Gastrointestinal and Hepatic Complications of Solid Organ and Hematopoietic Cell Transplantation

Upper Intestinal Symptoms and Signs

The approach to SOT patients with esophageal or gastric symptoms is influenced by a high frequency of nonspecific symptoms as harbingers of serious infection (e.g., CMV infection presenting as nausea and vomiting) and by the rapidity with which disease can progress. GERD is the most common cause of heartburn and mid-chest pain, particularly following LT, but viral and fungal esophagitis may underlie these symptoms, particularly after antimicrobial prophylaxis has been discontinued. Candidal esophagitis is seen with high frequency in those with diabetes; other risk factors include use of broad-spectrum antibiotics, high-dose immunosuppression, and the presence of a Roux-en-Y anastomosis in OLT recipients. Severe necrotizing fungal esophagitis can lead to perforation, which can have a fatal outcome in up to one third of cases. Odynophagia, dysphagia, or hematemesis should lead to consideration of an esophageal infection; herpesviruses (CMV, HSV) and fungal species (Candida) are responsible for the largest proportion, but unusual organisms can be seen. Dysphagia secondary to pill esophagitis may develop in SOT recipients who are ingesting antibiotics, antivirals, potassium chloride, bisphosphonates, NSAIDs, and iron pills. Esophageal strictures following severe esophageal infection have been reported and may present long after eradication of the organism.

Anorexia, nausea, and/or vomiting are common following SOT, particularly early in the post-transplant course. These symptoms are often related to herpesvirus infections or medications (including immunosuppressive drugs); thus endoscopic evaluation is necessary for diagnosis in most patients. Tacrolimus is a macrolide lactone that can cause nausea, abdominal pain, and diarrhea, often leading to anorexia, food aversion, and weight loss. These side effects are dose-dependent and can be managed with dose reduction or, more rarely, drug discontinuation. Sirolimus (Rapamune), a newer macrolide immunosuppressant, has a GI side-effect profile similar to tacrolimus. MMF is an inhibitor of nucleic acid synthesis with well-described GI side effects of nausea, vomiting, and diarrhea, often requiring dosing modifications. The formulation of mycophenolic acid delayed-release tablets has significantly fewer GI side effects, with similar therapeutic efficacy. Less common causes of anorexia and nausea include pancreatitis, cholecystitis, or cystitis.

Rarely following SOT (∼1%) and within the first 2 to 6 weeks after transplantation, GVHD presents with fever, rash, and GI symptoms, particularly nausea, vomiting, and diarrhea. Endoscopic evaluation with biopsy is essential if GVHD is suspected and skin lesions are absent, recognizing that other conditions such as viral infections and drug reactions can have a GVHD-like histologic pattern. Symptomatic gastroparesis is frequently seen in the setting of LT but is less often reported in the setting of other SOT. CMV and VZV may rarely involve intestinal neural plexuses, leading to intestinal dilation or gastroparesis. Hp infection may be associated with symptomatic dyspepsia, gastritis, and gastroduodenal ulceration, but there is no relationship between the use or degree of immunosuppression and Hp colonization; its incidence is similar to that seen in the nontransplant setting. Hp infection is common in dialysis and KT patients.

Diarrhea and Constipation

Colonic and small bowel complications (diverticulitis, ischemic colitis, malignancy, and infections) have been reported following all types of SOT. Early in the post-transplant setting, infections predominate, and diarrhea may be accompanied by fever (37%), abdominal pain (46%), nausea (32%), and vomiting (22%). The microbes predominantly responsible are CMV and C. difficile , but the literature describes a wide range of organisms in SOT recipients, particularly when they are cared for in infection-endemic areas (e.g., adenovirus, norovirus, rotavirus, coxsackievirus, bacterial enteric pathogens, enterohemorrhagic Escherichia coli, Yersinia enterocolitica, Giardia lamblia, Candida species, cryptosporidia, microsporidia (E. bieneusi), Isospora belli, S. stercoralis ). Bacterial intestinal tract infections occur more often if the patient also has concomitant systemic CMV. Diagnosis can be made by examination of stool specimens in nearly all cases; the exceptions are CMV, certain parasites, and EBV-associated lymphoproliferative disorders (EBV-LPD). Small intestinal involvement with CMV often causes profuse watery diarrhea with protein-losing enteropathy, particularly if the diagnosis is delayed. Colonic involvement may appear as an inflammatory colitis resulting in bloody diarrhea and is often associated with fever, abdominal distention, and pain. Diagnosis of colonic CMV requires mucosal biopsy, particularly if blood specimens are negative for CMV DNA or antigen. C. difficile occurs in 2% to 30% of hospitalized SOT recipients, a greater incidence than in the general hospitalized population (1% to 2%). C. difficile infection may present with a more severe course post SOT; patients with fulminant colitis, intestinal obstruction, abscess, and toxic megacolon require prompt surgical intervention to prevent perforation and peritonitis. Signs of colitis may be subtle and is because of concomitant immune suppression. Treatment is discussed in Chapter 112 . Recurrence may develop in up to 20% of cases.

