Diseases of the gall-bladder and biliary tract

based on www.harrisonsonline.com images.MD,

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GallstonesGrant Sanders, Andrew N Kingsnorth

BMJ 2007;335:295-9

NEJM and and many others Dr. Fenyvesi Tamás

04/10/2017

„Become a doctor, no lectures required.”

Saying Goodbye to Lectures in Medical School —Paradigm Shift or Passing Fad?Richard M. Schwartzstein, M.D., and David H. Roberts, M.D.

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Roberts, M.D.NEJM 2017;377:605

.Secretion of the bile in the hepatic lobuli :ductuli---interlobular ducti—right and and left ductus hepaticus;

Here joins the ductus cysticus,

The common ductus choledochus-ampulla

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The common ductus choledochus-ampulla

Vateri-duodenum

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.The bile is a pigmented isotonic fluid:

water 82%,bile acids 12%,

lecithin and other phospholipids 4%,

Non esteric cholesterol 0,7%,

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Non esteric cholesterol 0,7%,

etc ( ions, proteins,

mucus,metabolites)

The primary bile acids : cholic- and chenodeoxicholic-acid

derived from cholesterole andexcreded in conjugation with glycin or taurin.

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taurin. They are detergents in watery solution, above 2mM concentration they form

aggregates (micellum)

The enterohepatic circulation is a basic phenomenon Bile acids (b.a)are reabsorbed from the whole intestine in a passive way and activelyfrom the jejunum

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Tha b.a.reserv is ~ 2-4g , 5-10 recirculations daily

loss about 0.3-0.6gsynthesis is being hinderd by reabsorbed b.a.( 7αααα-hydroxylase )

.

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Richard.Bowen@colostate.edu

Function of the g.b. and of the Oddi sphincterThe O.s.controlls the excretion of bile and stops

reflux from the duodenumThe g.b. function is controlled by cholecystokininfrom duodenum mucosa (amino acids and fat…)

g.b. contraction

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g.b. contraction choledochus peristalticsO.s. resistance decreaseincrease of bile flow

Functioning of the gall bladder and of theSphincter of Oddi:

In an interdigestiv period 4-8/minphasic

anterograde peristaltic contraction:minute „gall injections” into the duodenum,

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minute „gall injections” into the duodenum,cleansing the sphincter of food remnants and small stones

Storage and excretion from the gall bladder

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Muscular layer of the gallbladder

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Mechanism of gallbladder function

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CholelithiasisFirst description 1341 Padua: Gentile de

Foligno 40 yo < women 20%- , men 8%- prevalence

cristallic structure formed from normaland pathol component of bilecholest and mixed stones 80%

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cholest and mixed stones 80%70% cholest, Ca salts, bile acids,

pigmentsPigment stones 20%

Ca bilirubin complex only 10% cholest

About 10-15% of the adult Western population willdevelop gallstones, with between 1% and 4% a year

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between 1% and 4% a yeardeveloping symptoms.

Cholesterol stones

• Most prevalent in the bladder • >90% cholesterol• Minim al Ca

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• Minim al Calarger than the pigment stones

Pigment stones (calcium bilirubinate)

1. Demographic-genetic factors: Asia!

2. Chronic haemolysis3. Alcoholic cirrhosis

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3. Alcoholic cirrhosis4. Chronic bile infections5. old age

Increased conjugated bilirubin in the bile ducts causes precipitation

Pathophysiology of cholesterol gallstone formation

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Gallstones occur when there is an imbalance in the chemical constituents of bile that results in precipitationof one or more of the components.

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of one or more of the components. Why this occurs is unclear, although certain risk factors are known.

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gall bladder stasis, sludge and stone formation

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10-15% prevalence in the US population

Surprisingly it leads to ~1.000 death/year

It is highly prevalent in American Indians

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It is highly prevalent in American Indians

Yearly~ 500 000 cholecystectomies the cost is˃ 6 Mld $ (or as used in theUS

billion)

Conditions to stone formation

1. formation lithogenic bileObesity, high calory diet, clofibrateincrease in HMG-CoA reductase

enzyme activity

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enzyme activitydecrease cholic acid secretionIncrease of cholesterin/cholic acid relation

2. Instabile cholesterole-richvesicules, cholesterol monohydrate

cristals3. Cholesterol nucleus formation

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3. Cholesterol nucleus formation4. Bile sludge formation(semilunar layer

at the wall of the g-bladder) pregnancy, very calory poor diet

5. Disease of the ileum or postopMalabsorption of bile acids

Decrease in bile acid pool,

Secretion of bile-salts

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7αααα-hydroxylase activity

6. Increase of ageIncrease in cholesterole secretion,

Decrease of bile acid pool

And secretion of bile acid salts

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And secretion of bile acid salts

7. Gall bladder hypomotility causes sludge/stone formation

a. Parenteral feedingb. starvationc. pregnancy

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c. pregnancyd. some drugs: octreotide

somatostatin analogue,

clofibrate

8. decreased bile-acid secretiona.primer biliary cirrhosis b.chronic intrahepatic

cholestasis 9. Etc

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9. Etca, high calory/fat diet b. spine trauma(?)

Pregnancy

a. in the third trimester the cholesterole saturationof the bile increases

b. the gall bladder contraction on food intake

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b. the gall bladder contraction on food intakedecreases

This leads to sludge formation in 20-30 %gall-stones in 5-12%

1.Demography

North Europe, USA> Asia,

Family, inherited traits

2.Obesity

Normal b.a. storage and secretion,

but increased cholesterole bile secretion

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but increased cholesterole bile secretion

3.Weight loss

tissue cholest mobilization leads to increased biliary cholest secretion

4. Female sex hormones

a. estrogens stimulate hepatic

lipoprotein receptors, stimulate cholesterole

absorption, biliar cholesterole secretion,

decreases chenodeoxycholic a. synthesis

b. anticoncipients decrease c.a. secretion

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b. anticoncipients decrease c.a. secretion

and cholesterol esterification

Diagnostics

1.Ultrasound2.CT3.MR cholangiopancreatography4.Nuclear cholangio-cholecystography

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4.Nuclear cholangio-cholecystography5.percutaneous transhepatic cholangiography6.ERCP

Dg of gallstones

Abdominal ultrasound is the method of choice

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( a stone and a „shadow”)2 mm is detectable, the false pozitive and false negative

ratio 2-4%

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US scan shows highly reflective echoes within the gallbladder (arrows), which indicate gallstones and shadowing.( RadiologyInfo.org)

Acalculous cholecystitis with dilated gallbladder and thickened gallbladder wall

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Appearance of gallstones

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Appearance of gallstones

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Cholesterol stones

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Cholangiography

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Cholangiography

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Gall stones are common but often do not give rise to symptoms.Pain arising from the gall bladder may be typical of biliary colic,but a wide variety of atypical

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but a wide variety of atypical presentations can make the diagnosis challenging.BMJ 2001;323:1170-3

N.B. angina pectoris P.D.White

Stone in ductuscholedochus

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g.bladder stoneto the ductuscysticus

Asymptomatic gallbladder diseases

Cholelithiasis is defined as asymptomatic^ when gallstones do not relate to symptoms such as pain or complications suchas acute cholecystitis, cholangitis, or pancreatitis

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pancreatitis The estimated prevalence of gallstones is 10–

25 % and50–80 % of the patients are asymptomatic at the diagnosis

Symptoms of cholelithiasis

Most common right upper quadrant painUsually not waxing and waning like intestinal colicthe stone may occlude the cistic duct, or the common bile duct (this leads to jaundice)

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It may radiate to the right scapula.

It is often causing cholecystitis

Moderate increase serum bilirubin( normal values 5-21µµµµmol/l) conjugated with glucuronic acid : „direct” bilirubin Fever is a sign of complication (-itis)epigastrialial fullness, flatulence

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epigastrialial fullness, flatulence

Possible precipitating cause fatty food or„gobbling”

Management of gall stones1. Surgical

Operate on asymptomatic? indications a. repeat colics, quality of life

b. events in history:

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b. events in history:cholecistitis, pancreatitis etc

c. different complicationsacut cholecystitis, porcelain g.bladder, small stones (?) ,

statistics on gall bladder cancer….

The„gold standard”) technique is

laparoscopic cholecystectomyfrom a study of 4.000 cases

1.complications 4%2. „upgrade” to laparotomy 5%

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2. „upgrade” to laparotomy 5%3. lethality < 0,1%4. injury to ducts 4%

intraop cholangio 30 %postop ERCP 1,5%

History of laparoscopic cholecystectomy

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1. Who should undergo LC?2. How should common bile stones be

managed?3. In what stage of technological development

is LC?4. Is LC safe and feasible?5. Is it beneficial to the patients?

