common problems in gastroenterology for internal...

Common problems in Gastroenterology for Internal medicine

Julajak Limsrivilai

Siriraj Hospital

Outline : GI tract

Upper tract Dyspepsia

H. pylori infection

PancreaticobiliaryGall stone and CBD stone

Acute cholecystitis

Ascending cholangitis

Lower tract IBS

C. difficile infection

CRC screening GI bleeding

NSAIDs and prophylaxis of bleeding

Antiplatelet, anticoagulant, DOAC and GI bleeding

Occult GI bleeding: FOBT/IDA

Outline : Liver disease

Chronic liver disease Viral hepatitis

Alcoholic hepatitis

NAFLD

Autoimmune liver disease

Cirrhosis Portal hypertension

Variceal bleeding

Ascites and complication

Hepatorenal syndrome

Hepatocellular carcinoma

Dyspepsia: Thailand Guidelines 2018

Pittayanon R, J Neurogastroenterol Motil 2019

Etiology

Functional dyspepsia Organic dyspepsia

Normal Nonerosive gastritis

Polyp

Erosive/Hemorrhagic gastritis Peptic ulcer

Gastric cancer

Normal finding

Etiology : other causes of upper abdominal pain

Chronic pancreatitisPancreatic cancer

Gall stone

Liver tumor

Alarming features

3.Dysphagia

1.GI blood loss• IDA • Hematemesis/Mele

na

2.Weight loss 4.Persistent vomiting

5. Significant early satiety

6. Family Hx of gastric cancer

H. pylori: Indication for eradication

การใช้ยา NSAIDs และ แอสไพรนิ ร่วมกบัยาต้านการแข็งตวัของเลือด (anticoagulant), clopidogrel หรือ corticosteroids

H. pylori: Diagnosis

12

3

H. pylori: Treatment

Outline : GI tract


H. pylori infection


Acute cholecystitis


Lower tract IBS






Gut 2018; 67:405-417

Recommendation in GIB

Single antiplatelet agent Withholding aspirin before endoscopy

Do not recommend platelet transfusion

Resume ASA in 3-5 D after endoscopic hemostasis

DAPT Withholding clopidogrel, continue ASA (controversial)

Resume clopidogrel or other new P2Y12 receptor inhibitors (prasugrel and ticagrelor) in 5 days (2-3 d for ticagrelor)

Warfarin Withholding warfarin

4-factor prothrombin complex concentrate (PCC) plus low-dose vit. K for life-threatening bleeding with an INR above 2.5

Not recommend higher doses of vit. K (>5 mg) in high thromboembolic risk

Do not recommend delaying endoscopy for life-threatening bleeding until normalisation of INR

Rechecking INR after reversal therapy is not mandatory before endoscopy

In high thromboembolic risk, Resume warfarin once adequate haemostasis is achieved.

Bridging anticoagulation with unfractionated heparin


• Non-valvular atrial fibrillation with a CHA2DS2-VASc score >5*

• Metallic mitral valve • Prosthetic valve with atrial fibrillation • <3 months after VTE • Severe thrombophilia (protein C or

protein S deficiency, antiphospholipid syndrome)

Direct oral anticoagulants (DOACs) Withholding DOACs

Activated charcoal for life-threatening bleeding if the last dose of DOAC is taken within 3 hours

Idarucizumab for the treatment of life-threatening bleeding in patients on dabigatran

Do not recommend vitamin K for treatment of bleeding associated with DOACs

Resuming DOACs after adequate haemostasis is achieved

Do not recommend bridging therapy in patients on DOACs


NSAID and Peptic ulcer


Melcarne L et al, EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY, 2016

Relative risk for GI events

Relative risk for CV events


Low GI risk High GI risk

Low CV risk Non-selective NSAIDs Non-selective NSAIDs + PPICelecoxib + PPI (several risk factors) Eradicate H. pylori

High CV risk Naproxen; add PPI if patient is taking ASA

No NSAIDsNaproxen + PPI Low-dose celecoxib + ASA + PPI

Lanas A, Lancet 2017

GI risk Age > 60 years History of peptic ulcers Concomitant medication with antiplatelet agents, anticoagulants, corticosteroids, or SSRIs

Cardiovascular riskUse risk charts (eg, Framingham risk scores or the European SCORE system) History of cardiovascular events or diabetes

Question

Which of the following statements about gFOBT (guiac test) is true?

1. Avoid Fe supplement before testing

2. Lower sensitivity than immunohistochemistry FOBT for upper GI bleeding

3. More than one sample of stools can increased test sensitivity

4. Vitamin C ingestion causes false-positive result

5. is recommended for annually surveillance in HNPCC family

FOBT

Hb

globin Heme

Reabsorption in prox intestine

porphyrins iron

pancreatic protease gastric pepsin protease

Pancreatic & intestinal protease

digestion

colonic bacteria

intestinal converted fractionColonic bacteria(1-99%)

15%

Have peroxidase activity

No peroxidase activity

Yamada. Principle of clinical gastroenterology. 2008

GuaiacImmuno-chemical

Heme-porphyrin

Fecal occult blood

Rockey. Gastroenterol Clin N Am 2005

Guaiac Heme-Porphyrin

iFOBT

False positives

• Animal Hb ++++ ++++ 0

• Dietary peroxidase

+++ 0 0

False negatives

• Vitamin C ++ 0 0

High false +ve and –ve

FOBT and bleeding site

Rockey DC, NEJM 1999

Fecal occult blood test : indication

Colorectal cancer screening :Decreased mortality from CRC

FOBT

Hewitson P. Am J Gastroenterol 2008

s s s s

Fecal occult blood test : indication

Colorectal cancer screening :Decreased mortality from CRC

Not indicate in symptomatic patients : IDA, abdominal pain

Low sensitivity Low specificity

iFOBT >> gFOBT

Role of FOBT in patients with IDA

Sensitivity

CA colon

gFOBT 33-50%

iFOBT 50-75%

Sensitivity

60 cc blood ingestion

gFOBT 16%

iFOBT 2%

Lieberman DA. NEJM 2009Rockey DC, Am J Gastroenterol 1999

No role of FOBT in the evaluation of IDA

Goddard AF, Gut 2013

Question

Which of the following statement about gFOBT (guiac test) is true?

