecystokinin (CCK) is responsible for about 70% of all pancreatic juice production for that meal. Therefore, it is correct to say that any failure in this circuit can be the cause of EPI.

Today we classify the etiologies of EPI as pancreatic and extra-pancreatic causes:

Among the pancreatic causes, we have:

• Chronic pancreatitis
• Pancreatic neoplasms
• Cystic Fibrosis
• Pancreatic Resections
• Hemochromatosis
• Severe acute pancreatitis, with extensive necrosis of the glandular parenchyma

And among the extra-pancreatic causes, we can list:

• Celiac Disease
• Crohn’s disease of high small intestine involvement
• Type I and II Diabetes
• Pancreatic aging
• Gastroduodenal surgeries

Pancreatic causes are better known, and are caused by diseases that lead to progressive fibrosis of the pancreas, such as chronic pancreatitis; pancreatic atrophy combined with obstruction of the main pancreatic duct (such as neoplasms, especially of the cephalic region) and loss of pancreatic parenchyma, secondary to acute pancreatitis or pancreatic resections. In addition to these, cystic fibrosis is the main genetic cause and causes liposubstitution of the pancreatic parenchyma, as well as alteration in the transport of pancreatic juice through the ducts.

The most well-established non-pancreatic causes are: celiac disease (due to duodenal atrophy and loss of stimulation by duodenal hormones – secretin and CCK), diabetes mellitus and derivative surgeries.

In more recent studies, diabetes has been pointed out as a cause of EPI, both DM-1 and DM-2. The reasons for this are diverse and involve:

• Atrophy of the exocrine parenchyma due to lack of insulin: the hormone produced by pancreatic endocrine cells exerts a paracrine trophic action on acinar cells. The decrease in insulin causes a decrease in the trophism of the exocrine parenchyma.
• Diabetes can lead to autonomic neuropathy, impairing vagal pathways and the stimulation of acetylcholine on pancreatic cells.
• The microangiopathy that leads to a course of chronic ischemia in the gland, decreasing enzymatic production.
• The infiltration of adipocytes in the pancreas, in addition to lymphocytes, increases the action of fibroblasts and causes a greater deposition of collagen in the organ.

The frequency of EPI in diabetics is still uncertain, and it seems to be higher in patients with DM-1 (30-56%) and lower in patients with DM-2 (30-40%). Despite the heterogeneity of the studies, the prevalence of EPI in diabetic patients should not be underestimated.

In relation to upper abdomen surgical procedures, we observe an increasing frequency of EPI in gastrectomies, duodenopancreatectomies and derivative surgeries, such as gastrojejunal bypass.

• In partial or total gastrectomies we have studies showing 30-73% of EPI after 3 months of surgery.
• After duodenopancreatectomies this percentage can reach 100%, however the average post-procedure indicated by pancreatic or periampullary neoplasia was 74%.
• This percentage is higher than that found in duodenopancreatectomies for benign diseases (53%).
• There is a study that shows 16% of EPI post esophagectomy, although it has a small N.

Finally, the frequency of EPI post gastrojejunal bypass has been shown to be a concern in the follow-up of these patients. Especially after a few years of surgery, a percentage of these patients may present EPI. In a retrospective cohort, 20.6% of patients had steatorrhea, but only 10.3% of them were diagnosed with EPI post bypass with Y-Roux reconstruction. However, despite the frequency not being high, the treatment of patients diagnosed with EPI is crucial for satisfactory nutritional evolution.

As we can see, the causes of Exocrine Pancreatic Insufficiency go beyond structural problems in the gland. It is imperative that the gastroenterologist remember EPI in the contexts presented above, and that he does not miss the opportunity for correct treatment of these patients.

