Liver Disease and Cirrhosis

Note: Some medications mentioned in this chapter may not be available on the VHA National Formulary. Consult VA pharmacists for alternatives.

Note: Current information on VHA policy, guidelines, and tools related to liver disease can be found on the VA Hepatitis C website.

Background

Any disease or injury that chronically affects the liver can cause fibrosis (scarring); this process ultimately may progress to cirrhosis.

Cirrhosis is characterized by diffuse interlacing bands of fibrous tissue dividing the hepatic parenchyma into micronodular or macronodular areas.

Epidemiology of HIV and Liver Diseases

• High morbidity and mortality: In the U.S. general population, cirrhosis accounts for 40,000 deaths per year and for the loss of more than 228,000 years of potential life.
• As HIV patients with access to ART survive longer, comorbidities such as chronic liver disease have become leading causes of illness and death. ESLD is now a leading cause of death in patients with HIV/HCV or HIV/HBV coinfection.
• HIV infection accelerates progression of liver disease associated with HCV or HBV.
• Other factors that cause more severe liver disease, including alcohol misuse, drug-associated hepatotoxicity, male gender, and fatty liver (steatosis), are also more common in the HIV-infected population.

Potential Causes of Liver Disease, Especially among HIV-Infected Patients

Prevalence of viral hepatitis among HIV-infected individuals in the United States

30-40% coinfected with HCV

• 9-27% of heterosexuals
• 1-12% of men who have sex with men
• 72-95% of injection drug users
• 31% of veterans

6-14% coinfected with HBV

• 4-6% of heterosexuals
• 9-17% of men who have sex with men
• 7-10% of injection drug users
• 14% of veterans

Risk factors for liver diseases other than viral hepatitis are common in the HIV-infected population.

Abnormalities in liver enzyme levels are common among HIV-infected persons, even in the absence of HCV or HBV infection.

• Cross-sectional studies have shown a high prevalence of elevated AST (20%), ALT (15%), and alkaline phosphatase (43%).

Alcohol consumption is common among people with HIV infection.

• Rates of heavy drinking among people with HIV are almost twice those found in the general population. Approximately 8% of persons with HIV report heavy drinking in the past month.
• Alcohol use disorders were diagnosed in 33% of HIV-infected veterans in VA care in 2007.

Other comorbidities associated with liver disease:

• Diabetes mellitus
• Hyperlipidemia
• Obesity
• Hemophilia
• Ulcerative colitis

Evaluation

• At initial assessment, HIV-infected patients should be evaluated for clinical, biochemical, and virologic evidence of chronic liver disease.
• Frequency of reassessments depends on the presence and severity of existing disease, risk factors for liver disease (eg, IDU, alcohol misuse), and prescription of potentially hepatotoxic medications (eg, NVP).

Clinical Features of Liver Diseases

Biochemical Features of Liver Disease and Common Causes

Elevated aminotransferases (AST, ALT)	Elevated alkaline phosphatase (with or without bilirubin elevation)	Elevated bilirubin (without increase in alkaline phosphatase)
(See web-based course on liver function test abnormalities.)
Chronic HCV Chronic HBV Autoimmune hepatitis Nonalcoholic steatohepatitis (NASH) Drug effect/hepatotoxicity Alcohol	Primary biliary cirrhosis Sclerosing cholangitis Drug-induced liver injury Infiltrative liver disease Sarcoidosis Granulomatous hepatitis	Cirrhosis Drug effect (eg, ATV and IDV commonly cause isolated elevation of unconjugated bilirubin)

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Laboratory Findings and Specific Liver Diseases

Cirrhosis

Definitions

Compensated cirrhosis: Cirrhosis is present but patient is without any specific clinical complication of cirrhosis.

Decompensated cirrhosis: Patient develops at least 1 complication of cirrhosis, such as ascites, jaundice, encephalopathy, or variceal hemorrhage.

Diagnostic Tests for Cirrhosis

Liver biopsy ("gold standard"): histological diagnosis made by liver biopsy or at autopsy.

Alternatives to liver biopsy:

• Diagnosis can be made clinically, using available clinical and laboratory data but without obtaining a liver biopsy.
• Diagnosis may be made radiologically.

Potential Laboratory Findings in Patients with Cirrhosis

Role of abdominal imaging in liver disease

• Radiological imaging can sometimes detect findings of cirrhosis and may obviate the need for liver biopsy. Findings that suggest the presence of cirrhosis include:
  • Small, contracted liver
  • Surface nodularity, increased echogenicity of liver
  • Splenomegaly
  • Ascites
  • Collateral veins (the most important finding indicative of cirrhosis)
  • (See Management of Complications of Cirrhosis and Chronic Liver Disease)
• The major use of abdominal imaging is for detecting complications of cirrhosis (eg, ascites, HCC, and hepatic or portal vein thrombosis) in cirrhotic patients.
• In patients with chronic liver disease but without cirrhosis, abdominal imaging can be completely normal or can show fatty liver, a nonspecific finding.
• