ANATOMIC ABNORMALITIES OF THE GASTROINTESTINAL TRACT

Approximately 7% of patients with FA are born with anatomic abnormalities in the gastro-intestinal tract [1]. The most common abnormalities include esophageal atresia (EA), EA with tracheoesophageal fistula (TEF), duodenal atresia (DA), and other anorectal malformations.Most anomalies are diagnosed and treated in early infancy, often before the diagnosis of FA. Gastrointestinal tract abnormalities may occur in isolation or appear with other birth defects, including the Vertebral, Anal, Cardiac, Tracheo-esophageal fistula, Esophageal atresia, Renal defects, upper Limb defects, and Hydrocephalus (VACTERL-H) spectrum of disorders (described in Chapter 2). Management of these disorders requires a multidisciplinary approach, with involvement from a gastroenterologist and pediatric surgeon.

Esophageal Atresia and Tracheoesophageal Fistula

Esophageal atresia (estimated to occur in 1.4% of FA individuals), with or without tracheoesophageal fistula (occuring in 3.5% of FA individuals), is typically diagnosed during pregnancy [2]. Symptoms of EA/TEF in newborns may include excessive drooling, feeding intolerance, or respiratory difficulties. Infants with EA/TEF who weigh more than 3 pounds 5 ounces (1500 g) at birth and lack major heart defects have a 98% survival rate to childhood and beyond [3]. Recent guidelines for management of this condition have been published elsewhere and can be referred to for additional detail [4].

The severity of the EA/TEF defect and the quality of the repair determine the long-term complications the patient may experience. Long gap atresia—defined as a gap length between the upper and lower esophageal segments of > 3 cm, or more than two vertebral bodies—is difficult to repair and increases the risk that the esophagus will narrow (or form a stricture), resulting in additional complications. A more severe form of EA/TEF is called ultra-long gap atresia, defined as a gap in the esophagus that spans five or more vertebrae. In the long and ultra-long forms of EA, the esophageal segments are very short and it is likely that significant complications will occur. The best practices for treating ultra-long gap EA/TEF are still under debate [3,5]; however, patients may require advanced surgical techniques, including staged repair, reconstruction of the esophagus using tissue from the colon or stomach, or operations that induce esophageal growth. These procedures can be associated with many complications, including leakage from the repaired esophagus connections and swallowing problems such as pain with solid foods, frequent reflux, and vomiting. There also may be a long-term risk of cancer in colon tissue used to reconstruct the esophagus[6].

Repair of EA/TEF in infancy frequently leads to gastroesophageal reflux disease (GERD), difficulty swallowing, and breathing problems in adulthood [7]. Diagnosis and management of GERD is essential to reduce discomfort, bleeding, and narrowing of the esophagus. Anti-reflux surgery can be necessary in some patients. Respiratory problems, including cough, pneumonia, and wheezing, may suggest the need for bronchoscopy. Recurrent TEF should be considered if aspiration pneumonia develops after a period of relatively good health. Recurrent TEF can lead to irreversible lung damage with bronchiectasis and persistent atelectasis[8].

Duodenal Atresia

Duodenal atresia occurs less frequently than EA/TEF. More than 50% of patients with duodenal atresia have other birth defects. Approximately 90% of infants survive the surgical repair of the intestines and will grow normally and develop few symptoms. However, 12-15% of patients develop complications in the months and years after the surgery, including abdominal pain, delayed gastric emptying, peptic ulcer, megaduodenum, reflux of fluids from the intestines into the stomach and esophagus, and blind loop syndrome. Patients with duodenal atresia frequently experience slow movement of food through the digestive tract above the intestinal passage formed by surgery. Enlargement of the duodenum can occur up to 18 years after surgery and is associated with poor weight gain, vomiting, abdominal pain, and blind loop syndrome, and usually requires additional surgery [9].

Anorectal Malformations

Anorectal malformations are a spectrum of birth defects in which the gastrointestinal tract is closed off and not connected to the anus or, instead, opens at an improper location, such as the urinary tract, reproductive system, or a different area of the perineum. The long-term outlook for patients with anorectal malformations varies and depends on the type of malformation, surgical technique used to repair the malformation, presence of additional disorders, ongoing medical care, and follow up. Long-term problems may include fecal incontinence and constipation with or without encopresis. In most cases, bowel control can be restored with medication, although some patients may require an antegrade continence enema[10].