References

1. Vikesh K Singh, Mark E Haupt, David E Geller, Jerry A Hall, Pedro M Quintana Diez. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol 2017 October 21; 23(39): 7059-7076
2. Martha Campbell-Thompson, Teresa Rodriguez-Calvo, and Manuela Battaglia. Abnormalities of the Exocrine Pancreas in Type 1 Diabetes. Curr Diab Rep. 2015 October ; 15(10): 79.
3. J. R. Huddy, F. M. S. Macharg, A. M. Lawn, S. R. Preston. Exocrine pancreatic insufficiency following esophagectomy. Diseases of the Esophagus (2013) 26, 594–597
4. Miroslav Vujasinovic, Roberto Valente, Anders Thorell, Wiktor Rutkowski, Stephan L. Haas, Urban Arnelo, Lena Martin and J.-Matthias Löhr. Pancreatic Exocrine Insufficiency after Bariatric Surgery. Nutrients 2017, 9, 1241;
5. Joshua Y Kwon , Alfred Nelson , Ahmed Salih , Jose Valery, Dana M Harris, Fernando Stancampiano , Yan Bi. Exocrine pancreatic insufficiency after bariatric surgery. Pancreatology, 2022 Nov;22(7):1041-1045.

How to cite this article

Marzinotto M. Exocrine Pancreatic Insufficiency: a look beyond the obvious. Gastropedia 2023, vol 1. Available at: https://gastropedia.com.br/sem-categoria/insuficiencia-pancreatica-exocrina-um-olhar-alem-do-obvio

It is well known that serology is an important tool in the diagnosis of Celiac Disease (CD), but the best way to use it is still a recurring doubt in the outpatient routine.

Each patient must be well evaluated before defining the best strategy. In patients with low probability of CD, for example, it is not recommended to combine several autoantibodies. Although this conduct increases sensitivity, it decreases specificity for diagnosis and, for this reason, it is not a good option in this group of patients.

On the other hand, when we are facing a patient with a high probability of the disease, even if the autoantibodies are negative, the investigation should continue with the performance of duodenal biopsies.

If you still do not know the pathophysiology of Celiac Disease, it is worth checking out this post (click here) before studying the related autoantibodies.

Autoantibodies in Celiac Disease

The antigliadin antibody has been used for decades in the diagnosis of CD, but its utility is quite limited today due to its low performance compared to other available tests.

The tissue transglutaminase IgA (anti-tTG IgA) is the first-line autoantibody because it has the highest sensitivity and is widely available. The higher its title, the greater the chance of CD and the greater the duodenal lesion. Titles greater than 5 times the upper limit of normal (ULN) have a high positive predictive value.

Due to the possible association of celiac disease with IgA deficiency, the collection of anti-tTG IgA should preferably be associated with the dosage of total IgA (especially in patients with a high probability of the disease). Another option is to associate the research of an IgG class autoantibody.

The deaminated gliadin or deaminated is an autoantibody against gliadin that came into contact with the tissue transglutaminase enzyme and underwent the process of deamination (release of its amine group). The association of anti-tTG IgA with deaminated gliadin IgG has shown the best performance (sensitivity and specificity) for the diagnosis of CD, but the research of this autoantibody is more expensive and little available in our environment currently. Thus, a good option is the association with anti-transglutaminase IgG, for example.

The anti-endomysium IgA antibody is the antibody with the best specificity (approximately 100%) and therefore has an important role in diagnostic confirmation (especially in patients with anti-tTG IgA with titles less than 2 times the ULN).

Performance of serological tests

The performance of serological tests in clinical practice is worse than in many of the major trials, as studies are usually conducted in a population with a high prevalence of CD. In addition, it is also important to remember that performance depends on the maintenance of a gluten diet. About 80% of patients negate autoantibodies in 6 to 12 months and more than 90% in 5 years. Weakly positive patients may negate their autoantibodies within a few weeks of dieting. It is rare that these autoantibodies do not normalize in the long term with a gluten-free diet. If this happens, it is necessary to rule out that gluten consumption is not happening unconsciously.

