Differential diagnosis of chronic liver diseases and...

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Differential diagnosis of chronic liver diseases and jaundice Krisztina Hagymási Internal Medicine IV. 2015/2016 SE-2nd DEPT OF INT MED

Transcript of Differential diagnosis of chronic liver diseases and...

Page 1: Differential diagnosis of chronic liver diseases and jaundicesemmelweis.hu/belgyogyaszat2/files/2015/12/2015_I_felev_blokk_V... · Differential diagnosis of chronic liver diseases

Differential diagnosis of chronic

liver diseases and jaundice

Krisztina Hagymási

Internal Medicine IV.

2015/2016

SE-2nd DEPT OF INT MED

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Suggestive symptoms of a liver

diseasejaundice

right subcostal pain

fatigue

somnolence

itching

skin bleeding, bleeding tendency

subfebrility, fever

meteorism, abdominal dyscomfort

diarrhoea, bad appetite

abdominal distension (ascites)

joint pain

neurological, psychiatrical symptoms

sexual dysfunction (amenorrhoea, impotence)

GI tract bleeding

weight loss

edema

foul breath (hepatic foetor), tasting problem

Not pathognomonic/

pathognomic !

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icterus (sclera, mucosa, skin)

spider naevi

erythema palmare et plantare

red, shiny tongue

thin, vulnerable skin

skin bleedings (petechia, purpura, echymosis, suffusion)

xanthoma, xanthelesma

gynecomastia

caput medusae

ascites

hernias (umbilical, scrotal, inguinal)

neurological signs (flepping tremor, consciousness)

Suggestive physical signs of a liver

disease

Not

pathognomonic/

pathognomic !

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Liver function tests

Liver enzymes: ALT(GPT), AST(GOT), ALP, GGT

Synthetic function: albumin, prothrombin time,

pseudocholinestherase

Metabolic function: cholesterol, glucose, NH3

Excretory function: bilirubin

Others: blood count abnormalities, MCV

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Etiological factorsNonalcoholic fatty liver disease (NAFLD/NASH) (diagnosis of exclusion)

Alcohol consumption, drug induced liver disease (DILI) (Anamnesis, diagnosis of exclusion)

Viral infections-not just primary hepatotropic viruses (HBsAG, a-HCV…)

Autoimmune Diseases:

– Autoimmune Hepatitis: (ANA, SMA, LKM1, SLA)

– PBC (AMA)

– PSC (ANCA)

Storage Diseases:

– Iron-hemochromatosis (Fe, TVK, Ferritin)

– Copper-Wilson disease (Cu, Ceruloplasmin)

- a1-Antitripsin deficiency (A1T)

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Liver diseases

Suspicion of a liver disease

Abnormal/Impaired

Liver Function

Acute: <6 Months Chronic: >6 Months

HepatocellularHepatocellular

Cholestatic Cholestatic

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Acute Damage to the Liver

.Hepatocellular

ALT↑↑

Combined: ALT↑ ALP↑

Cholestatic

ALP ↑↑

GGT ↑↑

ALT ↑

Pathognomonics:1. anti-HAV IgM

2. HBsAg

3. anti-HBc IgM

4. anti-HCV

5. ANA, SMA

6. EBV, CMV

7. Ceruloplasmin

8. Alcohol?

9. Drugs?

Pathognomonics:1. AMA

2. Drugs?

3. US/MR

4. ERCP/MRCP

Liver Biopsy: Only in those patients in whom

diagnosis can NOT be done by any other means.

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Chronic Liver Damage:

.Hepatocellular:

ALT↑↑

Combined: ALT↑ ALP↑

Cholestatic:

ALP ↑↑

GGT ↑↑

ALT ↑

Pathognomonics: 1. HBsAg

2. anti-HCV

3. Fe,Ferritin

4. Ceruloplasmin

5. a1-antitripsin

6. ANA, SMA

7. US

8. Alcohol?

Pathognomonics: 1. Drugs?