The use of certain probiotics (e.g., Saccharomyces boulardii ) in SOT recipients remains controversial because there have been reports of yeast dissemination and infection in the immunocompromised host. However, it appears that the use of bacterial probiotics may help prevent infection, and transplantation of normal colonic bacterial flora can be useful in treating recurrent C. difficile colitis (see Chapter 112 ). Intestinal fungal infections can be seen in up to 25% of SOT recipients. In the absence of prophylaxis, intestinal fungal overgrowth and diarrhea can result from antibiotic use or intestinal dysmotility. Common parasitic infections must also be considered in an immunocompromised host, particularly in areas of high endemicity. The protozoa and metazoan parasites are a much less frequent cause of acute diarrhea post-SOT but must be considered. Microsporida (E. bieneusi) is a more rarely reported cause of chronic diarrhea, perhaps reflecting the fact that it is often not sought out in the post-SOT setting. Clinically, patients with this infection experience fatigue, intermittent diarrhea, and weight loss. There are no clearly effective therapies for E. bieneusi . Symptoms of colitis or toxic megacolon are most often associated with infection, but in up to 20% of cases, no clear etiology can be found. Early recognition, diagnosis, and treatment of colitis can decrease disease-associated mortality. There are reports of donor-transmitted infections with S. stercoralis , which carries a high mortality rate. This pathogen should be considered when donors hale from endemic regions. Eosinophilic colitis with diarrhea has been reported with the use of both tacrolimus and cyclosporine. Histologically, this is characterized by eosinophilic colonic infiltrates and peripheral eosinophilia; elevated serum immunoglobulin (Ig)E may be present in some patients. Colonoscopy is generally only needed if noninvasive testing for infectious causes is unrevealing. Lower GI tract GVHD must be considered in those patients in whom an infectious etiology cannot be found.

Drug-related diarrhea is seen in up to two thirds of SOT patients, most commonly with tacrolimus or sirolimus. MMF causes watery diarrhea in up to 30% of patients, and may require dose reduction or discontinuation. The mechanism of MMF-induced diarrhea is unclear. It is dose dependent and may be related inhibition of de novo purine synthesis within the enterocyte. Histology shows focal inflammatory lesions similar to GVHD with loss of villous architecture of the duodenum. The use of enteric-coated mycophenolic acid has decreased this side effect. Antithymocyte globulin (ATG) and anti-T-cell antibody (OKT3) therapies are both associated with diarrhea, which predictably lasts for 3 to 4 days and resolves spontaneously. Most cases of immunosuppressant-induced diarrhea can be managed with dose manipulation, but some are so severe that discontinuation of the immunosuppressant is required. Diarrhea can also be caused by magnesium-containing preparations prescribed to correct renal magnesium wasting and by antibiotics prescribed either prophylactically or therapeutically. Noninfectious diarrhea has been reported to increase the risk of graft loss and mortality.

Constipation is seen in less mobile SOT recipients who are receiving certain medications (e.g., narcotics, calcium- and aluminum-containing antacids, anticholinergics). The constipation is generally responsive to increased patient mobility, decreased use of narcotics, use of methylnaltrexone in those receiving narcotics, and therapy with polyethylene glycol laxatives and senna.

Abdominal Pain

Abdominal complications are common following SOT, affecting up to 30% of patients. Symptoms may be mild despite the presence of life-threatening complications. All patients with abdominal pain should be aggressively evaluated, with attention as to whether the patient requires urgent surgery or a specific medical treatment. Most recipients with abdominal pain will not need surgery.

