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 and GI GVHD.

• Familiarize with characteristics and histologic findings of acute and chronic GVHD.

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.

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.

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).

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 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 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.

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.

Graft vs. Host Disease (GVHD)

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.

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

Blazar, et al, 2012

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

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.

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

Grading

Bombi, et al, 1995.

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

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

Tuncer, et al

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

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 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

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 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

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, etc.

• Increased risk of bleeding at duodenal biopsy sites? • Ross study (2008) in adults: rectosigmoid bx more

sensitive (retrospective).

Location of GI biopsies

Aslanian, 2012

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

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

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

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.

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

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.

• Diagnostic purposes to then guide treatment.

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

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

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?

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 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.

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.