Differential diagnosis of chronic liver diseases and...
Transcript of Differential diagnosis of chronic liver diseases and...
Differential diagnosis of chronic
liver diseases and jaundice
Krisztina Hagymási
Internal Medicine IV.
2015/2016
SE-2nd DEPT OF INT MED
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 !
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 !
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
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)
Liver diseases
Suspicion of a liver disease
Abnormal/Impaired
Liver Function
Acute: <6 Months Chronic: >6 Months
HepatocellularHepatocellular
Cholestatic Cholestatic
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.
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)
Score systems
Diagnosis of exclusion
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
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”)
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
Wilson’s Disease Diagnostic Criteria
.
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 %
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
-
--
-
-
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
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)
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
Overlaping-Syndromes
AIH
PBC PSC
6-8%8-9%
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
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
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
PENICILLAMIN-test
Urine Cu-excretion
2x600 mg
penicillamin/
nap/2 day<10x
day
Genetic analysis
His1069Gln és
pGlu1064Ala
His1069Gln His1069Gln
Treatment
0
50
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300ápr.08
jún.08
aug.0
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okt.
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jún.09
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okt.
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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
Differential diagnosis of jaundice
Bilirubin Metabolism
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
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
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
Patient with
Jaundice
Anamnesis
Physical Examination
Laboratory Analysis
Radiological Tests
Liver Biopsy ?
Just 2 questions !
Is it REALLY Bilirubinuria?
Hematuria
Porphyria
Rhabdomyolysis-
Myoglobinuria
Physical Examination
Pseudo-icterus VS. HypercarotinemiaIcterus
Physical Examination
Severity of the Jaundice
Pre-Hepatic
Hepatic
Post-Hepatic
CholestasisIcterus
Type: Serum Bilirubin Urine Feces
Indirect Direct Bilirubin UBG
Pre-Hepatic ↑↑ N N ↑ dark
Hepatic ↑ ↑(↑) ↑ ↑(↑) normal
Post-Hepatic N (↑) ↑↑ ↑↑ ↓ OR 0 acholic
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
Radiological Tests:
Abdominal US test – common bile duct dilatation?
Dilatated NO dilatation
ERCP
MRCP
PTC
CT?
MR?
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)
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
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
Abdominal ultrasound: dilatated common bile duct
and intrahepatic ducts
d.
choledochus
ERCP: Vater-papilla ulcerative mass (biopsy),
dilatated common bile duct and intrahepatic ducts
Vater-papilla
d.
choledochus
intrahep. bile
ducts
ERCP: stent implantation
US: stent in the
common bile duct
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.
Whipple-operation (pancreaticoduodenectomia: pancreas head,
duodenum, gallbladder, distal part of the common bile duct,
aboral part of the stomach; reconstruction: gastrojejunostomia,
choledochojejunostomia, pancreaticojejunostomia)
histological diagnosis: neuroendocrine tumor
Thank you!