1. Avoid Fe supplement before testing

2. Lower sensitivity than immunohistochemistry FOBT for upper GI bleeding

3. More than one sample of stools can increased test sensitivity

4. Vitamin C ingestion causes false-positive result

5. is recommended for annually surveillance in HNPCC family

Outline : GI tract


H. pylori infection


Acute cholecystitis


Acute pancreatitis

Lower tract IBS






Irritable bowel syndrome

Irritable bowel syndrome: Rome IV

Recurrent abdominal pain, on average, at least 1 day/wk in the last 3 months, associated with 2 or more of the following criteria:

Related to defecation

Associated with a change in frequency of stool

Associated with a change in form (appearance) of stool

Symptoms must be present for the last 3 months, with onset at least 6 months before diagnosis

Lacy BE, et al. Gastroenterology 2016:150;1393

Differential diagnosis

Adapted from Furman DL & Cash BD, Gastroenterol Clin North Am 2011

Differential diagnosis

CA colon Chronic colitis eg. IBD, infection• Age > 50 yr or have Familial Hx of

CRC • Bloody diarrhea, bowel habit change • Anemia • Weight loss

• Mucous bloody diarrhea • Fever • Anemia • Weight loss

Alarming features

New onset of symptoms at 50 years or older

Severe or progressively worsening symptoms

Nocturnal diarrhea

Bloody stools

Unexplained IDA

Unintentional weight loss

Family history of colon cancer or IBD

Chey WD et al, JAMA 2015

Investigation

Alarming features

• Blood test : CBC, serum chemistries, TFT

• Stool test : ova, parasite

Diarrhea Constipation

Colonoscopy BE or colonoscopy

Treatment

Lacy BE, et al. Gastroenterology 2016:150;1393

Crobach MJT, Clin Microbiol Infect 2016Putsathit P, New Microbe and New Infect 2017

C. difficile infection: Diagnosis

Test in Unexplained and new-onset ≥ 3 unformed stools in 24 hours

Gold standard: Toxigenic culture (TC), Cell cytotoxicity neutralization assay (CCNA) (expensive, need special media, take 48 hr)

Pooled sensitivity Pooled specificity ราคา

CCNA TC CCNA TC

Enzyme immunoassay for toxin A/B

83% 57% 99% 99% 500 บาท

Glutamate dehydrogenase (GDH)

94% 96% 90% 96%

Nucleic acid amplification test (NAAT)

96% 95%(SI 68.6%)

94% 98%(SI 95.1%)

1,400 บาท

C. difficile infection: Diagnosis

Ma J, Pol Arc Int Med 2018

C. difficile: treatment

Consult Sx

Colon cancer screening

Question

A 57 year-old man, has recently been diagnosed advance stage colon cancer. He concerns that this malignant disease might be inherited. What would you recommend to his 30 yr-old son?

1. Colonoscopy now 2. Colonoscopy at age 40 3. Colonoscopy at age 504. FOBT at age 40 5. FOBT at age 50

Average risk

High risk

Colon cancer screening

Test USPSTF 2016 Multi-society

Joint 2017Asia Pacific 2014

gFOBT (3 samples) 1 yr 1 yr Not recommend

iFOBT (1-2 samples) 1 yr 1 yr 1 yrSigmoidoscopy 5 yr 5 - 10 yr 5 yr Colonoscopy 10 yr 10 yr 10 yr CT colonography 5 yr 5 yr Not recommend

Average risk

Screening period: 50 to 75-85 years

High risk

Familial colorectal cancer

Hereditary colorectal cancer

History of adenoma

History of colorectal cancer

Inflammatory bowel disease

Colonoscopy


Lipton. Clin Gastroenterol Hepatol 2004Johns. Am J Gastroenterol 2001


RR Age to begin Test Comment

Either CRC or AP in • 1st degree < 60 yr or • 2 or more 1st degree at

any age

4x • 40 years, or • 10 years

before the youngest

Colonoscopy Every 5 years

Either CRC or AP in • 1st degree age > 60 yr

2-2.5x • 40 years Screening options as recommended for average-risk

Rex DK, Gastroenterol 2017

Hereditary colon cancer

Who should be screen Age to begin Tool for screening and age to stop

FAP -mutation carrier-family members at 50% risk if no mutation identified

Age 10 to 12 years -Annual FSIG or colonoscopy until age 30 years, -every 3-5 years thereafter until age 60

HNPCC -mutation carrier-family members at 50% risk if no mutation identified

Age 20 to 25 years, or 2-5 years before the youngest case

-At least biennial colonoscopy, until age 40 years, -annually thereafter to age 70-75 years or until co-morbidity makes it clinically inappropriate

AD pattern

HNPCC: How to diagnose?

Clinical criteria

Tumor testing

Germline testing

Clinical criteria: Amsterdam II

Amsterdam II criteria• 3 or more relatives with HNPCC-associated cancer (i.e. CRC, endometrial, renal

pelvis, SB, ureteral cancers), one of whom is a first degree relative of the other two

• Cancer in at least 2 generations of the same family

• At least one cancer case Dx before the age of 50

• FAP should be excluded

Major limitation = low sensitivity: 22% High specificity 98%

Clinical criteria: revised Bethesda guidelines

1. Colorectal cancer diagnosed in age < 50 years2. Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age. 3. Colorectal cancer with the MSI-H-like histology diagnosed in a age < 60 years. 4. Colorectal cancer diagnosed in a patient +

1 first-degree relatives with an HNPCC-related tumor at age < 505. Colorectal cancer diagnosed in a patient +

2 first- or second-degree relatives with HNPCC-related tumors,regardless of age.