In the last decade, many studies have been conducted with POCTs (point-of-care tests). These are quick tests that can be used both in the endoscopy sector and in the office. A meta-analysis published in 2019 found sensitivity and specificity of 94 and 94.4% respectively, considering histology as the gold standard. Despite these results showing high sensitivity and specificity, due to the great variety of work done and conflicting results, more studies are still suggested before using them in clinical practice. For now, the use of POCTs should still be reserved for places with limited access to laboratories.

Studies are also being conducted with research of autoantibodies in saliva for screening in children suspected of CD. Despite the favorable results, showing a non-invasive, cheap and reproducible option, the evidence so far is not sufficient to recommend its use.

On the other hand, the detection of autoantibodies in feces does not seem to be useful in disease screening, with work showing a sensitivity of only 10%.

Given that autoantibodies in CD are produced in the small intestine itself, work is being done with research of autoantibodies in the supernatant of the duodenal biopsy. This research seems to have its importance mainly in the diagnosis of patients in the early stages of the disease, when serum autoantibodies may still be negative. But more studies are still needed to confirm its role in clinical practice.

Conclusion

Autoantibodies are extremely relevant exams for the diagnosis of CD. However, there is no single algorithm to define which autoantibody to request. In addition to knowing the sensitivity and specificity of each of them, it is necessary to evaluate the pre-test probability of the disease in each patient and the accessibility to the different available exams to define the best strategy.

References

1. Green P, Stavropoulos S, Panagi SG, Goldstein S. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol 2001;96:126– 131.
2. Sanders DS. Changing face of adult coeliac disease: experience of a single university hospital in South Yorkshire. Postgrad Med J 2002;78(915):31–33.
3. Al-Toma A , Volta U, Auricchio R, Castillejo G, Sanders D, Cellier C, Mulder C, Lundin K. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J . 2019;7(5):583-613.
4. Singh P, Arora A, Strand T, Leffler D, Mäki M, Kelly C, Ahuja V, Makharia G. Diagnostic Accuracy of Point of Care Tests for Diagnosing Celiac Disease: A Systematic Review and Meta-Analysis. J Clin Gastroenterol 2019;53(7):535-542.
5. De Leo L, Bramuzzo M, Ziberna F, Villanacci V, Martelossi S, Di Leo G, Zanchi C, Giudici F, Pandullo M, Riznik P, Di Mascio A, Ventura A, Not T. Diagnostic accuracy and applicability of intestinal auto-antibodies in the wide clinical spectrum of coeliac disease. EBioMedicine . 2020 Jan;51:102567

How to cite this article

Vilela E. The role of autoantibodies in the diagnosis of celiac disease. Gastropedia 2023, Vol 1. Available at: https://gastropedia.com.br/gastroenterology/the-role-of-autoantibodies-in-the-diagnosis-of-celiac-disease

Infection with H. pylori and the use of non-steroidal anti-inflammatory drugs (NSAIDs) are widely accepted as the main causes of peptic ulcer. However, with more effective eradication, better sanitary conditions and widespread use of antibiotics, the prevalence of H. pylori is falling and, consequently, there is an increase in the diagnosis of non-H. pylori ulcers.

The proportion of non-H. pylori and non-NSAID/aspirin ulcers varies quite a bit (from 2 to 35%) according to the time, country and methodology of different studies:

• A multicenter prospective French study published a decade ago included 713 patients and concluded that 1 in 5 ulcers was not related to either H. pylori or the use of NSAIDs/aspirin.
• A retrospective Brazilian study published in 2015 (De Carli, DM et al), in turn, identified that, from 1997 to 2000, 73.3% of peptic ulcers were due to positive H. pylori, 3.5% due to NSAIDs, 12.8% due to H. pylori + NSAIDs and 10.4% idiopathic, while, from 2007 to 2010, this proportion became, respectively, 46.4%, 13.3%, 19.9% and 20.5%.

But what would be the other possible etiologies for gastric and duodenal ulcers?

Table 1: Possible etiologies for gastric and duodenal ulcers not associated with Helicobacter pylori and the use of NSAID

How to investigate, then, the etiology of the ulcer?

1. Confirm that there really is no H. pylori:

it is necessary to make sure that H. pylori was properly researched. It is considered that the main cause of negative H. pylori ulcer is actually the error in detecting the microorganism. We should check:

• Was the exam performed in the context of bleeding? If so, it is ideal to repeat. Hemorrhagic peptic ulcer can produce up to 25% false negative results in the urease test;
• Did the patient stop PPI and antibiotics before endoscopy? For practical purposes, diagnostic tests for H. pylori should be delayed for 4 weeks after the use of antibiotics, bismuth preparations, PPI and H2 blockers.
• What method used for research? If possible, it is interesting to perform at least two simultaneous tests to increase sensitivity. Histological research should include at least two biopsies of antrum and body.

2. Confirm that the patient really did not use NSAIDs:

Often, the patient forgets that they may have used or does not associate the class with the medication. It is important to actively ask for the medications (name them) and if they did not use treatments, for example, for headache, arthralgia, dental treatment or menstrual cramps. Chinese herbal medicines, compounded medications and alternative therapy products may contain anti-inflammatory compounds, which are not recognized by patients. Also check for the use of ASA, even at low doses.

If we really do not confirm that H. pylori was negative and that there is no report of NSAIDs, we should reinforce some important points in the clinical history:

• Use of other medications;
• Use of drugs;
• History of immunosuppression;
• History of gastric surgeries or radiation;
• History of comorbidities, such as Crohn’s Disease, sarcoidosis, systemic mastocytosis, MEN 1 (multifocal primary hyperparathyroidism, pancreatic islet tumors and pituitary adenomas)
• Associated symptoms, mainly diarrhea (which can be associated with Crohn’s Disease, Zollinger-Ellison Syndrome or systemic mastocytosis);
• Family history of ulcer or MEN 1.

3. Ulcer biopsy

Although often unspecific, the biopsy of the ulcer (especially gastric) is fundamental for the investigation of less usual etiologies. Immunohistochemical analysis can bring important additional information.

Additional complementary exams should be performed according to clinical suspicion, such as:
– Serum gastrin: If suspicion of Zollinger-Ellison;
– PTH and calcium: Investigation of hyperparathyroidism;
– VDRL: If suspicion of infectious ulcer;
– Serum tryptase: Can assist in the suspicion of systemic mastocytosis.

In patients with an ulcer without a well-established etiology, it is recommended to repeat endoscopy 8 to 12 weeks after treatment, with new biopsies if the ulcer is still present. It may also be interesting to biopsy the duodenum to detect isolated duodenal colonization of HP.

Conclusion

False negative test for H. pylori and failure to detect NSAID use are probably the most common causes of ulcers that apparently have no defined etiology. Once these possibilities are excluded, we should focus on a detailed anamnesis and a careful evaluation of the anatomopathological.

References

1. Chung CS, Chiang TH, Lee YC. A systematic approach for the diagnosis and treatment of idiopathic peptic ulcers. Korean J Intern Med 2015;30:559–70. doi:10.3904/kjim.2015.30.5.559.
2. Kim HU. Diagnostic and treatment approaches for refractory peptic ulcers. Clin Endosc 2015;48:285–90. doi:10.5946/ce.2015.48.4.285.
3. Charpignon C, Lesgourgues B, Pariente A, Nahon S, Pelaquier A, Gatineau-Sailliant G, et al. Peptic ulcer disease: One in five is related to neither Helicobacter pylori nor aspirin/NSAID intake. Aliment Pharmacol Ther 2013;38:946–54. doi:10.1111/apt.12465.
4. de Carli DM, Pires RC, Rohde SL, Kavalco CM, Fagundes RB. Different frequencies of peptic ulcer related to H. pylori or NSAIDs. Arq Gastroenterol 2015;52:46–9. doi:10.1590/S0004-28032015000100010.
5. Lanas A, Chan FKL. Peptic ulcer disease. Lancet 2017;390:613–24. doi:10.1016/S0140-6736(16)32404-7.

