Cirrhosis

Definition

• Definition: fibrosis and nodular regeneration resulting from hepatocellular injury Etiologies

• Viral hepatitis (chronic HBV. HCV. HDV infection)

• Autoimmune hepatitis (female, I IgG, ® ANA, anti-smooth muscle Ab)

• Metabolic diseases: hemochromatosis. Wilson's disease, ui-antitrypsin deficiency

• Biliary tract diseases: primary biliary cirrhosis, secondary biliary cirrhosis (calculus.

neoplasm, stricture, biliary atresia), primary sclerosing cholangitis

• Vascular diseases: Budd-Chiari syndrome. R-sided CHF. constrictive pericarditis

• Nonalcoholic fatty liver disease (NAFLD)

• Cryptogenic: may reflect terminal progression of nonalcoholic fatty liver disease Clinical manifestations

• Subclinical or may present as progressive liver dysfunction (jaundice, coagulopathy, encephalopathy) and or portal hypertension (ascites, varices) Physical exam

• Liver enlarged, palpable, firm, nodular shrunken and nodular

• Signs of liver failure: jaundice, spider angiomata. palmar erythema. Dupuytren's contractures, white nail lines (Muehrcke's lines) & proximal nail beds (Terry's nails), t parotid & lacrimal glands, gynecomastia, testicular atrophy, asterixis. encephalopathy, fetor hepaticus, clubbing, hypertrophic osteoarthropathy

• Signs of portal hypertension: splenomegaly, ascites, dilated superficial abdominal veins

(caput medusae), epigastric "Cruveilhier-Baumgarten" venous hum

Laboratory studies

• t bilirubin, t PT. i albumin. » Î aminotransferases and î A<j. (variable). 1 Na

• Anemia (marrow suppression, hypersplenism, Fe and or folate deficiencies), neutropenia

(hypersplenism). thrombocytopenia (hypersplenism. i Tpo production by liver) Workup

• Abdominal U S with Doppler: liver size, r o HCC. ascites, assess patency of portal.

splenic, and hepatic veins

• Hepatitis serologies (HBsAg, anti-HBs, anti-HCV). autoimmune hepatitis studies (IgG.

ANA. anti-smooth muscle Ab). Fe and Cu studies, m-AT. anti-mitochondrial Ab. echocardiogram (if concerned about right-sided heart failure)

• • Liver biopsy (percutaneous or transjugular)

• AFP to screen for hepatocellular carcinoma

Complications

• Portal hypertension hepatic venous pressure gradient (HVPG) -5 mmHg ascites (60% w in 10 y) i spontaneous bacterial peritonitis (19%) gastroesophageal varices (if HVPG 12 mmHg) • UGIB V prevention UGIB (indicated if mod-large varices): nonselective ^-blockers (titrate to 25% : HR): 50% 1 bleeding (ne/m 1991324:1532) optimal response defined as HVPG I to <12 mmHg or I z20% addition of nitrates may further i bleeding (Lancet 1996:348:1677) |}B no benefit for preventing development of varices (nejm 2005:353:2254). but have been shown to J progression from small — large varices (Gaum 2004:127:476) endoscopic band ligation: similar i in bleeding and mortality as c w with jiB reserve for intolerance, i response, or contraindications to 0B (Hepototo©- 2001.33 802) 2° prevention UGIB (indicated in all): 0-blocker • nitrates (goal 25% I HR) (nejm 2001:345669). or band ligation, or combination; if rebleed -«TIPS or transplant

• Hepatic encephalopathy: failure of liver to detoxify noxious agents (NH3 and others)

precipitated by excess dietary protein, constipation. GIB. medication noncompliance, infection, azotemia, hypokalemia, hepatic failure. HCC. portosystemic shunt, hypotension, alkalosis, dehydration, sedative psychoactive meds clinical manifestations: subde changes — asterixis & AMS -» decerebrate posturing, coma treatment: identify correct précipitants, restria dietary protein acutely, but only modestly (60-80 g d) long-term, lactulose (acidification of colon leading to NH) — NH« ' ; titrate to 2-4 stools per day); gut decontamination with rifaximin or neomycin (A gut flora I NHj-producing organisms)