J Natl Cancer Inst 2004; 96:261

Presence of tumor infiltrating lymphocytes. Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern

Sensitivity: 82% Specificity; 77%

If meet, MSI and or IHC should be evaluated

Suspected HNPCC

Analyse tumor MSI or IHC

MSS/MSI-low or Intact prot by IHC

Most likely not HNPCC

But if strong suspicious →genetic testing

Exclude FAP/AFAP

MSI-H or loss protein by IHC

Genetic germline testing

Germline MMR gene mutation

Dx HNPCC and genetic counseling

No germline mutation detected

MLH1 methylation studies and/or BRAF assessment if MLH1 loss by IHC

Hypermethylationor BRAF mutation

Not HNPCC

Normal

Most likely undetectable mutation

Question

A 57 year-old man, has recently been diagnosed advance stage colon cancer. He concerns this malignant disease might be inherited. What would you recommend to his 30 yr-old son?

1. Colonoscopy now 2. Colonoscopy at age 40 3. Colonoscopy at age 504. FOBT at age 40 5. FOBT at age 50

Outline : GI tract


H. pylori infection


Acute cholecystitis


Lower tract IBS






Gall stone and complications

Question

A 40 year-old woman presents with acute epigastric pain for 4 hr. LFTs : TB 0.6, DB 0.4, AST 350, ALT 320, ALP 120, A/G 4.4/2.6. U/S reveals gall stone, no biliary duct dilatation

What’s the most appropriate next management?

1. check for HAV, HBV, and HEV infection

2. LC

3. ERCP

4. Endoscopic ultrasonography

Gall stone and complications

Asymptomatic GS60-80%

Biliary pain20%

Acute cholecystitis10%

Biliary pain(with AST/ALT)

Obstructive jaundiceCholangitis

5%

GS pancreatitis<5%

Gallstone and CBD stone

Stone in GB : cholycystectomy in …

Do only in symptomatic cases

Kimura Y, J Hepatobiliary Pancreast Sci 2013

Acute cholecystitis 0-3%Jaundice 0-2%

Acute cholecystitis 5.8-11.4%Jaundice 3-7.5%

Cholecystectomy in asymptomatic gallstone

Special subgroups Comments

Chronic hemolytic syndromes - Sickle cell anemia and hereditary ovalocytosis

- Onset in younger age - ↑life-time risk of complication - Prophylactic LC at the time of

splenectomy

GB cancer - Porcelain GB- GB polyp ≥ 1 cm- [Large gallstones (≥ 3 cm)]

EASL guideline 2016

CBD stone

Difficult to diagnose

up to 50% developing complication Removal

Test SensitivityTransabdominalU/S

75% dilated ducts 50% non-dilated

CT scan 70-75%

MRCP 88-92% all comers90-95% dilated ducts

EUS 90-97%

CBD stone : clinical predictors in who have GS

Predictor

Very strong

CBD stone on US

clinical ascending cholangitis

bilirubin > 4 mg/dL

Strong

dilated CBD on US (>6 mm)

bilirubin 1.8-4 mg/dL

Moderate

abnormal LFT other than bilirubin

age > 55 yr

GS pancreatitis

Presence of any very strong High

Presence of both strong High

No predictors present Low

All other patients Intermediate

ASGE guideline 2010

Obstruction

ALP

AST or ALT

CBD stone

Symptomatic ptwith GS

Likelihood of CBD stone

Low Intermediate High

LC LC with IOC or

Preop EUS/MRCP ERCP

ASGE guideline 2010

Acute cholecystitis

Acute cholecystitis

RUQ pain , RUQ tenderness 90%

Fever 50%

prior history of biliary colic 75%

Murphy’s sign Sens 20-65%Spec 87%

Jaundice • Sepsis• CBD stone • Mirizzi’s syndrome

20%

Cholecystitis: Diagnosis

Item Signs Details

A Local signs of inflammation Murphy’s sign

RUQ mass/pain/tenderness

B Systemic sign of inflammation

Fever

Elevated CRP (> 3 mg/dl)

Elevated WBC (>10,000 mm3/dl)

C Imaging findings Characteristic of acute cholecystitis

Suspected diagnosis : A + B

Definite diagnosis : A + B + C

Sens 91.2%, Spec 96.9%Yokoe M, J

Hepatobiliary Pancreas Sci 2018

Cholecystitis : Diagnosis

US Sens 81%, Spec 83%

US Murphy sign Sens 63%, Spec 94%

Distention (8*4 cm) ,

Wall thickening (4 mm), Fat strand,

Pericholecystic fluid

Tc-HIDA scanSensitivity 80-90%

False positive 10-20%: (fasting, s/p

sphincterotomy)

Cholecystitis: Complications

Gangrenous cholecystitis

• Irregular wall thickening• Poor contrast enhancement

(interrupted rim sign), • intraluminal fap

Emphysematous cholecystitis

Gas in lumen or wall of gallbladder

Cholecystitis : Treatment

IV ATB and supportive

care

Specific Rx

Cholecys-tostomy

Cholecys-tectomy

Center experiencePatients surgical risk status

Acute cholecystitis : management

Grade II : 1/4 ofDuration > 72 hr,

palpable tender mass, WBC > 18,000/mm3,

Mark local inflam by image (presence of complications)

Grade I : mild

Okamoto K, J Hepatobiliary Pancreas Sci 2018

In pt with high Sx riskCCS ≥ 6, ASA ≥ 3

Percutaneuos cholecystostomy

ATB and general support care


Urgent/early GB drainage

Observation

Early LC

Delayed/ elective LC

Advanced LC technique available, low risk Sx

Successful Rx, high risk Sx

Failure Rx

Acute cholecystitis : management

Grade III : organ failure

Okamoto K, J Hepatobiliary Pancreas Sci 2018

Percutaneuoscholecystostomy


Urgent/early GB drainage

Early LC

Delayed/ elective LC

No negative predictive factor and presence of favorable organ system failure

Presence of negative

predictive factors and/or no FOSF

observation

Advanced centerGood PS

Not advanced centerpoor PS

poor PS

good PS

Negative predictive factors for withstanding LC: neurological dysfunction, respiratory dysfunction, and coexistence of jaundice (TB> 2)Favorable organ system failure: renal and CVS dysfunction