2. AMA

3. p-ANCA

4. US

5. ERCP/MRCP

Liver biopsy: sometimes it has a pathognomonic value

Prognostic: necroinflammation (grading), fibrosis (staging)

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Score systems

Diagnosis of exclusion

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PBC Diagnostic Criteria

Typical clinical & laboratory picture:

– itching skin, elevated ↑ALP, ↑GGT

– GOT, GPT only slightly elevated ↑

– serum bilirubin is initially normal

– (If >100 umol/l – poor prognosis)

– IgM

Antimitochondrial antibody (M2) positivity:

>1:80 titer (5% AMA negative)

Exclusion of extrahepatic bile duct obstruction:

– Ultrasound, MRCP, ERCP

Concurrent histological findings:

– I-IV. Stage/phase

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PSC Diagnostic Criteria

Typical Clinical & Laboratory picture:

– Itching of the skin, Tiredness/Fatigue, Weight loss, Steatorrhoea, Icterus

– GGT, ALP

– pANCA

– IgM

Typical Cholangiography contrast media differences:

– (ERCP)

– MRCP

Exclusion of Secondary Sclerosing Cholangitis:

(Liver Biopsy: forms/types involving small bile ducts: „Small Duct Primary Sclerosing Cholangitis”)

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AIH Diagnostic Criteria

Serum IgG-Elevation:

– IgG> 16 g/l: 1 point

– IgG>18,5 g/l: 2 points

Auto-Antibodies:

– ANA, SMA or LKM > 1:40: 1 point

– >1:80 or SLA positive: 2 points

Chronic Hepatitis Histology:

– Complient with AIH: 1 point

– Typical for AIH: 2 points

Víral Hepatitis Negative:

– 2 points

Rating: If > 5 points: = Probable AIH,

If >6 points: DEFINITELY AIH

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Wilson’s Disease Diagnostic Criteria

.

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Labs findings in NAFLD/NASH

AST, ALT (normal value 4-5x) 50-90 %

ALP (normal value 2x) ~30 %

AST/ALT<1 (DeRitis ratio) ~100 %

hypertrigliceridemia 20-80 %

bilirubin (↑) end stage

albumin (↓) end stage

protrombinidő (↑) end stage

ANA 15-20 %

Ferritin cc (>300 mmol/l) ~60 %

Transferrinsaturation (>55%) ~20 %

hepatic iron index (<1,9) ~100 %

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NAFLD/NASH

NAFLD/NASH

Viral hepatitis

HBsAg

anti-HCV

Alcohol consumption

<20 (female)-30 g

(male)/day

Secondary reasons of

fatty liver *

Autoimmune liver

diseases

ANA, AMA, SMA

IgG, IgM

Storage disorder

iron, ferritin

ceruloplasmin

vas, ferritin

a1-antitrypsin

-

--

-

-

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Drug Induced Liver Damage

Hepatocellularis Kevert Cholestaticus

Acarbose Amitriptyline Amoxicillin-clavulanic acid

Acetaminophen (paracetamol), NSAID Azathioprine Anabolikus szteroidok

Allopurinol Captopril Chlorpromazine

Amiodarone Carbamazepine Clopidrogel

Baclofen Clindamycin Erythromycinek

Fluoxetine Cyproheptadine Irbesartan

HAART Enalapril Mirtazapine

Herbs Flutamide Oral anticoncipient

Isoniazid Nitrofurantoin Estrogen

Ketoconazole Phanobarbital Phenothiazinok

Lisinopril Phenytoin Terbinafine

Losartan Sulfonamidok Tricyclic antidepressants

Methotrexate Trazodone

Omeprazole Trimethprim-sulfamethoxazole

Paroxetine Verapamil NSAIDs

Pyrazinamide Lipid lowering drugs

Sertraline HILI: herb-induced liver

injury

Antiinfectious agents

Stains Psychotropic drugs

Tetracycline

USA

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AST-

ALT

ALP

Acute damage

Hepatocellular

Necrosis 8-500 x <3x acetaminophen, halothane, isoniazid

Steatosis 8-20 x <3x amiodarone, methotrexate

Cholestasis <8 x >3 x cyclosporin, estrogenes

Mixed >8 x >3 x azathioprine, amoxycillin/clavulanic acid

Chronic damage

Hepatocellular

Necrosis 3-50 x 1-3 x valproic acid

Cirrhosis V x V x Methotrexate

Cholestasis 1-5 x 3-20 x (metylene-dianaline)

