Digestive and liver health

CVID can cause a GI condition called autoimmune atrophic gastritis (AAG) that has not been observed in other PIs [2]. AAG happens when your body makes autoantibodies against the stomach lining, particularly the cells that make stomach acid and a protein called intrinsic factor (IF). IF binds to vitamin B12 so your intestines can absorb it. Since your body needs vitamin B12 to make red blood cells, people with AAG sometimes have low red blood cells because of vitamin B12 deficiency, a condition called pernicious anemia.

AAG doesn’t always cause symptoms and when it does, they are related to the degree of B12 deficiency and the resulting anemia. These symptoms can include weakness, fatigue, pale skin, and tongue soreness.

Celiac disease, also called celiac sprue, is an autoimmune condition where the body develops antibodies against gluten, a harmless protein found mostly in wheat, rye, and barley. Celiac disease is a type of enteropathy, which means it causes inflammation in the small intestines. Symptoms include diarrhea, bloating and gas, and nausea and vomiting.

People with SIgAD are more likely to have celiac disease than people without SIgAD [20]. Because the standard test for celiac disease relies on IgA antibodies, people with SIgAD need to be tested for celiac disease in a different way that looks at IgG antibodies instead [21]. A gluten-free diet works for some, but not all, people with celiac disease.

Several types of PI can cause problems in the small intestines and/or colon that are difficult to classify. These conditions, collectively referred to as inflammatory bowel disease (IBD) or IBD-like, differ based on which organ(s) are affected and whether changes to the gut lining are visible to the eye or can only be seen by microscope in tissue samples.

Enteropathy

Although ‘enteropathy’ technically means any disease of the small intestines, in the context of PI, healthcare providers generally use it to mean diseases of the small intestines caused by inflammation or autoimmunity where the damage is mainly microscopic and can’t be seen by endoscopy. Enteropathy leads to large volume, watery bowel movements, weight loss, and malnutrition due to poor digestion of food and absorption of nutrients.

Enteropathy is common in people with CVID. Experts don’t know the exact cause. CVID-related enteropathy causes long-lasting diarrhea and difficulty absorbing nutrients from food, particularly protein, vitamins, and minerals. People with CVID-related enteropathy may lose significant weight unintentionally. Their small intestines may look normal during a visual exam. However, when viewed under a microscope, biopsied intestinal tissue shows signs of inflammation and damage. SIgAD is another antibody deficiency linked to enteropathy.

PIs that cause someone to have fewer T regulatory cells (Tregs) or Tregs that don’t work well can lead to enteropathy caused by autoimmunity. Examples include IPEX syndrome and STAT3 gain of function (GOF) [22,23]. Tregs help keep the immune system from attacking healthy tissue. In these conditions, lack of working Tregs leads to too much T cell activity. This can result in auto-reactive T cells attacking the lining of the intestines. These attacks cause watery, and less often bloody, diarrhea and makes it hard to absorb nutrients. Enteropathy in people with PIRD can cause poor weight gain and failure to thrive. It can be the first sign of a PIRD, or can develop later [24]. Treatment for these specific types of PIs ultimately requires a hematopoietic stem cell transplant (HSCT), but the enteropathy can be temporarily managed with steroids or immunosuppressants.

Crohn’s disease and ulcerative colitis

In people without PI, there are two main types of inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis. In Crohn’s disease, inflammation can happen anywhere in the GI tract from your mouth to your anus and patches of inflammation are mixed in with patches of healthy tissue. Ulcerative colitis (UC) causes chronic inflammation and sores (ulcers) in the wall of the colon and the inflammation happens over one continuous stretch of tissue. It causes painful, often bloody, bowel movements. The damage from both Crohn’s and UC is visible during an endoscopy. However, the IBD seen in people with PI sometimes is not considered classic Crohn’s or UC.