1.Fever 95%

2.RUQ tenderness 90%

3.Jaundice 80%

4.Confusion 15%

5.Hypotension 15%

1+2+3 = Charcot’s triad (20-70% of patients)1+2+3+4+5 = Reynolds’ pentad

Ascending cholangitis : Diagnosis Item Signs Details

A Systemic inflammation Fever (> 38 c) and/or shaking chills

Laboratory data evidence of inflammation (WBC < 4000 or > 10000/mcl, CRP ≥ 1 mg/dL)

B Cholestasis Jaundice (> 2 mg/dL)

Abnormal LFTs (AST,ALT,ALP,GGT > 1.5x STD)

C Imaging findings Biliary dilatation

Evidence of the etiology on imaging (stricture, stone, stent, etc.)

Suspected diagnosis : A + (B or C)

Definite diagnosis : A + B + CKiriyama S, J Hepatobiliary Pancreas Sci 2018

Cholangitis : Treatment

IV ATB and supportive

care

Specific Rx

PTBDERCP

Surgery

Ascending cholangitis : Treatment

Grade II : 2/5 ofAge≥75 yr, T ≥ 39°C,

TB ≥ 5mg/dl, Alb ≤ STD*0.7

WBC <4,000 or >12,000

Grade III : Any organ failure

Grade I : not grade II/III

Yokoe M, J Hepatobiliary Pancreas Sci 2018Kiriyama S, J Hepatobiliary Pancreas Sci 2018

ERCP, PTBD, Sx


Early (24-48 hr) biliary drainage


Urgent (ASAP) biliary drainage

Organ support, ATB

Finish course of

ATB

Biliary drainage

Treatment for etiology if still

needed (endoscopic Rx,

percutaneous Rx, or surgery)



Alcoholic hepatitis

NAFLD


Metabolic liver disease


Variceal bleeding

Ascites and complications



Question

Who should be started anti-HBV treatment?

1. 30 year-old man with HBsAg and HBeAg +ve, HBV VL > 170,000,000 IU/L, ALT 20, US – normal liver

2. 30 year-old man with HBsAg and HBeAg +ve, HBV VL 20,000 IU/L, ALT 50, US – normal liver

3. 50 year-old man with HBsAg +ve, HBeAg –ve, HBV VL 1,500 IU/L, ALT 30, US – cirrhotic liver

4. 40 year-old man with HBsAg +ve, HBeAg –ve, HBV VL < 10 IU/L, ALT 80, US – fatty liver

HBeAg positive HBeAg negative

Phase 1 Phase 2 Phase 3 Phase 4 Phase 5

Chronic HBV

infection

Chronic

hepatitis B

Chronic HBV

infection

Chronic

hepatitis B

Resolved HBV

infection

HBsAg HighHigh/

intermediateLow Intermediate Negative

HBeAg Positive Positive Negative Negative Negative

HBV DNA >107 IU/mL 104–107 IU/mL <2,000 IU/mL* >2,000 IU/mL <10 IU/mL‡

ALT Normal Elevated Normal Elevated† Normal

Liver disease None/minimalModerate/

severeNone

Moderate/

severeNone§

Old

terminologyImmune tolerant

Immune reactive

HBeAg positiveInactive carrier

HBeAg negative

chronic hepatitis

HBsAg negative

/anti-HBc

positive

New nomenclature for chronic phases

*HBV DNA levels can be between 2,000 and 20,000 IU/mL in some patients without signs of chronic hepatitis;†Persisitently or intermittently, based on traditional ULN (~40 IU/L). ‡cccDNA can frequently be detected in the liver;§Residual HCC risk only if cirrhosis has developed before HBsAg loss.

EASL CPG HBV. J Hepatol 2017;67:370–98

• The natural history of chronic HBV infection has been schematically divided

into five phases

Chronic HBV

infection

Chronic

hepatitis B

Indications for treatment

*Defined by HBV DNA >2,000 IU/ml, ALT >ULN and/or at least moderate liver necroinflammation or fibrosis;†Defined by persistently normal ALT and high HBV DNA levels;‡ Even if typical treatment indications are not fulfilled


• Primarily based on the combination of 3 criteria

– HBV DNA, serum ALT and severity of liver disease

Recommendations

Should be treated

• Patients with HBeAg-positive or -negative chronic hepatitis B* I 1

• Patients with cirrhosis, any detectable HBV DNA, regardless of

ALT levelI 1

• Patients with HBV DNA >20,000 IU/mL and ALT >2x ULN,

regardless of severity of histological lesionsII-2 1

May be treated

• Patients with HBeAg-positive chronic HBV infection†

>30 years old, regardless of severity of liver histological lesions

III 2

Can be treated

• Patients with HBeAg-positive or -negative chronic HBV infection

and family history of HCC or cirrhosis and extrahepatic

manifestations‡

III 2

Grade of evidence Grade of recommendation

Monitoring of patients currently not treated


• Patients with no current indication of antiviral therapy should

be monitored

– Periodical assessments of serum ALT, HBV DNA and non-invasive

markers for liver fibrosis

Recommendations

Follow-up at least every 3–6 months

• HBeAg-positive chronic HBV infection, <30 years oldII-2 1

Follow-up at least every 6–12 months

• HBeAg-negative chronic HBV infection and serum HBV DNA

<2,000 IU/ml

II-2 1

Follow-up every 3 months for the first year and every 6 months

thereafter

• HBeAg-negative chronic HBV infection, serum HBV DNA

≥2,000 IU/ml

III 1


Discontinuation of NA treatment


• Long-term therapy with NAs is usually required

– HBV eradication is not usually achieved

Recommendations

NAs should be discontinued

• After confirmed HBsAg loss (± anti-HBs seroconversion)II-2 1

NAs can be discontinued

• In HBeAg-positive patients, without cirrhosis, who

achieve stable HBeAg seroconversion and undetectable

HBV DNA and complete ≥12 months of consolidation

therapy

Close post-NA monitoring is warranted

II-2 2

NAs may be discontinued

• In selected HBeAg-negative patients, without cirrhosis,

who achieve long-term (≥3 years) virological

suppression, if close post-NA monitoring can be

guaranteed

II-2 2


Special patient groups: HIV or HDV co-infection


• The risk of fibrosis progression, cirrhosis and HCC is

greater in patients also infected with HDV or HIV

Recommendations (HIV)