Hepatorenal syndrome: progressive azotemia (Cr 1.5 mg dl; note, often overestimate renal fxn in cirrhotics b c i musde mass, f Cr renal tubular secretion, and 1 conversion of creatine • creatinine) and oliguria. Ut* <10 mEq L no response to volume challenge, exclusion of other causes of renal failure (drugs. ATN, obstruction) (lancet 2003:3611819) Type I: rapidly progressive, doubling of Cr to -2.5 In < 2 wks; usually occurs in Pts w severe liver failure, often following precipitating event (see below) Type II: more indolent course, median survival 6 mos; liver failure present, but less so than Type I; usually occurs in Pts w severe ascites w poor or no response to diuretics Précipitants: GIB. overdiuresis. infection, paracentesis, drugs (aminoglycosides, NSAIDs) Treatment: octreotide (200 meg SC tid) + midodrine (12.5 mg PO tid) beneficial (Hematology 1999;29:1690): albumin • vasoconstrictor (norepi, midodrine. terlipressin; Hepatotogy 2002,36 374)) and or TIPS may be beneficial: definitive treatment -» liver transplantation

Hepatopulmonary syndrome: pulm gas exchange abnl (Î A-a gradient : hypoxia), evidence of intrapulmonary vascular shunting and absence of intrinsic cardiopulmonary disease may see platypnea-orthodeoxia. clubbing, cyanosis: CXR normal Diagnosis: contrast echocardiography (R -» L shunt)

Treatment: supportive (Oj P»Oj 60 mmHg); liver transplant only definitive Rx Portopulmonary hypertension: Î PAP; unclear pathogenesis; poor prognosis Liver failure: precipitated by progressive hepatic damage or stressors (infxn, surgery) Infections: relative immunosuppression, thus susceptible to broad range of infxn Hepatocellular carcinoma (lancet 2003:362:1907): consider if î liver size. T ascites, abdominal pain, i encephalopathy, i weight. î AFP. or hepatic mass on U S. CT. MRI

Prognosis

• Correlates with Child-Turcotte-Pugh class (A >B>C)

Prognosis

• Correlates with Child-Turcotte-Pugh class (A >B>C)

Modified Child-Turcotte-Pugh Classification

Points scored

1

2

3

Ascites

None

Easily controlled

Poorly controlled

Encephalopathy

None

Grade 1 or II

Grade III or IV

Bilirubin (mg dl)

<2

2-3

>3

Albumin (g dl)

>3.5

2.8-3.5

<28

PT (sec - control)

< 4

4-6

>6

Classification

A

B

C

Total points

5-6

7-9

10-15

(8rit J Surg 1973:60:646)

(8rit J Surg 1973:60:646)

• MELD (Model for End-Stage Liver Disease): used to stratify Pts on liver transplant list;

based on Cr. INR. & total bilirubin to predict 3-mo survival in Pts w variety of underlying forms of liver disease; to calculate: http: www.mayodinic.org gi-rst mayomodcl6.html hyponatremia worsens prognosis Liver transplantation

• Evaluate • list when Child class B and MELD -10

• Indications: recurrent or severe encephalopathy, refractory ascites. SBP. recurrent variceal bleeding, hepatorenal or hepatopulmonary syndrome, hepatocellular carcinoma (if no single lesion is >5 cm or s3 lesions with largest s3 cm), fulminant hepatic failure

• Contraindic: advanced HIV. active substance abuse, sepsis, extrahepatic malignancy, severe comorbidity (cardiopulmonary in particular), persistent noncompliance

• Survival: 1 -year survival up to 90%, 5-year survival up to 80%

Other Etiologies of Cirrhosis Hemochromatosis (NEjm 2004:350:2383)

• Definition: iron overload due to genetic disorder or t ineffecL erythropoiesis (eg. thai.)

• Epidemiology (hereditary): 1 in 300; usually manifests in middle age and in men

• Manifestations of advanced disease: bronzing of the skin (melanin +■ iron. 90%).

hypogonadism, diabetes mellitus (65%). arthritis (2nd & 3rd MCPs. 25-50%). CHF. infections (Vibrio. Listeria. Yersinia)

• Dx: * iron saturation -45% (iron TIBC • 100%; earliest sign, more Se & Sp than ferritin).

