Upper Gastrointestinal 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 (for example, 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 midchest pain, particularly following lung transplantation (see lung transplant earlier), but viral and fungal esophagitis may underlie these symptoms, particularly after chemoprophylaxis has been discontinued. Candidal esophagitis is seen with particular 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 liver transplant recipients. Severe necrotizing fungal esophagitis can lead to perforation, which can have a fatal outcome in up to one third of patients. 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.⁶³ Dysphagia secondary to pill esophagitis may develop in SOT recipients, caused by antibiotics, antivirals, potassium chloride, bisphosphonates, and NSAIDs. Esophageal strictures following severe esophageal infection have been reported and may present a long time after eradication of the organism.

Anorexia, nausea, and/or vomiting are common following SOT, particularly early in the post-transplant course.^15,47,48 These symptoms are often related to herpesvirus infections or to medications (including immunosuppressive drugs), and thus, endoscopic evaluation is necessary for diagnosis in most patients. Tacrolimus (Prograf) 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 (CellCept) is an inhibitor of nucleic acid synthesis with gastrointestinal side effects of nausea, vomiting, and diarrhea, often requiring dosing modifications. A formulation of mycophenolic acid delayed-release tablets (Myfortic) appears to have significantly fewer gastrointestinal side effects with similar therapeutic efficacy.⁶⁴ Less common causes of anorexia and nausea include pancreatitis, cholecystitis, or cystitis. Rarely following SOT, graft-versus-host disease (GVHD) presents with fever, skin rash, and gastrointestinal symptoms, particularly nausea, vomiting, and diarrhea.^65,66 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 GHVD-like histologic pattern.⁶⁷ Symptomatic gastroparesis is frequently seen in the setting of lung transplant but is less often reported in the setting of other solid organ transplant.⁵² CMV and VZV may rarely involve intestinal neural plexuses, leading to intestinal dilation or gastroparesis. H. pylori infection may be associated with symptomatic dyspepsia, gastritis, and gastroduodenal ulceration, but there is no relationship between the use or degree of immunosuppression and H. pylori colonization; its incidence is similar to that seen in the nontransplant setting.²

Diarrhea and Constipation

Colonic and small bowel complications (diverticulitis, ischemic colitis, malignancy, and infections) have been reported to occur following all types of SOT. Early in the post-transplant setting, infections predominate. Diarrhea is commonly infectious and may be accompanied by fever,⁶⁸ abdominal pain (46%), nausea (32%) and vomiting (22%).^69,70 The microbes usually responsible are CMV and Clostridium difficile, but the literature describes a wide range of organisms in SOT recipients, particularly when they are cared for in infection-endemic areas (for example, adenovirus, rotavirus, coxsackievirus, bacterial enteric pathogens, enterohemorrhagic Escherichia coli, Yersinia enterocolitica, Giardia lamblia, Candida species, cryptosporidium, Enterocytozoon bieneusi, Isospora belli, and Strongyloides stercoralis).⁷⁰ Diagnosis can be made by examination of stool specimens in nearly all cases; the exceptions are CMV, certain parasites, and EBV-LPD. Small intestinal involvement with CMV often causes profuse watery diarrhea with protein-losing enteropathy, particularly if the diagnosis is delayed.⁷¹ Colonic involvement may appear as an inflammatory colitis resulting in bloody diarrhea and is often associated with fever, abdominal distention, and pain.⁷² Diagnosis of CMV may require mucosal biopsy, particularly if blood specimens are negative for CMV DNA or antigen. C. difficile infection may present with a more severe course post SOT, and patients with fulminant colitis and toxic megacolon require prompt surgical intervention to prevent perforation and peritonitis.⁷⁰ Signs of colitis may be subtle due to concomitant immunosuppression. Only about 70% of patients respond to treatment with metronidazole; persistent and more severe cases require oral vancomycin. Recurrence may develop in up to 20% of cases.⁷³ The use of probiotics (e.g., Saccharomyces boulardii) in SOT recipients remains controversial because there have been reports of yeast dissemination and infection in the immunocompromised host.⁷⁴ 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 also must be considered in an immunocompromised host, particularly in areas of high endemicity. The protozoa are a much less frequent cause of acute diarrhea post SOT. Microsporidia (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.^70,75 Early recognition, diagnosis, and treatment of colitis can decrease disease-associated mortality. Eosinophilic colitis with diarrhea has been reported with the use of tacrolimus and cyclosporine. Histologically this is characterized by eosinophilic colonic infiltrates and peripheral eosinophilia. Elevated serum immunoglobulin E may be present in some patients.

Drug-related diarrhea is seen in up to a third of SOT patients, most commonly with tacrolimus or sirolimus.^70,76 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. There have also been reports of altered tacrolimus metabolism and absorption in patients suffering from MMF-induced or other causes of chronic diarrhea. Antithymocyte globulin (ATG) and anti–T cell antibody (OKT3) therapies are associated with diarrhea, which predictably lasts for three to four 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 also can 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.⁷⁶

Constipation is seen in less mobile recipients who are receiving certain medications (e.g., narcotics, calcium- and aluminum-containing antacids, anticholinergics). This is generally responsive to increased patient mobility, decreased use of narcotics, use of methylnaltrexone,⁷⁷ and therapy with laxatives and senna.

Abdominal Pain

Abdominal complications are common, affecting up to 30% of patients following SOT.⁷⁸ Symptoms may be mild despite the presence of life-threatening complications. All patients with abdominal pain should be aggressively evaluated, with particular attention 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 increase in mortality. Most transplant patients with acute appendicitis have right lower quadrant pain. Overall, intestinal perforation occurs in less than 5% of SOT recipients, although the incidence may be slightly higher in the setting of lung transplant.^14,79 Perforation may occur spontaneously without clear etiology, but it is associated with colon diverticula in up to two thirds of cases (particularly renal transplant recipients) and ischemia in 15%. Perforation, especially of a diverticulum, carries a mortality of up to 55%.^30,72 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.^2,72 Abdominal radiographs and helical computed tomography (CT) scans 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. Pretransplant colonic screening for diverticulosis in patients less than 50 years of age has not been shown to predict post-transplant colonic perforations. SOT recipients also are at increased risk for the development of cholelithiasis.⁸⁰ Factors related to gallstones include cyclosporine, obesity, and cystic fibrosis as an underlying disorder. Abdominal pain is frequently associated with tissue-invasive CMV disease. Although generally producing a diffuse pattern of mucosal edema, CMV may also cause focal ulceration, perforation, high-grade stricture, and intestinal obstruction (see Fig. 34-1). The first manifestation of disseminated VZV infection is often severe abdominal pain related to intestinal 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 is seen in up to 19% of patients taking MMF and can significantly limit its use.⁸¹ The etiology of MMF-induced pain been postulated to involve local irritant and inflammatory effects as well as interference with rapidly dividing intestinal cells, a hypothesis supported by a study showing fewer gastrointestinal complications with delayed-release mycophenolic acid (Myfortic), than with MMF.⁶⁴ Narcotic-induced ileus 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.² Noninfectious pseudo-obstruction often can be managed conservatively with nasogastric decompression, vigorous correction of electrolyte imbalance, and withdrawal of opiates. Opioid-related gut symptoms can also be blocked with the use of methylnaltrexone while not interfering with central pain relief.⁷⁷ Neostigmine can be safely used for treatment of intestinal pseudo-obstruction in the transplant setting.⁷² 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 liver transplant recipients, and up to 18% of heart transplant recipients; it may have a fatal outcome.⁸² 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 non-transplant setting, except for the need to exclude viral infection and some immune suppressive medications.

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 is associated with CMV infection, C. difficile colitis, and sepsis and can be seen in patients receiving glucocorticoid therapy. The majority of 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 gastrointestinal bleeding occurs, it is often secondary to infectious ulcers. Noninfectious causes of hemorrhage include NSAID gastroduodenal ulcers, diverticular bleeding, anastomotic bleeding, and ischemic colitis. The current incidence of gastroduodenal ulcer disease in the transplant population is about 5%, with perforation rates of less than 1%.³ Prophylaxis with histamine (H₂)-receptor antagonists or proton pump inhibitors decreases the occurrence of ulcer disease in this population; both therapies are equally effective.³ Patients infected with H. pylori prior to transplantation are more likely to develop peptic ulcer disease following transplant.⁸³ In the absence of effective antiviral prophylaxis, viral ulcerations are the most common cause of intestinal 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. Although CMV esophageal ulcers are usually shallow (see Fig. 34-1A), ulcers elsewhere can be deep, erode into vessels, and lead to severe bleeding. CMV can also cause diffuse inflammation similar to that seen in idiopathic inflammatory bowel disease (see Fig. 34-1C and D). VZV and EBV are much less often associated with gastrointestinal (GI) bleeding. Although EBV itself does not cause mucosal ulceration, EBV-LPD can form mucosal tumors that can ulcerate and bleed (see Fig. 34-2). Massive bleeding has been reported in the setting of invasive fungal infection.

Gastrointestinal Malignancy

Post-transplant lymphoproliferative disorders (PTLDs), lymphoid proliferations, or lymphomas associated with EBV infection (EBV-LPD) occur in 1% to 20% of transplant recipients.⁸⁴ Although most PTLDs are 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.⁸⁵ PTLD manifesting later than a year after transplant is more insidious, often presenting with extranodal disease or visceral involvement. Gastrointestinal PTLD can present with diarrhea, intestinal obstruction (see Fig. 34-2B), bleeding, or perforation. Mucosa-associated lymphoid tissue-type (MALT) lymphomas have also been reported in the post-transplant setting.⁸⁶ Fortunately, they often respond to reduction in immunosuppression, antibiotics (if associated with H. pylori), surgery, or chemotherapy.

The risk of cancer in long-lived transplant recipients is higher than in the general population, particularly for lymphomas, skin cancers, colorectal and anal cancers, and Kaposi’s sarcoma.⁸⁷ Patients who underwent liver transplant for cirrhosis secondary to primary sclerosing cholangitis are at high risk for the development of colonic dysplasia and diffuse colon cancer related to underlying ulcerative colitis.⁸⁸ If severe colonic 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 a transplant because this diagnosis is often one of exclusion. Azathioprine hepatotoxicity presents as an elevation in serum aminotransferases in up to 10% of recipients; injury is generally cholestatic, with centrilobular hepatocyte damage. Azathioprine is being used less often following organ transplantation. A less common presentation is the slow insidious development of sinusoidal obstruction syndrome (veno-occlusive disease), which often manifests as portal hypertension, usually regressing following withdrawal of the drug. Cyclosporine- or tacrolimus-induced cholestasis can occur when blood levels are high. Sirolimus has been reported to cause dose-dependent elevations in serum aminotransferases. 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, with severe cholestasis the most common finding (a syndrome called cholangitis lenta).⁸⁹ CMV infection may lead to elevations in hepatic enzymes with either a cholestatic or hepatocellular picture. CMV hepatitis is more frequent and severe in liver transplant recipients, compared with recipients of other organs.⁶ VZV and HSV infection can lead to hepatitis and fulminant liver failure.²⁶ EBV hepatitis is seen in 2% to 3% of patients 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 be transmitted to the recipient by any solid organ from the donor. Immunosuppression leads to a marked increase in HCV titers and in some cases, to aggressive hepatic disease post-transplant, with progression to cirrhosis within 3 to 10 years.⁹⁰ The results of treatment of hepatitis C in the post-transplant setting with interferon-α (INF-α)–based regimens are disappointing. Sustained virologic clearance can be achieved in 10% to 30% of post-LT recipients, but use of interferon-based therapies is limited because of side effects.⁹¹ HCV can be successfully treated in renal transplant recipients, but because the rate of renal graft failure related to INF-α is unacceptable, treatment should not be attempted. It is unknown whether interferon alpha therapy for HCV in HT or LT recipients carries an increased risk of graft failure and its use is not recommended.⁹² Chronic HBV carriers (hepatitis B surface antigen-positive recipients) may develop a hepatitis flare following transplant, but disease often responds to antiviral agents.

Vascular injury associated with liver transplantation 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 following LT, are at high risk for biliary tract disease. Presentation includes acalculous cholecystitis, gallbladder sludge, thickened gallbladder wall, dilated bile ducts, or cholelithiasis.⁸⁰ Gallbladder and biliary disease necessitating cholecystectomy occurs in about 1% to 6% of transplant recipients. Emergent cholecystectomy in the post-transplant setting carries a high mortality (29%).⁸⁰ However, pretransplant screening for gallstones and prophylactic cholecystectomy remain controversial. The etiology of biliary tract disease is multifactorial, including obesity, use of total parenteral nutrition, fasting, biliary strictures, and medications. Cyclosporine is excreted in the bile, where it may precipitate and has been implicated in an increased incidence of cholelithiasis and cholangitis.^27,93 Some centers recommend that biliary calculi be removed prior to transplantation or immediately on discovery after transplantation, but this recommendation is not universal.