All HIV-positive patients with HBV co-infection should start

antiretroviral therapy (ART) irrespective of CD4 cell count II-2 1

HIV/HBV co-infected patients should be treated with a TDF- or

TAF-based ART regimen

I (TDF)

II-1 (TAF)1

Recommendations (HDV)

PegIFN for at least 48 weeks is the current treatment of choice

in HDV/HBV co-infected patients with compensated liver disease I 1

In HDV/HBV co-infected patients with ongoing HBV DNA

replication, NA therapy should be consideredII-2 1

PegIFN treatment can be continued until Week 48 irrespective

of on-treatment virological response if well tolerated II-2 2


Special patient groups: patients undergoing immunosuppressive therapy or chemotherapy


Recommendations

All candidates for chemotherapy and immunosuppressive

therapy should be tested for HBV markers prior to

immunosuppression

I 1

All HBsAg-positive patients should receive ETV, TDF, or

TAF as treatment or prophylaxis II-2 1

HBsAg-negative, anti-HBc-positive subjects should

receive anti-HBV prophylaxis if they are at high risk of HBV

reactivation

II-2 1


Question

Who should be started anti-HBV treatment?

1. 30 year-old man with HBsAg and HBeAg +ve, HBV VL > 170,000,000 IU/L, ALT 20, US – normal liver

2. 30 year-old man with HBsAg and HBeAg +ve, HBV VL 20,000 IU/L, ALT 50, US – normal liver

3. 50 year-old man with HBsAg +ve, HBeAg –ve, HBV VL 1,500 IU/L, ALT 30, US – cirrhotic liver

4. 40 year-old man with HBsAg +ve, HBeAg –ve, HBV VL < 10 IU/L, ALT 80, US – fatty liver

Viral hepatitis C

Acute alcoholic hepatitis

Management of alcoholic hepatitis: Definition and diagnosis

*Ascites and/or encephalopathy; †Defined histologically by steatosis, hepatocyte ballooning, and an inflammatory infiltrate with polymorphonuclear neutrophils

EASL CPG ALD. J Hepatol 2018;69:154–81

• Clinical

– Recent jaundice ± other signs of liver decompensation* in patients with ongoing

alcohol abuse

• Cardinal sign is a progressive jaundice, often associated with fever, malaise, weight loss

and malnutrition

• Histological

– Steatohepatitis†

• Laboratory

– Neutrophilia

– Hyperbilirubinaemia (>50 μMol/L)

– AST >2 x ULN and AST/ALT ratio typically greater than 1.5–2.0

– Severe: prolonged PT, hypoalbuminaemia, and decreased platelet count

Recommendations

A recent onset of jaundice in patients with excessive alcohol

consumption should prompt clinicians to suspect AH A 1

Grade of recommendation Level of evidence

Management of suspected alcoholic hepatitis: Treatment algorithm

*Particularly in null responders (Lille score ≥0.56).


Stop treatment* and assessment for early liver transplantation in

highly selected patients

Continue treatment for 28 days

Lille score ≥0.45Lille score <0.45

mDF <32 and GAHS <9

Assess treatment response at Day 7 (Lille score)

Prednisolone 40 mg/day ± NAC No specific therapy

mDF ≥32 or GAHS ≥9

Assessment of disease severity (prognostic scores)

• Systematic evaluation of nutritional status and energy intake

• Daily target 35–40 kcal/kg BW• Prefer oral route as first-line intervention• Supplementation with B-complex

vitamins

Consider liver biopsy if diagnosis is uncertain

Perform systematic extensive screening for infection

Treatment of alcohol dependence

Clinical diagnosis of AH

Absence of

infection

Management of alcoholic hepatitis: Evaluation of severity

*Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating

specific therapy


• Different prognostic models aim to identify patients at high risk of early death

– Often incorporate the same variables and have similar efficacy in predicting

short-term survival

• Lille model can predict pattern of response to corticosteroid treatment

– Based on pre-treatment data plus the response of serum bilirubin

Score Bilirubin PT/INR

Creatinine/

urea Leucocytes Age Albumin

Change in

bilirubin

(Day 0 to 7)

Maddrey

DF*+ + – – – – –

MELD + + + – – – –

GAHS + + + + + – –

ABIC + + + – + + –

Lille + + + – + + +

Management of suspected alcoholic hepatitis: Treatment algorithm

*Particularly in null responders (Lille score ≥0.56).


Stop treatment* and assessment for early liver transplantation in

highly selected patients

Continue treatment for 28 days

Lille score ≥0.45Lille score <0.45

mDF <32 and GAHS <9

Assess treatment response at Day 7 (Lille score)

Prednisolone 40 mg/day ± NAC No specific therapy

mDF ≥32 or GAHS ≥9

Assessment of disease severity (prognostic scores)

• Systematic evaluation of nutritional status and energy intake

• Daily target 35–40 kcal/kg BW• Prefer oral route as first-line intervention• Supplementation with B-complex

vitamins

Consider liver biopsy if diagnosis is uncertain

Perform systematic extensive screening for infection

Treatment of alcohol dependence

Clinical diagnosis of AH

Absence of

infection

Non alcoholic fatty liver disease (NAFLD)

Cirrhosis

Hepatocellularcarcinoma

Liver-relateddeath

NASH

20-25%

40% ?