People with CVID and XLA may develop inflammation of the gut that looks like Crohn’s disease or ulcerative colitis, although this is less common than other GI conditions in those with CVID [25,26]. People with WAS can develop colitis resembling UC with bleeding from the rectum, but this is rare [27,28]. The bleeding is worse if the person has low platelet counts.

Up to 50% of people with CGD develop what’s known as CGD-associated IBD or CGD-associated colitis [29]. It can cause:

• Sores and dental abscesses that cause pain in the mouth and make it hard to eat.
• Narrowing of the esophagus, caused by scarring, and changes in how the muscles work caused by inflammation from clumps of white blood cells (granulomas).
• Stomach wall thickening that causes the stomach not to work as well or hold as much, resulting in vomiting, pain, and weight loss.
• Enteropathy and colitis causing diarrhea.
• Blockages from granulomas in the small intestines and colon.
• Pain and bleeding from the rectum.

The most common GI problems in people with CGD are abdominal pain and diarrhea (with or without rectal bleeding). These can be due to very large granulomas that fill and block the bowel and decrease area available for normal nutrient absorption. GI symptoms usually begin before age 10, sometimes before the person is diagnosed with CGD, and can lead to delayed growth.

Experts have reported IBD in PIRDs like XIAP deficiency, IPEX syndrome, and IL-10 deficiency [30,31]. IL-10 deficiency is a PIRD that can cause very early onset IBD (VEO-IBD) by 6 years of age. This type of IBD shows colon inflammation that has features of Crohn’s disease, sometimes developing within weeks of birth. Experts have proposed that GI inflammation because of too much signaling from white blood cells called macrophages as the cause of IBD in infants and children with IL-10 or IL-10R deficiencies.

Though several types of PIRD tend to cause IBD by 2 years of age (infantile onset) or VEO-IBD, a significant proportion of people with PIRD develop IBD after age 6. IBD in older individuals can have a slow, gradual onset with frequent, small-volume diarrhea with blood and mucus. Due to the slow onset, it is common for these individuals to have been tested for food allergies and to have had multiple formula or food changes for allergies.

In contrast, IBD in infants with PIRD is usually much more dramatic. They typically have explosive, large-volume watery diarrhea. These symptoms are common in infants with IPEX and IPEX-like disorders. Biopsies show flattening of the cells that line the small intestines (villous atrophy) and signs of cell death (apoptotic enterocolitis).

It is important to identify people who have IBD as the first symptom of PIRD because diagnosing the underlying PIRD can help with treatment, resulting in better control of the GI condition. VEO-IBD is common, but the age of onset should not be the only reason to test for a PIRD. Healthcare providers should consider an underlying PIRD if a person with IBD has autoimmune conditions or conditions where the body makes too many white blood cells (lymphoproliferation), abnormal connections between the GI tract and the skin or organs (fistulae), recurrent fevers, or difficult to treat eczema. Someone with IBD may also have an underlying PIRD if they don’t respond to first- and second-line IBD therapies.

Nodular lymphoid hyperplasia (NLH) is when lymph nodes in the digestive system become inflamed and enlarged, developing into nodules or polyps. NLH happens most often in the small intestines but can also develop in other places in the GI tract.

NLH happens most often in people with CVID [32]. It has also been found in people with other antibody deficiencies like SIgAD. It usually doesn’t cause symptoms but can cause chronic diarrhea, make it hard to absorb nutrients from food (malabsorption), and block the GI tract if the nodules are large or there are a lot of them.

Autoimmune hepatitis refers to liver inflammation that does not involve the bile ducts caused by autoimmunity rather than an infection. APECED and CVID are both associated with autoimmune hepatitis [33]. It can cause fluid to build up in the belly (ascites), yellowing of the skin or eyes (jaundice), and problems with blood clotting. If it is not treated, autoimmune hepatitis can cause permanent scarring (cirrhosis) of the liver and liver failure.