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

Ulcers and Tumors in the Gastrointestinal Tract

Mucosal ulcerations may bleed profusely when platelet counts drop after HCT, and in immunocompromised patients, ulcers may have an infectious etiology (e.g., CMV, HSV or fungal infection) that requires specific antimicrobial treatment.⁹⁵ Intestinal ulcerations should be healed before the start of conditioning therapy. CMV, Entamoeba histolytica and C. difficile are causes of colonic ulceration that may mimic idiopathic inflammatory bowel disease. Selected patients with ulcerative colitis and Crohn’s disease have undergone allogeneic and autologous HCT without complications of bleeding, perforation, or dissemination of microorganisms.^96,97 The presence of fecal occult blood should prompt colonoscopy and upper endoscopy before HCT, especially in patients older than 50 years. Endoscopic biopsy may be required for staging some forms of lymphoma with a predilection for gut involvement, such as mantle cell lymphoma.

Diarrhea

Patients with diarrhea should be investigated for organisms that may cause morbidity during the period of immunosuppression after HCT (e.g., E. histolytica, strongyloides, G. lamblia, cryptosporidia, clostridial infections, CMV, rotavirus, adenovirus).⁹⁸ Cryptosporidiosis may be resistant to therapy in an immunosuppressed patient,⁹⁹ but restoration of normal immunity after allogeneic HCT can result in clearance of Cryptosporidia.¹⁰⁰ Similarly, protracted diarrhea related to immune dysregulation can be treated with allogeneic HCT, for example, by restoration of T regulatory cells in children with immundysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome.¹⁰¹ Typhlitis is a syndrome of cecal edema, mucosal friability, and ulceration in neutropenic patients, often associated with polymicrobial sepsis; its cause is usually an intestinal clostridial infection, particularly with Clostridium septicum.¹⁰² After treatment, the risk of post-HCT typhlitis is no different than that of other patients.

Perianal Pain

Pain near the anal canal in a granulocytopenic patient is assumed due to bacterial infection until proved otherwise. Extensive supralevator and intersphincteric abscesses may be present without being apparent on external examination. CMV infection of anal glands may lead to fistula formation. Perineal HSV infection causes painful skin ulcerations. Perianal infections must be treated before HCT.

Fungal Liver Infections

Diagnosis depends on liver imaging (using high-resolution CT or magnetic resonance imaging [MRI]) in conjunction with circulating fungal biomarkers (galactomannan and glucan assays),^103,104 polymerase chain reaction (PCR), or culture of liver biopsy material. Therapy with newer antifungal drugs (caspofungin or azole drugs) should be continued through HCT until engraftment is established, which can effect resolution of intractable fungal liver abscesses.^105–107

Viral Hepatitis in Allogeneic Hematopoietic Cell Transplant Donors

Donors who are viremic with HBV or HCV will transmit virus to their recipients.¹⁰⁸ When two equally HLA-matched donors are available, the uninfected donor is preferred. If the more suitable donor has chronic hepatitis B, it may be possible to prevent passage of virus by treating that donor.^109,110 HBV persisting in donor peripheral blood stem cells may have to be eliminated to prevent passage.^110,111 HBsAg negative/anti-HBc–positive donors can be used if their serum and peripheral blood stem cells are HBV DNA negative. A donor who is naturally anti-HBs positive may be the preferred donor if the recipient is HBsAg positive or anti-HBc positive because adoptive transfer of immunity can lead to clearance of virus.¹¹² If a donor is infected by HCV and if time permits, treatment of the donor prior to harvest of donor cells may render them nonviremic, and much less likely to transmit infection.¹¹³ If HCV is transmitted, the acute phase of HCV infection may cause elevated liver enzymes at two to three months post HCT, after recovery of T cell function; after 10 years the outcome is no different than in transplant recipients without hepatitis C infection.¹¹⁴ In the long term, HCV-infected transplant recipients are at risk for development of cirrhosis and hepatocellular carcinoma.¹¹⁵

Chronic Liver Disease in Candidates for Hematopoietic Cell Transplantation

The risks faced by patients with fibroinflammatory liver disease include fatal sinusoidal obstruction syndrome following some myeloablative regimens and fulminant hepatitis B. In the absence of antiviral prophylaxis, fatal fulminant hepatitis B develops in approximately 15% of hepatitis B-infected HCT recipients.¹⁰⁸ There is a 35% risk of post-HCT reactivation of HBV in patients with isolated anti-HBc antibodies, usually during treatment for acute GVHD.¹¹⁶ Severe hepatitis B has been seen in anti–HBc/anti–HBs-positive patients and in a patient with occult hepatitis B.¹¹⁷ Prior to HCT, liver biopsy should be considered if there is a clinical suspicion of cirrhosis or extensive fibrosis, as these are relative contraindications to transplant even with reduced intensity conditioning regimens.¹¹⁸ A reduced intensity conditioning regimen may allow congenitally immunodeficient children with chronic liver disease to be transplanted successfully, with resolution of liver disease.¹¹⁹

Recent Liver Dysfunction in Candidates for Hematopoietic Cell Transplantation

Patients who come to HCT following recent chemotherapy or radiation therapy that damaged the liver may be at significant risk from additional liver insults after HCT.¹²⁰ These patients must be carefully evaluated with regard to the risk posed by liver-toxic conditioning regimens, particularly those containing cyclophosphamide (CY) or total body irradiation.^121–123 Imatinib (Gleevec) and gemtuzumab ozogamicin (Mylotarg) deserve special mention in this context. Iminatib mesylate (and similar drugs) may cause acute hepatocellular necrosis and multiacinar collapse, with eventual healing by focal fibrosis^124,125; we have successfully given CY-based myeloablative conditioning to patients who recovered from the acute injury but who had patchy fibrosis on biopsy. Gemtuzumab ozogamicin causes sinusoidal liver injury in 3% to 15% of patients¹²⁶ and is a risk factor for fatal sinusoidal obstruction syndrome (SOS) if given in proximity to a liver-toxic myeloablative regimen.^126,127

Gallbladder and Bile Duct Stones

HCT candidates with asymptomatic gallstones (incidentally discovered during CT or ultrasonography) do not require operative intervention.¹²⁸ Patients with symptomatic cholelithiasis or stones in the common duct are at risk for biliary sepsis after HCT.

Iron Overload

HCT candidates with diseases such as thalassemia, aplastic anemia, and chronic leukemia or lymphoma may come to HCT with marked hepatic siderosis. The amount of liver iron can be accurately determined by iron-specific MRI (FerriScan or T2*).¹²⁹ In patients with extreme iron overload, effective pre-HCT iron chelation therapy improves post-HCT survival.¹³⁰ Although some studies suggest an association between excess tissue iron stores and regimen-related toxicity, others have failed to demonstrate this. In most patients the quantitation of tissue iron stores and a decision about iron mobilization can be deferred until after recovery from HCT.