The intra-abdominal conditions presenting with pain that require urgent surgery are abscess, perforation, severe colitis, appendicitis, intestinal obstruction, intestinal ischemia, and acute cholecystitis. These disorders may appear in the early post-transplant period. Immunosuppression may mask symptoms and suppress the host response, leading to a delay in diagnosis and an increase in mortality. Most transplant patients with acute appendicitis will have typical right lower quadrant pain, although complications are more frequent. Overall, intestinal perforation occurs in fewer than 5% of SOT recipients, although the incidence may be slightly higher in the setting of lung transplant. Perforation may occur spontaneously without clear etiology, but it is associated with colon diverticula in up to two thirds of cases (particularly kidney recipients) and ischemia in 15%. Perforation, especially diverticular, carries a high mortality. Risk factors for the development of colonic perforation include diverticular disease, immunosuppression (particularly glucocorticoids), CMV infection, fungal infections (e.g., mucormycosis), unrecognized lymphoma (EBV-LPD), colon cancer, and ischemia. Abdominal x-rays and CT can confirm the presence of perforation, but may not reveal its source before surgery. Diverticular perforation is especially common after renal transplant, often leading to abscess formation and fistulization, sometimes without causing severe pain or findings of peritonitis. Pre-transplant colonic screening in patients younger than 50 years does not predict post-transplant colonic perforations. SOT recipients are also at increased risk for the development of cholelithiasis. Factors related to gallstones include cyclosporine, obesity, and CF as an underlying disorder. Abdominal pain is frequently associated with tissue-invasive CMV disease. CMV may also cause focal ulceration, perforation, high-grade stricture, and intestinal obstruction (see Fig. 36.1 ) while generally producing a diffuse pattern of mucosal edema.. The first manifestation of disseminated VZV infection is often severe abdominal pain related to pseudo-obstruction and visceral neuropathy. Early treatment of both CMV and VZV infection results in improved survival.

Abdominal pain may also be a manifestation of transplant-related complications that do not usually have a dire outcome. Pain has been reported with oral tacrolimus, sirolimus, and MMF. Abdominal pain secondary to MMF is seen in up to 19% of those receiving it and can significantly limit its use. The etiology of MMF-induced pain been postulated to involve inflammatory ulcers (seen at endoscopy), as well as interference with rapidly dividing intestinal cells, a hypothesis supported by studies showing fewer GI complications with delayed-release mycophenolic acid, compared to MMF. Narcotic- or anticholinergic-induced pseudo-obstruction is common after surgery. Care must be taken to rule out an infectious etiology such as CMV or VZV, both of which can involve the intestinal nerve plexuses. Noninfectious pseudo-obstruction often can be managed conservatively, with nasogastric decompression, vigorous correction of electrolyte imbalance, and withdrawal of opiates. Mu-agonist opioid-related gut symptoms can also be blocked with the use of methylnaltrexone without interfering with central pain relief. Neostigmine can be safely used for treatment of pseudo-obstruction in the transplant setting. Surgical intervention may be required in the setting of massive colon dilation. Acute pancreatitis has been reported in 1% to 2% of renal transplant recipients, up to 6% of LT recipients, and up to 18% of HT recipients; it may have a fatal outcome. Acute pancreatitis is associated with CMV infection, hypercalcemia, cholelithiasis, biliary manipulation, malignancy, recent alcohol ingestion, and medications such as azathioprine, cyclosporine, tacrolimus, and glucocorticoids. Treatment of pancreatitis in the post-transplant setting is identical to that in the nontransplant setting, except for the need to exclude CMV infection and some immunosuppressive medications (see Chapter 58 ).

Pneumatosis intestinalis may be discovered during abdominal imaging after SOT as an incidental finding, but can also be a manifestation of life-threatening intestinal ischemia or infection with a gas-forming organism. Pneumatosis intestinalis can be associated with CMV infection, C. difficile colitis, and sepsis and can be seen in patients receiving glucocorticoid therapy. Most patients require no specific intervention, and the gas collections resolve spontaneously unless caused by ischemia or an infection with a clostridial organism.

Gastrointestinal Bleeding

When GI bleeding occurs, it is often secondary to infectious ulcers. Noninfectious causes of hemorrhage include NSAID-induced gastroduodenal ulcers, diverticular bleeding, anastomotic bleeding, and ischemic colitis. The current incidence of gastroduodenal ulcer disease in the transplant population is now about 5%, with perforation rates of less than 1%. Prophylaxis with H2RAs or PPIs decreases the occurrence of ulcer disease in this population; these 2 therapies are equally effective in KT recipients. Patients infected with Hp prior to transplantation are more likely to develop PUD following transplant. In the absence of effective antiviral prophylaxis, viral ulcerations are the most common cause of GI bleeding. HSV-associated esophageal ulcers may present with severe bleeding even in the absence of esophageal symptoms. CMV can lead to ulceration throughout the entire intestinal tract. Whereas CMV esophageal ulcers are usually shallow (see Fig. 36.1 A ), ulcers in the stomach or intestine can be deep, erode into vessels, and lead to severe bleeding. CMV can also cause diffuse colonic inflammation resembling that seen in IBD (see Fig. 36.1 C and D ). VZV and EBV are much less often associated with GI bleeding. Although EBV itself does not cause mucosal ulceration, EBV-associated LPD can form mucosal tumors that can ulcerate and bleed (see Fig. 36.2 ). Massive bleeding has been reported in the setting of invasive fungal infection.

