%F9%E9%F2%E5%F8 %EE%F1%27 4 - %EE%E7%EC%E5%FA %EB%E1%E3 %EB%E5%EC%F1%E8%E8%E9%E5%FA 22.11.07

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Prof. Ziv Ben-Ari

Liver InstituteRabin Medical Center


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Cholestatic Liver Diseases

Primary Biliary Cirrhosis (PBC)

Primary Sclerosing Cholangitis

(PSC)


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Case Presentation 1

A 36 years old male

Israeli origin

Was diagnosed 6 years ago as inflammatory

bowel disease (ulcerative colitis)

Pancolitis, 4 years in remission

Treatment rafassal 500mg x4/d

A cousin ,was diagnose 1 year ago ascrohns disease


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Case Presentation 1 cont

On routine check up:

Hepatomegaly 3cm below costal margin

No other stigmata of chronic liver disease

Increase serum cholestatic liver enzymes:

Alk phos 420U/l, GGT 400U/l, AST 42U/l, ALT

50U/l, total bilirubin 1.1 mg/dl, albumin

4.1g/dl, other chemistry results normal, CBCnormal

Increased serum cholestatic Vs. hepatocellular liver enzymes


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Primary sclerosing cholangitis (PSC)

Definition and epidemiology

PSC is a rare but important cause of chronic liverdisease

The disease is characterized by chronic

inflammation and obliterative fibrosis of the intra-and/or extra-hepatic biliary tree which leads to bilestasis, hepatic fibrosis, and cirrhosis

This can be complicated by portal hypertension,hepatic failure requiring transplantation

First-degree relatives of patients with PSC have anearly 100-fold increased risk of developing PSC


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Annual incidence rates between 0.9 and 1.3 cases per 100,000 population


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Etiology

PSC occurs primarily in patients with underlyingIBD; 70% to 80% UC

2%-7.5% of patients with UC and 1.4% - 3.4% ofpatients with Crohns disease develop PSC

An increased prevalence of HLA alleles A1, B8, andDR3 is observed in PSC

An autoimmune disease

Homing of memory lymphocytes to the biliary tract;

Colonic inflammation produces memory T cells thathave the ability to bind biliary cells


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Pathogenesis


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ANA Ab and smooth muscle Ab occur in 20% - 50% of patients

AMA are rarely found in patients with PSC

The dominant autoantibodies in PSC is perinuclear antineutrophilic

autoantibodies (pANCA), which are found in approximately 80% of

patients but lack diagnostic specificity for PSC


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Normal ERCP

The gold standard for the diagnosis of PSC is ERCP


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Typical radiologic findings include multifocal strictures and dilation

involving the intrahepatic or extrahepatic biliary tract or both, thecharacteristic beads-on-a-string appearance

The gold standard for the diagnosis of PSC is ERCP


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Radiographic Features

ERCP is successful in 95% of cases

75% have involvement of both small

and large ducts, 15% small ducts only,

and 10% large ducts only.

Serious complication pancreatitis,

cholangitis, intestinal or bile duct

perforation, and bleeding. Risks greater

in patients with PSC


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MRCP is the best initial approach to diagnosis of PSC

Depicting ducts proximal to high grade strictures. Provides imaging of the rest of the abdomen.

MRCP is purely diagnostic, not allowing intervention.

The two methods yield similarsensitivity and specificity in demonstrating bile ductabnormalities leading to the diagnosis of PSC


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Periductal fibrosis with inflammation,

bile duct proliferation, and ductopenia.

Fibro-obliterative cholangiopathy,

periductal fibrosis (onion-skinning)

the pathologic hallmark of PSC, is

uncommonly observed (13.8%)

The histologic findings of PSC are nonspecific


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CLINICAL FEATURES

Males are twice as commonly affected as females, between25-45 years of age

Majority are asymptomatic 15%- 40% of cases,

ALP is the most commonly elevated X 3-10 times

AST and ALT levels are usually X 2-3 higher than normallevels

Serum -globulin and IgA are increased in 40-50% Even asymptomatic the patient may have underlying

advanced liver disease: cirrhosis and portal hypertension

Fever, chills, right upper quadrant pain,

itching and jaundice: ascending cholangitis

One third episodes of bacterial cholangitis especiallyfollowing biliary interventions in patients with dominantstenosis