How to cite this article

Lages RB. Ulcers not related to Helicobacter pylori and anti-inflammatory drugs (NSAIDs): how to proceed? Gastropedia 2023, Vol 1. Available at: https://gastropedia.com.br/gastroenterology/ulcers-not-related-to-helicobacter-pylori-and-anti-inflammatory-drugs-nsaids-how-to-proceed/

Celiac disease is an autoimmune disease caused by an abnormal immune response to gluten peptides in the upper small intestine. It is important to understand its pathophysiology to know how to interpret the serological tests that assist in the diagnosis of celiac disease.

Gluten is a protein found in wheat, barley, and rye. In the small intestine, gluten is digested and breaks down into gliadin.

In celiac disease, gliadin manages to cross the epithelial barrier in the small intestine and reach the underlying lamina propria. The cause of gliadin epithelial permeability is uncertain, but it may be due to an underlying pathological process (for example, infection) or changes in intercellular junctions (tight junctions).

Immune response in the mucosa

When gliadin comes into contact with the lamina propria, it is deaminated by tissue transglutaminase (TTG). The deaminated gliadin then reacts with HLA-DQ2 or HLA-DQ8 receptors on antigen-presenting cells that stimulate the activation of T and B cells, leading to the release of cytokines, antibody production, and lymphocyte infiltration. Over time, inflammation causes villous atrophy, crypt hyperplasia in epithelial cells, and intraepithelial lymphocytosis.

Genetic Factors

The familial occurrence of celiac disease suggests that there is a genetic influence in its pathogenesis. Celiac disease does not develop unless a person has alleles that encode for the HLA-DQ2 or HLA-DQ8 proteins, products of two of the HLA genes.

However, many people, most of whom do not have celiac disease, carry these alleles; therefore, their presence is necessary, but not sufficient for the development of the disease.

Studies in siblings and identical twins suggest that the contribution of HLA genes to the genetic component of celiac disease is less than 50%.14 Several non-HLA genes that may influence susceptibility to the disease have been identified, but their influence has not been confirmed.

Environmental Factors

Epidemiological studies have suggested that environmental factors play an important role in the development of celiac disease. These include a protective effect of breastfeeding and the introduction of gluten in relation to weaning. Initial administration of gluten before 4 months of age is associated with an increased risk of developing the disease, and the introduction of gluten after 7 months is associated with a marginal risk. However, the overlap of gluten introduction with breastfeeding may be a more important protective factor in minimizing the risk of celiac disease.

The occurrence of certain gastrointestinal infections, such as rotavirus infection, also increases the risk of celiac disease in childhood.

Now understand how the research of autoantibodies can help in the diagnosis of celiac disease: The role of autoantibodies in the diagnosis of celiac disease

References

1. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007 Oct 25;357(17):1731-43. doi: 10.1056/NEJMra071600. PMID: 17960014.
2. Kaminarskaya Yu?. Celiac disease, wheat allergy, and nonceliac sensitivity to gluten: topical issues of the pathogenesis and diagnosis of gluten-associated diseases. Clinical nutrition and metabolism. 2021;2(3):113–124.