Fatty liverrare

Metabolic syndrome

NAFLD : Noninvasive Diagnosis of Liver Fibrosis in NAFLD

Score Serum markersAge BMI FBS TG AST ALT PLT ALB

FIB-4 O O O O

NAFLD fibrosis score

O O O O O O O

BARD O O O O

BAAT O O O O

NAFLD : Noninvasive Diagnosis of Liver Fibrosis in NAFLD

Transient elastrography

(fibroscan)

MR elastrography

NAFLD : Treatment

Treatment Recommen-dation

Comment

Weight reduction Yes • 3-5 % : improve steatosis• 10% : improve necroinflammation

Metformin No 6-12 mo of MF did not improve aminotransferases or liver histology

Pioglitazone Yes Improve histology in biopsy-proven NASH, in both with and without DM

Vitamin E Yes Dose 800 IU/d improves histology in non-diabetic adults with biopsy-proven NASH

UDCA No No histological effect

Omega-3 fatty acid N/A May be 1st line agent to Rx hyperTg in NAFLD

Statin Can be used to Rx dyslipidemia in NAFLD AASLD guideline 2018


Liver parenchyma :

AIH Small duct : PBC

Large duct : PSC

AIH : Clinical clues

Type 1 Type 2

Clinical presentation• Acute hepatitis on top chronic hepatitis 40-50%• Chronic hepatitis 40-50%• Acute hepatitis 10%

AIH : Investigation

Antibody Type Prevalence ANA 1 60-80%SMA 1 60-80%

LKM-1 2 4%

Plasma cell infiltration

Interface hepatitis

Hepatocyte rosette formation

AIH : diagnosis

Pretreatment aggregate score : Definite Dx > 15

Probable Dx 10-15Posttreatment aggregate score :

Definite Dx > 17Probable Dx 12-17

IAIHG simplified scoring system (2008)

Hennes EM, et al. Hepatology 2008;48:169–76; EASL CPG AIH. J Hepatol 2015;63:971–1004

Feature/parameter Discriminator Score

Antibodies (max 2 points)

ANA or SMA+

ANA or SMA+

or LKM+

or SLA/LP+

≥1:40

≥1:80

≥1:40

Any titre

(0−2 points total)

+1

+2

+2

+2

IgG or γ-globulins level>ULN

>1.1x ULN

+1

+2

Liver histology

(evidence of hepatitis is required)

Compatible with AIH

Typical of AIH

Atypical

+1

+2

0

Absence of viral hepatitis No

Yes

0

+2

Score ≥7 = Definite AIH

Score ≥6 = Probable AIH

• Diagnostic criteria for routine clinical use

AIH treatment

Therapeutic algorithm

*Treatment probably no longer indicated in decompensated, burned-out cirrhosis, unless high inflammatory score on liver biopsy

EASL CPG AIH. J Hepatol 2015;63:971–1004

Diagnosis of AIH

Advanced fibrosis/

cirrhosis*

Active disease

(HAI ≥ 4/18)

Mild disease

(ALT <3x ULN; HAI <4/18)

and no advanced fibrosis

Treatment optional

Individual decision based on:

• Age

• Co-morbidities

• Patient preference

• Serology

Treatment

required

If no treatment, monitor every

3 months (ALT, IgG)

Follow-up liver biopsy if there is

increase of ALT and/or IgG

Induction

therapy

AIH treatment

Primary biliary cirrhosis (PBC)

Small duct (interlobular bile ducts) destruction

by autoimmune inflammatory process

PBC : Clinical

Finding Frequency (%)Fatigue 21-85

Pruritus 19-55

Jaundice 3-10

Right upper quadrant pain 8

Hyperpigmentation 25

Hepatomegaly 25

Splenomegaly 15

Xanthelasma 10

None (ALP elevation) 25-61

PBC : Diagnosis

• AMA +ve• ALP > 1.5x • AST < 5x

PPV > 98%DuctopeniaGranuloma

PBC : Treatment

UDCA 13-15

mg/kg/d

Cirrhosis complication

Cholestatic complication • Pruritus : Cholestyramine,

rifacimin, opiod antagonist• Steatorrhea : MCT• Bone disease : Vit D + Ca• Coagulopathy : Vit K

Add 2nd line:• obeticholic acid 5 mg• fibrate

Inadequate response

Primary sclerosing cholangitis

Large duct destruction

by autoimmune inflammatory process

PSC : Clinical features

Intermittent biliary obstruction

Secondary biliary cirrhosis

PSC : Treatment

UDCA

Immunosuppressive and other agents

ERCP and endoscopic therapy

Liver transplantation

Less benefit



Alcoholic hepatitis

NAFLD


Metabolic liver disease


Variceal bleeding

Ascites and complications



Question

Which condition can cause varix only at fundus of stomach?

1. Primary biliary cirrhosis

2. Essential thrombocytosis with portal vein thrombosis

3. Chronic pancreatitis

4. Budd-Chiari syndrome

5. Schistosomiasis

Portal hypertension

Left sided portal HT : Isolated fundal varices

Caput medusa : Cirrhosis

Portal hypertension : Etiologies

Prehepatic• Portal V thrombosis• Splenic V thrombosis

Posthepatic• Budd-Chiari syndrome• Constrictive pericarditis • Rt-sided HF

Intrahepatic • Presinusoidal :

Schistosomiasis• Sinusoidal : cirrhosis • Postsinusoidal : VOD

Variceal bleeding Variceal bleedingAscites (low prot)

Variceal bleedingAscites (high prot)

hepatomegaly

Question

Which condition can cause varix only at fundus of stomach?

