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Cirrhosis (MAJOR COMPLICATIONS OF CIRRHOSIS (PORTAL HTN (Clinical Features…

- - - - Splenomegaly, hypersplenism
      - Ascites
        
        Spontaneous bacterial peritonitis
      - Gastroesophageal varices
        
        common practice to screen known cirrhotics w/ endoscopy to look for esophageal varices: 1/3 have varices.
        5–15% of cirrhotics/year develop varices, and majority develop varices over their lifetimes.
        1/3 of pxs w/ varices will develop bleeding.
        factors predicting risk of bleeding: severity of cirrhosis (Child’s class, MELD score); height of wedged-hepatic vein pressure; size of varix; location of varix; and certain endoscopic stigmata (red wale signs, hematocystic spots, diffuse erythema, bluish color, cherry red spots, or white-nipple spots); pxs w/ tense ascites also at incr risk for bleeding from varices.
        
        Diagnosis
        development of portal HTN u. revealed by presence of thrombocytopenia; appearance of an enlarged spleen; or development of ascites, encephalopathy, and/or esophageal varices w/ or w/o bleeding.
        In previously undx pxs , any of these features should prompt further evaluation to determine presence of portal HTN and liver disease.
        Varices: identified by endoscopy.
        Abdominal imaging, either by CT or MRI, helpful in demonstrating a nodular liver and in finding changes of portal HTN w/ intraabdominal collateral circulation.
        If necessary, interventional radiologic procedures can be performed to determine wedged and free hepatic vein pressures that will allow for calculation of a wedged-to-free gradient, which is equivalent to portal pressure. average normal wedged-to-free gradient is 5 mmHg, and pxs w/ a gradient >12 mmHg are at risk for variceal hemorrhage.
        
        Treatment:
        
        Treatment
        (1) primary prophylaxis
        routine screening by endoscopy of all cirrhosises--> varices at incr risk for bleeding identified--> primary prophylaxis:
        nonselective beta blockade: lowers risk of variceal hemorrhage + decr mortality related to variceal hemorrhage.
        degree of reduction of portal P a significant feature to determine success of therapy--> repeat measurements of hepatic vein P gradients used to guide pharmacologic therapy; however, cost-prohibitive.
        
        variceal band ligation and variceal sclerotherapy
        Endoscopic variceal ligation (EVL): cirrhosis who are screened for portal HTN and have large varices: either beta blockade or primary prophylaxis w/ EVL.
        
        approach to pxs once they have had a variceal bleed:
        
        treat the acute bleed: both fluid and blood-product replacement 2. prevent further bleeding: repeated variceal band ligation until varices obliterated.
        
        medical management of acute variceal hemorrhage:
        use of vasoconstricting agents, u. somatostatin or octreotide (Vasopressin no longer)
        Ballon tamponade: in who cannot get endoscopic therapy immediately or need stabilization prior to endoscopic therapy.
        Control of bleeding achieved in vast majority; however, bleeding recurs in majority if definitive endoscopic therapy not been instituted.
        Octreotide (direct splanchnic vasoconstrictor) given at dosages of 50–100 µg/h by continuous infusion.
        Endoscopic intervention:
        first-line treatment to control bleeding acutely.
        some use variceal injection therapy (sclerotherapy) as initial therapy, partic when bleeding vigorous.
        Variceal band ligation used to control acute bleeding in >90% of cases and should be repeated until obliteration of all varices accomplished. When esophageal varices extend into proximal stomach, band ligation less successful--> when bleeding continues from gastric varices: TIPS: a portosystemic shunt by a percutaneous approach using an expandable metal stent, which is advanced under angiographic guidance to hepatic veins and then through liver to create a direct portocaval shunt (an alternative to surgery for acute decompression of portal HTN); Encephalopathy can occur in 20% of pxs after TIPS and is partic problematic in elderly pxs and in patients w/ preexisting encephalopathy. TIPS should be reserved for individuals who fail endoscopic or medical management or who are poor surgical risks. TIPS can sometimes be used as a bridge to transplantation. Surgical esophageal transsection is a procedure that is rarely used and generally is associated with a poor outcome
        (2) prevention of rebleeding once there has been an initial variceal hemorrhage.
        