How to Cite this article

Martins BC. Pathogenesis of Celiac Disease. Gastropedia, 2023, vol I. Available at: https://gastropedia.com.br/gastroenterology/intestine/pathogenesis-of-celiac-disease

A topic that has been gaining attention from pancreas scholars lately is pancreatic steatosis. This is a generic term that infers the accumulation of fat in the pancreas. However, there are 2 main mechanisms to justify pancreatic steatosis:

• The first is called “fatty replacement”, that is, the replacement of pancreatic cells by adipocytes after the death of acinar cells. This occurs in genetic and congenital syndromes, such as Cystic Fibrosis, Shwachman-Diamond and Johanson-Blizzard, in addition to alcohol abuse, use of some medications (such as corticosteroids, gencitabine, octreotide and rosiglitazone), viral infections, malnutrition and post necrotizing acute pancreatitis (the area of necrosis is often replaced by adipocytes).
• The second mechanism is fatty infiltration (or “fatty infiltration”), in which adipocytes accumulate in the gland, without loss of acinar cells. Unlike what happens with liver fat, which is intracellular, pancreatic fat accumulates in the interlobular region, both of the exocrine parenchyma and of the islets of endocrine parenchyma. This mechanism is most associated with obesity, DM-2 and with Metabolic Syndrome.

Epidemiology

Data on the incidence and prevalence of pancreatic steatosis are still scarce, especially in the west. In the east, 16-35% of people have this finding on imaging exams. In individuals undergoing endoscopic ultrasound, the finding of pancreatic steatosis was in 27% of patients.

In a meta-analysis conducted by Singh and collaborators of 11 studies with 12,675 patients, the global prevalence was 33%. These patients had a 67% higher risk of hypertension, a 108% higher risk of diabetes and a 137% higher risk of Metabolic Syndrome.

Obesity proved to be the main risk factor for the finding of pancreatic steatosis. And some studies also related the finding of non-alcoholic fatty liver disease (NAFLD) with pancreatic steatosis, although the accumulation of pancreatic fat precedes the appearance of liver fat.

Diagnosis

The definitive diagnosis of pancreatic steatosis is with histological analysis, however it is rare to have pancreatic biopsies in the context of benign diseases. Therefore, it is necessary to use non-invasive imaging exams, such as:

• Trans-abdominal ultrasound: it is a very available exam that does not use radiation or contrast. However, being the pancreas a retro-peritoneal organ, the evaluation of the gland is impaired by gas interposition and by the patient’s own biotype. The ultrasonographic characteristic is of a hyperechoic pancreas, compared to the hepatic and splenic parenchyma.
• Endoscopic ultrasound: the most used method for diagnosis and grading of pancreatic steatosis (which can vary from I to IV, with types I and II considered normal pancreas, and types III and IV considered steatotic pancreas). The grading is done in comparison with the spleen parenchyma. However, there is still little inter-observer agreement, and multicenter studies with a larger number of participants are needed for this grading to be validated.
• Abdominal tomography: in abdominal tomography without contrast, we can observe a hypoattenuating pancreas in relation to the splenic parenchyma. There is a good correlation between tomographic attenuation indices and histology. In the study without contrast, however, the diagnosis of pancreatic masses that can also present as hypoattenuating may be missed.
• Magnetic resonance imaging: a safe and effective method in diagnosing pancreatic steatosis, as it has greater accuracy for evaluating soft parts. More studies are needed, however, to determine the “normal” amount of fat in healthy individuals

Clinical impact

Some situations related to pancreatic steatosis are being raised in the most recent studies. There are still many doubts about the real clinical impact of this finding, but what we have positive so far is:

• Relationship of pancreatic steatosis with obesity: there is a correlation of pancreatic steatosis and obesity, as well as a reduction of steatosis with weight loss. In individuals undergoing bariatric surgery (by-pass or vertical gastrectomy) there was a significant decrease in pancreatic fat, regardless of weight loss or control of comorbidities (such as diabetes, for example).
• Relationship of pancreatic steatosis with Diabetes mellitus: in diabetic individuals, the finding of pancreatic steatosis is common, and increases with the duration of the disease. However, there are doubts whether the presence of pancreatic steatosis can potentiate the dysfunction of pancreatic beta cells, and contribute to a worsening of glycemic control.
• Relationship of pancreatic steatosis and Non-alcoholic fatty liver disease (NAFLD): it seems that pancreatic steatosis precedes hepatic steatosis in patients with Metabolic Syndrome. Almost all individuals with NAFLD (97%) have concomitant pancreatic fat infiltration.
• Relationship of pancreatic steatosis and pancreatic cancer: it is known that obesity is considered a risk factor for pancreatic adenocarcinoma and, it seems, fatty infiltration in the pancreas plays a role in carcinogenesis, regardless of obesity. This finding is due to lipotoxicity and the release of substances resulting from oxidative stress, such as oxygen free radicals. In the fatty pancreas, the incidence of intraepithelial neoplasia (PanIN) and invasive ductal adenocarcinoma is higher. It is even suggested that patients with pancreatic steatosis would have a greater severity of the disease, with more lymph node metastases.