T ferritin (acute phase reactant, can be elevated in inflammatory conditions; can be normal in young Pts w hemochromatosis); "black liver" noted on MRI is suggestive if T iron saturation - ✓ HFE gene mutation (C282Y C282Y or C282Y H63D) liver biopsy if HFE mutation © and ferritin >1000 ng ml. t LFTs. or hepatomegaly to discern liver damage (can quantify using hepatic iron concentration)

• Treatment: phlebotomy (500 cc - 1 unit) qwk until Fe sat <30% and ferritin <50. then as needed to keep in range; deferoxamine if cardiac involvement or unable to undergo phlebotomy: genetic counseling Wilson's disease (Lancet 2007:369:397)

• Definition: autosomal recessive disorder (mutation in ATP7B) of copper overload

• Epidemiology: 1 in 40.000. usually manifests before age 30; almost always before 40

• Extrahepatic: neuro i|> disorders. Kayser-Fleischer rings, hemolytic anemia, renal dis. | • Dx: * serum & 24-h urinary copper, I serum ceruloplasmin. hepatic copper content

•250 pg g dry wt Ad> often low in fulminant Wilson's disease (A.|. bili <2 suggestive of Wilson's). AST ALT >1 reflecting damage to hepatocellular mitochondria

• Treatment: chelation therapy with penicillamine - pyridoxine; alternative is trientine.

which is i toxic and prob effective; oral zinc if asymptomatic (must be given 4-5 h apart from chelators as they will neutralize each other and be rendered ineffective) ai-antitrypsin deficiency (ai-AT)

• Abnormal ui-AT -* polymerization in liver (cirrhosis) & uninhibited protease activity in lung

(emphysema)

• Additional clinical manifestations: emphysema, necrotizing panniculitis

• Dx: absence of oi-AT globulin on SPEP. v PAS inclusion bodies on liver bx;

gold standard abnl protease inhibitor (Pi) phenotype (usually TJL null null, or null Z)

• Treatment liver transplantation (for cirrhosis); m-AT replacement (for emphysema) Primary biliary cirrhosis (PBC) (N£/M 2005353:1261; lancet 2003Ml S3)

• Definition: autoimmune destruction of intrahepatic bile ducts

• Epidemiology: middle-aged women, concomitant autoimmune diseases

• Clinical manifestations: often asx; fatigue, pruritus, jaundice, fat malabsorption.

xanthelasma, xanthoma

• Dx: T A$. T bilirubin. © anti-mitochondrial Ab (AMA) in 95%. t cholesterol

• Treatment ursodeoxycholic acid (13-15 mg kg d); fat-soluble vitamins; cholestyramine for pruritus; transplantation; colchicine • methotrexate if incomplete response to UDCA Primary sclerosing cholangitis (PSC) (NE/m 1995:332:924)

• Definition: idiopathic cholestasis with fibrosis, stricturing and dilatation of intra- and extrahepatic bile ducts

• Epidemiology: young men (age 20-50). associated with IBD in 70% of cases (UC CD)

• Clinical manifestations: fatigue, pruritus, jaundice, fevers, tfUQ pain, cholangiocarcinoma

• Dx: T bilirubin. T A*. © p-ANCA in 70%. MRCP ERCP ♦ multifocal beaded bile duct strictures; "onion-skin" appearance of fibrosis around bile ducts on liver bx

? high dose ursodeoxycholic acid (20-30 mg kg d). ? cholestyramine, fat-soluble vit endoscopic dilation and short-term stenting of dominant bile duct strictures liver transplantation (t risk of posttransplant duct strictures) Budd-Chiari syndrome (Nejm 2004;3S0 578)

• Definition: occlusion of the hepatic veins or IVC — sinusoidal congestion and portal HTN

• Etiologies: hypercoagulable states (typically MPD. PNH. OCP. APLA protein C S def. JAK2

mutation), tumor invasion (HCC renal, adrenal), membranous webs, trauma, idiopathic

• Clinical manifestations: hepatomegaly. RUQ pain, ascites, dilated venous collaterals (if IVC)

• Dx: - f aminotransferases & A.;.; Doppler U S of hepatic veins (85% Se & Sp); CT (I')

or MRI MRA; "spider-web" pattern on hepatic venography: liver bx showing congestion (in Pt w o evidence of right-sided CHF)

• Treatment anticoagulation (heparin — warfarin), thrombolysis if acute thrombosis;

TIPS (portocaval gradient 10) or surgical shunt (gradient 10); liver transplantation Sinusoidal obstruction syndrome (SOS) (Moyo 2003:78:589)

• Previously known as veno-occlusive disease (VOD)

• Definition: occlusion of hepatic venules and sinusoids

• Etiology: stem cell transplant (SCT), chemotherapy. XRT. Jamaican bush tea

• Clinical manifestations: hepatomegaly. RUQ pain, ascites, weight gain, f bilirubin

• Dx: U S usually not helpful; dx made clinically or, if necessary, by liver bx

• Treatment supportive: diuresis, analgesia, paracentesis for tense ascites:

ursodeoxycholic acid prophylaxis in high risk SCT population

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