        Endoscopic variceal ligation (EVL) has achieved a level of success
        
        and comfort with most gastroenterologists who see patients with these complications of portal hypertension. Thus, in patients with cirrhosis who are screened for portal hypertension and are found to have large varices, it is recommended that they receive either beta blockade or primary prophylaxis with EVL.
- - - - cytosolic ADH
      - microsomal ethanol oxidizing system (MEOS)
      - peroxisomal catalase
  - - - liver and spleen may be enlarged (liver edge firm and nodular)
      - Other frequent findings: scleral icterus, palmar erythema, spider angiomas, parotid gland enlargement, digital clubbing, muscle wasting, or development of edema and ascites.
      - Men: decr body hair and gynecomastia, testicular atrophy (maybe a consequence of hormonal abnormalities or a direct toxic effect of alcohol on testes)
      - Women: menstrual irregularities u., and some amenorrheic (often reversible following cessation of alcohol)
    - - may be completely normal in early compensated alcoholic cirrhosis; in advanced liver disease, many abnorms u. present.
      - May be anemic either from chronic GI blood loss, nutritional deficiencies, or hypersplenism related to portal HTN, or as a direct suppressive effect of alcohol on bone marrow.
      - A unique form of hemolytic anemia (w/ spur cells and acanthocytes)=Zieve’s syndrome: in severe alcoholic hepatitis.
      - Platelet counts often reduced early in disease, reflective of portal HTN w/ hypersplenism.
      - Serum total bilirubin: normal or elevated w/ advanced disease. Direct bilirubin frequently mildly elevated in normal total bilirubin, but abnormality typically progresses as disease worsens.
      - PT often prolonged and u. do not respond to parenteral vit K.
      - Serum Na levels u. normal unless pxs have ascites and then can be depressed, largely due to ingestion of excess free water.
      - Serum ALT, AST typically elevated, partic in pxs who continue to drink, w/ AST levels higher than ALT, usually by a 2:1 ratio.
  - - - --> several different types of chronic liver disease
      - --> liver damage in other liver diseases
      - -->fibrosis in absence of accompanying infl +/ necrosis (Fibrosis: centrilobular, pericellular, or periportal)
- - - - Pxs exposed: 80% develop chronic hepatitis C: of those, 20–30% will develop cirrhosis over 20–30 yrs.
      - Many of these pxs have had concomitant alcohol use, and the true incidence of cirrhosis due to hepatitis C alone unknown.
      - Worldwide, about 170 million have hepatitis C
      - a noncytopathic virus, and liver damage probably immune-mediated.
    - - adult pxs exposed to HBV: 5% develop chronic hepatitis B: of those, 20% will develop cirrhosis.
      - Special stains for HBc +HBs Ag positive, and ground-glass hepatocytes signifying HBsAg may be present.
      - In parts of world where HBV endemic (i.e., Asia, Southeast Asia, subSaharan Africa), up to 15% of population may be infected, having acquired infection vertically at time of birth. Thus, over 300–400 million have hepatitis B worldwide. 25% of these may ultimately develop cirrhosis.
  - - - quantitative HCV RNA testing + analysis for HCV genotype
      - hepatitis B serologies: HBsAg, anti-HBs, HBeAg, anti-HBe, and quantitative HBV DNA levels
  - - - antiviral therapy: viral suppression--> decr AST ALT + HBV DNA levels + decr infl and fibrosis.
      - decompensated liver disease can become compensated w/ use of antiviral therapy against hepatitis B.
      - lamivudine, adefovir, telbivudine, entecavir, and tenofovir.
      - Interferon α should not be used in cirrhotics.
    - - more difficult bc side effects of pegylated interferon and ribavirin therapy often difficult to manage. Dose-limiting cytopenias (platelets, white blood cells, red blood cells) or severe side effects can result in discontinuation of treatment (if platelets <100,000, albumin <3.5 g/dL, MELD score >10, risk of severe complications of interferon-based antiviral therapy significant)
- - - - earliest lesion: chronic nonsuppurative destructive cholangitis: a necrotizing infl process of portal tracts. Medium and small bile ducts infiltrated w/ lymphocytes and undergo duct destruction. Mild fibrosis and sometimes bile stasis can occur.
      - Infl infiltrate becomes less prominent, but # of bile ducts reduced + there is prolif of smaller bile ductules.
      - Incr fibrosis w/ expansion of periportal fibrosis to bridging fibrosis.
      - Cirrhosis (micronodular or macronodular)
    - - Most diagnosed before end-stage manifestations--> most are asymptomatic. When symptoms present:
        
        most prominently include a significant degree of fatigue out of proportion for either severity of liver disease or age of px.
        
        Pruritus: in 50% at time of dx, and can be debilitating; might be intermittent and u. most bothersome in evening; In some can develop toward end of pregnancy (examples of pxs having been dx w/ cholestasis of pregnancy rather than PBC); Pruritus that presents prior to development of jaundice indicates severe disease and a poor prognosis.
      - P/E
        
        jaundice and other complications of chronic liver disease
        
        Other features unique to PBC: hyperpigmentation (evident on trunk + arms + seen in areas of exfoliation and lichenification a. w/ progressive scratching related to pruritus), xanthelasma, and xanthomata, (related to altered cholesterol metabolism)
        
