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Gastrointestinal and Liver
Graft Versus Host Disease (GVHD)
• Discuss a case of pediatric GVHD.
• Review background on GVHD.
• Understand differential diagnosis of liver and
• Familiarize with characteristics and histologic
findings of acute and chronic GVHD.
• 22 month old boy with familial HLH
• s/p matched, unrelated cord bone marrow
transplant on 10/24/2011.
• He had been conditioned with busulfan,
etoposide, cyclophosphamide, and ATG.
• Diagnosed with skin GVHD early on (worst on
face) and placed on solumedrol (day +1 to day
+19) and transitioned to tacrolimus and IVIg ppx.
• He had hospitalizations for skin GVHD needing
steroid pulse 4mg/kg/day in Jan 2012, Feb 2012.
• Skin GVHD up to grade 3 (>50% BSA but no
• He had on/off diarrhea which always
improved with increased immunosuppression
so no biopsies were obtained.
• In May 2012, he was admitted with diarrhea
(no quantification, “watery” stool “all day”).
At that time he was on prograf 0.8 mg bid and
cellcept 250 mg bid. Wt ~10kg.
• Stool studies including c diff, campy bacterial, rota,
adeno, noro, and cells all negative.
• Medications included prograf, enalapril, cellcept,
pepcid, magnesium, fluconazole, and valycte.
• CMV and EBV PCR were negative.
• Endoscopy in May 2012 c/w colonic GVHD.
• Placed on solumedrol 4mg/kg/day and IV cellcept. He
was also put on PO budesonide and continued on IVIg.
• He was put on trophic NG feeds and TPN/IL.
• LFTs have also been elevated, thought to be from HHV6
chronic infection (liver biopsy obtained).
except for loss of
mucosa in rectum,
colon with loss of
EGD Pathology Report
• Duodenum and antrum were normal
• Mid body of stomach with mild active
inflammation. H. pylori negative.
• Overall: Not consistent with GVHD.
Flex Sig Pathology Report
• Sigmoid: mild active inflammation with
increased crypt apoptotic bodies, consistent
with GVHD grade 1. No PTLD or viral
• Rectum: moderate active inflammation with
increased crypt apoptotic bodies c/w GVHD
grade 2-3. No PTLD or viral inclusions.
• Comment: Also consider drug injury and less
Flex Sig Pathology Report
• There is crypt dilation, increased crypt
apoptoses, mild lamina propria neutrophilic
• Crypt abscesses and crypt dropout is
• CMV stains negative.
• GVHD is one of the most common complications
of hematopoietic stem cell transplant (HSCT).
• In 1955, Barnes and Loutit described diarrhea,
skin changes, and “wasting syndrome” in mice.
• Involvement can include skin, liver, GI tract, and
more rarely, lung.
• It is a leading cause of morbidity and mortality
after HSCT. It can be fatal in up to 15% of
• Transplanted immune cells (graft or donor)
recognize patient’s (host) cells as foreign.
• Primarily T cell mediated disease
• 3 phases
– 1: conditioning regimen damages and activates host
tissues to secrete cytokines that upregulate MHC
– 2: donor T cell activation
– 3: Multiple inflammatory cascades
• Th1 CD4 -> TNFa, IL1 -> apoptosis
When can you get GVHD?
• Hematopoietic stem cell transplant
– Non autologous (allogeneic)
• Blood transfusion
• Solid organ transplantation
10-40% of patient develop significant (grade 2-4)
GVHD and ½ of these patients will die from
GVHD or therapy related complications
• Acute: less than 100 days after transplant.
• Chronic: more than 100 days after transplant.
• But there is now a shift towards defining acute
and chronic based on clinical and histologic
• Hyperacute: mismatched or underprophylaxed
patients without engraftment.
• Skin rash (classically first and most common)
• Jaundice (liver is 2nd most common)
– Rarely do patients have moderate to severe hepatic GVHD
without evidence of cutaneous disease or GI disease
– Rise in direct bili and alk phos (damage to bile canaliculi,
leading to cholestasis)
• Hepatitic variant (acute transaminitis >10x)
• Diarrhea and abdominal cramping
– Watery diarrhea +/- blood
– Edema (PLE)
• Anorexia, nausea, dyspepsia, vomiting
• Most definitive method is biopsy.
• If not feasible (low platelets), can do transjugular
• Stains can include CMV, EBV, adenovirus, herpes
– Bile duct atypia and degeneration (“vanishing bile
– Epithelial cell dropout
– Lymphocytic infiltration of small bile ducts
– Severe cholestasis
GI tract: Diagnosis
• Flex sig +/- EGD (20% of pts have GVHD in upper
• Normal gross exam in up to 21% of histologically
– Crypt cell necrosis with accumulation of degenerative
material in the dead crypts
– Denuded areas with total loss of epithelium if severe
• Don’t forget to stain for CMV
Iqbal, et al, 2000
Roy, et al, 1991
Histology: Grading of GI tract
• Grade 1: isolated apoptotic epithelial cells
without crypt loss
• Grade 2: loss of isolated crypts without loss of
contiguous crypts; apoptosis with crypt abscess
• Grade 3: loss of 2 or more contiguous crypts;
• Grade 4: extensive crypt loss with mucosal
*grain of salt: inter-observer agreement among
pathologists is only moderate
Histology: Gastric GVHD
Washington, et al, 2009
Histology: Acute SB GVHD
Washington, et al, 2009
Histology: Acute Colonic GVHD
Washington, et al, 2009
Histology: Acute Colonic GVHD
Ross, et al, 2008
Optimal GI tract biopsy sites
• Not well established.
• Discordance between upper and lower tract sensitivity.
