Evaluation of Liver Disease:
Liver dz can range from Asx - ESLD
H & P
Dxtic tests, Bx, imaging
History: Focus on the following:
HPI
Medicine usage, toxin exposure (EtOH)
Edema, encephalopathy, GIB
FH of liver disease
Dietary habits
Risk factors: IDU, IH drug use, body piercings, tattooing, sexual history, travel to foreign countries, occupation
Physical examination:
Stigmata of liver disease
Icterus
Ascites - shifting dullness, peripheral edema
Hepatomegaly, splenomegaly, caput medusae, spider nevi/angiomata
Gynecomastia, testicular hypertrophy
Muscle wasting
Telangiectasias, palmar erythema, pubic hair changes
Specific liver abnormalities with distinctive physical abnormalities: arthritis, acne, skin color changes, Kayser-Fleischer rings, clubbing, S3 gallop.
Diagnostic Testing:
Lab:
Serum enzymes:
Hepatocellular: ▲ aminotransferases (AST and ALT >1,000 U/L)
AST/ALT >2 in alcoholic liver disease.
AST/ALT <1 in viral hepatitis.
Milder elevations in acute or chronic hepatocellular injury, infiltrative diseases, biliary obstruction
Cholestatic: ▲ alkaline phosphatase - ALP (present in bone, intestine, kidney, leukocytes, liver, pancreas, placenta)
GGT or 5'-nucleotidase, ▲ concomitantly in establishing ALP is from liver.
GGT may be ▲ in persons who ingest barbiturates, phenytoin, or alcohol even when other liver enzyme and bilirubin levels are normal.
5'-nucleotidase is comparable to ALP in sensitivity in detecting biliary obstruction, cholestasis, and inflitrative hepatobiliary diseases.
▲ ALP; biliary obst, space-occupying lesion, infiltrative d/o of liver, intrahepatic cholestasis (PBC, PSC)
Synthetic products
Serum albumin ▼ in chronic liver disease, chronic inflammation, expanded plasma volume, GI or renal losses. Since t1/2 of albumin is long (20 days), serum levels may be normal in acute liver disease.
Proteins involved in fibrinolysis and hemostasis: alpha2-antiplasmin, antithrombin, heparin cofactor II, HMWK, prekallikrein, protein C and S.
Factors II, VII, IX, and X, and protein C and S depends on presence of Vitamin K. The adequacy of hepatic synthetic function can be estimated by PT/INR. Normlaization of PT/INR after administration of vitamin K indicates vit K def.
Cholesterol is synthesized by the liver. Pt. with advanced liver disease may have very low cholesterol levels. However, in PBC, levels of serum cholesterol may be markedly elevated.
Alpha1-antitrypsin and ceruloplasmin.
Excretory products:
Total Bilirubin = conjugated (direct) + unconjugated (indirect) bilirubin fractions.
Unconjugated hyperbilirubinemia: excess bilirubin production (neonatal or physiologic jaundice, hemolysis, and hemolytic anemias, ineffective erythropoiesis, resorption of hematomas)
Reduced hepatic bilirubin uptake (Giblert's syndrome and drugs such rifampin and probenecid)
Impaired bilirubin conjugation: Gilbert's or Crigler-Najjar syndrome
▲ conjugated and unconjugated fractions: Dubin-Johnson's and Rotor's synd, intrahepatic cholestasis (hepatocellular, canalicular, or ductular damage) and extrahepatic cholestasis (mechanical obstruction)
Bile acids
Alpha-fetoprotein (AFP): normally produced by fetal liver cells. Its, production is <10 ng/mL within 1 year of life, to normal adult levels. Insensitive marker for HCC. Levels of >400 ng/mL, or rapid doubling time is suggestive of HCC. Mild to moderate elevation can be seen in acute and chronic liver inflammation.
Imaging:
US: screen to dilation of the biliary tree and for gallstones and cholecystitis in Pts with RUQ abdominal pain and abnormal LFTs.
Liver masses, abscesses, and cysts
Color flow dopper US can check patency and direction of blood flow in the portal and hepatic veins.
