Diese Präsentation wurde erfolgreich gemeldet.
Wir verwenden Ihre LinkedIn Profilangaben und Informationen zu Ihren Aktivitäten, um Anzeigen zu personalisieren und Ihnen relevantere Inhalte anzuzeigen. Sie können Ihre Anzeigeneinstellungen jederzeit ändern.
Gastrointestinal and Liver
Graft Versus Host Disease (GVHD)
Peds GI
Case Conference
Joanna Yeh
9/27/2012
Objectives
• Discuss a case of pediatric GVHD.
• Review background on GVHD.
• Understand differential diagnosis of liver a...
Case
• 22 month old boy with familial HLH
(hemophagocytic lymphohistiocytosis).
• s/p matched, unrelated cord bone marrow
...
Case
• Skin GVHD up to grade 3 (>50% BSA but no
bullae).
• He had on/off diarrhea which always
improved with increased imm...
Case
• Stool studies including c diff, campy bacterial, rota,
adeno, noro, and cells all negative.
• Medications included ...
EGD: Normal
except for loss of
vascularity in
duodenum.
Flex sig:
Strawberry like
mucosa in rectum,
cleared by
sigmoid. Sigmoid
colon with loss of
vascularity.
EGD Pathology Report
• Duodenum and antrum were normal
• Mid body of stomach with mild active
inflammation. H. pylori nega...
Flex Sig Pathology Report
• Sigmoid: mild active inflammation with
increased crypt apoptotic bodies, consistent
with GVHD ...
Flex Sig Pathology Report
• There is crypt dilation, increased crypt
apoptoses, mild lamina propria neutrophilic
inflammat...
Graft vs. Host Disease (GVHD)
Overview
• GVHD is one of the most common complications
of hematopoietic stem cell transplant (HSCT).
• In 1955, Barnes an...
Pathogenesis
• Transplanted immune cells (graft or donor)
recognize patient’s (host) cells as foreign.
• Primarily T cell ...
Blazar, et al, 2012
When can you get GVHD?
• Hematopoietic stem cell transplant
– Non autologous (allogeneic)
– autologous
• Blood transfusion...
Definitions
• Acute: less than 100 days after transplant.
• Chronic: more than 100 days after transplant.
• But there is n...
Symptoms
• Skin rash (classically first and most common)
• Jaundice (liver is 2nd most common)
– Rarely do patients have m...
Grading
Bombi, et al, 1995.
Differential Diagnosis
Liver
– VOD (relatively common toxicity associated with high dose
therapy or specific conditioning ...
Differential Diagnosis
Gastrointestinal
– Infection
• Clostridium difficile
• CMV*
– Antibiotic associated diarrhea
– Medi...
Tuncer, et al
Liver: Diagnosis
• Most definitive method is biopsy.
• If not feasible (low platelets), can do transjugular
approach.
• St...
Histology:
Hepatic GVHD
Shulman, 2006
GI tract: Diagnosis
• Flex sig +/- EGD (20% of pts have GVHD in upper
tract only)
• ?Colonoscopy
• Normal gross exam in up...
Cruz, et al, 2002
Cruz, et al, 2002
Histology: Grading of GI tract
• Grade 1: isolated apoptotic epithelial cells
without crypt loss
• Grade 2: loss of isolat...
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 GVH...
Location of GI biopsies
Aslanian, 2012
Pediatric Data on GI GVHD
• JPGN Feb 2012
• 48 patients, single center (Wisconsin) retrospective cohort
• Common symptoms ...
Novel biomarkers
GI
• REG3alpha (antimicrobial protein expressed in
Paneth cells)
GI & liver
• HGF (hepatocyte growth fact...
Chronic GVHD
• Occurs in more than 50% of long term survivors of HLA
identical sibling transplants.
• Acute GVHD has stron...
Chronic liver GVHD
• Lobular hepatitis, chronic hepatitis, reduced
or absence of small bile ducts with cholestasis.
• Path...
Chronic GI tract GVHD
• Oral mucosa: dry, ulcerations, erythematous
lesions
• Esophagus: dysphagia, ulcers, weight loss,
w...