GASTROINTESTINAL SYMPTOMS

Many patients with FA experience gastrointestinal symptoms, including nausea, abdominal pain, and/or diarrhea. These symptoms cause significant discomfort and may contribute to poor food intake and poor weight gain in patients with FA. A thorough history and examination are necessary to identify the cause for these symptoms. Contribution of an unrepaired anatomic abnormality (or history of a repaired abnormality) needs to be considered.

Psychological stress, anxiety, and depression also can lead to gastrointestinal symptoms by causing Disorders of Gut-Brain Interaction (DGBI), such as irritable bowel syndrome and functional abdominal pain. This group of disorders are characterized by the presence of chronic gastrointestinal symptoms in the absence of structural abnormalities or inflammation. The pathophysiology of these conditions is poorly understood, but current research suggests that an interplay between gastrointestinal motility, the immune system, pain sensation in the GI tract, the autonomic nervous system and psychosocial factors may contribute towards the development of these disorders[11]. The diagnosis and management of these disorders is tailored based on the presenting symptoms, and will not be covered in this chapter. The Rome Foundation is a non-profit organization that drives research pertaining to DGBI. The latest publication from The Rome Foundation, “Rome IV” was published in 2016 [12] and contains criteria to aid in the diagnosis of these disorders. Updated guidance for practitioners, “Rome V” is expected to be published in 2026.

Initial Evaluation of Gastrointestinal Symptoms

In all cases, the initial evaluation of gastrointestinal symptoms in FA patients begins with a medical history and physical exam. Most problems can be diagnosed at this level without need for additional testing.At times, evaluation for evidence of an unobvious inflammation or infection may be useful. Infection or systemic inflammation may be identified through laboratory studies, including urine culture, measurement of serum C-reactive protein, and red blood cell sedimentation rate. Patients with diarrhea should have stool examination for ova and parasites (including giardia and cryptosporidium antigen), and other opportunistic infectious agents. To diagnose suspected overgrowth of bacteria in the small intestine, hydrogen breath test or an empiric trial of antibiotics can be utilized. Imaging studies can be helpful, particularly when attempting to rule out a complication from a structural abnormality.

Nausea

Nausea can result from infections, delayed gastric emptying caused by infection, medications, or as a complication from an anatomic abnormality. Nausea is usually temporary, resolving once the infection has resolved, or the trigger medication is discontinued. Disorders of gut-brain interaction can cause nausea, at times.

Abdominal Pain

This may result from partial blockage of the digestive tract, which can be caused by complications of structural defects in the gastrointestinal system. Abdominal pain also can result from abnormal gastrointestinal motility, inflammation of the gastrointestinal tract, infections, overgrowth of bacteria in the small intestine, gallbladder disease, constipation or disorder of gut-brain interaction.

Diarrhea

This can occur for a variety of reasons, including inflammation of the gastrointestinal tract, opportunistic infection of the gastrointestinal tract, overgrowth of bacteria in the small intestine, medications, and short bowel syndrome. Constipation with accidental leakage of stool (encopresis) may be mistaken for diarrhea. Certain disorders of gut-brain interaction can also lead to diarrhea.

Gastroesophageal Reflux

A recent study of eight patients with FA who underwent endoscopy, demonstrated the presence of reflux-related inflammation in the esophagus (or esophagitis), in all patients at baseline, with five of the eight patients having moderate or severe disease[13]. All patients with moderate or severe disease were experiencing symptoms of reflux, including difficult swallowing. Age at initial endoscopy ranged from 10 to 39 years. Two individuals with the most severe esophagitis, including the child in the study, developed esophageal squamous cell carcinoma within two years. This study highlights the importance of surveillance endoscopies and recommends the consideration of an annual endoscopy to screen for esophagitis and esophageal cancer in patients with FA. Best practice guidelines for evaluation and management of GERD in patients in the general population have been published for both adults and children[14, 15]. For patients with FA, symptoms of reflux must be queried at each visit. Typical symptoms of reflux include heartburn, and regurgitation. Additional symptoms include chest pain, vomiting, abdominal pain at the midepigastric area, belching, hiccups, and dysphagia. Extraesophageal symptoms that are often attributed to reflux include chronic cough, sore throat, and change in voice. Children with GERD can be treated without further testing if they are old enough to reliably explain their symptoms. However, in a patient with non-classical symptoms, or extraesophageal symptoms alone, it may be prudent to pursue additional confirmatory objective testing before treating for presumed GERD. Treatment begins with proton pump inhibitors (e.g., omeprazole or lansoprazole or similar medication). H2-antagonists should be avoided because these drugs increase the risk of bone marrow suppression [16, 17]. In the adult population, there has been a paradigm shift to obtain objective data sooner to avoid the unnecessary use of long-term anti reflux medications [14, 18, 19]. Objective testing includes upper endoscopy, wireless pH testing, catheter-based 24hr pH impedance testing, and high-resolution esophageal manometry.