Vascular

Peliosis hepatis <3 x <3 x (vinyl-chloride)

VOD 1-3 x V x cytosine-arabinoside, busulphan

Portal HTN 1-3 x V x (vinyl-chloride) vitamin A

Tumors V x V x

Adenoma Estrogens, anabolic steroids

HCC (estrogens?,arsenic)

Haemangiosarcoma (vinyl-chloride)

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DILI

Drug induced liver diseases

Viral hepatitis

anti-HAV IgM

HBsAg

anti-HCV

anti-HEV

Alkoholfogyasztás

Anamnézis

Alkoholszint

AST/ALT>2:1

szénhidrátszegény

transzferrin

Biliary tract disoreders

US

CT

MR, MRCP

ERCP

Hemodynamic

disorders

Hypotension

Sock

Heart failure

Autoimmun

betegségek

ANA

SMA

IgG

Anyagcsere-

betegségek

Vas, Ferritin

Cöruloplazmin

a1-antitripszin

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Overlaping-Syndromes

AIH

PBC PSC

6-8%8-9%

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CASE presentation 1.

26-y ♂

BMI= 26,54 kg/m2

total cholesterol cc: (6,4) mmol/l

LDL-cholesterol-cc.: 3,47 (3,94) mmol/l

GOT 108 U/l

GPT: 273 U/l

GGT:200 U/l

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Labs

AFP, TSH: normal value

HBsAG, a-HCV: negative

ANA 1:40: pos., 1:160: poz., homogene pattern

AMA, SMA, LKM, liverspec. prot.-at, ANCA: neg.

IgG, IgA, IgM: norm.

Fe: 21,4 umol/l, TVK: 70,6 uM/l, ferritin: 561ug/l

Cu: 12,4 umol/l, ceruloplasmin: 0,15 g/l, urine Cu-excretion: 2,1 umol/die

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Abdominal ultrasound – hepatomegaly, diffuse lesion

Histological examinationdegeneratio adiposa hepatis maioris gradus (60-70%: macroves.)+fibrosis hepatis

– high suspicion of toxic liver disease

– the etiology can not be proven by histology

– the pattern of inflammation is not characteristic for AIH

– no accumulation of Cu, but Cu accumulation can be focal in Wilson’s disease, Wilson’s disease can not be excluded

Neurological examination– No abnormality

Opthalmological examination– No abnormality

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PENICILLAMIN-test

Urine Cu-excretion

2x600 mg

penicillamin/

nap/2 day<10x

day

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Genetic analysis

His1069Gln és

pGlu1064Ala

His1069Gln His1069Gln

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Treatment

0

50

100

150

200

250

300ápr.08

jún.08

aug.0

8

okt.

08

dec.0

8

febr.

09

ápr.09

jún.09

aug.0

9

okt.

09

dec.0

9

febr.

10

U/l

GOT

GPT

GGT

Artamin-treatment (3x500

mg penicillamin/die)

2x1 Legalon/die+3x250

mg Ursofalk/die +400

mg E- vitamin/week

penicillamin test

86 kg 81 kg

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Differential diagnosis of jaundice

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Bilirubin Metabolism

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Classification of Icterus

According to Anatomical Locations:

1. Pre-Hepatic, Hemolytic

2. Hepatic, Parenchymal

3. Post-Hepatic

Based on the type of Bilirubin Metabolism Disorder:

1. increased production

2. decreased uptake by the liver

3. decreased conjugation in the liver

4. decreased excretion of conjugated bilirubin due to intra orextrahepatic causes

Chemical Labratory Basis:

1. Un-Conjugated (indirect)

Total Bilirubin: >80%-85% unconjugated

2. Conjugated (direct)

Total Bilirubin: >50% conjugated

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Types Of Icterus/Jaundice I.