US is frequently used modality for HCC, but may not be able to pick up tumors with <2 cm, compared with CT or MRI.
Helical CT with IV contrast is useful for evaluation of parenchymal liver disease
Abscess, tumor, calculation of liver volume
Triple-phase CT (noncontrast, arterial phase, and venous phase) for liver mass evaluation. Delayed phase is useful when cholangiocarcinoma is suspected.
MRI better characterizes the liver lesions, fatty infiltration, and iron deposition.
modality of choice in allergy to iodinated contrast
MRCP for visualizing intra- and extrahepatic ducts
PET useful for assessing hepatic mets in CRC, cholangiocarcinoma
Dxtic procedures:
Percutanenous transhepatic cholangiography (PTC) and ERCP: useful after preliminary determination of abnormalities detected on US, CT, or MRI/MRCP.
Dxtic, Tx - biopsy, brushings, stenting, and placement of drains
Percutaneous liver biopsy w/ w/o US or CT guidance. If Pt. is coagulopathic, thrombocytopenic, and/or ascites, a bx can be obtained via the transjugular route.
Noninvasive testing to assess fibrosis/cirrhosis: aspartate aminotransferase to platelet ratio index (APRI), Fibrotest, transient elastography, and MR spectroscopy are under investigation as complementary to liver bx.
Hepatitis - infective, serologies
HAV: IgM anti-HAV, IgG anti-HAV
HBV: HBsAg, Anti-HBs, IgM anti-HBc, IgG anti-HBc, HBeAg,
Anti-HBe, HBV-DNA
HCV: Anti-HCV, if +ve do RIBA, HCV-RNA
Acute HCV infection = +ve HCV PCR x 2 in a row.
Spontaneous clearance = HCV PCR is -ve monthly x 3 mo, along with formation of HCV antibodies.
Chronic HCV infection = HCV RNA in serum for longer than 6 mo.
HDV: IgM, anti-HDV, IgG, anti-HDV
HbcAg is never detectable in serum. It is intracellular ag. Expressed in infected hepatocytes.
Hepatitis-C
HCV is an RNA virus belonging to the flavivirus family. Flavivirdiae hepacivirus.
Single stranded RNA virus mutates rapidly, so changes in the envelope proteins may help it to invade the immune system.
HCV does not incorporate into the host DNA, resulting in the ability to cure the infection indefinitely.
Epidemiology:
6 HCV genotypes. Genotype 1 accounts for 75% and genotypes 2, and 3 account for 20% of HCV infections in the U.S.
200 million carriers worldwide. 4 million in U.S. 2.7 have chronic infections and constitutes cause of death from chronic liver disease.
Chronic HCV. After 6 months of infection, spontaneous! clearance of the virus is rare.
Most common chronic blood-borne infection.
Most common cause of HCC.
Frequent cause of liver transplantation.
Prevalence in U.S is 1.8%.
Risk factors:
Birth to mother with positive antibodies to HCV
Blood transfusion or clotting factors before 1992
Hemodialysis
H/o cocaine use, h/o tattoos, IVDU, mutiple sexual partners, needlestick or mucosal exposure (in health care worker), sharing "straws" for intranasal cocaine use, sharing razors, military service, incarceration, organ transplant before 1992, sex with HCV-infected partner, treatment with clotting factor for hemophilia before 1987, unexplained elevations for liver enzymes.
AASLD (American Association for the Study of Liver Disease) recommends screening for Hep-C in the following persons:
Injection drug users (even if they have used once)
HIV infected persons
Hemodialysis
Hemophiliac who received blood products prior to 1987
Organ transplant recepients prior to 1992
Elevated LFTs, unexplained
Children born of Hep-C mothers
HCW exposure to needle stick injuries
Current sexual partners of Hep-C persons
Person using intranasal cocaine
Pathophysiology:
Immune mediated liver damage after HCV
Prevention:
No vaccine, no preexposure prophylaxis.
Prevention of high-risk behavior and lifestyle modification.