1. Primary biliary cirrhosis

2. Essential thrombocytosis with portal vein thrombosis

3. Chronic pancreatitis

4. Budd-Chiari syndrome

5. Schistosomiasis

Variceal bleeding

No varices

Small varicesNo hemorrhage

Med/Large varicesNo hemorrhage

Varicealhemorrhage

Recurrenthemorrhage

8% per year

8% per year

5-15% per year

60%

Variceal bleeding

V = I x R

↑Resistance to portal flow

↑Portal pressure

↑Variceal growth →rupture

Splanchnic vasodilatation

↑Portal blood flow

cirrhosis↑NO

TIPS, Shunt

EVL

Somatostatin, telipressin,

Non-select BB

OLT

T = tp x rw

AASLD guideline 2017

No varices

Small varicesNo hemorrhage

Med/Large varicesNo hemorrhage

Varicealhemorrhage

Recurrenthemorrhage

8% per year

8% per year

5-15% per year

60%

Variceal bleeding• Prevent variceal formation : no benefit • Prevent variceal progression : BB in

CTP-C or presence of red wale sign• Repeat EGD :

No varices: 2 y (active), 3 y (quiescent) Small varices:1 y(active),2 y (quiescent)

BB

• Prevent variceal rupture

BB or EVL

• Stop variceal bleeding

Somatostatin/telipressin + EVL, if fail → TIPS or OLT

• Prevent rebleedingBB & EVL, if fail → TIPS or OLT

EGD in all cirrhosis except in pt with LS < 20 kPa and Plt > 150,000

Ascites

Ascites : What’s SAAG

Exudate VS TransudateHigh protein Low protein

Right-sided CHF : High protein SBP : Low protein

Ascites : What’s SAAG

Sinusoid (S)

Peritoneal Cavity (PC)

Hs

Hpc

Os

Opc

SH – SO = PCH - PCO

SH = SO+ PCH - PCO

Portal pressure = Serum Alb – Ascites Alb

Ascites

Cirrhotic ascitesCardiac ascites

Peritoneal malignancy

1.1

4.

0

3.

0

2.

0

1.

0

0

Serum –

ascites

albumin

gradient

(g/dL)

(75)

Ascitic fluid

total protein

(g/dL)

7.

0

5.

0

3.

02.

0

0

2.5

Runyon, Ann Intern Med 1992; 117:215

97% accuracy

Ascites

Low gradient < 1.1 gm/dl▪ Peritoneal disease▪ Peritoneal carcinomatosis▪ TB peritonitis▪ Pancreatic ascites▪ Bowel obstruction /infarction▪ Biliary ascites▪ Postop lymphatic leak▪ Serositis in CNT diseases

▪ Nephrotic syndrome

High gradient > 1.1 g/dl▪ Sinusoid ▪ Cirrhosis▪ Alcoholic hepatitis▪ Mixed ascites

▪ Post sinusoid ▪ Veno-occlusive diseaseBudd-

Chiari syndrome▪ Cardiac ascites

▪ Myxedema

Runyon BA. Ann Intern Med 1992;117:215

Ascites

False low SAAG Different in time

Hypoalbuminemia < 1.1 mg/dl

Hyperglobulinemia : glob contribute to serum oncotic P

Hypotension : decrease portal pressure

False high SAAG Chylous ascites : lipid interfere with albumin measurement

Treatment of cirrhotic ascites

Grade Definition Treatment

1 Only detectable by US No treatment

2 Moderate symmetrical distension of abdomen

Restriction of salts and diuretic

3 Large or gross ascites with marked abdominal distention

LVP

Consensus Report of the International Ascites Club. Hepatology 2003;38:258-66EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

Grade 2 ascites

No peripheral edema

Low-sodium diet (80 – 120 mmol/day)Diuretics

Maintenance therapy

Spironolactone+ furosemide

Peripheral edema

Spironolactoneor Amiloride

Goal:Weight loss 0.5 kg/day

Goal:Weight loss 1 kg/day

Grade 3 ascites

< 5 L

Large-volumeParacentesis/TIPS

> 5 LSynthetic plasma expanders

Low sodium diet (70-90 mEq/day)Diuretics

Albumin(6-8 g/L of ascites tapped)

Consensus Report of the International Ascites Club. Hepatology 2003;38:258-66EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

↓ Post paracentesiscirculatory dysfunction

Ascites infection

Type of infection PMN (/mm3)

Culture result Treatment

Spontaneous bacterial peritonitis

≥ 250 Positive

(usually 1 Organism)

ATB + alb

Culture-negative neutrocytic ascites

≥ 250 Negative ATB + alb

Monomicrobial nonneutrocytic bacterascites

< 250 Positive

(1 Organism)

Symp : as SBP

Asymp : repeat

Secondary bacterial peritonitis

≥ 250 Positive (polymicrobial)

Surgery

SBP : Albumin infusion

• 1.5 g/kg within 6 hr and 1 g/kg on day 3

• ↓ type I HRS (30%->10%) and MR (29%->10%)• Indicated in

1. Cr >1mg/dL

2. BUN >30 mg/dL

3. TB > 4mg/dL

Ascites infection




≥ 250 Positive


ATB + alb




< 250 Positive

(1 Organism)

Symp : as SBP

Asymp : repeat



Surgery

Ascites infection

TREATMENTINDICATED

PMN>250?

Culture Positive?

TREATMENT NOT INDICATED

NO

Repeat Paracentesis

YES

PMN>250?

Culture Positive?

