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Cholestasis Danilo A. Encarnacion, M.D.

, FPSG October 8, 2013 Group 1-N1nja St0nes

Definition - Cholestasis is the failure of normal bile to reach the duodenum. *Bile secretion is a secretory function of the liver Syndrome of Cholestasis: Functional Morphological Clinical Functionally - decrease in canalicular bile flow: Decreased hepatic secretion of water and organic anions (bilirubin and bile acids). Morphologically - accumulation of bile in liver cells and biliary passages. Clinically - retention in the blood of all substances normally excreted in the bile: -bile acids -cysteinyl-leukotrienes. Two basic types: Obstructive (EXTRAHEPATIC CHOLESTASIS) -mechanical blockage in the duct system such as can occur from a gallstone or malignancy Metabolic (INTRAHEPATIC CHOLESTASIS) -disturbances in bile formation that can occur because of genetic defects or acquired as a side effect of many medications.

Bile Salt Physiology Bile salts are the main organic solutes in bile A number of genes are involved in bile salt synthesis and transport Disturbances of bile salt transport are important causes of acquired and genetic forms of cholestatic liver disease in humans.

Human hepatobiliary transport proteins are involved in bile formation, secretion and reabsorption. Transporter proteins located in the basolateral membrane are responsible for hepatic uptake of bile salts (NTCP, OATPs), bulky organic anions, uncharged compounds (OATPs) and cations (OATPs, OCT1). Transporter proteins located in the canalicular membrane are responsible for the biliary secretion of bile salts, phosphatidylcholine, cholesterol and glutathione and the excretion of drugs and toxins. These are the bile salt export pump BSEP (ABCB11), the phosphatidylcholine translocator MDR3 (ABCB4), the multispecific organic anion transporter MRP2 (ABCC2) and the multidrug transporter MDR1 (ABCB1). The organic anion transporters MRP3 (ABCC3), MRP4 (ABCC4) and MRP1 (ABCC1) are present at very low levels in normal human liver but their expression is strongly increased during cholestasis. Both MRP3 and MRP4 are able to transport bile acid conjugates out of the hepatocyte. FIC1 (ATP8B1) has been characterized as an aminophospholipid translocase. In the terminal ileum, the apical sodium-dependent bile acid transporter (ASBT) is responsible for bile acid reabsorption. Genetic defects have been described for FIC1 (PFIC type 1, BRIC), BSEP (PFIC type 2), MDR3 (PFIC type 3, ICP), MRP2 (DubinJohnson syndrome) and ASBT (bile acid malabsorption).

GENETIC CHOLESTASIS (refer table at the back ) I. Progressive Familial Intra-hepatic Cholestasis (PFIC) Autosomal recessive diseases Cholestasis in infancy PFIC type 1 (Bylers disease) PFIC type 2 PFIC type 3

For a first differentiation of various PFIC subtypes, measurement of the serum gammaglutamyltransferase (gamma-GT) activity is useful. Diseases associated with a low bile salt concentration in bile have a low serum gamma-GT activity. These diseases have an intrahepatocellular blockade of bile salt secretion in common. Gamma-GT in human liver is mainly located in the membranes lining the biliary tree. Elevation of serum gamma-GT results from a detergent, membranolytic effect of bile salts on these membranes. Thus an intra- or extrahepatic obstruction of bile flow, or bile devoid of phosphatidylcholine (as in PFIC type 3), causes gamma-GT to be released in the circulation.

1. PFIC type 1 (Byler disease) Often begins with cholestatic episodes progressing to permanent cholestasis with fibrosis, cirrhosis and liver failure in the first two decades of life. Children affected : small for their age often have diarrhea occasionally pancreatitis. The larger bile ducts are anatomically normal and liver histology shows bland canalicular cholestasis without much bile duct proliferation, inflammation, fibrosis or cirrhosis. The coarse granular bile in the canaliculi is called Byler bile. Serum gamma-GT activity is not elevated Primary bile salt levels, in particular chenodeoxycholic acid, are increased. Serum cholesterol is usually normal. Liver transplantation maybe necessary in the first decade. Defect in chromosome 18q21-q22 Patients belonging to the Byler kindred are descendants of Jacob and Nancy Byler, who emigrated in the late 18th century from Germany to the United States. The PFIC syndrome has also been described in families in the Netherlands, Sweden, Greenland and an Arab population .

2. PFIC type 2 As in PFIC type 1, the serum gamma-GT activity in these patients is not elevated and bile duct proliferation is absent. Different from PFICType 1 as: The disease often starts as nonspecific giant cell hepatitis, which is indistinguishable from idiopathic neonatal giant cell hepatitis; Patients are frequently or permanently jaundiced Rapidly progresses to persistent and progressive cholestasis requiring liver transplantation within the first decade. The liver histology shows more inflammation than in PFIC type 1, with giant cell transformation, lobular and portal fibrosis. Amorphous or filamentous bile in contrasts with the coarsely granular bile of PFIC type 1 patients. Extrahepatic manifestations are uncommon. Mutations in the BSEP 3. PFIC type 3 Symptoms present somewhat later in life than in PFIC types 1 and 2, and liver failure also occurs at a later age. Jaundice may be less apparent during the early stages of disease. The serum gamma-GT activity is usually markedly elevated in these patients and the liver histology shows extensive bile duct proliferation, portal and periportal fibrosis. Mutations in MDR3 gene (phospholipase) Bile salt enters the canaliculus and bile ducts without protective phospholipid making them toxic to the hepatocytes and cholangiocytes. 4. Benign Recurrent Intrahepatic Cholestasis (BRIC) Also as Summerskil syndrome. Autosomal recessive No progression to chronic liver disease in a majority of patients. During the attacks: (self limiting) severely jaundiced Pruritus Steatorrhoea weight loss. As in PFIC 1 the serum gamma-GT is not elevated.

Some patients also have renal stones, pancreatitis and diabetes. The gene involved in recurrent familial intrahepatic cholestasis has been mapped to the FIC1 locus . Ursodeoxycholic acid is of no benefit in BRIC . Case reports indicate that rifampicine may reduce the number of cholestatic episodes.

Physiological Consequences: The Liver in Pregnancy Pregnant women more likely to become jaundiced if cholestatic or hepatocellular injury occur Spider angiomata and palmar erythema develop in up to 2/3 pregnancies due to effects of estrogen and progesterone Cholecystectomy generally safe 3rd Trimester see increased alk phos 2/2 developing placenta (not liver) Intrahepatic Cholestasis of Pregnancy (IHCP) Incidence 0.1% - 1% of pregnancies Recurrence in subsequent pregnancies Pruritis develops in late 2 nd and 3rd trimester High transaminases - 40% > 10 x (Hay) Bilirubin < 5mg/dL Total bile acids increase 100 fold ICHP Clinical Features: Pruritis is the defining characteristic About 50% develop jaundice Disappears rapidly after delivery Severity is variable Rarely see a familial, progressive course to cirrhosis IHCP Therapy: Ursodeoxycholic acid 10mg- 10mg/Kg/day Cholestyramine Vitamin K p.r.n. Reassurance and support Consider early delivery in severe cases Unbearable maternal pruritis or risk of fetal distress/death Deliver at 38 weeks if mild, at 36 weeks for severe cases if jaundice IV. Primary Biliary Cirrhosis A disease of unknown cause Progressive destruction of intra-hepatic ducts Associated elevation of cholesterol and skin xanthomas ( xanthomatous biliary cirrhosis) Etiology Immunological disturbance Cytotoxic T-cells attack the biliary epithelium Mitochondrial antigens and antibodies 100 % of PBC M2 serum antigen specific for PBC

II. Drug Induced Cholestasis Drug-induced cholestatic liver injury can result from direct damage to the hepatic parenchyma by : immunoallergic or toxic mechanisms impaired transmembrane transport of cholephilic compounds destined for biliary secretion. *Prototypic Cholestatic Hepatotoxins and Mechanisms Of Injury (refer to table at the back ) III. Intrahepatic Cholestasis of Pregnancy Liver Diseases in Pregnancy High estrogen state: Intrahepatic cholestasis of pregnancy Gallstones and sludge occur more frequently Altered fatty acid metabolism: Acute fatty liver of pregnancy Vascular diseases affect the liver: Pre-eclampsia HELLP Syndrome Viral hepatitis: Vertical transmission of hepatitis B & C Pathophysiology Liver is an estrogen sensitive organ Estrogen affects organic anion transport (bilirubin, bile acids) Bilirubin excretion very mildly impaired during normal pregnancy Biliary phospholipids secretion may be impaired (gene mutation, estrogen effect) Pregnancy is associated w/ decreases in GI motility, including gall bladder motility

ANA (antinuclear antibody) in 1/3 of cases Anti-M9 in early PBC; healthy relatives Association with infection Mycobacterium gordonae Retroviral infection Inconclusive observations Clinical Features Presentation 99% are female 40-60 years old Insidious: pruritus without jaundice Jaundice: 6 months to 2 years within the onset of pruritus Clinical Features Presentation RUQ discomfort is frequent as well as fatigue Well-nourished, sometimes pigmented woman Liver is usually enlarged and firm and spleen is palpable Symptomatic Serum bilirubin is twice the normal Serum Alk. Phos. : 4x the normal SGPT: 2x the normal Serum albumin is normal Serum AMA 1:40 ERCP: normal hepatic ducts Asymptomatic Routine laboratory screen serum alk. Phos. (+) AMA Investigation of other disease, especially collagen or thyroid Hepatomegaly Course Asymptomatic patients: 10 years survival Symptomatic : 7 years survival Weight loss is slow Diarrhea: steatorrhea The course is afebrile and abdominal pain is unusual DU and hemorrhage is common Bleeding esophageal varices Hepatocellular carcinoma is rare. Associated diseases: Collagenoses (almost any autoimmune disease) Rheumatoid arthritis Dermatomyositis Mixed connective tissue disease SLE

Biochemical tests Serum bilirubin : < 35ummol/l (2 mg/100ml) Alk. Phos. is raised Increased total cholesterol; serum albumin is normal Prognosis Determinants Serum bilirubin o >100ummol/l (6mg/dl) unlikely to survive > 2 years Serum albumin <3g/dl. Symptoms advancing age Hepatosplenomegaly Ascites Treatment Maintenance of nutrition and fat soluble vitamin replacement. Ursodeoxycholic acid Non-hepatotoxic, hydrophilic bile acid Protects cell membrane against the detergent effect of hydrophobic bile acids. Stimulates the excretion of toxic bile acids It increases anion exchange in the liver Improved liver function and slowed progression. Liver transplant Indications Poor quality of life, intractable pruritus Hepato-cellular failure or bleeding varices. Survival: o 85% to 90% for one year o 60%-70% for 5 years Disease recurs V. Sclerosing cholangitis Progressive fibrosis and ultimately disappearance of intra-and extra hepatic ducts or both. 1. Primary Sclerosing Cholangitis Unknown cause All parts of biliary tree can be involved. Ultimately will end up with biliary cirrhosis. Etiology - aassociation with inflammatory bowel disease (75% with UC) Strong genetic predisposition

Immunologic Infections o Cryptosporidiosis o Immunodeficiency diseases Clinical features Males 2x than females Weight loss, fatigue, RUQ pain and pruritus. Pediatric disease o 2-13 years o 50% with inflammatory bowel disease o Alk. Phos can be normal in 50% o Intra-hepatic disease predominates. Laboratory Cholestasis with alk. Phos. 3x normal. SMA may be present. ERCP Diagnostic Areas of stricture and dilatation (beading) Cholangiocarcinoma A complication in 10% Mean survival is only 6 months after diagnosis ERCP for diagnosis Colorectal cancer Seems to be low risk Prognosis Mean survival is about 10-12 years Treatment Endoscopic (stent application ) Transplantation No satisfactory treatment *Overview of VIRAL HEPATITIS (refer to table at the back ) I. Hepatitis A

Jaundice by age group: 6-14 yrs: 40%-50% <6 yrs :<10% >14 yrs :70%-80% Complications Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis Chronic sequelae: None

Clinical Symptoms Prodromal fatigue and weakness anorexia nausea and vomiting abdominal pain fever, headache, arthralgia, myalgia, and diarrhea are less common signs and symptoms. 90%: the development of jaundice and dark urine occurs within 1 to 2 weeks of the onset of prodromal symptoms. 3.5 % are anicteric; usually in children Prodromal symptoms tend to abate with the onset of jaundice except for anorexia 90% of children under 5 are asymptomatic 70% to 90% of adults are symptomatic. Clinical Signs tender mild hepatomegaly in 85% splenomegaly in 15% posterior cervical lymphadenopathy in 15% complete clinical and biochemical recovery in 2 months at 60% and nearly 100 % in 6 months.

27 nm RNA HEPATOVIRUS

Clinical Features Incubation period Average 30 days Range 15-50 days

Atypical Courses Prolonged cholestasis jaundice more than 12 weeks

pruritus, fatigue, loose stools and weight loss SGPT is less than 500 U/L Spontaneous recovery Relapsing hepatitis 6% to 12% of cases Acute infection then remission (4-15weeks) with subsequent relapse. SGPT is normal during remission but increase to more than 1000 U/L during relapse. Pathogenesis is unknown Extrahepatic Manifestations evanescent rash (14%) arthralgias (11%) Leucocytoclastic vasculitis, glomerulonephritis, and arthritis, in which immune complex disease is believed to play an etiologic role. Complications Post-hepatitis syndrome prolonged malaise elevated serum SGPT persistence of IgM anti-HAV acute liver failure is rare Prevention General measures Hygienic practices Passive Immunoprophylaxis 1. Human immune globulin (IG) 85% to 95% for pre-exposure 1-2 weeks of exposure will prevent or attenuate infection beyond 2 weeks will be ineffective. 0.02mL/kg provides for 3 months and 0.05 mL/kg for 4 to 6 months. Active Immunoprophylaxis 1. Live attenuated Vaccines 2. Inactivated Vaccine ( Havrix) Highly immunogenic 90% to 98% seroconversion after a single 25U dose and 100% seroconversion rate after three doses. 3. Recombinant Polypetide Vaccines II. Hepatitis B Virus (HBV)

Late 1960s : Australia antigen was discovered by Blumberg and associates. Envelope of the hepatitis B virus. Serves as the marker of the virus differentiating it from hepatitis A Giving it a name hepatitis B (formerly known as serum hepatitis) 1970: Dane visualized the virus as a 42 nm particle ( Dane particle) How Do You Acquire the Infection in the Western region? Transfusion and transplant recipients Individuals with multiple sexual partners Healthcareworkers Intravenous drug users Prisoners and other institutionalised people How Do You Acquire the Infection in the Western region? Newborns of long-term carriers

Interpretation of hepatitis B virus serologic markers HBsAg HBV infection acute or chronic HBeAg High levels of HBV replication and infectivity Anti-HBe Low levels of HBV replication and infectivity HBV DNA Genetic material of the hepatitis B virus Anti-HbC (IgM) Recent HBV infection Anti-HBc (IgG) Recovered or chronic HBV infection Anti-HBs Immunity to HBV infection Anti-HBc (IgG) + anti- Past HBV infection HBs Anti-HBc (IgG) + Chronic HBV infection HBsAg Clinical Features Incubation period: Average 60-90 days Range 45-180 days Clinical illness (jaundice) <5 yrs: <10% >5 yrs: 30%-50% Acute case-fatality rate 0.5%-1% Chronic infection <5 yrs: 30%-90% >5 yrs: 2%-10% Premature mortality from chronic liver disease 15%-25% Signs and Symptoms of HBV Infection: The majority of patients with chronic hepatitis B have no symptoms Short-Term Infection (acute)

Tiredness or flu-like symptoms Nausea or stomach ache Diarrhea Skin rash Yellow eyes/skin (jaundice) Light-colored stools Dark yellow urine Long-Term Infection(chronic ) Same symptoms as acute Muscles and joints ache Weakness Signs and symptoms of cirrhosis Signs and symptoms of liver cancer

Prevention of Hepatitis B HBV infection can be prevented in non-infected individuals by vaccination with HBV vaccine. However the millions of infected people will not benefit By 1998, 80 countries had introduced vaccination programmes Hepatitis B Vaccines Engerix-B Recombivax Children 10g 2.5g Adults 20g 10g Each at 0, 1 and 6 months AASLD Practice Guideline Hepatitis B Update in Recommendations for Treatment o Series of 3 injections at 0, 1 and 6 months o Vaccination is effective in over 90% of recipients

