Diseases of the gall-bladder and

based on www.harrisonsonline.com images.MD, Grant Sanders, Andrew N Kingsnorth BMJ 2007;335:295-9

NEJM and and many others

Dr. Fenyvesi Tamás

04/10/2017 11 „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. NEJM 2017;377:605

2 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 Vateri-

33 44 . The bile is a pigmented isotonic fluid: water 82%,bile acids 12%, lecithin and other phospholipids 4%, Non esteric cholesterol 0,7%, etc ( ions, proteins, mucus,metabolites)

55 The primary bile acids : cholic- and chenodeoxicholic-acid derived from cholesterole and excreded in conjugation with glycin or taurin. They are detergents in watery solution, above 2mM concentration they form aggregates (micellum)

66 The enterohepatic circulation is a basic phenomenon Bile acids (b.a)are reabsorbed from the whole intestine in a passive way and actively from the Tha b.a.reserv is ~ 2-4g , 5-10 recirculations daily loss about 0.3-0.6g synthesis is being hinderd by reabsorbed b.a. ( 7 α-hydroxylase )

77 .

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88 Function of the g.b. and of the Oddi sphincter The O.s. controlls the excretion of bile and stops reflux from the duodenum The g.b. function is controlled by cholecystokinin from duodenum mucosa (amino acids and fat…) g.b. contraction choledochus peristaltics O.s. resistance decrease increase of bile flow

99 Functioning of the gall bladder and of the Sphincter of Oddi:

In an interdigestiv period 4-8/min phasic anterograde peristaltic contraction: minute „gall injections” into the duodenum, cleansing the sphincter of food remnants and small stones

1010 Storage and excretion from the gall bladder

1111 Muscular layer of the gallbladder

1212 Mechanism of gallbladder function

1313 Cholelithiasis First description 1341 Padua: Gentile de Foligno 40 yo < women 20%- , men 8%- prevalence cristallic structure formed from normal and pathol component of bile cholest and mixed stones 8 0% 70% cholest, Ca salts, bile acids, pigments Pigment stones 20% Ca bilirubin complex only 10% cholest

1414 About 10-15% of the adult Western population will develop gallstones, with between 1% and 4% a year developing symptoms.

1515 Cholesterol stones

• Most prevalent in the bladder • >90% cholesterol • Minimal Ca larger than the pigment stones

1616 Pigment stones (calcium bilirubinate)

1. Demographic-genetic factors: Asia! 2. Chronic haemolysis 3. Alcoholic 4. Chronic bile infections 5. old age

Increased conjugated bilirubin in the bile ducts causes precipitation

1717 Pathophysiology of cholesterol formation

1818 1919 Gallstones occur when there is an imbalance in the chemical constituents of bile that results in precipitation of one or more of the components. Why this occurs is unclear, although certain risk factors are known.

2020 2121 gall bladder stasis, sludge and stone formation

2222 10-15% prevalence in the US population

Surprisingly it leads to ~1.000 death/year

It is highly prevalent in American Indians

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

2323 Conditions to stone formation

1. formation lithogenic bile Obesity, high calory diet, clofibrate increase in HMG-CoA reductase enzyme activity decrease cholic acid secretion Increase of cholesterin/cholic acid relation

2424 2. Instabile cholesterole-rich vesicules, cholesterol monohydrate cristals 3. Cholesterol nucleus formation 4. Bile sludge formation (semilunar layer at the wall of the g-bladder) pregnancy, very calory poor diet

2525 5. Disease of the or postop of bile acids Decrease in bile acid pool, Secretion of bile-salts 7α-hydroxylase activity

2626 6. Increase of age Increase in cholesterole secretion, Decrease of bile acid pool And secretion of bile acid salts

2727 7. Gall bladder hypomotility causes sludge/stone formation

a. Parenteral feeding b. starvation c. pregnancy d. some drugs: octreotide somatostatin analogue, clofibrate

2828 8. decreased bile-acid secretion a.primer biliary cirrhosis b.chronic intrahepatic 9. Etc a, high calory/fat diet b. spine trauma(?)

2929 Pregnancy a. in the third trimester the cholesterole saturation of the bile increases b. the gall bladder contraction on food intake decreases This leads to sludge formation in 20-30 % gall-stones in 5-12%

3030 1.Demography North Europe, USA> Asia, Family, inherited traits 2.Obesity Normal b.a. storage and secretion, but increased cholesterole bile secretion 3.Weight loss tissue cholest mobilization leads to increased biliary cholest secretion

3131 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 and cholesterol esterification

3232 Diagnostics

1.Ultrasound 2.CT 3.MR cholangiopancreatography 4.Nuclear cholangio -cholecystography 5.percutaneous transhepatic 6.ERCP

3333 Dg of gallstones

Abdominal ultrasound is the method of choice

( a stone and a „shadow”) 2 mm is detectable, the false pozitive and false negative ratio 2-4%