Delayed Gastric Emptying

Delayed gastric emptying should be suspected in patients who experience nausea, feel full sooner than usual, and vomit food eaten several hours earlier. The test most commonly used to diagnose delayed gastric emptying in the general population is the nuclear medicine gastric emptying study. Although age and weight based pediatric gastric emptying parameters are yet to be defined and validated, adult normal values are often used [20]. To avoid radiation exposure from a gastric emptying study in patients with FA, this may be omitted altogether, and a trial of treatment can be initiated, provided that the patient has classic symptoms, normal physical exam, and no evidence of obstruction in the digestive tract. Ultrasound-based diagnosis of delayed gastric emptying may be used when available.

Patients who report symptoms such as nausea or abdominal pain within 30 minutes of starting a meal might have impaired gastric accommodation, a condition in which the stomach fails to relax and accept food. These patients may benefit from treatment with the medication cyproheptadine. In cases of severe, uncontrollable nausea without a detectable cause, a trial of the medication ondansetron may be warranted if there is no improvement with cyproheptadine.

The first line and mainstay of therapy for delayed gastric emptying is dietary change. The patient should undergo dietary counseling with a dietitian to adjust meal content and frequency: small and frequent meals that restrict fats and nondigestible fibers while maintaining adequate caloric intake should be favored. Consultation with a clinical nutritionist is advised if dietary changes are initiated.

Other therapeutic options for gastroparesis include prokinetics, 5-HT4 agonists, and antiemetics. Cases of delayed gastric emptying that do not improve with medication may require surgical procedures, such as endoscopic therapy with pyloric dilatation and botulinum toxin injection, gastric-peroral endoscopic myotomy (G-POEM),  jejunostomy, or gastro-jejunostomy. Guidelines for the management of gastroparesis in adults are often relied on by clinicians. Although a similar pediatric guideline does not exist, individual center experiences are published in the medical literature and may be referred to [21, 22]. An in-depth conversation between the patient and gastroenterologist is important to discuss the risks and benefits of these treatment strategies.

NUTRITIONAL DISORDERS/CONCERNS

Many children with FA experience poor weight gain and growth. Weight and height should be measured at each clinical visit using methods appropriate for the age of the child and plotted on a graph called a growth curve. Measurements of weight relative to height should be plotted for children less than two years of age, and measurements of body mass index (BMI) relative to age should be plotted for children more than two years of age. FA-specific growth charts have been developed and should be referenced when evaluating a pediatric FA patient for nutritional disorders [23]. It is important to note that BMI may not provide the most accurate assessment of nutritional status for all individuals with FA. Preliminary evidence from a single center suggests that individuals with FA may have a normal BMI, while also having an excessive amount of visceral fat. Visceral fat is known to increase an individual’s risk for metabolic dysfunction and cancer [24]. Therefore, it is recommended that body composition analysis be performed to aid our understanding of an individual’s nutritional status, to guide subsequent intervention.

Poor Height Gain/Short Stature

Children with FA may be shorter than expected based on the genetic condition itself, the (non-FA related) genetics contributing to growth patterns in their families, multiple hormonal abnormalities [25], or growth suppression due to inflammation associated with infection. Approximately 60% of children with FA have short stature as part of the genetic disease. Evaluation by a pediatric endocrinologist may be needed for children with FA who exhibit poor height/linear growth. Normal/expected growth parameters in children with FA have been studied and recently published [26].