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5. Is it beneficial to the patients?6. What are the special aspects to be

considered during LC?7. What are the training recommendations

for LC?Consensus Conference 2015

Indications for laparoscopic cholecystectomy

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Conservative management ofcholelithiasis

UDCA and CDCA decrease the HMG-CoA reductase activity the cholesterol synthesis decreases in the liver

UDCA decreases the stone formation and some

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UDCA decreases the stone formation and some of the stones dissolve, but

very expensive , and difficult complianceand the stones recur in 50%

extracorporeal shock-wave lithotripsy (electrohidraulic, piezoceramic, electromagnetic)practically disapeared with laparoscopy

Evacuation of gallstone fragments after shockwave lithotripsy

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Acute @ chronic cholecystitis

Acute: ductus cysticus obstruction by stone 1. mechanical inflammation from

stretch

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stretch2. chemical infl. from lysolecithin

and other tissue products3. bacterial infl. 50-85%of cases

Characteristic symptomsstarts as bile colic irradiates

to the right scapulavomiting, exsiccosisfever, even chills, a RUQ pain may cause a sudden halt ininspiration (Murphy sign )

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inspiration (Murphy sign )A „triad”: RUQ tenderness

feverleukocytosis

Laboratory signs : many

Some cases without gall-stones5-10 %

causes: traume , burnsafter deliveryadenocarcinoma

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adenocarcinomavasculitisdiabetestorsion of the gall-bladder

Complications of cholecystitis

Empyema: d.cysticus obstruction

hydrops : long-standing obstruction,usually one big stone in the bladder

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usually one big stone in the bladderpalpable!!

Must be operated on

Gangrena and perforationischemia of the dilated bladder , abscess may develop

urgent operation„free” perforation is rare :lethality 30%Fistule formation :mostly cholecysto-duodenal. Air in the bile ducts or contrast

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duodenal. Air in the bile ducts or contrastreflux during barium meal

Gall-stone ileusbig stones to the duodenum through a fistule

porcelain gall-bladdercarcinoma !!

Treatment of cholecystitis

medical: stabilization of patient’s general statecarceration, nasogastric tube, volume suppl, i.v. antibioticspainkiller :

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painkiller :

preparation to surgery

Surgery early surgery is preferred (24-72 hours)urgency postpone 1.in complications

2. very severe general state of patient3. uncertainty in dg.

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3. uncertainty in dg.in acute cholecystititis surgery is

now the preferred approach

Cholecystectomy is „curative” in 75-90%-of casesPostcholecystectomy complication:

1. stricture of ducts2. remaining stones 3. cystic stump syndrome?4. Oddi sphyncter stenosis,

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4. Oddi sphyncter stenosis,dyskinesis sphyncterotomy

5. Cholic acid gastritis Mostly unrelated to surgery .„postcholecystectomic sy”

may be a misnomer

Cholangitis

Cholestasis : stone , stricture, tumor, infection( E.coli,Klebsiella, Pseudomonas, enterococci,

clostridium)Characterized by triad of Charcot:

pain, jaundice, fevertender, enlarged liver

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tender, enlarged liverlabor: bilirubin, leukocytosis, APT,CRP, sedimentation

rateUltrasound : dilated bile ductsBlood culture••

Cholangitis

Therapy:

Urgently antibiotics ( gentamycin, ampicillin, metronidazol)

and decompression ERC,

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and decompression ERC, (sphyncterotomy!!)

In chronic cases signs are less characteristic

Primary sclerosing cholangitisIdiopathic, heterogenous, cholestatic liver diseaseisolated or mostly combined (HLA-B8, HLA-DRB1)

Male 60%,median 41 years,prevalence 0-16/100.000small and large bile ducts(MRCP,ERCP)jaundice, ALP, RUQ pain, autoimmune

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jaundice, ALP, RUQ pain, autoimmune hepatitis,varix haemorrghoften+colitis ulcerosa

therapy ? Cholestyramin, antibiot, ERCPsphyncterotomy,4-10 years death or

liver transplantation

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NEJM 2016;375:1161

Hyperplastic cholecystosis

Adenomyomatosis:epithelial proliferation of bladder (Rokitansky Aschoff sinus)

Cholesterinosislipid deposits in lamina propria, „cholesterol polyps” into the

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propria, „cholesterol polyps” into thelumen or diffuze „strawberry gallbladder”

usually with cholesterole stones

Tumor

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.