Anorexia, Nausea, and Vomiting

Myeloablative conditioning therapy makes most patients nauseated and anorexic,¹³¹ findings associated with delayed gastric emptying.¹³² Serotonin-antagonist drugs are very effective in relieving symptoms during chemotherapy. Mucositis caused by myeloablative conditioning therapy may lead to oral mucosal swelling, pain, and in severe cases sloughing of pharyngeal and esophageal epithelium, intense gagging, an inability to swallow, vomiting, retrosternal pain, and airway obstruction. Opioid therapy is effective in relieving pain but can lead to gastric stasis and intestinal ileus with worse anorexia and vomiting. Methylnaltrexone, a peripheral mu-opioid receptor antagonist, can block gut opioid symptoms while allowing pain relief.⁷⁷ Appetite and food intake may remain poor for up to three weeks after myeloablative therapy, an effect that is mediated by cytokines that affect appetite (interleukin [IL]-2, IL-6, tumor necrosis factor-α [TNF-α]).¹³¹ Some regimens, notably those that contain very high-dose melphalan or multiple alkylating agents, may cause unusually severe intestinal mucosal necrosis and anorexia.

An early sign of acute GVHD is loss of appetite, often followed by nausea and vomiting. Before day 20, these symptoms overlap with effects of conditioning therapy. After day 20, more than 80% of patients with intractable anorexia, nausea, or vomiting will have gastric and duodenal GVHD as the sole explanation.¹³³ Endoscopy shows edema of the gastric antral and duodenal mucosa, patchy erythema, and bilious gastric fluid, and histology demonstrates epithelial cell apoptosis and drop-out, often with localized lymphocytic infiltrates (Fig. 34-4).¹³⁴ However, there is a false-negative rate with histology because of the patchiness of GVHD lesions. Immunosuppressive therapy using a 10-day course of prednisone 1 mg/kg/day plus oral beclomethasone dipropionate 8 mg/day is an effective therapy that avoids prolonged systemic immunosuppression and results in better outcomes.^135,136 Recipients of autologous grafts may also develop a syndrome of anorexia, nausea, and vomiting that is associated with diffuse gastric edema and erythema.¹³⁷ Gastric histology shows typical GVHD. Symptoms respond to a 10-day course of prednisone 1 mg/kg/day. Endoscopy also serves to rule out intestinal infection with herpesviruses, bacteria, and fungi. CMV infection of the esophagus and upper intestine accounted for a third of patients with unexplained nausea and vomiting during the pre-ganciclovir era. These infections are usually diagnosed between days 50 and 150,¹³⁸ but can present earlier if patients have activated CMV before transplant.⁹⁵ Gut CMV infections can be seen in the absence of evidence of CMV in the bloodstream. HSV esophagitis may present similarly in patients not receiving prophylactic acyclovir. Intestinal CMV and HSV infections are now rare. Fungal esophagitis may cause anorexia but not the incessant vomiting often seen with GVHD or herpesvirus infections. Studies of gastric emptying and myeloelectric activity in HCT patients have shown that symptoms of nausea and vomiting are frequently accompanied by retention of radionuclide meals and disordered electrical activity.¹³⁹ Promotility agents such as metoclopramide, domperidone, and low-dose erythromycin are occasionally useful, but in patients with persistent symptoms, endoscopic evaluation should precede empirical promotility therapy. Anorexia and vomiting may also be manifestations of central nervous system (CNS) disease; other neurologic signs and symptoms usually dominate the clinical picture in patients with CNS disorders. In patients with a history of glucocorticoid exposure, adrenal insufficiency may also cause upper gut symptoms.

Figure 34-4. Endoscopic and histologic manifestations of acute graft-versus-host disease (GVHD) of the gastrointestinal tract. A, Esophagus: desquamation of squamous epithelium of the distal esophagus in severe GVHD. B, Stomach: diffuse mucosal edema and erythema in the gastric antrum in moderately severe GVHD. C, Small intestine: mucosal edema, focal bleeding, and ulceration in severe GVHD. D, Rectum: focal apoptosis (arrow) caused by GVHD in crypt epithelium (Hematoxylin and eosin, alcian blue). E, Colon: the bottom of a colon crypt (arrows) is missing epithelial cells; apoptotic debris is admixed with mucus at the base of the crypt (Hematoxylin and eosin, alcian blue). F, Small intestine: gross and histologic findings in fatal GVHD. Autopsy photograph of a small intestinal segment opened to reveal sloughing of the mucosa (top); histology shows complete absence of epithelial cells, a lymphoid infiltrate, and submucosal edema (bottom) (Hematoxylin and eosin).

Oral medications such as calcineurin inhibitors, MMF, trimethoprim-sulfamethoxazole, itraconazole, posaconazole, voriconazole, imatinib and similar drugs, and high-dose opioids also cause nausea and vomiting.^106,107 Mycophenolic acid causes fewer GI symptoms than MMF.⁶⁴ Parenteral infusions of fat, glucose, and amino acids reduce food intake, slow gastric emptying, and cause nausea. Even after total parenteral nutrition has been stopped, appetite suppression may linger for one to three weeks.¹⁴⁰

Jaundice, Hepatomegaly, and Abnormal Liver Biochemical Tests

Development of jaundice following HCT is an ominous prognostic sign, with increased nonrelapse mortality in patients whose total serum bilirubin exceeds 4 mg/dL.¹⁴¹ Fortunately the frequency of severe liver injury after HCT is much lower than it was 10 years ago because of less frequent use of drugs that cause sinusoidal injury and because of prophylaxis of cholestatic injury with ursodiol.^142–144 There are multiple causes of jaundice after HCT (Table 34-2).

Sinusoidal Obstruction Syndrome (Veno-occlusive Disease)

Some myeloablative conditioning regimens may damage hepatic sinusoids, leading to hepatomegaly, fluid retention and weight gain, and elevated serum bilirubin.¹⁴⁵ Individual variability in cyclophosphamide metabolism, irradiation dose, use of gemtuzumab ozogamicin, and preexisting liver inflammation and fibrosis are risk factors.^121,123,126 Reduced intensity regimens rarely affect hepatic sinusoids.¹¹⁸ A clinical diagnosis of SOS may suffice if typical signs develop before day 20 post transplant, but Doppler ultrasonography, measurement of the wedged hepatic venous pressure gradient, and liver histology may be needed in difficult cases.^146–148 Initial histologic changes of SOS are dilation of sinusoids, extravasation of red cells through the space of Disse, necrosis of periventricular hepatocytes, and widening of the subendothelial zone in central veins (Fig. 34-5A).¹⁴⁵ The later stages are characterized by extensive collagenization of sinusoids and venules (see Fig. 34-5B). More than 80% of patients with SOS recover completely. A poor prognosis correlates with the degree of bilirubin elevation and weight gain, higher serum aminotransferase enzyme (AST and ALT) values, higher wedged hepatic venous pressure gradient, development of portal vein thrombosis, and multiorgan failure. Treatment of severe SOS is unsatisfactory; the best results are with intravenous defibrotide (25 mg/kg/day), a porcine oligonucleotide that has effects on microvascular endothelial cells.¹²⁷ SOS can be prevented by identifying patients at risk and altering the transplant regimen using (1) conventional, not transplant therapy; (2) a reduced-intensity conditioning regimen¹¹⁸; (3) a myeloablative regimen that does not contain cyclophosphamide (e.g., targeted busulfan-fludarabine for allogeneic HCT^149,150 or BEAM (BCNU [carmustine], etoposide, arabinoside [cytarabine], melphalan) for autologous HCT¹⁵¹); (4) modification of CY-based regimens.^152,153 Patients with cirrhosis may decompensate even after a reduced-intensity allograft.¹¹⁸

