Gastrointestinal Sarcoidosis

1. Gastrointestinal Sarcoidosis Katherine Doktor, MD PGY-2

2. The Patient 52yoF, AA p/w exacerbation of chronic N/V/abd pain, a/f decreased PO intake PMHx: HTN, DM, sarcoidosis, chronic pancreatitis, evidence of carcinoid in duodenum, ?autoimmune hepatitis dx’d 10yrs ago PSurgHx: removal of sarcoid nodule on dorsum of L hand, s/p Whipple & J-tube placement April ’10 Dx of Sarcoidosis: in Sept ’09 by needle Bx of medistinal node & skin mass on hand ROS: N/V since Sept ’09, w/bilious vomiting intermittently since Whipple Sx at time of dx of sarcoid: initially presenting w/progressive SOB and DOE (DOE after 1 flight of stairs). Had productive cough w/yellow/green sputum in sept that persistent for awhile, but resolved several months ago. Also c/o intermittent tightness in chest, also described as pressure. Had seen dr william morowitz in voorhees who treated her w/steroids 60mg x2wks, not tolerate by pt (elevated BP (SBP in 200s), elevated BG and shakiness) Since then, doe has worsened now sob after ½ flighto f stairs. In jan ’10: N/V w/intermittent abd pain.ROS: N/V since Sept ’09, w/bilious vomiting intermittently since Whipple Sx at time of dx of sarcoid: initially presenting w/progressive SOB and DOE (DOE after 1 flight of stairs). Had productive cough w/yellow/green sputum in sept that persistent for awhile, but resolved several months ago. Also c/o intermittent tightness in chest, also described as pressure. Had seen dr william morowitz in voorhees who treated her w/steroids 60mg x2wks, not tolerate by pt (elevated BP (SBP in 200s), elevated BG and shakiness) Since then, doe has worsened now sob after ½ flighto f stairs. In jan ’10: N/V w/intermittent abd pain.

3. The Patient’s Workup Labs CA 19-9 Alk phos ERCP x2 (Feb & March ’10): findings c/w pancreatic divisum, chronic pancreatitis & demonstrated pancreatic mass in head Gastric emptying scan: delayed gastric emptying in March, but not during this admission s/p Whipple (4/10): surgical management bc of pt’s nutritional decline, presence on pancreatic head mass and elevated CA 19-9 Obstruction series: no evidence of obstructing lesions

4. Sarcoidosis First described by Hutchinson in 18773 Non-caseating granulomas Multisystem disease: lungs, skin, cardiac, neurologic, LN Frequency of organ involvement: lung (90%) > LN (75%) > liver (60-90%) GI involvement: gastric: 2.5%, intestinal: 3.4% Age group: 20-40s Prevalence: 1-40/100,000 At least 3x higher in AA than Caucasians Main cause of death: due to involvement of lungs and heart Liver involvement: 67-70% by autopsy, in 50-79% by biopsyLiver involvement: 67-70% by autopsy, in 50-79% by biopsy