Schulman, 2006
Washington, et al, 2009
Washington, et al, 2009
Akpek, 2003
Capsule Endoscopy
• Most literature in adult population.
• 1 case report of a 8 year old with large volume
bloody diarrhea...
Treatment
• Steroids are first line (1-2 mg/kg/day)
• CSA, FK, ATG, cellcept, the list goes on…
• Infliximab is helpful in...
Complications with
liver biopsy and endoscopy
• Bleeding (goal plt>50)
• Hematoma (particularly duodenal?)
• Bacteremia (p...
Important questions to ask:
• Date of transplant, post transplant course
• Other organ involvement of GVHD
• Conditioning ...
How should a pediatric
gastroenterologist called to evaluate
nonspecific GI symptoms that could
be from GVHD proceed?
Berquist and Dvoark, 2006
Summary & Conclusions
• GI and hepatic complications represent a major cause
of morbidity and mortality in pediatric BMT r...
References
• Akpek, et al, Gastrointestinal Involvement in Chronic GVHD: A Clinicopathologic Study, Biology of Blood and
M...
Gvhd
Nächste SlideShare
Wird geladen in …5
×
  • Als Erste(r) kommentieren

Gvhd

  1. 1. Gastrointestinal and Liver Graft Versus Host Disease (GVHD) Peds GI Case Conference Joanna Yeh 9/27/2012
  2. 2. Objectives • Discuss a case of pediatric GVHD. • Review background on GVHD. • Understand differential diagnosis of liver and GI GVHD. • Familiarize with characteristics and histologic findings of acute and chronic GVHD.
  3. 3. Case • 22 month old boy with familial HLH (hemophagocytic lymphohistiocytosis). • 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.
  4. 4. Case • Skin GVHD up to grade 3 (>50% BSA but no bullae). • 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.
  5. 5. Case • 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).
  6. 6. EGD: Normal except for loss of vascularity in duodenum.
  7. 7. Flex sig: Strawberry like mucosa in rectum, cleared by sigmoid. Sigmoid colon with loss of vascularity.
  8. 8. EGD Pathology Report • Duodenum and antrum were normal • Mid body of stomach with mild active inflammation. H. pylori negative. • Overall: Not consistent with GVHD.
  9. 9. Flex Sig Pathology Report • Sigmoid: mild active inflammation with increased crypt apoptotic bodies, consistent with GVHD grade 1. No PTLD or viral inclusions. • 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 likely ischemia.
  10. 10. Flex Sig Pathology Report • There is crypt dilation, increased crypt apoptoses, mild lamina propria neutrophilic inflammation. • Crypt abscesses and crypt dropout is appreciated. • CMV stains negative.
  11. 11. Graft vs. Host Disease (GVHD)
  12. 12. Overview • 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 transplant recipients.
  13. 13. Pathogenesis • 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 antigens – 2: donor T cell activation – 3: Multiple inflammatory cascades • Th1 CD4 -> TNFa, IL1 -> apoptosis
  14. 14. Blazar, et al, 2012
  15. 15. When can you get GVHD? • Hematopoietic stem cell transplant – Non autologous (allogeneic) – autologous • 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
  16. 16. Definitions • 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 manifestations. • Hyperacute: mismatched or underprophylaxed patients without engraftment.
  17. 17. Symptoms • 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
  18. 18. Grading Bombi, et al, 1995.