1. Un-Conjugated (Mostly Indirect) Hyperbilirubinemia

Pre-Hepatic

increased bilirubin production

Hemolysis, Hematoma, Infarction

Hepatic

Decreased Bilirubin uptake

Gilbert-Syndrome, Post-Hepatitis

Hyperbilirubinemia, Effect of some drugs

Decreased Bilirubin Conjugation

Gilbert-Syndrome, Crigler-Najjar-Syndrome

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Types Of Icterus/Jaundice II.2. Conjugated (Mainly Direct) Hyperbilirubinaemia

* Hepatic:

Failure of conjugated Bilirubin excretion

Dubin-Johnson, Rotor

Biliary Epithelial Damage

Hepatitis, Cirrhosis

Intrahepatic, Cholestasis

Viral Hepatitis, Alcoholic Hepatitis, Drugs, PBC

* Other:

Mononucleosis Infection (EBV), Lymphoma, Cholangitis

* Posthepatic:

Obstructive (Mechanical Jaundice)

Choledocholithiasis, Biliary Atresia, Tumor, Stenosis, Sclerosing Cholangitis, Choledochal-cyst, Worm Infection (Ascaris), Pancreatitis, Pancreatic Tumor

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Patient with

Jaundice

Anamnesis

Physical Examination

Laboratory Analysis

Radiological Tests

Liver Biopsy ?

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Just 2 questions !

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Is it REALLY Bilirubinuria?

Hematuria

Porphyria

Rhabdomyolysis-

Myoglobinuria

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Physical Examination

Pseudo-icterus VS. HypercarotinemiaIcterus

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Physical Examination

Severity of the Jaundice

Pre-Hepatic

Hepatic

Post-Hepatic

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CholestasisIcterus

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Type: Serum Bilirubin Urine Feces

Indirect Direct Bilirubin UBG

Pre-Hepatic ↑↑ N N ↑ dark

Hepatic ↑ ↑(↑) ↑ ↑(↑) normal

Post-Hepatic N (↑) ↑↑ ↑↑ ↓ OR 0 acholic

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Laboratory Parameters

Hemolysis: Haptoglobin, LDH, Reticulocyte number

Hepatocellular Damage: GOT(AST), GPT(ALT)

Cholestatic Damage: GGT, ALP

Synthesis Enzyme: pCHE

Other:

– Albumin, Prothrombin Time (PT), NH3

– Ceruloplasmin, a1-antitripsin, Ferritin

– Immunglobulins

– Auto-Antibodies

– Virus Markers: HBsAG, a-HCV, a-HAV IgM, EBV, CMV serology

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Radiological Tests:

Abdominal US test – common bile duct dilatation?

Dilatated NO dilatation

ERCP

MRCP

PTC

CT?

MR?

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CASE presentation 1.

90y female patient

past history:

appendectomy, tonsillectomy, hysterectomy,

cholecystectomy, op. pp. fissura ani, hypertension, ISZB, COPD, depression

2008: epigastric pain, GGT-elevation, dilatatedcommon bile duct (10 mm): ERCP, EST (Oddi-sphincter dysfunction)

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2011. August: admission: nausea, vomiting

physical examination: right subcostal tenderness

Lab results

– ALP ↑ (357 U/l)

– sedimentation rate ↑ (29 mm/óra)

– creatinine ↑ (97 mmol/l)

– other lab markers were in the normal range

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CASE presentation 2.

55y male patient

past history: hypertension

2014: admission: epigastric pain

lab results

– bilirubin cc: total: 80 umol/l direct: 67 umol/l

– GOT: 150 U/l, GPT: 210 U/L, GGT: 870 u/l, ALP: 1100 U/l

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Abdominal ultrasound: dilatated common bile duct

and intrahepatic ducts

d.

choledochus

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ERCP: Vater-papilla ulcerative mass (biopsy),

dilatated common bile duct and intrahepatic ducts

Vater-papilla

d.

choledochus

intrahep. bile

ducts

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ERCP: stent implantation

US: stent in the

common bile duct

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Lab results: normalized

US: regression of biliary ducts dilatation, stent in the

common bile ducts

Vater-papilla histology: adenocarcinoma

Chest, abdominal CT vizsgálat: no met.

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Whipple-operation (pancreaticoduodenectomia: pancreas head,

duodenum, gallbladder, distal part of the common bile duct,

aboral part of the stomach; reconstruction: gastrojejunostomia,

choledochojejunostomia, pancreaticojejunostomia)

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histological diagnosis: neuroendocrine tumor

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Thank you!