5. Sarcoidosis: Making the Diagnosis History Demonstration of granulomas in two different organs Rule-out drug-induced disease ACE is produced by epithelial cells in the granulomata; serum levels reflect the total granulomatous load in the body ACE levels Elevated in 60% of pts w/sarcoidosis Correlates w/granuloma load (Crit Rev Clin Lab Sci ’91): “is a peptidyldipeptide hydrolase that is located mainly on the luminal surface of vascular endothelial cells, but also in cells derived from the monocyte-macrophage system. In the RAS, it converts AT1 into ATII & inactivates the vasodilator bradykinin. Increased serum ACE been reported in pathologies involving a stimulatin of the monocytic cell ilne, primarily granulomatous dz. Other dz in which ACE can be increased: (ie nonsrcoidotic pulmonary granulomatous dz): silicosis, asbestosis, in extrathoracid granulomatous pathlogies such as Gauchers disease and leprosis, and to a lesser extent, in nongranulmatous disorders such as hyperthryodism or cholestasis. Decreased ACE: vascular pathologies involving endothelial abnl (DVT). (SVDLD): “ACE is thought to influence susceptibility, disease progression &/or outcome of sarcoidosis by functional mutations/polymorphisms of the ACE gene, such as the ACE geen deletion/insertion (D/I) polymorphism or the agiotensin receptors like the angiotensin II receptor type 1 (AT2R1) A1166 ? C polymorphism. Conclusion was that neither the ACE D/I nor the AT2R1 A1166 ? C polymorhism has a role in sarcoidosis disease progression. ACE is produced by epithelial cells in the granulomata; serum levels reflect the total granulomatous load in the body ACE levels Elevated in 60% of pts w/sarcoidosis Correlates w/granuloma load (Crit Rev Clin Lab Sci ’91): “is a peptidyldipeptide hydrolase that is located mainly on the luminal surface of vascular endothelial cells, but also in cells derived from the monocyte-macrophage system. In the RAS, it converts AT1 into ATII & inactivates the vasodilator bradykinin. Increased serum ACE been reported in pathologies involving a stimulatin of the monocytic cell ilne, primarily granulomatous dz. Other dz in which ACE can be increased: (ie nonsrcoidotic pulmonary granulomatous dz): silicosis, asbestosis, in extrathoracid granulomatous pathlogies such as Gauchers disease and leprosis, and to a lesser extent, in nongranulmatous disorders such as hyperthryodism or cholestasis. Decreased ACE: vascular pathologies involving endothelial abnl (DVT). (SVDLD): “ACE is thought to influence susceptibility, disease progression &/or outcome of sarcoidosis by functional mutations/polymorphisms of the ACE gene, such as the ACE geen deletion/insertion (D/I) polymorphism or the agiotensin receptors like the angiotensin II receptor type 1 (AT2R1) A1166 ? C polymorphism. Conclusion was that neither the ACE D/I nor the AT2R1 A1166 ? C polymorhism has a role in sarcoidosis disease progression.

6. Organ involvement Liver: most common Hollow organs: stomach, small bowel, colon Pancreas 1st described in 1937 Can have incidental granulomas in a normal stomachCan have incidental granulomas in a normal stomach

7. Sarcoidosis of the Liver Involvement seen in 50-79% of pts by Bx and 67-70% by autopsy Pts w/ fever &/or arthralgias or extensive erythema nodosum tend to have abnl liver Bx Sx: pruritis & abd pain > jaundice DDx of hepatic granulomas: sarcoidosis Drug-induced disease Underlying liver disease (esp PBC) TB 2x as common in AA than Caucasians Fever can be more common in pts w/liver involvement Ddx: must exclude other causes by obtaining a detailed occupational Hx, staining for mycobacteria and fungi, ordering an antimitochondrial Ab, ANA and a PPD. Must prove sarcoidosis by demonstrating granulomas in another organ, have radiologic features and/or an elevated ACE level. The postiivity of liver bx in sarcoidosis does not correlate w/liver size, LFTs or duration of the disease. Those w/fever and/or arthralgias or extensive erythema nodosium, however, tend to have abnl liver bx Hepatomegaly: clinically in 21% of pts and more than 50% on CT Granulomas; classic sarcoid granulmas mainly found in portal triads w/a cluster of lg epithelioid cells, often w/ multinucleated giant cells. Rarely seen schaumann bodies (dx’ic of sarcoid granulomas) rarely seen in hepatic granulomas Granluomas may be of differing ages Can cause progressive liver dz w/a wide array of histo changes: cholestatic, necroinflammatory and vascular. Cholestatis may be intrahepatic or extrahepatic Some have bile duct lesions similar to primary biliary cirrhosis Edeath from liver failure is rare, occuring in only 1 of 28 pts at autopsy and in 1 of 18 pts w/portal hHTN2x as common in AA than Caucasians Fever can be more common in pts w/liver involvement Ddx: must exclude other causes by obtaining a detailed occupational Hx, staining for mycobacteria and fungi, ordering an antimitochondrial Ab, ANA and a PPD. Must prove sarcoidosis by demonstrating granulomas in another organ, have radiologic features and/or an elevated ACE level. The postiivity of liver bx in sarcoidosis does not correlate w/liver size, LFTs or duration of the disease. Those w/fever and/or arthralgias or extensive erythema nodosium, however, tend to have abnl liver bx Hepatomegaly: clinically in 21% of pts and more than 50% on CT Granulomas; classic sarcoid granulmas mainly found in portal triads w/a cluster of lg epithelioid cells, often w/ multinucleated giant cells. Rarely seen schaumann bodies (dx’ic of sarcoid granulomas) rarely seen in hepatic granulomas Granluomas may be of differing ages Can cause progressive liver dz w/a wide array of histo changes: cholestatic, necroinflammatory and vascular. Cholestatis may be intrahepatic or extrahepatic Some have bile duct lesions similar to primary biliary cirrhosis Edeath from liver failure is rare, occuring in only 1 of 28 pts at autopsy and in 1 of 18 pts w/portal hHTN