3434 US scan shows highly reflective echoes within the gallbladder (arrows), which indicate gallstones and shadowing .( RadiologyInfo.org) 35 Acalculous with dilated gallbladder and thickened gallbladder wall

3636 Appearance of gallstones

3737 Appearance of gallstones

3838 Cholesterol stones

3939 Cholangiography

4040 4141 Cholangiography

4242 Gall stones are common but often do not give rise to symptoms. Pain arising from the gall bladder may be typical of , but a wide variety of atypical presentations can make the diagnosis challenging. BMJ 2001;323:1170-3

N.B. angina pectoris P.D.White 43 Stone in ductus choledochus

g.bladder stone to the ductus cysticus

44 Asymptomatic gallbladder diseases

Cholelithiasis is defined as asymptomatic^ when gallstones do not relate to symptoms such as pain or complications such as acute cholecystitis, cholangitis, or The estimated prevalence of gallstones is 10– 25 % and 50–80 % of the patients are asymptomatic at the diagnosis

4545 Symptoms of cholelithiasis

Most common right upper quadrant pain Usually not waxing and waning like intestinal colic the stone may occlude the cistic duct, or the common (this leads to )

It may radiate to the right scapula.

It is often causing cholecystitis

4646 Moderate increase serum bilirubin ( normal values 5-21 µµµmol/l) conjugated with glucuronic acid : „direct” bilirubin Fever is a sign of complication (-itis) epigastrialial fullness, flatulence

Possible precipitating cause fatty food or „gobbling”

4747 Management of gall stones 1. Surgical

Operate on asymptomatic? indications a. repeat colics, quality of life b. events in history: cholecistitis, pancreatitis etc c. different complications acut cholecystitis, porcelain g.bladder, small stones (?) , statistics on gall bladder cancer….

4848 The„gold standard”) technique is laparoscopic from a study of 4.000 cases 1.complications 4% 2. „upgrade” to laparotomy 5% 3. lethality < 0,1% 4. injury to ducts 4% intraop cholangio 30 % postop ERCP 1,5%

4949 History of laparoscopic cholecystectomy

5050 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? 6. What are the special aspects to be considered during LC? 7. What are the training recommendations for LC? Consensus Conference 2015 5151 Indications for laparoscopic cholecystectomy

5252 Conservative management of cholelithiasis UDCA and CDCA decrease the HMG-CoA reductase activity the cholesterol synthesis decreases in the liver UDCA decreases the stone formation and some of the stones dissolve, but very expensive , and difficult compliance and the stones recur in 50% extracorporeal shock-wave lithotripsy (electrohidraulic, piezoceramic, electromagnetic)

practically disapeared with laparoscopy 5353 Evacuation of gallstone fragments after shockwave lithotripsy

5454 Acute @ chronic cholecystitis

Acute: ductus cysticus obstruction by stone 1. mechanical from stretch 2. chemical infl. from lysolecithin and other tissue products 3. bacterial infl. 50-85% of cases

5555 Characteristic symptoms starts as bile colic irradiates to the right scapula vomiting, exsiccosis fever, even chills , a RUQ pain may cause a sudden halt in inspiration (Murphy sign) A „triad”: RUQ tenderness fever leukocytosis Laboratory signs : many

5656 Some cases without gall-stones 5-10 % causes: traume , burns after delivery adenocarcinoma vasculitis diabetes torsion of the gall-bladder

5757 Complications of cholecystitis

Empyema: d.cysticus obstruction hydrops : long-standing obstruction, usually one big stone in the bladder palpable!! Must be operated on

5858 Gangrena and perforation ischemia 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 reflux during barium meal Gall-stone big stones to the duodenum through a fistule porcelain gall-bladder carcinoma !!

5959 Treatment of cholecystitis medical: stabilization of patient’s general state carceration, nasogastric tube, volume suppl, i.v. antibiotics painkiller :

preparation to surgery

6060 Surgery early surgery is preferred (24-72 hours) urgency postpone 1.in complications 2. very severe general state of patient 3. uncertainty in dg. in acute cholecystititis surgery is now the preferred approach

6161 Cholecystectomy is „curative” in 75-90%-of cases Postcholecystectomy complication: 1. stricture of ducts 2. remaining stones 3. cystic stump syndrome? 4. Oddi sphyncter stenosis, dyskinesis sphyncterotomy 5. Cholic acid Mostly unrelated to surgery .„postcholecystectomic sy” may be a misnomer

6262 Cholangitis Cholestasis : stone , stricture, tumor, infection ( E.coli,Klebsiella, Pseudomonas, enterococci, clostridium) Characterized by triad of Charcot: pain, jaundice, fever tender, enlarged liver labor : bilirubin, leukocytosis, APT,CRP, sedimentation rate Ultrasound : dilated bile ducts Blood culture • •

6363 Cholangitis Therapy: Urgently antibiotics ( gentamycin, ampicillin, metronidazol) and decompression ERC, (sphyncterotomy!!)