• Is GI GVHD a panintestinal process? Not always…
• Stomach more likely to show change of GVHD than
distal sites? Early on?
• Can miss up to 38% of GI GVHD if only biopsy rectum.
• Standard of care at different centers vary immensely:
pan biopsies, flex sig first, gastric first, avoid duodenum,
• Increased risk of bleeding at duodenal biopsy sites?
• Ross study (2008) in adults: rectosigmoid bx more
Pediatric Data on GI GVHD
• JPGN Feb 2012
• 48 patients, single center (Wisconsin) retrospective cohort
• Common symptoms prompting endoscopy
– Diarrhea (70%)
– Nausea and vomiting (67%)
• GVHD diagnosed in 83% of patients.
• 55% patients had both upper and lower endoscopy
• Most common endoscopic finding was normal mucosa.
• Rectosigmoid and combined upper endoscopic biopsies
were equally sensitive for diagnosis of acute GVHD in
• “If GVHD is found on rectosigmoid biopsy, upper endoscopy
would not be needed.”
• REG3alpha (antimicrobial protein expressed in
GI & liver
• HGF (hepatocyte growth factor)
• KRT18 (cytokeratin fragment 18) – apoptotic
Harris, et al
• Occurs in more than 50% of long term survivors of HLA
identical sibling transplants.
• Acute GVHD has strong inflammatory component;
chronic GVHD displays more autoimmune and fibrotic
• More B cell involvement. Antibodies deposit in tissues?
• Risk factors
– High recipient age
– Previous acute GVHD
– Female donor to male recipient
Blazar, et al
Chronic liver GVHD
• Lobular hepatitis, chronic hepatitis, reduced
or absence of small bile ducts with cholestasis.
• Pathophysiology is suggestive of primary
• Portal fibrosis suggests long term persistence
• Cirrhosis has been reported but is rare.
• Most literature in adult population.
• 1 case report of a 8 year old with large volume
• Diagnostic purposes to then guide treatment.
• Steroids are first line (1-2 mg/kg/day)
• CSA, FK, ATG, cellcept, the list goes on…
• Infliximab is helpful in refractory GI tract
• Oral budesonide (non absorbable) can be
• Abx? Ppx? Ciprofloxacin, rifaximin?
• Rare cases of liver tx
liver biopsy and endoscopy
• Bleeding (goal plt>50)
• Hematoma (particularly duodenal?)
• Bacteremia (ppx abx if ANC<1000)
2006 pediatric study of 191 patients (endoscopy)
– 13 complications out of 418 procedures (3%), 8 of
which occurred in the first 100 days
Khan, et al, 2006
Important questions to ask:
• Date of transplant, post transplant course
• Other organ involvement of GVHD
• Conditioning regimen and immunosuppression
• R/o other diagnoses before invasive procedures
– Infection (what antivirals, antibiotics, antifungals they
are and have been on)
– Check CMV PCR
• Response of sx to increasing/decreasing
• How will biopsy change management?
How should a pediatric
gastroenterologist called to evaluate
nonspecific GI symptoms that could
be from GVHD proceed?
Summary & Conclusions
• GI and hepatic complications represent a major cause
of morbidity and mortality in pediatric BMT recipients.
• Symptoms of liver and GI GVHD are nonspecific.
• Currently, need tissue for diagnosis thus essential role
of endoscopy and liver biopsy to guide therapy.
• Chronic GVHD is not well defined, is often seen with
some type of other acute GVHD.
• Flex sig is safest and most productive method of
diagnosing GI GVHD but EGD may be needed especially
for upper GI sx (nausea, vomiting).
• Liver and GI GVHD can be difficult to diagnosis. Often,
have to exclude other causes.
• Akpek, et al, Gastrointestinal Involvement in Chronic GVHD: A Clinicopathologic Study, Biology of Blood and
Marrow Transplantation, 2003.
• Aslanian, et al, Prospective Evaluation of Acute GVHD, 2012.
• Berquist and Dvorak, Optimizing care for GI disorders in children after HSCT, Gastrointestinal Endoscopy, 2006.
• Blazar, et al, Advances in GVHD biology and therapy, Nat Rev Immunol, 2012.
• Cruz-Correa, et al, Endoscopic Findings Predict the Histologic Diagnosis in Gastrointestinal GVHD, Endoscopy,
• Harris, et al, Plasma biomarkers of lower GI and liver acute GVHD, Transplantation, 2012.
• Iqbal, et al, Diagnosis of Gastrointestinal Graft Versus Host Disease, American Journal of Gastroenterology, Nov
• Khan, et al, Diagnostic endoscopy in children after hematopoietic stem cell transplantation, Gastrointestinal
• Ma, et al, Hepatitic GVHD after HSCT, Transplantation, 2004.
• Melin-Aldana, et al, Hepatitic Pattern of GVHD in Children, Pediatr Blood Cancer, 2007.
• Ross, et al, Endoscopic Biopsy Diagnosis of Acute Gastrointestinal GVHD: Rectosigmoid biopsies are more
sensitive than upper gastrointestinal biopsies, American Journal Gastroenterology, 2008.
• Shulman, et al, Histopathologic Diagnosis of GVHD: NIH Consensus Development Project on Criteria for Clinical
Trials in Chronic GVHD, Biology of Blood and Marrow Transplantation, 2006.
• Sultan, et al, Endoscopic Diagnosis of Pediatric Acute Gastrointestinal GVHD, JPGN, 2012.
• Tuncer, et al, GI and hepatic complications of hematopoietic stem cell transplantation, World J
• Washington and Jagasia, Pathology of GVHD in the gastrointestinal tract, Human Pathology, 2009.