Gastrointestinal Malignancy

PTLD, lymphoid proliferations, or lymphomas associated with EBV infection occur in up to 20% of transplant recipients. Although most PTLD is of B-cell origin, T-cell lymphoma has been reported. EBV reactivation generally presents in the early post-transplant setting as a mononucleosis-like syndrome with diffuse adenopathy and fever; detection of EBV DNA in the bloodstream may allow preemptive therapy, with lower doses of immune suppression or treatment with rituximab. PTLD manifesting later than a year after transplant is more insidious, often presenting with extranodal disease or visceral involvement. GI PTLD can present with diarrhea, intestinal obstruction (see Fig. 36.2 B ), bleeding, or perforation. Mucosa-associated lymphoid tissue (MALT)–type lymphomas have also been reported in the post-transplant setting. Fortunately, they often respond to reduction in immunosuppression, antibiotics (if associated with Hp ), surgery, or chemotherapy (see Chapter 32 ).

The risk of cancer in long-lived transplant recipients is higher than in the general population, particularly for lymphomas, skin cancers, colon and anal cancers, head and neck cancers, and Kaposi sarcoma. Patients who underwent OLT for cirrhosis secondary to PSC are at high risk for the development of colonic dysplasia and diffuse colon cancer related to underlying ulcerative colitis. If severe dysplasia is discovered, colectomy can be performed safely as early as 10 to 12 weeks following transplant.

Hepatobiliary Complications

Drug-induced hepatotoxicity can be problematic after SOT because this diagnosis is often one of exclusion. Azathioprine hepatotoxicity presents as an elevation in serum aminotransferase enzyme levels in up to 10% of recipients; injury is generally cholestatic with centrilobular hepatocyte damage. A less common presentation is the slow, insidious development of sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease), which often manifests as portal hypertension, usually regressing following withdrawal of the drug. Azathioprine is used less often now following organ transplant, having been largely replaced by mycophenolic acid. Cyclosporine- or tacrolimus-induced cholestasis can occur when their blood levels are high. Sirolimus has been reported to cause dose-dependent elevations in serum aminotransferase levels. Transplant recipients are exposed to numerous other pharmacologic agents that alone, or in combination, can produce cholestasis, fatty liver, hepatitis, or a mixed histologic picture.

Bacterial sepsis can have profound effects on liver function (see Chapter 37 ), with severe cholestasis the most common finding (a syndrome sometimes called cholangitis lenta or hyperbilirubinemia of sepsis ). CMV infection may lead to elevations in hepatic enzymes, with either a cholestatic or hepatocellular picture. CMV hepatitis is more frequent and severe in LT recipients compared to recipients of other organs. VZV and HSV infection can lead to hepatitis and fulminant liver failure. EBV hepatitis is seen in 2% to 3% after SOT but is generally mild. Primary or recurrent disease with either HCV or HBV can lead to liver disease in the post-transplant setting. These viruses may also be passaged by any solid organ. Fortunately, antiviral therapy for both has improved outcomes significantly The treatment of HCV in the post-transplant setting has improved greatly with development of direct acting antivirals, curing up to 98% to 99% of recipients. In fact, at the time of this writing, the success of these medications has led to the consideration of use of HCV viremic donors for HCV negative recipients. Chronic HBV carriers (hepatitis B surface antigen–positive recipients) may develop a flare following transplant, but disease responds well to antiviral agents (see Chapter 79 ).

Vascular injury associated with OLT may lead to liver dysfunction. Nodular regenerative hyperplasia with subsequent portal hypertension and peliosis hepatis have both been reported following renal transplantation.

Organ transplant recipients, particularly those with LT, are at high risk for biliary tract disease. Presentation includes acalculous cholecystitis, gallbladder sludge, thickened gallbladder wall, dilated bile ducts, or cholelithiasis. Diseases of gallbladder and biliary necessitating cholecystectomy have a post-transplant incidence of 1% to 6%. Emergent cholecystectomy in the post-transplant setting carries a high mortality (29%). However, pre-transplant biliary screening and prophylactic cholecystectomy remain controversial. The etiology of biliary tract disease is multifactorial, including obesity, use of TPN, fasting, biliary strictures, and medications. Cyclosporine, excreted in the bile where it may precipitate, has been implicated in an increased incidence of cholelithiasis and cholangitis. Some centers recommend that biliary calculi be removed prior to transplantation or immediately upon discovery after transplantation.

Patients who have undergone OLT for hepatocellular carcinoma are at risk for recurrence in the graft, particularly if the lesions were multiple or large prior to transplant. PTLD may also involve the liver.

Evaluation of Intestinal and Liver Disorders Before Hematopoietic Cell Transplantation