Diagnosis
Incubation period varies from 15 - 150 days
Acute hepatitis can be sub-clinical (silent) in young adults and children. May present as fulminant hepatic failure (FHF). Malaise, fatigue, anorexia, and fever, joint pain, myalgia, jaundice
Chronic hepatitis has fatigue as a common symptom. Associated with advanced liver disease.
Extrahepatic manifestations include mixed cryoglobulinemia (10 - 25% of patients with HCV), glomerulonephritis, porphyria cutanea tarda, cutaneous necrotizing vasculitis, lichen planus, lymphoma, diabetes mellitus, and other autoimmune disorders.
With the advent of PIs, liver bx is not required. However, if the patient is unsure whether to proceed with treatment, a liver bx can document the grade of inflammation in the liver and the stage of liver fibrosis.
Dental work must be done prior to treatment
Hep A and B vaccination.
Dxtic testing:
Initial w/up: serum alpha-fetoprotein, ANA, Chem-7, CBC, Hep-A, B (total ab), HBsAg, HIV, iron studies, PTT, PT, Thyroid function, depression scale.
Anti-HCV may be undetectable for first 8 weeks after infection. Detected by immunoassay. Do not confer immunity. 95% - 99% sensitive and a lower specificity.
Autoimmune hepatitis or hypogammaglobulinemia may give a false-positive test (anti-HCV positive with HCV RNA being negative).
Immunosuppressed HCV infected individuals may have false-negative test (anti-HCV negative with HCV RNA positive), as well as those on with HCV on hemodialysis.
Anti-HCV screening: EIA or the enhanced chemiluminescence immunoassay (CIA). Positive test should be confirmed with HCV-PCR RNA to measure viral load.
HCV RNA can be detected by PCR in serum 1 - 2 weeks after infection (qualitative and quantitative assays). Expressed in IU/mL, with lower limits of detection approaching 10 IU/mL. HCV RNA is useful for both diagnosis and treatment purposes.
HCV genotypes 1, 2, and 3. This influences the duration, dosage, and response to treatment.
Liver biopsy is useful to grade the amount of liver steatosis and guides treatment decisions. It is useful to score the degree of inflammation (grade) and fibrosis (stage) in the liver of chronically infected patients.
Tx:
Goals:
Eradication of HCV
Decrease disease progression
Histological improvement
Histological improvement
Decrease HCC frequency
Treatment outcome based on a number of pretreatment and on-treatment factors.
Pretreatment factors include viral genotype, viral load, advanced liver disease (amount of liver fibrosis), metabolic factors such as obesity, steatosis, and insulin resistance. Also race/ethnicity.
On-treatment factors
Compliance to prescribed regimen and duration of ribavirin and pIFN.
Rapidity of response.
Treatment definitions
Rapid virologic response (RVR): HCV RNA negative at 4 weeks of treatment.
Early virologic response (EVR): HCV RNA negative, or >2 log10 drop at 12 weeks of treatment.
Complete EVR (cEVR): No RVR, but HCV RNA negative at week 12.
Partial EVR (pEVR): No RVR, detectable HCV RNA but >2 log10 drop at 12 weeks of treatment.
Slow responder: >2 log10 drop at 12 weeks of treatment and HCV RNA negative at week 24.
Partial responder: 2 log10 drop at 12 weeks of treatment and HCV RNA positive at week 24.
Relapse: HCV RNA negative at end of treatment but HCV RNA positive after treatment cessation.
Sustained virologic response (SVR): absence of HCV RNA 6 months postantiviral treatment.
Defining the virologic response to treatment at weeks 4 and 12 is useful in predicting an SVR.
Acute infection: IFN-alpha (standard or pegylated) for 6 months has been associated with a high rate of sustained HCV RNA clearance. Ribavirin is still under investigation.
Chronic infection:
Combination of pIFN (peginterferon alfa-2a 180 mcg/wk or peginterferon alfa-2b 1.5 mcg/kg/wk, subcutaneous) and oral ribavirin (genotype I: <75 kg: 1000 mg PO daily, >75 kg: 1,200 mg PO daily; genotypes 2 and 3: 800 mg PO daily) is administered for 6 months for genotypes 2 and 3, and 12 months for gentoytpe 1.
