Steven Klein, MDWilmington Gastroenterology
PearlsSpecialists write questions
Endoscopy usually the answer
Emphasis on outpt. Eval of common GI disordersWhen to refer for endoscopic evaluation
OutlineCRC Screening/Hereditary cancer syndromesCommon UGI disorders IBD Abnormal Liver enzymes
Colorectal Cancer ScreeningRisk Assessment
Family hx of CRCFamily hx of adenomatous colon polypsPossible HNPCC/FAP
Important factorsFirst degree relativesAge at diagnosis
Younger than 60?
Hereditary CRC SyndromesHNPCC
Account for 2-3% of CRC50 -70 % risk of CRC, early in life (30’s)Average number of polyps, but more aggressiveGermline mutation in MMR GeneAssociated Malignancies
Endometrial (70%) Ovary,stomach,SI, panc, GU
Surveillence – colonoscopy every 1-2 yrs starting at age 20
Hereditary CRC SyndromesFamilial Adenomatous Polyposis
Autosomal dominant germline mutation APCGreater than 100 polyps
Cancer risk 100% by age 45 Attenuated version with fewer polyps
Management Total proctocolectomy Surveillence for extracolonic lesions –
gastric/duodenal carcinoma, thyroid ca, CNS tumors
Hereditary CRC SyndromesMUTYH Associated Polyposis
Autonomic recessive (MYH gene)Similar to FAP
Peutz-Jeghers SyndromeAutosomal DominantPigmentation of buccal mucosa,
harmatomatous polyps throughout GI tract
UGI DisordersGERD
Emperic tx with PPI in those that are young without alarm symptoms
Endoscopy for those with alarm symptoms – age greater than 50, dysphagia, blood in stool, anemia, vomiting, hemetemesis, wt.loss, failure of sx. To respond to PPI
UGI DisordersBarrett’s esophagus
Intestinal metaplasia of squamous epitheliumCaucasions, Hispanic >> Blacks,AsiansMale:Female 2:18-15% of those undergoing EGD for GERD
5% in those without!!
UGI DisordersBarretts
associated with dysplasia (1%) , adenocarcinoma (0.5%) HGD – 4 – 6% risk of cancer within the year
Screening – chronic GERD, those > 50? Scant evidence to support mortality benefit Most people die for other reasons
UGI DisordersBarretts
Screening controversisalIf found, 4 quadrant biopsy q 2 cmRepeat endo in 1 year, if no dysplasia, then q 3
yrsLow grade dysplasia – 6 months then yearlyHigh grade dysplasia – repeat endo in 3
months Ablative techniques, vs. surgery
UGI DisordersDysphagia – difficulty swallowing
Oropharyngeal – neurogenic/myogenic originEsophageal – body, or LES, motility vs.
obstruction Solids vs liquids?
Odynophagia – pain with swallowing
UGI DisordersEosinophilic esophagitis
Young adults, hx. of atopyMultiple rings, often present with food bolus
obstruction
UGI DisordersH. Pylori infection
50% of world population More prevalent in developing world Acquired at early age
Associated diseases Chronic gastritis Duodenal ulcer Gastric ulcer Gastric cancer dyspepsia
UGI DisordersH Pylori – Diagnostic testing
Non invasive – urea breath test (most accurate), serology(perhaps best initial test) stool antigen
“test and treat” - dyspepsia, no alarm symptoms, young pt.
Invasive – CLO, histology – reserved for those undergoing diagnostic endoscopy
Confirm eradication – with breath test off PPI 1 month later for those with complications
IBDEpidemiology
prevalence CD 201 per 100,000 UC 238 per 100,000
Peak incidence Between 15 – 30 yrs Second peak between 50 – 80
Smoking Negative correlation with UC, positive for CD
IBDUC
Chronic colonic inflammation limited to mucosa
Presentation Mild – tenesmus, mucous, < 4 BM/day Moderate – mild anemia, up to 10BM/day Severe – fever, cramps, wt loss, >10 stools per day
Diagnosis Hx. + endoscopy with bx
Chronic inflammation Infectious, ischemic colitis in differential
IBD
IBDCrohns Disease
Transmural inflammation – leading to fibrosis, obstruction, fistulae
Can involve the entire GI tractPresentation
More variable than UC Fatigue, abdominal pain, wt. loss. 10% without diarrhea
Diagnosis Chronic inflammation, skip lesion, granuloma
IBD
IBDTreatment
Goals are induction and maintenance of remission
Similar for both UC/CrohnsMild disease
Mesalamine, SSZ for colitis Abx , entocort for CD
Moderate disease Add steroids, consider immunomodulator
(AZA/6MP)
IBDTreatment
Severe Disease Hospitalizaion Consider TPN IV Corticosteroids
Rapid improvement – add immunomodulator Steroid Refractory
CD – biologic agent (infliximab), UC – biologic, cyclosporine, surgery
IBDTreatment
Fistulizing CD No role for steroids Abx, AZA/6MP, biologic
SurgeryUC – proctocolectomy with IPAACD – limited resection based on disease extent
No pouch
Extraintestinal Manifestations40% of pts
Elevated Liver TestsLiver performs a wide variety of biochemical,
synthetic, and excretory functionNo one test provides a global assessmentRecognition of common patterns of
abnormalities will help guide further evaluation
Markers of Hepatocyte NecrosisAminotransferases
Aspartate aminotransferase (AST/SGOT) Not specific for liver – present in muscle, kidney,
RBC Present in both hepatocyte cytosol and
mitochondria
Alanine aminotransferase (ALT/SGPT) Relatively specific for liver Present in the cytosol
Markers of Hepatocyte NecrosisAST/ALT ratio
Usually less than or equal to oneGreater than 2 in several settings
ETOH – secondary to pyridoxine deficiency Cirrhosis Wilson’s disease (ratio greater than 4)
Markers of Hepatocyte NecrosisAST and ALT levels