Other associations are not possible to be made at the moment, such as: association with acute pancreatitis, chronic pancreatitis or pancreatic fibrosis, exocrine pancreatic insufficiency or appearance of pancreatic fistula in the postoperative period. These relationships are still controversial, and require further studies.

References

1. Sepe, PS et al. A prospective evaluation of fatty pancreas by using EUS. Gastrointestinal Endoscopy, 2011. doi:10.1016/j.gie.2011.01.015
2. Majumder, S et al. Fatty Pancreas: Should We Be Concerned? Pancreas. 2017 ; 46(10): 1251–1258. doi:10.1097/MPA.0000000000000941.
3. Catanzaro, R et al. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease. World J Gastroenterol 2016 September 14; 22(34): 7660-7675. DOI: 10.3748/wjg.v22.i34.7660
4. Chang, ML. Fatty Pancreas-Centered Metabolic Basis of Pancreatic Adenocarcinoma: From Obesity, Diabetes and Pancreatitis to Oncogenesis. Biomedicines 2022, 10, 692. https://doi.org/10.3390/biomedicines10030692.

How to cite this article

Marzinotto, M. Pancreatic Steatosis – Where are we? Gastropedia 2021, vol. 1. Available at: https://gastropedia.com.br/gastroenterology/pancreas/pancreatic-steatosis-where-are-we

Risk factors commonly associated with the development of gastric cancer (GC) include chronic infection with Helicobacter pylori (H. pylori), low intake of fruits and vegetables, high salt consumption, smoking, and alcohol consumption.

Another known but rarely mentioned risk factor is the presence of Primary Immunodeficiencies (PID), which not only increase the risk of developing GC but also cause its manifestation at earlier ages than in the general population.

PIDs are a set of diseases that encompass more than 300 innate immunity defects, most of which are of unknown cause. PID carriers have an increased risk of recurrent and chronic infections, autoimmune diseases, and neoplasms throughout life.

Following infections, the occurrence of neoplasms is the second most common cause of death in this population. It is estimated that 4 to 25% of PID carriers will develop some neoplasm. Specifically, the risk of developing GC is around 3 to 4 times higher in this population.

Regarding patients with PID, the presence of gastrointestinal disorders is quite frequent, occurring in 5% to 50% of cases. This occurs, in part, because the intestine is the largest lymphoid organ in the human body, containing most of the lymphocytes and producing large amounts of Immunoglobulins. Gastrointestinal manifestations can be related to infection, inflammation, autoimmune diseases, and neoplasms.

Common Variable Immunodeficiency (CVID)

Common Variable Immunodeficiency (CVID) is the most common form of PID, and its prevalence is estimated at 1 in every 25,000 to 50,000 people.

Its pathogenesis has not yet been fully clarified, however mutations of various genes related to the development of B cells into immunoglobulin-producing plasma cells and memory B cells have been described.

Affected individuals commonly present with recurrent bacterial infections of the upper and lower respiratory tract, autoimmune diseases, granulomatous infiltrative disease, and neoplasms. The most common tumors are lymphoma, gastric cancer, and breast cancer.