Poor Weight Gain/Malnutrition

Poor weight gain, whether the result of poor food intake, high energy utilization, or malabsorption, initially results in a growth curve demonstrating low weight relative to height or low BMI relative to age. Eventually, chronically low weight can lead to stunting or poor height gain. One study found that 22% of patients with FA were underweight, indicative of malnutrition [25]. The overall nutritional status of patients with FA can be determined during each routine physical exam by checking/tracking weight and height measurements, assessing muscle mass, energy and activity levels.

Since short stature is common in children with FA, and these individuals will have proportionately lower weights, medical providers should discuss with parents of patients with FA the pattern of their child’s growth curves, particularly the changes in weight relative to height from birth to two years of age, and BMI after age two. FA-specific growth charts should be referenced when possible. Aggressively trying to increase the child’s food intake will not increase their height or overall health and may create disordered eating.

Poor food intake can result from many factors, including complications of anatomic gastrointestinal abnormalities (narrowing of the digestive tract or complications of repair), chronic inflammation, infection, medication side effects, or neurologic/behavioral problems. Thorough workup for these causes with a gastroenterologist is recommended. Parents of children with FA often are concerned about their child’s poor weight gain and picky/restrictive eating. Analysis of the patient’s 3-day dietary record may indicate inadequate protein and calorie intake. Dietary counseling, with or without evaluation by a feeding specialist, may be needed to improve oral intake in some patients. At times, increasing caloric intake may be considered. Special consideration is recommended when trying to increase the caloric intake of individuals with FA. Preliminary data from Cincinnati Children’s Hospital indicates that individuals with FA have altered ability to detect and metabolize glucose. This altered ability seems to be related to insulin secretion, and leads to these individuals having higher blood glucose values than expected. This is particularly concerning since glucose is known to be the primary energy source for most cancer cells. Therefore, based on this work and impending publication, it is recommended that individuals with FA be provided with foods containing higher protein, fat and complex carbohydrates, over those that contain simple sugars, when possible, to prevent increased blood glucose values. Since most formula supplements have high simple carbohydrate content, consultation with a dietitian (ideally at an FA center) may be necessary to increase caloric intake.

Children who are picky or restrictive in their eating may benefit from behavioral therapies to increase the variety of foods eaten. These therapies have not been studied in patients with FA but have been effective in other patient populations with poor food intake. For example, in patients with cystic fibrosis, behavioral modification has demonstrated long-term improvements in food intake [25]. Review of these interventions is beyond the scope of this chapter.

If an individual’s caloric intake is deemed sufficient, malabsorption of nutrients must be considered. Additional testing (blood work and stool tests) may be needed to make this diagnosis.

Supplemental Feeding in Children with Fanconi Anemia

Supplemental feeding may be needed to achieve a healthy nutritional status in individuals who are chronically malnourished, or who have failed to gain weight over a three to six-month period. Supplemental feeding via feeding tube, known as enteral supplementation, is preferable to supplementation by intravenous infusion, known as parenteral nutrition. Supplemental parenteral nutrition requires placement of a central catheter and is associated with significant risks such as life-threatening infection and liver disease. Therefore, parenteral nutrition should only be considered in those patients unable to meet their needs with oral or enteral nutrition supplementation.

Enteral supplementation may be delivered by nasogastric (NG), nasojejunal (NJ), gastrostomy (G) or gastrojejunostomy (GJ) tubes. It is recommended that patients with FA have a nasogastric feeding trial before proceeding to gastrostomy. The nasal route is best for patients who require supplemental feedings for less than three months.

Gastrostomy tubes provide more permanent access to the gastrointestinal tract for administration of enteral feedings. Complications of gastrostomy tubes are limited to local irritation and/or infection. In addition, if the patient’s platelet level is very low at the time of surgery, excessive bleeding is a risk. At times, a patient may experience intolerance to enteral feedings. A physician or dietitian may make modifications to the feeding regimen to help alleviate these symptoms or consider feeding into the small intestine via a nasojejunal (NJ) or gastrojejunostomy (GJ) tube.

Appetite Stimulants

Before prescribing appetite stimulants, physicians must first investigate and appropriately manage diagnosable causes of poor appetite and inadequate weight gain in FA patients. Appetite stimulants will not treat delayed gastric emptying, infection, inflammation, structural anomalies, or other treatable causes of inadequate weight gain and growth. Several medications have appetite-stimulating effects (e.g., cyproheptadine, megestrol acetate, and the atypical antipsychotic agents, olanzapine and mirtazapine). Although these drugs were not originally formulated or prescribed as appetite stimulants—and none have been tested in patients with FA—they have been used to try to prevent unwanted weight loss in patients with cancer, HIV/AIDS, and cystic fibrosis [27, 28].