Hepatitis C Virus Infection Typical Serologic Course

Prevention of Hepatitis C Screening of blood, organ, tissue donors High-risk behavior modification Blood and body fluid precautions Treatment of Viral Hepatitis Hepatitis C interferon 3 MU t.I.w. and Ribavirin 1 to 1.2 gm/day for 12 months No response (after 6 months) Sustained response: 40%

III. Hepatitis C Virus

Interferon x 6 months Clinical Features Incubation period: Average 6-7 wks Range 2-26 wks Clinical illness (jaundice): 30-40% (20-30%) Chronic hepatitis:70% Persistent infection: 85-100% Immunity: No protective antibody response identified Side effects: hemolytic anemia ( 20% ) due to Ribavirin

Miscellaneous causes of cholestasis Bacterial infection In childhood or post-operatively Hepato-cellular Endotoxin effect on Na+/K+-ATPase Prolonged parenteral nutrition Neonates especially Due to lithocholate formed by bacterial 7- -dehydroxylation of chenodeoxycholic acid in the intestinal tract. Hodgkins disease Biliary precipitation of insoluble solutes Unconjugated bilirubin precipitate forming as intra-hepatic pigment stones Protoporphyrins precipitates in erythrocytic protoporphyria Intrahepatic atresia (infantile cholangiopathy) Viral injury to intra-hepatic bile ducts

Zellwegers syndrome Presents before 6 months of age with progressive cholestasis and hepatomegaly. Mental retardation, characteristic facies, hypotonia and renal cyst. Defective hepatic peroxisomes Short survival Primary biliary cirrhosis Primary sclerosing cholangitis

Treatment Medical Surgical Medical management 1. Pruritus Routine : Cholestyramine Variable effect: Anti-Histamine; UDCA;phenobarbitone Careful use: Rifampicin Experimental: Naloxone; nalmefene; ondansetron; S-adenosyl-L-methinine; propofol *Drugs for Pruritus Cholestyramine Known to bind bile salts in the intestines so eliminating them in the feces Unclear mechanism Nausea and vomiting; reluctance on the part of the patient Good for primary biliary cirrhosis, primary sclerosing cholangitis, biliary atresia and bilary stricture. UDCA Choleretic effect or by reducing toxic bile salts Only in primary biliary cirrhosis Anti-histamine As sedatives Phenobarbitone For resistant itching Naloxone Opiate antagonist Not appropriate for long term use Ondansetron (5HT3) Small placebo controlled trials Propofol Hypnotic product Short-term benefit; give IV S-adenosyl-L-methionine o

Improves membrane fluidity Inconsistent effects Rifampicin Inhibits bile acid uptake Potential side efects Hepatotoxicity Emergence of resistant organism Formation of gallstone Steroids Glucocorticoids will relieve itching but at the expense of severe bone thinning particularly in postmenopausal women. Bright light therapy 10,000 lux Based on circadian pattern of cholestatic pruritus Beneficial Ileal diversion In children with intractable itching

Palsmapheresis Intractable pruritus with hypercholesterolemia and xanthomatous neuropathy Effective but temporary and costly as well as labour intensive Hepatic transplantation Intractable itching 2. Nutrition Acute cholestasis Vit K deficeincy Vit K (10 mg) daily for 2-3 days Chronic cholestasis Vitamin A,D,K replaced as necessary Potential bile salt deficiency Chronic cholestasis Dietary fat (if steatorrhea) reduce neutral fat(40 g daily) add medium chain triglycerides (up to 40 g daily)

Fat soluble vitamins Oral K A D IV K IM A

10 mg/day 25000U/day 400-4000U/day 10 mg/month 100 000 U / 3-monthly

Calcium extra low fat milk oral calcium Bone changes Predominantly osteoporosis Monitoring of serum 25-hydroxyvitamin D levels Treatment with vitamin D 50 000 units orally 3x a week or 100 000 units IM monthly. Parenteral is more appropriate than oral route. Daily oral intake of elemental Ca; extra skimmed milk; exposure to sunlight; encourage mobility Avoid corticosteroids

Two roads diverged in a wood, and I I took the one less traveled by, And that has made all the difference. -Robert Frost Authors/Editors: Boni & Janine *Tatak SaGaD!