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Clinical Manifestations

Fatigue and pruritus are common

Jaundice and weight loss, or portal hypertension

in advanced stages. A rare presentation variceal

hemorrhage, end-stage liver disease, or

cholangiocarcinoma

Serum bilirubin usually is normal or slightly

elevated, in advanced disease, superimposedmalignancy, or choledocholithiasis, serum

bilirubin values can reach very high levels


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Clinical Presentation of PSC

Symptom

Jaundice

Pruritus

Abdominal pain

Weight loss

Fatigue

Fever/cholangitis

Asymptomatic

% of pts

30-72

28-69

24-72

29-79

65-66

13-45

7-44


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Natural history of PSC


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Survival in PSC


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PSC and IBD

70% patients with PSC have IBD as well, typically UCand less commonly Crohns disease with colonicinvolvement

IBD is diagnosed before PSC in 75% of cases andafterward in the remainder

There is no correlation between the severity of PSCand that of the associated IBD

IBD in PSC is characterized by a high prevalence ofpancolitis

PSC-IBD patients require thorough colonoscopicsurveillance with extensive biopsy sampling

Therapy of IBD has little effect on the course of PSC,and vice versa


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Colonic neoplasia


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Colorectal neoplasia in PSC-IBD

The cumulative incidences of colorectal carcinoma at 10, 20, and 25 years

in PSC-IBD patients are 5%, 31%, and 50%, respectively

Ch l i i


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Cholangiocarcinoma

Cholangiocarcinoma (CCA) occurring in 4%- 20% of PSC patients;30% to 50% diagnosed within 2 years of identifying PSC

Serum CA19-9 remains the most used marker for a cutoff of 129U/mL provided sensitivity of 78.6%, specificity of 98.5%

US, CT, and MRI have inadequate sensitivity to distinguishcholangiocarcinoma from PSC

Endoscopic biopsy and biliary brushing for cytology, digital imageanalysis, and FISH have good specificity but poor sensitivity

Complete resection is the only treatment offering long-term survival Treatment : Neoadjuvant chemoradiotherapy with subsequent liver

transplantation


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25/62

Ursodeoxycholic Acid (UDCA)

A non-hepato-toxic,hydrophilic bile acid

It protects cell membranes against the

detergent effect of hydrophobic bile acid

It stimulates the excretion of toxic bile acids

Reduce HLA class 2 experssion on bile-ducts

Decrease cytotoxic attack of T-cells on bile-

ducts

Immunosuppressive and other agents


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Immunosuppressive and other agents

Ursodeoxycholic acid (cont)

A choleretic effect, direct and indirect cytoprotective effects,immunomodulatory effects, and downregulation of apoptosis

Treatment with standard-dose (10-15 mg/kg) UDCA did notshow significant improvements in histology or survival

High-dose UDCA (2030 mg/kg) might cause an improvement in

liver biochemistry, histology, and cholangiographicappearance???.

Ineffective: D-penicillamine, Colchicine, methotrexate,cyclosporine, and transdermal nicotine, pentoxifylline,silymarin, oral nicotine, pirfenidone, budesonide, cladribine,etanercept, mycophenolate mofetil, glucocorticoids andtacrolimus


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Liver Transplantation

Liver transplantation remains the only

proven long term treatment for PSC

Major indications include: recurrent bacterialcholangitis despite intensive medical and

endoscopic therapy, jaundice that cannot betreated endoscopically or medically,decompensated cirrhosis

The 1-, 2-, and 5-year survival rates for

patients who received a first liver allograft forPSC were 90%, 86%, and 85%, respectively

PSC recurred in 37% of patients at a medianof 36 months


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PSC patients survival after liver transplantation


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In our patient

Previous diagnosis of IBD

Increased cholestatic liver enzymes

Hepatomegaly

Proceed to ERCP/MRCP (preferable)

No need for a liver biopsy for diagnosing

PSC


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In our patient

URSO (25mg/kg) (select the higher dose)

Periodical follow-up visits to

hepatology/GI clinic

In case liver cirrhosis develop considerliver transplantation

Check periodically serum markers for

cholangiocarcinoma (CA19-9)