8. Sarcoidosis of the Liver: the work-up Liver enzymes: elevated in up to 35%, unrelated to degree or extent of disease Elevated “Alk phos is more reliable than GGT in predicting liver involvement” US: “parenchymal echogenicity, coarsening of the liver parenchyma w/or w/o discrete nodules, and focal calcifications as well as contour irregularity” CT: “HSM, adenopathy, particularly of the porta hepatis, paraaortic region and celiac axis, followed in frequency by low-attenuation lesions of the liver and spleen” MRI: “multiple, diffuse, densely packed, uniform nodular foci w/nml to slightly increased signal intensity.” T2-weighted images show decreased signal intensity Nodules may form bc of coalescence of the microscopic granulomata and tend to become confluent w/increase sizeNodules may form bc of coalescence of the microscopic granulomata and tend to become confluent w/increase size

9. Sarcoidosis of the Liver Granulomas: 24-94% of liver Bx & autopsies Granulomas; classic sarcoid granulmas mainly found in portal triads w/a cluster of lg epithelioid cells, often w/ multinucleated giant cells. Schaumann bodies rarely seen in hepatic granulomas Granluomas may be of differing ages Progressive Liver disease calcium and protein inclusions inside of Langhans’ giant cells as part of a granuloma. calcium and protein inclusions inside of Langhans’ giant cells as part of a granuloma.

10. Sarcoidosis of the Stomach Most common in antrum Sx: most common is postprandial epigastric pain (dull, burning or cramping); also N/V, heartburn, early satiety and weight loss (common, can be severe), occ UGIB Manifestations due to ulcers or lumen narrowing 2/2 fibrosis Endoscopy: nodular changes, gastritis, thickened mucosa, greater or lesser curvature deformities or benign or malignant-appearing ulcers UGI series: most commonly shows segmental mucosal thickening & nondistensibility (mimicking linitis plastica) &/or deformities in antrum Pernicious-type anemia, chronic gastritis w/antiparietal cell Ab, antibodies against the H+/ATPase pump resulted in increased gastrin levels Pernicious-type anemia, chronic gastritis w/antiparietal cell Ab, antibodies against the H+/ATPase pump resulted in increased gastrin levels Pernicious-type anemia, chronic gastritis w/antiparietal cell Ab, antibodies against the H+/ATPase pump resulted in increased gastrin levels Pernicious-type anemia, chronic gastritis w/antiparietal cell Ab, antibodies against the H+/ATPase pump resulted in increased gastrin levels

11. Sarcoidosis of the Bowel Small bowel: least commonly involved organ in GI sarcoidosis Presentation: diarrhea, malabsorption, protein-losing enteropathy, periumbilical or epigastric pain or hemorrhage Colon: multiple nodules, polyps, stenosis, obstructive lesions, aphthous erosions, or small punctate bleeding sites Over 50% pts have abd pain Most common cause of intestinal obstruction: external compression by LAN Assoc’n found between sarcoidosis and celiac dz. Antigliadin ab detected in 15-41% of pts w/sarcoidosis, of which 1-4% had endomysial ab positivity Assoc’n found between sarcoidosis and celiac dz. Antigliadin ab detected in 15-41% of pts w/sarcoidosis, of which 1-4% had endomysial ab positivity