Figure 34-5. Histology of liver diseases following hematopoietic cell transplantation. A, Sinusoidal obstruction syndrome (SOS; also known as veno-occlusive disease of the liver) at 23 days post-transplant: high-power view of hemorrhage into the space of Disse, hepatocyte necrosis, disrupted sinusoids, and subendothelial edema of the central vein (arrow). The lumen of the vein is patent (Hematoxylin and eosin). B, SOS caused by gemtuzumab ozogamicin: high-power view of zone 3 of the acinus showing extensive sinusoidal fibrosis, hepatocyte dropout, and a patent central vein (Masson trichrome stain). C, Acute graft-versus-host disease (GVHD) at day 82 post-transplant: portal area containing abnormal small bile ducts (arrows) with epithelial cell dropout, cytoplasmic eosinophilia, and vacuolization (Hematoxylin and eosin). D, Chronic GVHD at day 184 post-transplant: high-power view of a portal area, with damaged small bile ducts (arrows) infiltrated by lymphocytes (Hematoxylin and eosin). E, Varicella-zoster virus hepatitis: Low-power view of confluent necrosis of hepatocytes (arrows, pointing to pale area) adjacent to hepatocytes that are normal (periodic acid–Schiff). F, Adenovirus hepatitis: low-power view of a focal area of confluent hepatocyte necrosis (arrows, pointing to basophilic area) with remnants of hepatocytes that contain intranuclear inclusions typical of adenovirus (“smudge cells”), best seen at higher power (Hematoxylin and eosin).

Gastrointestinal Bleeding

Bleeding that does not require transfusion is very common after HCT, particularly when platelet counts are low. Causes include retching-induced trauma to the esophageal or gastric mucosa (Fig. 34-6A), mucosal injury from conditioning therapy, peptic esophagitis, C. difficile colitis, anal fissures and hemorrhoids, and mild acute GVHD. The incidence of severe GI bleeding, particularly in patients with adequate platelet counts, is less than 1% because of effective prophylaxis against viruses, fungi, and acute GVHD.¹⁷⁵ Mortality from severe intestinal bleeding, however, remains at 40%.^175,176 The most common cause of severe bleeding is refractory acute GVHD, which can result in bleeding from extensive ulceration in the small intestine and cecum (see Fig. 34-4). In some patients with GVHD, bleeding may appear to be coming from specific areas of the mucosa, but when such patients are operated on or come to autopsy, diffuse rather than focal mucosal ulceration is the rule. Ulcers in the stomach or duodenum that develop after HCT are usually caused by acute GVHD or CMV infection, but with preemptive ganciclovir therapy, bleeding CMV ulcers have become rare.¹⁷⁵ Gastric ulcerations also may be caused by infection by VZV, bacteria (phlegmonous gastritis), or EBV (lymphoproliferative disease) (see Chapter 51). Gastric antral vascular ectasia, is also a cause of severe upper intestinal bleeding in HCT recipients who received oral busulfan as part of conditioning therapy.^177,178 Diffuse areas of hemorrhage are seen in the gastric antrum and proximal duodenum, but the underlying mucosa is intact (see Fig. 34-6B). Histology is diagnostic, revealing abnormal dilated capillaries, thromboses, and fibromuscular hyperplasia in the lamina propria (see Fig. 34-6C). Endoscopic laser therapy is the treatment of choice to control bleeding, but multiple laser treatments may be required to obliterate ectatic lesions.¹⁷⁸ Rare gastroduodenal causes of bleeding post HCT include ulcers caused by molds (see Fig. 34-6D), Dieulafoy lesions, Curling (stress) ulcers, duodenal biopsy sites, adenovirus colitis (see Fig. 34-6E), and C. septicum infection (typhlitis).¹⁷⁹ There is no effective therapy for mucosa that is diffusely oozing blood other than raising the platelet count and treating the underlying condition. In GVHD, re-epithelialization of ulcerated intestinal mucosa occurs very slowly (see Fig. 34-4F). Focal bleeding lesions, especially those caused by mucosal infection, can be treated with endoscopic cautery, heater probe, or epinephrine injection provided platelet counts are adequate. Unless the underlying disease process is eliminated, these endoscopic methods will not cure the bleeding problem. Attempts to resect large segments of diffusely bleeding intestine involved with GVHD have not been successful.

Figure 34-6. Uncommon gastrointestinal problems in hematopoietic cell transplant recipients. A, Esophagus: barium contrast radiograph of an intramural hematoma that occupies one wall of the esophagus from the aortic arch to the lower esophagus. The red line approximates the normal esophageal contour. This hematoma was caused by retching in a thrombocytopenic patient. B, Stomach: diffuse oozing of blood through the mucosa of the gastric antrum in gastric antral vascular ectasia (GAVE). When the blood was washed off, the underlying mucosa was not ulcerated, yet blood reappeared. C, High-power view of an antral biopsy specimen illustrating the features of GAVE: capillary dilation, thrombosis, and fibromuscular hyperplasia (Hematoxylin and eosin). D, Duodenum: linear ulceration with yellow exudates (arrows) caused by Rhizopus infection in a transplant patient receiving immunosuppressive therapy for graft-versus-host disease (GVHD). The surrounding mucosa is abnormal because of GVHD. E, Colon: sigmoid colon in adenovirus colitis showing diffuse mucosal edema, ulceration, and hemorrhage.

Dysphagia

Mucositis, acid-peptic esophagitis, and pill esophagitis are the leading causes of dysphagia. Infections of the esophagus have largely disappeared because of antiviral and antifungal prophylaxis. Desquamation of oropharyngeal epithelium caused by conditioning therapy may lead to pain on initiating a swallow and inability to move a bolus past the cricopharyngeus. Rarely, non-healing esophageal ulcerations, strictures, and dysphagia result from conditioning therapy. The abrupt onset of severe retrosternal pain, hematemesis, and painful swallowing suggests a hematoma in the wall of the esophagus, a result of retching when platelet counts are very low (see Fig. 34-6A).¹⁸⁰ Endoscopy is relatively contraindicated because many intramural hematomas represent contained perforations. The course of intramural hematomas is one of slow resolution over one or two weeks. In patients with severe GVHD, esophageal edema, erythema, and a peeling epithelium lead to ulcerations (see Fig. 34-4A).¹⁸¹ Pill esophagitis occurs after ingestion of medications that might be used after HCT, such as phenytoin, foscarnet, captopril, oral bisphosphonates, ascorbic acid, ciprofloxacin, clindamycin, and oral potassium chloride.