        Bone pain (from osteopenia or osteoporosis) occasionally seen
    - - cholestatic liver E abnorms w/ an elevation in GGT and ALP along w/ mild elevations in ALT and AST
      - Igs, partic IgM, typically incr
      - Hyperbilirubinemia u. seen once cirrhosis developed
      - Thrombocytopenia, leukopenia, and anemia may be seen in portal HTN and hypersplenism.
      - Up to 10% of PBC will have features of AIH as well (“overlap” syndrome): u. treated as PBC and may progress to cirrhosis w/ same frequency as typical PBC. Some require immunosuppressive medications as well.
    - - UDCA: improve both biochemical and histologic features; improvement greatest when therapy initiated early; likelihood of significant improvement low in PBC who present w/ manifestations of cirrhosis; doses of 13–15 mg/kg per day; u. well-tolerated, although some have worsening pruritus; small proportion may have diarrhea or headache as a side effect; slows rate of progression, but it does not reverse or cure;
      - Certain pxs may need to be considered for liver transplantation
      - main symptoms of PBC: fatigue and pruritus, and symptom management important.
      - fatigue: no treatment successful; frequent naps should be encouraged.
      - Pruritus: antihistamines, narcotic receptor antagonists (naltrexone), and rifampin. Cholestyramine, a bile salt–sequestering agent, has been helpful in some; Plasmapheresis used rarely in severe intractable pruritus;
      - incr incidence of osteopenia and osteoporosis in cholestatic liver disease, and bone density testing should be performed. Treatment w/ a bisphosphonate should be instituted when bone disease identified.
    - - In 100–200/million, strong female preponderance, median age of around 50 yrs at time of dx
      - Cause: unknown
      - charac by portal infl + necrosis of cholangiocytes in small- and medium-sized bile ducts + elevated bilirubin + progressive liver failure.
      - Liver transplantation: treatment of choice in decompensated cirrhosis due to PBC; ursodeoxycholic acid (UDCA): only approved treatment (slowing rate of progression)
      - Antimitochondrial antibodies (AMA) present in 90% of pxs: recognize intermitochondrial membr prs that are Es of PDH complex (PDC), the branched-chain 2-oxoacid DH complex, and the 2-oxogluterate DH complex (Most relate to PDH dehydrogenase); not pathogenic but useful markers for dx
  - - - (cholestatic liver disease): fatigue, pruritus, steatorrhea, deficiencies of fat-soluble vits, associated consequences;
      - fatigue profound and nonspecific.
      - Pruritus often debilitating and related to cholestasis: severity does not correlate w/ severity of disease.
      - Metabolic bone disease can occur
    - - identified in course of an evaluation of abnormal liver Es:
      - Most have at least a 2x incr in ALP and may have elevated AST,ALT as well.
      - Albumin may be decr, and PT prolonged in a substantial proportion at time of dx (Some degree of correction may occur w/ parenteral vit K)
      - small subset: aminotransferase elevations >5x the upper limit of normal and may have features of AIH on biopsy: overlap syndrome betw PSC and AIH. AutoAbs frequently positive in pxs w/ overlap syndrome but typically negative in pxs who only have PSC. p-ANCA: positive in 65% of PSC.
      - 50% of PSC also have ulcerative colitis (UC); once a dx of PSC established--> colonoscopy for evidence of UC.
    - - definitive dx: cholangiographic imaging.
      - MRI w/ MRCP: for initial evaluation; after that some feel that ERCP should also be performed to be certain whether dominant stricture is present.
      - Typical cholangiographic findings: multifocal stricturing and beading (intrahepatic and extrahepatic biliary tree; more commonly, both are involved): strictures typically short and w/ intervening segments of normal or slightly dilated bile ducts that are distributed diffusely--> classic beaded appearance.
      - gallbladder and cystic duct can be involved in up to 15%
      - high-grade, diffuse stricturing of intrahepatic bile ducts: overall poor prognosis. Gradually, biliary cirrhosis develops, and pxs will progress to decompensated liver disease
    - - no specific proven treatment
      - high-dose UDCA harmful
      - Endoscopic dilatation of dominant strictures helpful
      - ultimate treatment: liver transplantation (but development of cholangiocarcinoma is a relative contraindication to liver transplantation)
      - Approach to pruritis similar to PBC
    - - Cause: unknown (various mechs related to bacterial and viral infections, toxins, genetic predisposition, and immunologic mechanisms)
      - charac by diffuse infl + fibrosis involving entire biliary tree--> obliteration of both intra- and extrahepatic biliary tree--> biliary cirrhosis, portal HTN, and liver failure.
      - Pathologic changes:
        
        bile duct prolif + ductopenia + fibrous cholangitis (pericholangitis).
        
        Often, liver biopsy changes not pathognomonic, and establishing dx must involve imaging of biliary tree. Periductal fibrosis occasionally seen on biopsy + quite helpful in making dx
        
        biliary cirrhosis: final, end-stage manifestation