Overall SVR is better for genotypes 2 and 3 compared to genotypes 1, 4, 5, and 6.
SVR is dependent upon pretreatment factors and rapidity of achieving HCV RNA clearance.
Overall SVR in HCV patients varies from 54% to 63% (genotype1: 30% to 40%; genotypes 2 and 3: 80% to 85%). Patients who achieve SVR have a low rate of recurrence <1%, and are therefore considered cured of their infection.
Side effects of interferon-based therapy include flu-like symptoms, neuropsychiatric disorders, endocrine dysfunction, and bone marrow suppression.
Side effects of ribavirin include teratogenicity, hemolytic anemia, and pulmonary symptoms (dyspnea, cough, and pneumonitis). Contraindications include pregnancy or unwillingness to practice birth control, chronic renal insufficiency, and the inability to tolerate anemia (15% to 30%)
When used alone, ribavirin is ineffective and does not reduce HCV RNA levels, but ribavirin enhances the efficacy of IFN by reducing the likelihood of virologic relapse after the achievement of an end-treatment response (response measured during, and maintained to the end of, treatment).
Monitoring and follow-up
The progression of fibrosis determines the ultimate prognosis and thus the need and urgency of therapy.
Liver biopsy is the gold standard to assess fibrosis.
Hepatic fibrosis, cirrhosis, hepatocellular ca, end-stage liver disease needing liver transplant, extrahepatic manifestations.
Extrahepatic manifestations:
Hematologic (anemia, lymphoma)
Dermatologic (lichen planus, and vasculitis)
Renal (GN and nephritic syndromes)
Endocrine (hypothyroidism, and diabetes)
Neuropsychiatric disease
Ocular (corneal ulcer and uveitis)
Vascular (PAN, necrotizing vasculitis)
Neuromuscular (arthralgias and arthritis)
Autoimmune (CREST syndrome)
Outcome / Prognosis
Acute hepatitis is frequently clinically silent.
Up to 40% of people infected with HCV will have spontaneous resolution, while 60% progress to have chronic infection.
Progression to cirrhosis is slow (two to three decades) and seen in a quarter of patients with chronic HCV.
HCC develops in approximately 1% to 2% of patients per year, and rarely occurs in the absence of cirrhosis.
Alcohol consumption of >50 g/day will increase Hep-C PCR RNA viral load.
Hep C:
Although death in the hepatitis group is more likely to result from liver failure, and although hepatic decompensation may occur in ~15% of such patients over the course of a decade, the majority (almost 60%) of patients remain asymptomatic and well compensated, with no clinical sequelae of chronic liver disease. Overall, then, chronic hepatitis C tends to be very slowly and insidiously progressive, if at all, in the vast majority of patients, while in approximately a quarter of cases, chronic hepatitis C will progress eventually to end-stage cirrhosis. In fact, because HCV infection is so prevalent, and because a proportion of patients progress inexorably to end-stage liver disease, hepatitis C is the most frequent indication for liver transplantation
Progression of liver disease in patients with chronic hepatitis C has been reported to be more likely in patients with older age, longer duration of infection, advanced histologic stage and grade, genotype 1, more complex quasispecies diversity, increased hepatic iron, concomitant other liver disorders (alcoholic liver disease, chronic hepatitis B, hemochromatosis, 1-antitrypsin deficiency, and steatohepatitis), HIV infection, and obesity.
Treatment contraindications:
MDD (untreated, uncontrolled)
Solid organ transplant (kidney, lung, or heart)
Autoimmune hepatitis and other autoimmune conditions that can be worsened with treatment.
Thyroid disease - undiagnosed and untreated.
Pregnancy unwillingness to comply with contraception
Severe HTN, CHF, CAD, DM, COPD - all not well controlled.
Hypersensitivity to peginterferon alfa-2a (Pegasys) and alfa-2b (PEG-Intron), ribavirin (Copegus, Rebetol, Riba Tab, Ribasphere), telaprevir (Incivek), Boceprevir (Victrelis).