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