12. Sarcoidosis of the Pancreas Sx: rare; assoc’d w/parenchymal disease or duct obstruction abd pain, wt loss, jaundice, nausea, anorexia “the findings may simulate carcinoma w/pain improving w/corticosteroids” Findings: a mass, usually in the head or a diffusely firm, nodular pancreas Involved in 5% of autopsies ¾ pts w/pancreatic involvement have b/l hilar LAN Can see chronically elevated lipase and amylase Involved in 5% of autopsies ¾ pts w/pancreatic involvement have b/l hilar LAN Can see chronically elevated lipase and amylase

13. Sarcoidosis of the Pancreas:the workup Labs: chronically elevated lipase/amylase MRI: “masses w/low signal intensity on T1-weighted images, mild high signal intensity on T2-weighted images, and reduced enhancement w/gadolinium” Endoscopic US: glandular fibrosis Results of corticosteroid Tx: decreased lipase/amylase, reduced size of liver & spleen, but no improvement in fibrosis

14. Additional Involvement of Sarcoidosis with the GI Tract Acute cholecystitis Obstructive jaundice Abdominal adenopathy Increased in number of normal-sized nodes Most common in the porta hepatis LN smaller and more discrete than in lymphoma IFN-a therapy for Hepatitis C Due to intrinsic compression of the cystic duct by granulomatous LN or granulomatous inflamm. LN obstrux of CBD Subacute or chronic cholecystist w/granulomas in GB wall has been discovered after cholecystectomy Sarcoidosis usually develops during Tx though it can occur after termination of the IFN. Usually resolves in 3-8 mos Due to intrinsic compression of the cystic duct by granulomatous LN or granulomatous inflamm. LN obstrux of CBD Subacute or chronic cholecystist w/granulomas in GB wall has been discovered after cholecystectomy Sarcoidosis usually develops during Tx though it can occur after termination of the IFN. Usually resolves in 3-8 mos

15. Treatment of GI Sarcoidosis Partial response to PPI and antacids Corticosteroids Start when organ function is threatened 66% of people show improvement in Sx Hepatic sarcoid Tx only symptomatic pts Only minimal effect on hepatic lesions Reduces liver size & number of granulomas No effect on portal HTN No improvement seen in cases involving chronic intrahepatic cholestasis Some improvement in LFTs in cases of mild-mod elevation, but no significant improvement in severe elevation Organ funx threatened: eyes, lung , CNSOrgan funx threatened: eyes, lung , CNS

16. Treatment: Steroid-sparing Agents Methotrexate Shown to be effective in an RCT 10% pts have toxic rxns Others: chloroquine, azathioprine and cyclophosphamide Infliximab Ursodeoxycholic acid Presence of sarcoid-induced liver dz is not a c/I to tx w/MTX Ursodeoxycholic acid: tx elevated bile acid concentrations, thereby reducing the a mounts of endogenous hydrophobic acids, which are hepatotoxic. May have immunomolulating properties. Case reports show tha tit may benefit patietns w/sarcoidosis w/improvement in Sx and LFTsPresence of sarcoid-induced liver dz is not a c/I to tx w/MTX Ursodeoxycholic acid: tx elevated bile acid concentrations, thereby reducing the a mounts of endogenous hydrophobic acids, which are hepatotoxic. May have immunomolulating properties. Case reports show tha tit may benefit patietns w/sarcoidosis w/improvement in Sx and LFTs

17. REFERENCES Ebert EC, Kierson, KD Hagspiel. Gastrointestinal and Hepatic Manifestations of Sarcoidosis. Am J Gastroenterol 2008; 103:3184-3192. Sharma OP. Gastrointestinal sarcoidosis. In: UpToDate, Hollingsworth, H (DE), UpToDate, Waltham, MA 2010. #3: caceres m, sabbaghian s, braud r, wilks s, b michael. Pancreatic sarcoidosis: Unusual Presentation Resembling a Periampullary Malignancy. Curr Surg, 63 (2006):179-185.

18. DDx of granulomas Sarcoidosis Drug-induced disease Underlying liver disease (esp PBC) TB Whipple’s dz Crohn’s dz Syphilis Fungal infections Foreign body rxn