Cancers of the gallbladder and biliary tractare invasive adenocarcinomas that arise from the epithelial lining of the gallbladder, intrahepatic (peripheral) and

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intrahepatic (peripheral) andextrahepatic (hilar and distal common)

bile ducts,accounting for an estimated 7480 new cases and 3340 deathsin the United States, in 2005

Hennedige et al. Cancer Imaging 2014, 14:14 Page 2 of 21http://www.cancerimagingjournal.com/content/14/1/14

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Gall bladder adenocarcinomaRare tumor. Often accompaniedwith gallstonesExcept of big stones etiological role not proved.A continous irritation of the bladder wall ,porcelain bladder may be in the background.

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bladder may be in the background.Usually a late dg , 80% during bladder operation.

Very dim prognosis.

Bile tract carcinoma• Less prevalent than bladder cc

• No stones in the background

• Genetics ? P53 mutation

Operative intervention :

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Operative intervention : pancreatoduodenectomy, with biliodigestive anastomosis.

Palliative possibility endoscopic endoprsthesis Very bleak prognosis

Vater-papilla carcinoma• The clinical signs are the sequela of

obstruction.

• A specific entity developing from adenoma

• Clinically it presents like a duodenal,

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• Clinically it presents like a duodenal, pancreatic or choledochus tumor

. Courvoisier-sign :(jaundice without colics, palpable , „elastic” gall b.

Operative intervention :Pancreatoduodenectomy

Five year survival ~ 50%

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Diseases of the biliary tractCongenitalbiliaric atresia and hypoplasia: obstruction with

jaundicecholedochus cysts: by 10 years of age ectasia of:

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choledochus cysts: by 10 years of age ectasia of:intrahepatic ducts (Caroli)

:cholangitis , abscess,cirrhosis,cholangiocarcinoma-

Choledocholithiasis

In 10-15% of cholelith patients. prevalence increases with agemostly cholesterole and mixed stones

Pigment stones are the „primary” caused

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Pigment stones are the „primary” caused by haemolysis, recurrent cholangitis,

congenital anomalies

Obstructive jaundice

mostly stones, or tumor (pancretic head)Courvoisier rule!!An obstruction by stone : no palpable g.b. ,tumor: elastic resistance

cholecystitis és mild jaundice suspect stone

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cholecystitis és mild jaundice suspect stonedeep jaundice (sebi>300µmol/l) tumor

normal: 2-18)PancreatitisBiliary cirrhosis

Important basic tests

• -serum bilirubin-alkalic phosphatase increas

– prothrombin decrease

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– prothrombin decrease

– urine bilirubin increase

– No urobilinogen in urine

Trauma, stricture benign 95%-surgical complication

1/500 cholecystectomyTumor: pancreas carcinoma („head”)

cholangiocarcinoma,(a bifurcatioban Klatskin)nonobstructiv paraneoplasticus cholestasis

Stauffer syhaemobilia

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haemobiliaműtéti sérülésabscessusvérző tumoresetleg choledocholith , parazitás betegség

szövődményeDg.:epekőkólika,sárgaság,melaena

Parasitic diseases : trematodes Far-East

Clonorchis sinensis, Opistorchis viverriniworld-wide: Fasciola hepatica

HIV cholangiopathy, stone-free cholecystitis,focalis distalis biliaris stenosisin the background immudeficiency and

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in the background immudeficiency andopportunistic cryptosporidium, microsporidiumcolonisation

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Akinek nem tetszett,

O. Nagy Gábor. Magyar szólások és közmondások

8282O. Nagy Gábor. Magyar szólások és közmondásokGondolat-Talentum,1994

.

a Hungarian adage

„Who did not like this, the bile -malice-is talking for him/her”

O. Nagy Gábor. Magyar szólások és közmondásokGondolat-Talentum,1994

END

5. Ileal disease or resection Malabsorption of bile acids leads

to decreased bile acid pool,

decreased biliary secretion of bile salts,

and decreased 7αααα-hydroxylase activity

Increasing age

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6. Increasing ageIncreased biliary secretion of cholesterol,

decreased size of bile acid pool,

decreased biliary secretion of bile salts

8585O. Nagy Gábor. Magyar szólások és közmondásokGondolat-Talentum,1994

Where bile goes during fasting

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Healthy subject compared with patient with cholelithiasis

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Healthy subject compared with patient with cholelithiasis

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Healthy subject compared with patient with cholelithiasis

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Healthy subject compared with patient with cholelithiasis

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Healthy subject compared with patient with cholelithiasis

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Diagnosis of stone disease by ultrasound

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The effect of the migratory myoelectric complex

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The effect of the migratory myoelectric complex

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Overview of the structure and function of the biliary tract

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96BMJ 2001;323:1170