In chronic cases signs are less characteristic

6464 Primary sclerosing cholangitis Idiopathic, heterogenous, cholestatic isolated or mostly combined (HLA-B8, HLA-DRB1)

Male 60%,median 41 years,prevalence 0-16/100.000 small and large bile ducts(MRCP,ERCP) jaundice, ALP, RUQ pain, autoimmune ,varix haemorrgh often+ ulcerosa therapy ? Cholestyramin, antibiot, ERCP sphyncterotomy, 4-10 years death or liver transplantation 6565 66 NEJM 2016;375:1161 67 Hyperplastic cholecystosis

Adenomyomatosis :epithelial proliferation of bladder (Rokitansky Aschoff sinus)

Cholesterinosis lipid deposits in lamina propria, „cholesterol polyps” into the lumen or diffuze „strawberry gallbladder” usually with cholesterole stones

6868 Tumor

.

6969 Cancers of the gallbladder and biliary tract are invasive adenocarcinomas that arise from the epithelial lining of the gallbladder, intrahepatic (peripheral) and extrahepatic (hilar and distal common) bile ducts, accounting for an estimated 7480 new cases and 3340 deaths in the United States, in 2005 7070 Hennedige et al. Cancer Imaging 2014, 14:14 Page 2 of 21 http://www.canc erimagingjourna l.com/content/14 /1/14

7171 Gall bladder adenocarcinoma Rare tumor. Often accompanied with gallstones Except of big stones etiological role not proved. A continous irritation of the bladder wall ,porcelain bladder may be in the background. Usually a late dg , 80% during bladder operation. Very dim prognosis.

7272 Bile tract carcinoma • Less prevalent than bladder cc • No stones in the background • Genetics ? P53 mutation Operative intervention : pancreatoduodenectomy, with biliodigestive anastomosis. Palliative possibility endoscopic endoprsthesis Very bleak prognosis

7373 Vater-papilla carcinoma • The clinical signs are the sequela of obstruction. • A specific entity developing from adenoma • Clinically it presents like a duodenal, pancreatic or choledochus tumor . Courvoisier-sign :(jaundice without colics, palpable , „elastic” gall b.

7474 Operative intervention : Pancreatoduodenectomy

Five year survival ~ 50%

7575 Diseases of the biliary tract Congenital biliaric atresia and hypoplasia : obstruction with jaundice choledochus cysts : by 10 years of age ectasia of : intrahepatic ducts (Caroli) :cholangitis , abscess, cirrhosis,cholangiocarcinoma-

7676 Choledocholithiasis

In 10-15% of cholelith patients. prevalence increases with age mostly cholesterole and mixed stones Pigment stones are the „primary” caused by haemolysis, recurrent cholangitis , congenital anomalies

7777 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 deep jaundice (sebi>300µmol/l) tumor normal: 2-18) Pancreatitis Biliary cirrhosis

7878 Important basic tests

• -serum bilirubin -alkalic phosphatase increas – prothrombin decrease – urine bilirubin increase – No urobilinogen in urine

7979 Trauma, stricture benign 95%-surgical complication 1/500 cholecystectomy Tumor: pancreas carcinoma („head”) cholangiocarcinoma,(a bifurcatioban Klatskin) nonobstructiv paraneoplasticus cholestasis Stauffer sy haemobilia műtéti sérülés abscessus vérz ő tumor esetleg choledocholith , parazitás betegség szöv ődménye Dg.:epek őkólika,sárgaság,melaena 8080 Parasitic diseases : trematodes Far-East Clonorchis sinensis, Opistorchis viverrini world-wide: Fasciola hepatica HIV cholangiopathy, stone-free cholecystitis, focalis distalis biliaris stenosis in the background immudeficiency and opportunistic cryptosporidium, microsporidium colonisation

8181 Akinek nem tetszett ,

. O. Nagy Gábor. Magyar szólások és közmondások Gondolat-Talentum,1994

a Hungarian adage „Who did not like this, the bile -malice- is talkingO. Nagy forGábor. him/her” Magyar szólások és közmondások 8282 Gondolat-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 7 ααα-hydroxylase activity 6. Increasing age Increased biliary secretion of cholesterol, decreased size of bile acid pool, decreased biliary secretion of bile salts

8484 O. Nagy Gábor. Magyar szólások és közmondások 8585 Gondolat-Talentum,1994 Where bile goes during fasting

8686 Healthy subject compared with patient with cholelithiasis

8787 Healthy subject compared with patient with cholelithiasis

8888 Healthy subject compared with patient with cholelithiasis

8989 Healthy subject compared with patient with cholelithiasis

9090 Healthy subject compared with patient with cholelithiasis

9191 Diagnosis of stone disease by ultrasound

9292 The effect of the migratory myoelectric complex

9393 The effect of the migratory myoelectric complex

9494 Overview of the structure and function of the biliary tract

9595 96 BMJ 2001;323:1170