The diagnosis is based on a significant reduction in serum levels of IgG, IgA and/or IgM, in addition to reduced antibody production after the application of vaccines. Most patients are diagnosed between the ages of 20 and 40, and treatment consists of monthly administration of immunoglobulin.

CVID and Gastric Cancer

The increased risk of GC in patients with CVID varies according to the incidence rate of GC in patients without CVID in the country evaluated. In this sense, a Scandinavian study estimated a 10-fold increased risk, while an Australian study showed a 7.23-fold increased risk.

Although there is no conclusive evidence, the most accepted mechanism for the increased risk of GC in the presence of CVID is due to the reduction in the production of gastric IgA and hydrochloric acid – factors that promote chronic gastritis and facilitate colonization by H. pylori, triggering the carcinogenesis process. This mechanism is supported by the finding that patients with pernicious anemia, who also have achlorhydria and chronic gastritis, have a three times higher risk of developing GC. The decrease in local immune response is also a factor that may play a role in neoplastic development, due to the lower presence of B cells in the gastric mucosa of patients with CVID.

The age of cancer diagnosis in patients with CVID usually occurs at an earlier age, on average 15 years earlier than in the general population.

In relation to the histological diagnosis of the tumor, the Intestinal type of Lauren is usually the most frequent, presenting moderate or poorly differentiated degree. In addition, atrophic pangastritis with little presence of plasma cells, nodular lymphoid aggregates, and apoptotic activity are usually present due to the associated autoimmune gastritis.

Given the evidence of a higher risk of developing GC, it is important that patients with CVID are included in screening programs. Dutch data showed that there is a high incidence of pre-malignant histological and/or endoscopic lesions in patients with CVID, such as atrophic gastritis, intestinal metaplasia, and dysplasia, even in those who are asymptomatic. Up to 88% of CVID patients with no previous gastrointestinal history may present pre-malignant lesions on endoscopy. The rates of progression of these lesions to GC vary from 0–1.8% per year in atrophic gastritis; from 0–10% per year for intestinal metaplasia; and from 0–73% per year when there is already presence of dysplasia.

Intervals between follow-up exams normally employed may not be appropriate for patients with CVID, as the development of GC may occur more quickly. Indeed, there is no standardized screening protocol, and its use should take into account the regional incidence of GC. Patients with CVID can develop high-grade cancer 12 to 14 months after an endoscopy without signs of dysplasia. This justifies the proposal to at least perform EGD in all patients with CVID at the time of diagnosis; repeat it every 24 months in patients with normal histology; every 12 months in patients with atrophic gastritis or intestinal metaplasia; and every 6 months in patients with dysplasia. Routine eradication of H. pylori is also recommended.

Treatment

There are no specific protocols for the treatment of cancer in patients with CVID. Once the diagnosis of GC is made, these patients should undergo standard treatment – the same offered to the immunocompetent population.

Preoperative nutritional support and administration of Immunoglobulin are recommended measures. Patients with CVID can receive the same chemotherapy protocols used in immunocompetent patients. However, short-duration protocols are preferable to long-duration regimes, with special attention to infection control. When possible, the chemotherapy regimen should be adapted according to individual risk factors and tolerance.

Reference

Krein P, Yogolare GG, Pereira MA, Grecco O, Barros MAMT, Dias AR, Marinho AKBB, Zilberstein B, Kokron CM, Ribeiro-Júnior U, Kalil J, Nahas SC, Ramos MFKP. Common variable immunodeficiency: an important but little-known risk factor for gastric cancer. Rev Col Bras Cir. 2021 Dec 15;48:e20213133. English, Portuguese. doi: 10.1590/0100-6991e-20213133. PMID: 34932733.

How to cite this article

Ramos MFKP. Common Variable Immunodeficiency and Gastric Cancer. Gastropedia 2023 vol. 1. Available at: https://gastropedia.com.br/gastroenterology/strongcommon-variable-immunodeficiency-and-gastric-cancer/