Diarrhea (see Table 34-3)

Diarrhea caused by mucosal damage from myeloablative conditioning therapy is seldom severe, usually resolving by days 12 to 15. Cytarabine-containing regimens, high-dose melphalan, and multiple alkylating regimens cause more severe, protracted diarrhea. Intravenous octreotide and oral loperamide at (4 mg by mouth every six hours) may be effective for severe diarrhea associated with conditioning therapy. Acute GVHD is the most common cause of diarrhea after day +15.^176,182 The onset of diarrhea can be sudden, with daily stool volumes in excess of 2 L in severe cases. The diarrheal fluid is watery and green, with ropy strands of mucoid material that reflect transmucosal protein loss. In an allografted patient with skin and liver abnormalities typical of acute GVHD, this diarrheal syndrome is almost diagnostic of intestinal GVHD, particularly when there is falling serum albumin and negative stool studies for infection. In GVHD, abdominal imaging (CT, positron-emission tomography [PET]-CT, or focused ultrasonography) may reveal intestinal edema, but this finding does not differentiate acute GVHD from CMV infection.^148,183,184 Pneumatosis intestinalis, which may be associated with GVHD or CMV enteritis, may be seen by plain x-ray, CT, or MRI. A definitive diagnosis of GVHD in problematic cases requires mucosal biopsy. In mild cases, the gastroduodenal and rectosigmoid mucosa are grossly normal, but moderately severe GVHD causes diffusely edematous and erythematous mucosa (see Fig. 34-4).¹³⁴ Severe GVHD may lead to ulcerations and large areas of mucosal sloughing in the stomach, small intestine and colon (see Fig. 34-4F). Even when the endoscopic appearance is normal, biopsies often reveal intestinal crypt cell necrosis and apoptotic bodies diagnostic of acute GVHD (see Fig. 34-4D). In severe cases of GVHD, whole crypts are destroyed, then adjacent crypts, and finally whole segments of intestinal mucosa (see Fig. 34-4E and F). Other histologic findings that support the diagnosis of GVHD include pericapillary hemorrhage,¹⁸⁵ infiltrating neutrophils,¹⁸⁶ or eosinophils.¹⁸⁷ The use of capsule endoscopy for diagnosis of GVHD can provide visual inspection of the small intestine that cannot be seen with routine endoscopy, but does not allow biopsy.¹⁸⁸ The negative predictive value of a capsule endoscopy examination of the small intestine appears to be high and is thus useful for excluding more severe acute GVHD.¹⁸⁸ Bleeding often accompanies diarrhea in patients with mucosal ulceration.¹⁷⁵ Successful treatment of acute GVHD with immunosuppressive therapy results in a dramatic reduction in stool volume, with resolution of accompanying symptoms of abdominal pain, nausea, and vomiting. The management of patients whose diarrhea and other symptoms of intestinal GVHD persist after 7 to 14 days of immunosuppressive therapy is unsatisfactory because the rate of failure of secondary therapy is high.¹⁸⁹ Overall prognosis in patients with GVHD can be estimated by use of the acute GVHD Activity Index.¹⁹⁰

In allograft recipients, infectious causes of diarrhea are far less common than GVHD, accounting for only 10% to 15% of diarrheal episodes.^176,182 In countries where intestinal parasitism and bacterial contamination of water are endemic, the spectrum of infections may be wider.⁹⁸ C. difficile colitis is usually a relatively mild, treatable disease when diagnosed at the onset of diarrhea, but the recent emergence of more virulent strains of C. difficile has changed the natural history of this infection. The inappropriate use of proton pump inhibitors for marginal indications¹⁹¹ increases the risk of C. difficile colitis twofold.¹⁹² Other relatively common causes of infectious diarrhea include astrovirus, norovirus, rotavirus, CMV, and adenovirus.^{99,182,193,194} Some serotypes of adenovirus cause necrotizing enteritis and rapidly fatal multiorgan failure involving the gut, liver, lungs, and kidneys (see Fig. 34-6E).^157,158,195 There should be a sense of urgency in identifying adenovirus as a cause of enteritis, as early treatment with cidofovir appears to be effective.^161,162 CMV is the only cause of enteritis after HCT that requires an intestinal biopsy for diagnosis.¹⁸² Otherwise the negative predictive value of a stool examination (including PCR) for other viruses, bacteria, fungi, and parasites is high. Watery diarrhea secondary to intestinal parasite infection (Cryptosporidium, G. lamblia, and E. histolytica) and mycobacteria infection are rare outside of endemic areas.^{100,194,196,197} Diarrhea may also result from carbohydrate malabsorption (particularly in patients on antibiotics), oral magnesium salts, tacrolimus (a motilin agonist), metoclopramide, and MMF.^198,199 MMF gut toxicity can be addressed by switching to mycophenolic acid.⁶⁴

Abdominal Pain

It is extremely important to distinguish abdominal pain as an indicator of a rapidly progressive, fatal condition from illnesses with a benign natural history that require only conservative management. The causes of abdominal pain after HCT are listed in Table 34-4. The illnesses that may progress rapidly include intestinal perforation, some infections (e.g., typhlitis caused by C. septicum, adenovirus, and VZV), gallbladder necrosis, liver abscess, and acute GVHD presenting only as abdominal pain.²⁰⁰ Fortunately, these disorders are far less common than intestinal pseudo-obstruction, hepatic pain related to SOS, multisystem acute GVHD, and hemorrhagic cystitis. Intestinal perforation may develop in the setting of lysis of a transmural lymphoma or metastatic carcinoma shortly after conditioning therapy, or later on, from CMV ulcers or diverticular perforation. Perforation may present with only mild to moderate abdominal pain and pneumoperitoneum on plain abdominal x-ray. Dilation of the bowel in the absence of a mechanical obstruction is the most common cause of moderate to severe abdominal pain. Most patients with pseudo-obstruction have an underlying intestinal disease, such as enteritis from conditioning therapy, GVHD, or infection, but frequently the acute presentation is related to increasing use of mu-opioid medications. Pseudo-obstruction is more frequent among patients with lymphoma, a result of intestinal neuropathy from repeated use of vincristine (see Chapter 120). To allow pain relief without affecting colon motility, methylnaltrexone can be used.⁷⁷ Alternatively, colon distention may decrease after switching from a mu-opioid to a kappa-opioid agonist (for example, to butorphanol). Neostigmine (2 mg intravenously) has been successfully used in patients with acute colonic pseudo-obstruction after HCT.²⁰¹ In visceral VZV infection, abdominal distention, severe pain, fever, and rising serum ALT may precede cutaneous manifestations by up to 10 days.¹⁶⁰ In rare instances, a skin rash never develops. Acyclovir should be started on clinical suspicion while serum is analyzed by PCR for VZV DNA.¹⁶⁰

More severe acute intestinal GVHD may present with nausea, anorexia, periumbilical crampy abdominal pain, and diarrhea. The sudden onset of intestinal edema (see Fig. 34-4B and C) can cause a rigid abdomen with rebound tenderness preceding the development of a skin rash or diarrhea. The decision to treat a patient empirically with prednisone when definitive evidence of GVHD is not at hand can be difficult, but when the pretest probability of GVHD is high (e.g., an HLA-mismatched or unrelated donor; engraftment; a nascent skin rash) and that of perforation or infection low, treatment should be started while GVHD is sought by endoscopic mucosal biopsy (see Fig. 34-4).