Certain infections, like viral hepatitis (A, B, or C), cytomegalovirus (CMV), and Epstein-Barr virus (EBV), can also lead to severe liver inflammation (hepatitis) and damage. Because the symptoms of infection and autoimmunity are similar, people with liver problems should always be tested for these specific viruses. The treatment for an infection is different from the treatment for autoimmunity [33].

Nodular regenerative hyperplasia (NRH) is when the liver develops small clusters, or nodules, of dividing liver cells that press into surrounding tissue [34]. While NRH is not well understood, it may be a response to damage of the small blood vessels inside the liver. Healthcare providers see NRH most often in people with CVID or XLA, but it has also been reported in other PIs like CGD, CD40 ligand deficiency, and STAT3 gain of function (GOF) [33].

NRH usually develops without symptoms but can eventually cause increased blood pressure in the vein that carries blood from your intestines into your liver (portal hypertension). Signs of portal hypertension include retaining fluid in your limbs (edema), itching, yellowing of the eyes or skin (jaundice), and buildup of fluid in the belly (ascites). Portal hypertension can then disrupt the spleen’s function, leading to low blood cell counts (cytopenias). It can also cause more blood to flow through veins in the lower esophagus, causing them to become larger than usual (varices) and risking bleeding if they rupture [35].

Generally, healthcare providers use medications that lower the immune system's activity (immunosuppressants) to treat autoimmune or inflammatory GI conditions in people with PI. However, the treatment plan must weigh the risks of the treatment, including a higher risk of infections, against the risks of the autoimmune or inflammatory condition itself. In some cases, like GI conditions in people with CVID or CGD, providers prescribe corticosteroids as the first treatment. They may be enough to manage symptoms.

It can also be helpful to consult a registered dietician for advice on a nutritional plan to make sure you’re getting enough calories, which may include adding medium chain triglyceride oil. Be aware that there are many online sources and social media influencers that promote anti-inflammatory diets or nutritional supplements with little evidence to back them up. A registered dietician, however, is trained and certified to address medical conditions through diet.

In some cases, tube feeding via either a nasogastric (NG) tube or gastrostomy tube (GT) helps by delivering calorie sources that are easier to absorb, such as simple sugars and amino acids, directly to either the stomach or small intestines. Finally, parenteral nutrition, or delivery of nutrients directly into a vein, may be necessary in some cases.

Severe GI conditions related to PIRDs like IPEX syndrome usually need stronger immunosuppressants than corticosteroids. It is important to understand that there is no single defined treatment plan for managing GI conditions in people with PIRDs. They may not respond to medications that usually work for other people with autoimmune/inflammatory GI conditions, such as anti-TNF medications like infliximab or adalimumab.

Immunologists will often select medications that are most likely to work based on which specific PIRD the person has. The provider may consider second-line treatments, such as vedolizumab or ustekinumab, earlier. The provider may also try immunosuppressants that aren’t usually prescribed for GI conditions but that target a particular inflammatory cell, molecule, or protein. These medications include ruxolitinib, tacrolimus, cyclosporine, sirolimus, abatacept, and anakinra. Some people have to try multiple different medications to find the combination that works best for them.

Though GI conditions in a person with PIRD might be well-controlled, long-term quality of life may not be good with medication alone. People with PIRD may have flares, become less responsive to medication over time, and develop other autoimmunity, infections, or uncontrolled growth of white blood cells (lymphoproliferation). As a result, immunologists are recommending allogeneic hematopoietic stem cell transplantation (HSCT) more often for people with PIRDs than they used to.

Usually, HSCT in someone with PIRD is not an emergency. The medical team will try to get their autoimmunity and inflammation under control, since HSCT outcomes are better if the immune system is better controlled beforehand. The medical team will also try to get the person nutritionally stable and up to a healthy body weight as much as possible. HSCT can be a one-time, long-term treatment for PIRDs, but it's important to think carefully about the long-term risks from conditioning, the chance of graft versus host disease or other complications after the transplant, the risk of infection, and the small, but real, risk of the transplant failing.