GENETIC CHOLESTASIS-gin labayan lang ni ni Doc Disease PFIC type 1 (Bylers Disease) Chromosome 18q21 Gene FIC 1 (ATP8B1) P-type ATPase, acts as an aminophospholipid translocator Phenotype First recurrent, later permanent cholestasis, bile duct proliferation is a late phenomenon. Diarrhea, pancreatitis, pruritus, short stature. Coarse granular bile on EM. Normal gamma-GT Recurrent episodes of cholestasis with severe pruritus, steatorrhea and weight loss. Normal gamma-GT Neonatal hepatitis, progressive cholestasis, pruritus, short stature, bile duct proliferation is a late phenomenon, lobular and portal fibrosis. BSEP protein absent. Amorphous bile on EM. Normal gamma-GT Cholestasis, portal hypertension, extensive bile duct proliferation and periportal fibrosis. MDR3 is not expressed. Elevated gammaGT Cholestasis in third trimester of pregnancy. High gamma-GT in case of MDR3 defect; low gamma-GT cases may be caused by genetic Therapy Ursodeoxycholic acid, bile diversion, liver transplantation

Benign recurrent intrahepatic cholestasis

18q21

FIC1 (ATP8B1)

Cholestyramine and/or rifampicine as symptomatic antipruritus therapy

PFIC type 2

2q24

BSEP (ABCB11), bile salt export pump

Ursodeoxycholic acid bile diversion, liver transplantation

PFIC type 3

7q21

PGY3 (ABCB4, MDR 3), Pglycoprotein 3

Ursodeoxycholic acid, liver transplantation

Intrahepatic cholestasis of pregnancy

e.g. 7q21

e.g. MDR3

Ursodeoxycholic acid causes symptomatic relief in the mother and decreases fetal loss

Aagenaes syndrome

15q

LCS1, LCS2

Familial Hypercholanemia

9q12q13 9q22q32

TJP2/ZO-2 BAAT

Bile acid synthesis defects

e.g. 8q2.3

3-5-C27-hydroxysteroid oxidoreductase; 4-3oxosteroid-5 reductase; 3hydroxy C27 steroid dehydrogenase/isomerase; oxysterol 7-hydroxylase; 24,25-dihydroxy-cholanoic cleavage enzyme.

defects of other transporter proteins. High incidence of fetal loss Episodic cholestasis, lymphedema, normal gamma-GT Elevated bile acids, severe pruritus, fat malabsorption, failure to thrive, rickets, vitamin K coagulopathy Intrahepatic cholestasis, neonatal giant cell hepatitis. Normal or elevated gamma-GT, low or elevated serum total bile acids

Liver transplantation but persistence of lymphedema Liver transplantation

Ursodeoxycholic acid, chenodeoxycholic acid or cholic acid alone or in combination, depending on subtype

Prototypic Cholestatic Hepatotoxins and Mechanisms Of Injury Clinical Manifestation Causative Agents Cholestatic hepatitis Chlorpromazine Phenothiazines Tricyclic antidepressants Erythromycins Clavulanic acid NSAIDs Bland cholestasis Estrogens Oral contraceptive steroids 17-alkylated androgenic steroids Cyclosporine A Tamoxifen Griseofulvin Glibenclamide Aniline-contaminated rapeseed oil -Naphthyl isothiocyanate Paraquat Floxuridine Sporidesmin Rifamycin SV / rifampicin Cholecystographic dyes

Mechanism of Injury Idiosyncrasy/hypersensitivity

Selective interference with bile excretory mechanisms

Cholangiodestructive cholestasis

Injury to bile ducts

Unconjugated hyperbilirubinemia/ hypercholanemia

Selective interference with sinusoidal uptake

Viral Hepatitis - Overview A Source of Virus Feces

Route of transmission Chronic infection Prevention

Fecal-oral No Pre/postexposure immunization

B Blood/bloodderived body fluids Percutaneous permucosal Yes Pre/postexposure immunization

C Blood/bloodderived body fluids Percutaneous permucosal Yes Blood donor screening; risk behaviour modification

D Blood/bloodderived body fluids Percutaneous permucosal Yes Pre/postexposure immunization

E Feces

Fecal-oral No Ensure safe drinking water

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