Pancreatitis is an uncommon cause of abdominal pain in HCT patients, but in a study of autopsied patients the prevalence of acute pancreatitis was 28%.²⁰² Symptoms of pancreatitis had been absent in many of the patients who were found to have florid pancreatitis at autopsy, suggesting that symptoms had been masked by immunosuppressive drugs. Patients with low platelet counts or prolongation of blood clotting may rarely bleed into the retroperitoneum, abdominal wall, or intra-abdominal viscera, particularly after duodenal biopsy, causing significant pain.

Intestinal infections presenting with significant pain are listed in Table 34-4. Typhlitis (C. septicum infection) occurs in granulocytopenic patients but is not common after HCT. Symptoms include fever, right lower quadrant pain, nausea and vomiting, diarrhea, occult blood in stool, and shock.¹⁰² Typhlitis is usually diagnosed using imaging studies; laparotomy is rarely necessary.²⁰³ If typhlitis is a possibility, imipenem and oral vancomycin therapy should be started along with coverage for luminal bacteria and fungi.²⁰⁴

Perianal Pain

Perianal pain after HCT can be caused by an anal fissure, a thrombosed external hemorrhoid, cellulitis related to tissue maceration, fistulas, and abscesses. In patients with granulocytopenia, infections in the perineum or perianal spaces are usually polymicrobial, arising either from anal crypts or from tears in the anal canal. After HCT these infections can be difficult to recognize because they may not produce abscesses but rather a spreading cellulitis. Extensive supralevator and intersphincteric abscesses may be present without being apparent on external examination. CT, MRI, or endoscopic ultrasonography can give a clear view of the anatomy involved, particularly if there is pus present.²⁰⁵ When antibiotics covering anaerobic and aerobic bacteria are given to patients with incipient perianal infection, far fewer patients require surgical drainage than in the past.

Liver Disease Caused by Graft-Versus-Host Disease

Long-term survivors of transplant who have hepatic GVHD usually have other evidence of chronic GVHD, a pleomorphic immune disorder characterized by oral and ocular sicca; ulceration in squamous epithelium of the skin, mouth, esophagus, and vagina; subcutaneous fibrosis; contractures and myositis; immunodeficiency; and other manifestations of immune dysregulation. Liver involvement in these patients, like gut mucosal inflammation, is considered to be a protracted form of acute GVHD because clinical and histologic changes in these organs are identical to those in patients with acute GVHD that occurs in the months following HCT.²⁰⁶ Patients with isolated elevations of serum alkaline phosphatase or ALT related to GVHD should be followed closely, but may not require high-dose immunosuppressive therapy. By the time that jaundice develops in patients with chronic GVHD, liver biopsy shows extensive damage to small bile ducts and, in severe cases, ductopenia. In patients receiving no, or tapering doses of, immunosuppression, liver GVHD may also present as an acute hepatitis, with abrupt elevations of serum aminotransferase levels to more than 2000 U/L.¹⁵⁵ A similar presentation can be seen after donor lymphocyte infusion (DLI).¹⁵⁶ In patients presenting with an acute hepatitis, blood samples for viral DNA or ribonucleic acid (RNA) or liver biopsy are essential in excluding acute viral hepatitis due to a herpesvirus (HSV or VZV) or a hepatitis virus and to make a definitive diagnosis of hepatic GVHD (see Fig. 34-5D and E). A serum autoantibody test for CYP1A2 may prove diagnostically useful in the diagnosis of hepatitic GVHD because this enzyme appears to be a target antigen in GVHD.²⁰⁷ Immunosuppressive drug treatment of chronic GVHD is successful in 50% to 80% of patients with extensive multiorgan disease, but refractory chronic GVHD is a fatal illness. The addition of ursodeoxycholic acid (15 mg/kg/day) may result in biochemical improvement.²⁰⁸ Ductopenic GVHD is potentially reversible if ongoing immunologic destruction of biliary epithelium ceases, but this process may take months before resolution of jaundice.¹⁵⁵ Liver transplantation, including living-donor transplantation from the original stem cell donor,²⁰⁹ has been performed for patients with liver failure due to chronic hepatic GVHD, although frequently there are contraindications to this approach.²¹⁰

Chronic Viral Hepatitis and Cirrhosis

HCV infection in HCT survivors almost always results in chronic hepatitis.^114,115 In the first 10 years of HCV infection after HCT, there is little liver-related morbidity.¹¹⁴ However, a third of patients transplanted before the 1990s will develop cirrhosis related to chronic HCV infection over a 20- to 40-year time frame.¹¹⁵ The reasons for more rapid progression of fibrosis after HCT may be related to concomitant liver involvement with GVHD, immunosuppression, and iron overload.²¹¹ Iron overload is particularly severe in thalassemic patients who have undergone HCT.²¹² Patients with chronic HCV should be offered therapy with combination pegylated INF-α plus ribavirin, unless there are contraindications.^167,213 Pegylated interferons, with their longer half-lives, should be administered with caution because some HCT patients experience rapid falls in platelet and granulocyte counts. INF-α may also activate chronic GVHD. Liver transplantation should be considered in any HCT survivor with incipient liver decompensation; in some cases, the original allogeneic cell donor can be a partial liver donor.²¹⁴

The prevalence of chronic HBV infection among HCT survivors varies widely depending on the country. Patients who remain viremic or HBsAg positive after HCT are at risk of flares of hepatitis B at times of reduction of immunosuppression, such as during tapering or cessation of treatment for chronic GVHD. All long-term survivors with chronic hepatitis B should be regularly monitored to assess the need for antiviral therapy. Hepatitis B e antigen and antibody status should be determined in all patients, and liver enzymes monitored every 6 to 12 months. The need for antiviral treatment with an oral nucleoside or nucleotide analog (for instance, entecavir, telbivudine, adefovir, tenofovir) is based on the ALT and HBV DNA levels and the severity of hepatic fibrosis.²¹⁵ These levels may change over time, emphasizing the need to continually reassess patients who are not on treatment. As in the peritransplant period, patients with viremia or positive HBsAg should receive an antiviral agent whenever they receive immunosuppressive or cytotoxic therapy.²¹⁶