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Case Presentation 2

46 years old female

Born in Ucreinia, 32 years in Israel

Medical history: rec UTIs

On routine check-up tests incrased serumcholestatic liver enzymes : ALP 480U/L,

GGT 380U/L, normal transaminases, total

bilirubin 1mg/dl, albumin 4.1g/dl, protein

8.1g/dl


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Case Presentation 1cont

Medical history: no pruritus, rec UTI due to

E. coli, no drugs, mother had hypothyroidism

Laboratory tests: autoAbs

(ANA,AMA,ANCA), Igs (IgG&IgM), r/o otheretiologies, serology for hepatitis C and B

Imaging abdominal U/S


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Primary Biliary Cirrhosis

A slowly progressive autoimmune disease, primarily affectswomen

Peak incidence in the fifth decade of life, uncommon < 25 years

Histopathologically characterized by portal inflammation andimmune-mediated destruction of the intrahepatic bile ducts

Loss of bile ducts leads to decreased bile secretion and theretention of toxic substances within the liver, resulting infibrosis, cirrhosis, and eventually, liver failure

Serologically characterized by AMA, present in 90 95% ofpatients, detectable years before clinical signs appear

The immune attack is predominantly organ-specific, althoughthe AMA are found in all nucleated cells


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The prevalence differs considerably in different geographic areas, ranging from 40 to

400 per million


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Pathogenesis

The paradox of PBC is thatmitochondrial proteins are present

in all nucleated cells, yet the

autoimmune attack is directed with

high specificity to the biliary epithelium.

The specificity of pathological changes

in the bile ducts, the presence of

lymphoid infiltration in the portal tracts,

and the presence of major-histocompatibility

-complex class II antigen on the biliary

epithelium suggest that an intense

autoimmune response is directed

against the biliary epithelial cells.

The destruction of biliary cells is

mediated by liver-infiltrating

autoreactive T cells

E id i l i d ti f t


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Epidemiologic and genetic factors

PBC is considerably more common in first-degree relatives ofpatients than in unrelated persons

There is little association between PBC and the presence of anyparticular major-histocompatibility-complex alleles

There are no clear genetic influences on the occurrence

of PBC

The ratio of women to men with the disease can be as high as

10 to 1


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Environmental factors

Molecular mimicry is the most widely proposed

mechanism for the initiation of autoimmunity in PBC

Bacteria; E coli, elevated incidence of urinary tractinfections in patients with PBC and the highly conserved

nature of the mitochondrial autoantigens autoantigens.Antibodies against the human pyruvate dehydrogenasecomplex react well against the E. colipyruvatedehydrogenase complex

Xenobiotic-metabolizing, gram-negative bacterium called

Novosphingobium aromaticivorans. it has four lipoyldomains with striking homology with human lipoylatedautoantigens

Pathological findings


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The liver is not affected uniformly, and a single biopsy

may demonstrate the presence of all four stages at the

same time. Asymmetric destruction of the bile ducts

within the portal triads

Pathological findings

Stage 1 localization of inflammation to theportal triads. In stage 2, the number of normalbile ducts is reduced, and inflammation extendsbeyond the portal triads into the surrounding

parenchyma. In stage 3, fibrous septa linkadjacent portal triads. Stage 4 represent end-stage liver disease, characterized by cirrhosiswith regenerative nodules


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Diagnosis

The diagnosis of PBC is based on threecriteria: the presence of detectable AMA inserum, elevation of liver enzymes (mostcommonly ALP) for more than six months,

and compatible histologic findings 5-10 % of patients have no detectable AMA,

but their disease appears to be identical tothat in patients with AMA

ANA are found in approximately 50 % ofpatients with PBC


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Mitochondrial Antibodies

Circulating IgG Ab against

mitochondria are found in 95% of

patients

They are non-organ and non-species

specific. The significance of the AMA

and its relationship to the etiology is

uncertain


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The targets of the AMA are members of

the family of the pyruvate dehydrogenase

complex (PDC)