  19. 19. Differential Diagnosis Liver – VOD (relatively common toxicity associated with high dose therapy or specific conditioning regimens like busulfan or cytoxan) – Infection (most often viral hepatitis) • CMV, EBV • Hepatitis A, B, C • Herpes simplex virus, HHV6 • Bacterial/fungal – Medication • Chemo agents • Immunosuppressants – CSA (cyclosporine) – Methotrexate – Biliary sludge/gallstones/cholecystitis – Iron overload / hemosiderosis
  20. 20. Differential Diagnosis Gastrointestinal – Infection • Clostridium difficile • CMV* – Antibiotic associated diarrhea – Medication effect • MMF (cellcept) : colitis – Drug reaction (i.e. chemo) – Radiation effect – Chemotherapy effect *Send tissue for CMV PCR / stain (characteristics overlap) *One center routinely sent gastric and sigmoid bx for CMV and herpes simplex virus culture Toxicity usually resolved 1 month later
  21. 21. Tuncer, et al
  22. 22. Liver: Diagnosis • Most definitive method is biopsy. • If not feasible (low platelets), can do transjugular approach. • Stains can include CMV, EBV, adenovirus, herpes simplex virus. • Histology: – Bile duct atypia and degeneration (“vanishing bile duct syndrome”) – Epithelial cell dropout – Lymphocytic infiltration of small bile ducts – Severe cholestasis
  23. 23. Histology: Hepatic GVHD Shulman, 2006
  24. 24. GI tract: Diagnosis • Flex sig +/- EGD (20% of pts have GVHD in upper tract only) • ?Colonoscopy • Normal gross exam in up to 21% of histologically confirmed GVHD. • Histology: – 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
  25. 25. Cruz, et al, 2002
  26. 26. Cruz, et al, 2002
  27. 27. 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; crypt necrosis • Grade 4: extensive crypt loss with mucosal denudation *grain of salt: inter-observer agreement among pathologists is only moderate
  28. 28. Histology: Gastric GVHD Washington, et al, 2009
  29. 29. Histology: Acute SB GVHD Washington, et al, 2009
  30. 30. Histology: Acute Colonic GVHD Washington, et al, 2009
  31. 31. Histology: Acute Colonic GVHD Ross, et al, 2008
  32. 32. 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, etc. • Increased risk of bleeding at duodenal biopsy sites? • Ross study (2008) in adults: rectosigmoid bx more sensitive (retrospective).
  33. 33. Location of GI biopsies Aslanian, 2012
  34. 34. 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 children. • “If GVHD is found on rectosigmoid biopsy, upper endoscopy would not be needed.” Sultan, 2012
  35. 35. Novel biomarkers GI • REG3alpha (antimicrobial protein expressed in Paneth cells) GI & liver • HGF (hepatocyte growth factor) • KRT18 (cytokeratin fragment 18) – apoptotic protein Harris, et al
  36. 36. Chronic GVHD • 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 features. • More B cell involvement. Antibodies deposit in tissues? • Risk factors – High recipient age – Previous acute GVHD – Female donor to male recipient – CML Blazar, et al
  37. 37. Chronic liver GVHD • Lobular hepatitis, chronic hepatitis, reduced or absence of small bile ducts with cholestasis. • Pathophysiology is suggestive of primary biliary cirrhosis. • Portal fibrosis suggests long term persistence of GVHD. • Cirrhosis has been reported but is rare.
  38. 38. Chronic GI tract GVHD • Oral mucosa: dry, ulcerations, erythematous lesions • Esophagus: dysphagia, ulcers, weight loss, webs, strictures – Esophagus usually spared in acute GVHD • Chronic diarrhea, malabsorption, fibrosis, sclerosis
  39. 39. Schulman, 2006
  40. 40. Washington, et al, 2009
  41. 41. Washington, et al, 2009
  42. 42. Akpek, 2003
  43. 43. Capsule Endoscopy • Most literature in adult population. • 1 case report of a 8 year old with large volume bloody diarrhea. • Diagnostic purposes to then guide treatment.
  44. 44. 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 GVHD • Oral budesonide (non absorbable) can be helpful • Abx? Ppx? Ciprofloxacin, rifaximin? • Rare cases of liver tx
  45. 45. Complications with liver biopsy and endoscopy • Bleeding (goal plt>50) • Hematoma (particularly duodenal?) • Bacteremia (ppx abx if ANC<1000) • Perforation 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
  46. 46. 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 immunosuppression • How will biopsy change management?
  47. 47. How should a pediatric gastroenterologist called to evaluate nonspecific GI symptoms that could be from GVHD proceed?
  48. 48. Berquist and Dvoark, 2006
  49. 49. 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.
  50. 50. References • 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, 2002. • 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 2000. • Khan, et al, Diagnostic endoscopy in children after hematopoietic stem cell transplantation, Gastrointestinal Endoscopy, 2006. • 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 Gastroenterology 2012. • Washington and Jagasia, Pathology of GVHD in the gastrointestinal tract, Human Pathology, 2009.

×