Hemosiderosis

Iron overload is caused by a combination of multiple red cell transfusions (e.g., for thalassemia) and dyserythropoiesis leading to increased iron transport by the intestine. After HCT, iron accumulation stops and body iron stores fall slowly over time.²¹⁷ The consequences of extreme iron overload in HCT survivors are primarily those of cardiac, pituitary, and endocrine pancreatic dysfunction. Iron overload may be an important cofactor in liver disease in long-term survivors of HCT and should be part of a screening panel.^218,219 In the past, liver biopsy with liver iron determination was required, but increasingly noninvasive methods (e.g., MRI¹²⁹) are being used to provide assessments of liver iron concentration and distribution. Patients with liver iron content greater than 15,000 µg/g dry weight should be treated aggressively with phlebotomy and chelation; when liver iron content is 7000 to 15,000 µg/g dry weight, phlebotomy is indicated; when liver iron content is less than 7000 µg/g dry weight, treatment is indicated only if there is evidence of liver disease.²²⁰ Mobilization of iron from heavily overloaded patients improves cardiac function, normalizes serum ALT levels, and results in improved liver histology.^219–222

Hepatic Drug Toxicity

Drug-induced liver injury may be related to drugs in common use by transplant survivors, including antihypertensive drugs, lipid-lowering agents, hypoglycemic agents, NSAIDs, antidepressants, antibiotics, and herbal preparations.²²³ Some drug reactions may result in chronic liver disease.²²⁴

Fungal Liver Infections

Fungal abscesses can recur after apparently successful antifungal therapy when high-dose immunosuppressive drugs are started for GVHD. Oral, nonsterile herbal remedies contaminated by molds may lead to liver abscesses in immunosuppressed HCT survivors.²²⁵

Liver Cancer

Compared with the general population, patients who survive more than 10 years post HCT have an eightfold risk of developing a new solid malignancy. The risk of hepatocellular carcinoma is particularly elevated.²²⁶ Transplant survivors with risk factors for hepatocellular carcinoma (HCV or HBV infection, obesity, diabetes, low platelet count) should be screened at yearly intervals (see Chapter 94).^227,228 Chronic hepatitis C may also be a risk factor for development of lymphoma²²⁹ and other lymphoproliferative disorders²³⁰ after transplant.

Other Hepatobiliary Disorders

There is a higher than expected incidence of gallstones and stone-related biliary problems after HCT than in an age-matched population, probably related to earlier formation of biliary sludge. Chronic cyclosporine dosing also may lead to gallstones and biliary symptoms. Patients who have experienced SOS from either chemotherapy or a myeloablative conditioning regimen may rarely develop hepatic nodularity caused by atrophy of zone three and hypertrophy of zone one hepatocytes, without fibrosis.²³¹ This process (nodular regenerative hyperplasia) is usually clinically silent unless portal hypertension develops, manifested by variceal bleeding, ascites, splenomegaly, and thrombocytopenia, but with preserved liver function. Focal nodular hyperplasia (nodules readily seen by liver imaging, with characteristic central scars) has been described as an incidental finding in 12% of a cohort of HCT survivors, up to 14 years after transplant.²³² These lesions are likely the result of sinusoidal liver injury caused by myeloablative conditioning regimens.

Esophageal Disorders

Some patients with extensive chronic GVHD have esophageal desquamation, webs, submucosal fibrous rings, bullae, and long, narrow strictures in the upper and mid-esophagus.^233–236 Although the most common symptom is dysphagia, some patients present with insidious weight loss, retrosternal pain, and aspiration of gastric contents. The diagnosis is made by barium contrast radiography and endoscopy,²³⁶ which should be done with caution because perforations have been reported.²³³ Tight strictures are difficult to dilate safely, but failure to dilate strictures may lead to progressive esophageal narrowing. Esophageal involvement can be prevented by prompt treatment of chronic GVHD at its early stages. Therapy with proton pump inhibitors should be considered if there is uncontrolled acid reflux. Myasthenia gravis may also complicate chronic GVHD, with dysphagia as its presenting complaint.²³⁷ Sporadic cases of fungal and rarely viral esophagitis may occur in patients with chronic GVHD on immunosuppressive and antibiotic therapy. Esophageal strictures may be sequelae of earlier herpesvirus infection or mucositis. Squamous cell carcinoma of the esophagus has been reported in HCT survivors, usually with concomitant chronic GVHD of the oropharynx.²³⁸

Gastrointestinal Disorders

The incidence of diarrhea falls sharply after day 100 except in patients who have received allografts following reduced intensity conditioning therapy²³⁹ and in those whose acute GVHD has never resolved. Patients with protracted acute GVHD, however, often have symptoms that wax and wane with intensity of immunosuppressive therapy for up to 15 years after HCT, with each exacerbation similar to the presenting signs of GVHD that occurred earlier after HCT (satiety, poor appetite, nausea, episodic diarrhea, and weight loss).^240,241 The endoscopic and histologic appearance of intestinal mucosa is identical to that seen in acute GVHD (see Fig. 34-4). Use of oral beclomethasone dipropionate can be effective in treating patients with protracted acute GVHD involving the GI tract.²⁴² Before the introduction of more effective immunosuppressive drugs, chronic GVHD resulted in extensive collagen deposition in submucosal and subserosal areas of the intestinal tract, resulting in refractory malabsorption²⁴³; this process has not been seen in recent years. There are sporadic cases of C. difficile, CMV,¹³⁸ and rarely G. lamblia and cryptosporidiosis in long-term survivors. Chronic intestinal viral infection can be seen in patients who remain on immunosuppressive drugs, including rotavirus, norovirus, and adenovirus. Intestinal diseases in donors have been reported in their recipients, such as idiopathic inflammatory bowel disease and celiac disease.²⁴⁴

Pancreatic Disease

Acute pancreatitis has been described in transplant survivors, usually related to passage of gallstones or sludge. Cyclosporine and tacrolimus also may cause pancreatitis.^245–247 Diarrhea, steatorrhea, and weight loss secondary to pancreatic insufficiency have developed in some HCT survivors.^248,249 The cause is unclear; previous pancreatic necrosis, prolonged glucocorticoid exposure, and tacrolimus toxicity are the leading possibilities.²⁰² Transient pancreatic insufficiency has been noted in patients with gut and liver GVHD.²⁵⁰ Chronic GVHD and extreme iron overload also may contribute to pancreatic damage.