These target antigens are located

in the inner mitochondrial membrane

The dominant epitope recognized by AMA is located within the lipoyl domain

he antigenic component specific for PBC is M2

Four M2 antigen polypeptides were identified, all components of the PDC


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Clinical findings

PBC is diagnosed earlier in its clinical

course; 50 -60% of patients are

asymptomatic at diagnosis, one third of

patients may remain symptom-free for manyyears

Overt symptoms develop within 2-4 years in

the majority of asymptomatic patients


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Asymptomatic patient

Routine biochemical screening: ALP&GGT

Survival at least 10 years

Course is variable and unpredictable

Some will stay asymptomatic and some

will run a progressive downhill course


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Fatigue has been noted in up to 78 % of patients and can be a

significant cause of disabilityPruritus occurs in 20-70 % of patients, can be the mostdistressing symptom. Onset usually precedes the onset of

jaundice by months to years. Endogenous opioids may have arole

Discomfort in the right upper quadrant occurs in approximately

10% of patients


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Clinical findings

Hyperlipidemia, osteopenia/osteophorosis, andcoexisting autoimmune diseases, including Sjogrenssyndrome, scleroderma and hypothyroidism

Malabsorption, deficiencies of fat-soluble vitamins, andsteatorrhea are uncommon except in advanced disease

Portal hypertension does not usually occur until later inthe course of the disease

Rarely, patients present with ascites, hepaticencephalopathy, or hemorrhage from esophagealvarices

The incidnece of hepatocellular carcinoma is elevatedamong patients with long-standing histologicallyadvanced disease


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Other diseases associated with PBCinclude interstitial pneumonitis,

celiac disease, sarcoidosis, renaltubular acidosis, hemolytic anemia, andautoimmune thrombocytopenia


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Physical Examination

Normal in early disease stage

Might be later: jaundice, hyperpigmentation,

xanthelasmas, tendinous & planar

xanthomas, hepatomegaly, splenomegaly,clubbing, bone tenderness, ecchymoses


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Biochemical tests

ALP and GGT and bilirubin Cholesterol IgM


50/62

Diagnosis

Middle-aged woman

Increase cholestatic liver enzymes

(ALP&GGT)

AMA (M2) positive (>1:80)

Liver biopsy could be performed to

confirm the diagnosis and for

staging


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In Our Patient

A middle-aged asymptomatic women

Family history of thyroid disease

Past history of recurrent UTI

Elevated ALP & GGT

Positive M2, hypercholesterolemia, eyelid

xanthelasma

Normal liver & spleen (abdominal U/S)

Liver biopsy

N t l hi t d i


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Natural history and prognosis

The prognosis is much better now than itformerly was as a result of treatment inearlier stages of disease

In at least 25-30 % of patients with PBC whoare treated with URSO, a complete responseoccurs, characterized by normal biochemicaltest results and stabilized or improvedhistologic findings in the liver

In untreated patients, the median time untildeath or referral for liver transplantation isonly 9.3 years


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Survival of PBC patients asymptomatic and

symptomatic

Treatment of symptoms and complications


54/62

y p ppruritus

Ammonium resin cholestyramine, at a dose of 8 to 24 g daily, willrelieve pruritus in most patients.

Rifampin, at a dose of 150 mg twice daily, is effective in patients

who do not respond to cholestyramine.

The opioid antagonists naloxone and naltrexone may be effective in

patients who do not respond to cholestyramine or rifampin

U d h li id (URSO)


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Ursodeoxycholic acid (URSO)

URSO 12-15 mg/kg per day, is the only approved drug

Improve biochemistry

URSO significantly reduced the likelihood of livertransplantation or death after four years

Ursodiol appears to be safe and has few side effects It delays the progression of hepatic fibrosis in early-stage

PBC and delays the development of esophageal varices,but it is not effective in advanced disease

Two meta-analyses questioned the efficacy of ursodiol Colchicine and methotrexate Cyclosporine,Azathioprine,

mycophenolate, Penicillamine , ChlorambucilThalidomide, Silymarin

Eff t UDCA i l


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UDCA-treated

Placebo group

Effect on UDCA on survival

Predicted group


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Steroids

Prednisone has little efficacy and

increases the incidence of osteoporosis

Budesonide improves liver histology and

the results of biochemical tests of liverfunction when used with URSO, but it may

worsen osteopenia


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59/62


Liver transplantation has greatly improved

survival in patients with PBC, and it is the

only effective treatment for those with liver

failure

The survival rates are 92% 85% at one

and five years, respectively

AMA status does not change. PBC recurs

in 15 % of patients at 3 years and in 30 %at 10 years


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In Our Patient

URSO in a dosage up to 15 mg/kg

until normalization of ALP & GGT achieved

Bone densitometry

Serum cholesterol control


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Date post:	14-Apr-2018
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