Levels < 500 are found in wide variety of liver diseases
Massive elevations (>2000 IU) are almost exclusively related to acute viral hepatitis, drug induced liver disease, or ischemia
Markers of Hepatocyte NecrosisLactate Dehydrogenase (LDH)
Very wide tissue distribution, so rarely helpfulExtreme elevation with ischemia (greater than
5000 IU)
Markers of CholestasisAlkaline phospatase (AP)
Present in a variety of tissues (liver, bone, intestine, leukocytes)
Elevation results from increased synthesis induced by cholestasis
Striking elevations seen in infiltrative liver disease, intra or extrahepatic biliary obstruction
Markers of CholestasisGamma Glutamyl Transpeptidase (GGTP)
Also found in a variety of other tissue, but not bone
Can confirm hepatic origin of elevated APInduced by EtoH and drugs – GGTP/AP ratio >
2.5 suggests EtoH
Markers of Cholestasis5’ – Nucleotidase
Again has wide tissue distribution, but sig elevations are fairly specific for liver disease
Less sensitive compared to GGTP to confirm hepatic origin of elevated alk phos
Markers of CholestasisBilirubin
Product of heme metabolismSerum concentration usually < 1mg/dl, is
unconjugated Normally, less than 5% conjugated Jaundice evident with bilirubin > 3
Markers of CholestasisHyperbilirubinemia
Impaired biliary excretion – conjugated hyperbilirubinemia Biliary obstruction
With choledocholithiasis, bilirubin rarely exceeds 8 mg/dl
Hepatocellular diseaseIncreased production usually results in an
unconjugated hyperbilirubinemiaHereditary disorders of bilirubin metabolism
Markers of Synthetic CapacityProthrombin Time (PT)
Liver synthesizes all coagulation factors except VIII
Vit K required for carboxylation of II, VII, IX, XDiff dx of prolonged PT includes Vit K def, DIC,
and Liver disease Measurement of factor VIII is low in DIC, nml or
high in liver disease If malabsorption, Vit K should reduced the PT by
30% within 24 hrs
Markers of Synthetic CapacityAlbumin
About 10gm synthesized and secreted by hepatocytes daily
Synthesis decreases with progressive liver disease
Other factors such as nutrition, renal or GI losses, important as well
Half life of 20 days, so less helpful for acute liver disease
Causes of HepatitisViral
HCV – 1% of US population infected Percutaneous transmission – needlestick,
transfusion 80% develop chronic infection
Of these, 20% will develop cirrhosis Screen with HCV antibody Confirm with HCV PCR Tx with interferon, ribaviron
Causes of HepatitisViral Hepatitis
HBV – about 1 million in US with chronic infection 5% of worlds population infected Parental transmission HBSag – best screen for chronic HBV Tx with nucleoside analogs, interferon
Burden of Chronic HBV
Causes of HepatitisEtoH
Affects more than 2 million in USThreshold of 600 kg cumulative
8 drinks/day for 20 yrs Lower in women
Broad clinical spectrum Mild elevation of AST>ALT, severe cholestasis,
cirrhosis with ESLD Often additive with other liver dz
Causes of HepatitisNonalcoholic Steatohepatitis (NASH)
Broad spectrum of fatty liver disease (NAFLD)Often associated with obesity, insulin
resistanceMild elevation of ALT > ASTBiopsy indistinguishable from EtoHTx with wt loss, insulin sensitizers?
Causes of HepatitisDrugs
Less than 5% of jaundice or acute hepatitisVast majority idiosyncraticImportant dose dependent – tylenol,
methotrexateGenerally a diagnosis of exclusion, take careful
history
Causes of HepatitisTylenol
Most common cause of severe drug induced liver injury
Fatal doses usually 15 – 25 gm, 7.5 gm min in adults
ALT between 2000 – 10,000 IUN – Acetylcysteine stimulates glutathione
synthesis
Causes of HepatitisMetabolic liver diseases
Hereditary hemochromatosis Fe deposition in liver, pancreas, CNS, heart Mildly elevated transaminases Prevalence in northern europeans of 1:200 Screen with ferritin and Fe sat Confirm with genetic test Treat with phlebotomy
Causes of HepatitisMetabolic liver disease
Wilson’s disease – copper overload Usually mild transaminase elevation – rarely
fulminate failure Ceruloplasm and 24 hr urinary copper Treatment with penicillamine
Alpha one antitrypsin deficiency
Causes of HepatitisAutoimmune hepatitis
Type 1 most common 78% women, bimodal age distribution Broad clinical spectrum – ranging from mild
hepatitis to cirrhosis ANA, ASMA, hypergammaglobulinemia Treat with steroids, azathioprine
Causes of HepatitisCholangiopathies
Primary Biliary Cirrhosis Progressive inflammation and destruction of the
small bile ducts Mainly women in their 40’s Fatigue, jaundice Alk phos 3-4x normal Antimitochondrial ab (AMA)
Causes of HepatitisCholangiopathies
Primary Sclerosing Cholangitis Men:women 2:1 70% are associated with IBD Inflammation and scarring of the large bile ducts Dx. With ERCP or MRCP No effective treatment
Causes of HepatitisInfiltrating
Alk phos usually 5 – 10x normalBilirubin may be normal or near normalTransaminases minimally elevatedSystemic infection, malignancy, sarcoid,
SummaryDifferential is very broad for mildly elevated
liver enzymesIf predominately hepatocellular, viral most
commonIf cholestatic, start with imaging to r/o
obstructionMarked elevation of transaminases (> 500
IU) has relatively narrow differentialAcute viral hepatitis, tylenol overdose,
ischemia