Megestrol acetate has been shown to increase appetite and weight gain in small trials for relatively short periods [29]. It has a high potential for serious side effects, including adrenal insufficiency [30, 31]. While possibly suitable for situations where short-term treatment is needed (for example, during chemotherapy, palliation therapy), it is not recommended for individuals with FA, who may need long-term appetite stimulation.

Cyproheptadine, an antihistamine used to treat allergic reactions, is a popular appetite stimulant because it has few side effects besides temporary sleepiness. A recent systematic review concluded that Cyproheptadine is safe, well-tolerated, and helps facilitate weight gain [32]. Additionally, patients may benefit from cyproheptadine, as it reduces dyspepsia and retching [33].

Cannabinoids have been shown to reduce nausea and vomiting in many circumstances [34]. Although some patients try various forms of cannabinoids to stimulate appetite, use should be limited to investigational trials until more is learned.

OVERWEIGHT AND OBESITY IN FANCONI ANEMIA

As in the general population, some patients with FA are overweight or obese. In one study, 27% of patients with FA were overweight or obese; furthermore, these overweight or obese patients also tended to have diabetes [21]. Children who have a BMI greater than the 85th percentile and less than the 95th percentile for age are considered overweight, and those who have a BMI greater than the 95th percentile for age are considered obese. Both diagnoses must be confirmed by physical exam. Significant complications may result from overweight and obesity, including elevated levels of fat and cholesterol in the blood, diabetes, obstructive sleep disorder, and other aspects of metabolic syndrome.

While a full discussion of the management of overweight and obesity is beyond the scope of this chapter (see references [22] and [23] for more information), modification of lifestyle is an essential starting point. Physicians should ask patients to keep a 6-day diary of diet and daily activity, both of which provide the foundation for counseling regarding dietary and exercise changes. Most families will require monthly counseling sessions for a time to ensure achievement of appropriate weight. Psychological counseling also may help, especially if an eating disorder is suspected. Patients should be urged to avoid fad diets and over-the-counter weight loss preparations and to focus on healthy lifestyle modifications.

The obese patient should be assessed for the primary health consequences of obesity. At a minimum, measurements should include blood pressure using an appropriately sized cuff, fasting lipid profile, oral glucose tolerance with insulin levels, and blood levels of the liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Obese patients with sleep disturbance or snoring will require a sleep study and may need an echocardiogram to assess heart function.

LIVER DISEASE

Liver disease is generally a complication of treatment of FA and patients should be referred to a gastroenterologist with expertise in treating liver disease. The following sections provide an overview of the most common liver-related problems that affect patients with FA.

Liver Complications Associated with Androgens

The androgenic steroids used to treat low blood cell counts in patients with FA can cause multiple liver complications, including a rare condition called peliosis hepatis, subcellular changes in liver cells called hepatocytes, and benign liver tumors known as hepatocellular adenomas [24]. One study of patients with FA found a 5-fold increase in liver enzyme levels—an indicator of liver injury—in patients with a history of androgen therapy compared with those without a history of androgen therapy; furthermore, three of the 20 patients treated with androgens developed liver tumors [25]. Thus, careful monitoring for hepatic complications of androgen therapy is essential. Figure 1 provides a schematic for liver complication management strategies for FA patients on androgen therapy.

Figure 1. Management of potential hepatic complications in FA patients on androgen therapy. Abbreviations: AST, aspartate transaminase; ALT, alanine transaminase; INR, international normalized ratio; PPT, partial thromboplastin time; US, ultrasound; RF, radiofrequency; Ppc, platelet count.

 

Peliosis Hepatis

Peliosis hepatis (PH) occurs when blood vessels in the liver called sinusoids become excessively dilated and form large blood-filled spaces, like cysts, that are scattered throughout the liver. This condition can occur with any dose of androgen therapy and at any time during treatment. Although many cases of PH are asymptomatic, symptoms may include abnormal enlargement of the liver, and pain and tenderness in the upper right portion of the abdomen. This condition can be life-threatening if the sinusoids rupture. Patients with PH display normal levels of liver enzymes, bilirubin, and tests of liver function. This condition is best diagnosed via liver biopsy, although imaging techniques (e.g., ultrasound, angiography, and computed tomography) may reveal large lesions. Liver biopsy may be impossible in patients who have a high risk of bleeding. The lesions may regress after androgen therapy ends [18, 19].