NO

NO

YES

YES

YESNO

Ascites infection




≥ 250 Positive


ATB + alb




< 250 Positive

(1 Organism)

Symp : as SBP

Asymp : repeat



Surgery

Primary VS Secondary peritonitis

*Only for free perforation

Ascitic profiles Sensitivity* Specificity*

2/3 of• Total protein > 1g/dL• LDH > ULN of serum LDH • Glucose < 50 mg/dL

100 45

• CEA > 5 ng/mL or• ALP > 240 units/L

92 88

Akriviadis EA, Runyon BA. Gastroenterology 1990Wu SS et al. J Hepatol 2001


Functional renal failure in cirrhosis ↑NO, CO, endogenous canabinoids

Decompensated cirrhosis

Splanchnic vasodilatation

↓effective circulatory volume

Renal failure

RAAS → Renal vasoconstriction

Infection : SBP, UTI

Type 1

Liver function

Type 2

Renal impairment: definitions of kidney disease

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

• KDIGO group definitions

Definition Functional criteria Structural criteria

AKI

Increase in sCr ≥50% within 7 days,

OR

increase in sCr ≥0.3 mg/dl within 2 days

No criteria

AKD

GFR <60 ml/min per 1.73m2 for <3 months,

OR

decrease in GFR ≥35% for <3 months,

OR

increase in sCr ≥50 % for <3 months

Kidney damage

for <3 months

CKD GFR <60 ml/min per 1.73 m2 for ≥3 monthsKidney damage

for ≥3 months

Stage 1A (sCr <1.5mg/dl)*

Stage 1B (sCr ≥1.5mg/dl)*

ICA management algorithm for AKI in cirrhosis

*Initial AKI stage is defined as AKI stage at the time of first fulfilment of the AKI criteria;†Treatment of spontaneous bacterial peritonitis should include albumin infusion according to current guidelines

Adapted from Angeli P, et al. J Hepatol 2015;62:968–74;

EASL CPG decompensated cirrhosis. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.024

• Investigation and management should begin immediately

Initial AKI* stage 1A Initial AKI* stage >1A

Close monitoring

Remove risk factors (withdrawal of nephrotoxic

drugs, vasodilators and NSAIDs, taper/withdraw

diuretics and β-blockers, expand plasma volume,

treat infections† when diagnosed)

Withdrawal of diuretics (if not yet

applied) and volume expansion with

albumin (1 g/kg) for 2 days

Persistance ProgressionResolution

Further treatment of

AKI decided on a

case-by-case basics

Close follow-up

Response

YES NO

Does AKI meet

criteria of HRS?

NO

Specific treatment for

other AKI phenotypes

YES

Vasoconstrictors

and albumin

Hepatorenal syndrome : Diagnosis

1. Cirrhosis with ascites2. Serum creatinine > 1.5 mg/dL3. No improvement after at least 2 days with diuretic withdrawal and

volume expansion with albumin (1g/kg/d, max 100 g/d)4. Absence of other causes

1. shock2. recent treatment with nephrotoxic drugs3. parenchymal renal disease (proteinuria > 0.5 g/d, rbc > 50/HF, abnormal U/S)

Type 1 Rapidly progressive (Cr >2.5 mg/dL or

Ccr <20 ml/min in 2 wk)

Type 2 Slow (months)

Refractory ascites

Hepatorenal syndrome : Treatment Treatment Type I Type II

Correct precipitating factor +++

Vasoactive drugs plus albumin +++ +

Renal replacement therapy +

TIPS + +

Liver dialysis +

Liver transplantation +++ +++• Vasoactive agents : Terlipressin (1 mg q 6 hr, titrate q 2 days,

max 12 mg/d), Norepinephrine, Midodrine • 20%Albumin: IV 20 – 40 g/d


US + AFP q 6 months

• Cirrhosis CTP-A,B• Cirrhosis CTP-C if on

transplantation waiting list • Chronic HBV infection

• Asian male > 40 yr • Asian female > 50 yr• Family history of HCC

• Non-cirrhotic F3, based on an individual risk

Screening

Bruix J, AASLD practice guideline 2010Heimbach JK, AASLD practice guideline 2018, EASL guideline 2018

Diagnosis

Bruix J, AASLD practice guideline 2010EASL guideline 2018

Cirrhosis/CH-B with liver nodule

< 1cm

Repeat US q 4 mo

Growing Stable for 1 yr

Ix according to size

Routine surveillance

> 1cm

4-phase MDCT/ dynamic CE MRI

Typical lesion

Typical HCC on 3-phase CT

A phase 30 sec V phase 80 sec

V. or delayed phase wash outA. hypervascular

AND

Diagnosis

Bruix J, AASLD practice guideline 2010EASL 2018

Cirrhosis/CH-B with liver nodule

< 1cm

Repeat US q 3 mo

Growing Stable for 2 yr

Ix according to size

Routine surveillance

> 1cm

4-phase MDCT/ dynamic CE MRI

Typical lesion

HCC Other CE study

Bx

Y

YN

N

Modified BCLC staging system and treatment strategy

*Child–Pugh A without ascites. Applies to all treatment options apart from LT; †PS 1; tumour-induced modification of performance

capacity; ‡Multiparametric evaluation: compensated Child–Pugh class A liver function with MELD score <10, matched with grade

of portal hypertension, acceptable amount of remaining parenchyma and possibility to adopt a laparoscopic/minimally invasive

approach; §The stage migration strategy applies; ‖Sorafenib has been shown to be effective in first line, while regorafenib is

effective in second line in case of radiological progression under sorafenib. Lenvatinib has been shown to be non-inferior to

sorafenib in first line, but no effective second-line option after lenvatinib has been explored. Cabozantinib has been demonstrated

to be superior to placebo in 2nd or 3rd line with an improvement in OS. Nivolumab has been approved in second line by FDA but

not EMA based on uncontrolled Phase 2 data. Please see notes for full details.

EASL CPG HCC. J Hepatol 2018; doi: 10.1016/j.jhep.2018.03.019

Very early stage (0)

Single <2 cm

Preserved liver

function*

PS 0

Early stage (A)

Solitary or

2–3 nodules <3 cm

Preserved liver

function*

PS 0

Intermediate stage (B)

Multinodular,

unresectable

Preserved liver

function*

PS 0

Advanced stage (C)

Portal invasion/

extrahepatic spread

Preserved liver

function*

PS1†–2

Terminal stage (D)

Not transferable HCC

End-stage

liver function

PS 3–4

Prognostic

stage

Solitary2–3 nodules

≤3 cm

Optimal surgical

candidate‡

Yes No

Yes No

Transplant

candidate

Treatment§

Survival >5 years >2.5 years ≥10 months 3 months

Chemoembolization Systemic therapy‖ BSCAblation Resection Transplant

HCC in cirrhotic liver

Ablation

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