 

Nonspecific Damage to the Cells of the Liver

Androgen therapy can lead to cholestatic jaundice, hypertransaminasemia, or liver cirrhosis in patients on continued androgen therapy [18]. Cessation of androgen therapy usually will lead to complete resolution of symptoms. However, if liver enzyme levels do not return to normal after androgen withdrawal, then liver biopsy may be indicated (see Chapter 3 for more information on androgens).

Hepatocellular Adenomas

Androgen therapy also can result in hepatocellular adenoma. An adenoma is a benign tumor that does not invade surrounding tissue; however, it can rupture, leading to life-threatening bleeding. There also is a risk of malignant transformation, particularly in some subsets of adenomas [26]. The risk of bleeding in hepatocellular adenomas is increased in patients with thrombocytopenia. Patients with FA may develop hepatocellular adenomas rapidly, often within 3 months of beginning androgen therapy [27, 28, 29]. Hepatocellular adenomas are generally diagnosed by ultrasound. Contrast-enhanced CT scans and MRI are more sensitive than ultrasound in detecting hepatocellular adenomas. Despite the radiation exposure from CT, it is strongly recommend that all patients receive both CT and MRI scans before hematopoietic cell transplantation (HCT) if they have previously undergone androgen therapy [30]. Hepatocellular adenomas may regress after cessation of androgen therapy, but if they persist, surgical removal or radiofrequency ablation may be necessary, particularly prior to HCT.

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), or malignant liver cancer, is reported occasionally in association with androgen use. Some studies have suggested that patients with FA may have an in¬creased risk for HCC resulting from androgen use. The HCC associated with androgen therapy is characterized by the absence of α-fetoprotein in the blood, distinguishing it from other forms of HCC [18]. Patients who develop HCC should discontinue androgen therapy.

Prevention and Management of Liver Disease

General protective measures for patients with FA at risk of liver disease include screening, immunization, and avoidance of substances that may be toxic to the liver. Screening for liver disease includes measuring blood levels of the hepatocellular enzymes, ALT and AST, and the biliary enzymes, alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), and/or 5′-nucleotidase. To screen for bile cell injury in children, measurements of GGT and 5′-nucleotidase are preferred over alkaline phosphatase, as alkaline phosphatase can be elevated by bone injury or bone growth.

Elevated levels of conjugated bilirubin reflect obstruction of bile flow in the liver or significant liver cell injury. Liver cell function can be investigated by testing how quickly the blood clots and ultrasound examination may reveal the accumulation of fat or scar tissue, impaired blood flow, and obstruction of bile flow in the liver.

Patients with elevated liver enzymes should have a full evaluation of their liver by a hepatologist or pediatric hepatologist. In some cases, liver biopsy may be required to assess severity of liver disease. Patients should be immunized against varicella zoster virus (unless live virus vaccines are contraindicated), hepatitis A virus, and hepatitis B virus. The levels of antibodies against these viruses should be measured to insure that the patient has acquired immunity. Drugs that are toxic to the liver, including alcohol, should be avoided when possible. Levels of fat-soluble vitamins should be monitored on a yearly basis in patients with most forms of liver disease, particularly in cases of cholestatic disease.

GASTROINTESTINAL AND LIVER COMPLICATIONS OF HEMATOPOIETIC CELL TRANSPLANTATION

To treat the blood abnormalities associated with Fanconi anemia (FA), many patients undergo hematopoietic cell transplantation (HCT), a procedure in which abnormal stem cells are replaced with healthy stem cells. Prior to HCT, patients must undergo a complete gastrointestinal, liver, and nutritional evaluation. If undiagnosed chronic abdominal pain exists, endoscopy for detection of potential sources of bleeding or infection may be required. Patients who require supplemental feeding via a gastrostomy tube would ideally have it inserted at least three months prior to HCT to ensure complete healing of the insertion site. Infections or irritation at the insertion site should be treated prior to HCT. In addition, diarrhea should be evaluated to detect opportunistic organisms, optimal nutritional status should be achieved, and the liver cell injury and/or function should be evaluated prior to the transplant. Patients who previously received androgens must be evaluated for adenomas with ultrasound, CT scan, and an MRI.

A review of the full spectrum of liver- and gastrointestinal-related complications of HCT is beyond the scope of this work (for a recent review, see [31]).

Historically, patients with FA who undergo HCT had an increased risk of graft-versus-host disease (GvHD) (see Chapter 3), in which the transplanted cells regard the recipient’s body as foreign and attack the body, damaging the intestines, skin, and liver [32]. Patients with FA who develop chronic GvHD after undergoing HCT may experience diarrhea with poor absorption of nutrients from the diet, resulting in difficulty maintaining weight. Occasionally, the intestinal tract narrows, causing pain. Pancreatic insufficiency is uncommon, but should be considered in patients with poor absorption of fat.

Patients with chronic liver GvHD typically experience cholestasis in the liver, with elevated levels of the liver enzymes ALT and AST. Both enzymes may increase rapidly if the patient has GvHD and as the doses of immune system-suppressing medications are reduced. It is uncommon for patients to acquire chronic viral hepatitis from HCT, but this should be considered if liver enzymes are increasing. If the diagnosis of chronic liver GvHD is uncertain, liver biopsy is indicated. Chronic GvHD of the liver is treated with immune system-suppressing medications and ursodeoxycholic acid (20 mg/kg/day). Cholestasis may lead to poor absorption of the fat-soluble vitamins A, D, E, and K; therefore, levels of these vitamins should be monitored to determine whether vitamin supplementation is needed. Levels of vitamins A, D, and E can be measured via blood tests, and vitamin K levels can be inferred by measuring the clotting tendency of blood [33].

GASTROINTESTINAL SYSTEM CANCER SCREENING

Cancers of the gastrointestinal system are potential complications of Fanconi anemia (FA). Only one case of colon cancer in a person with FA has been documented in the literature to date; however, reports from FA adults who attended the Fanconi Anemia Research Fund’s annual meeting in 2019 revealed that several adults in the FA community have been diagnosed with colon cancer. The Fanconi Anemia Research Fund is currently evaluating whether colon cancer screening is warranted. Patients with FA are at increased risk for esophageal cancer (see Chapters 4 and 5) and screening guidelines are discussed in Chapter 5. As mentioned above, ultrasound imaging is recommended to screen for hepatocellular carcinoma for patients taking androgens.

SUPPLEMENTATION RISKS AND BENEFITS

Currently, no evidence-based studies have shown that large doses of vitamins, antioxidants, or other micronutrients are effective at treating FA. However, it has been shown that products containing supplemental iron, vitamins A (including beta carotene), C, and E, and omega-3 fatty acids may lead to health risks in patients with FA [34]. Large doses of omega-3 fatty acids, commonly found in fish oil supplements, can increase the risk of bleeding due to inactivation of platelets. Because patients with FA have reduced levels of platelets, products that impair platelet function should be avoided. In addition, vitamins A, C, D, and niacin may be toxic in excess.

Micronutrient supplementation to prevent cancer in patients in the general population has shown supplementation may reduce cancer risk in populations with nutrient deficiency, but populations with healthy nutrient levels see no effect or, in some cases, increased cancer risk [35]. In addition, large studies in the general population have shown that both vitamin A and vitamin E supplements are associated with an increased risk of some cancers; therefore, FA patients should avoid additional supplementation with these vitamins until further study indicates otherwise.

Counteracting oxidative damage by using antioxidants may be important for patients with FA [36]; however, research has not conclusively proven that supplementation with oral antioxidants changes the course of the disease. Currently, an ongoing clinical trial at the University of Cincinnati is examining whether oral delivery of quercetin, a naturally occurring flavonoid, reduces reactive oxygen species and DNA damage in cells of patients with FA. Interim results of the phase II prospective squamous cell carcinoma (SCC) chemoprevention study show that oral quercetin led to improved surrogate markers of genomic instability/DNA damage in buccal mucosal cells from the patients and no adverse events have been reported [37]. The preliminary results from the trial are encouraging; however, it is too early to confirm whether quercetin supplementation decreases risk of SCC in FA patients.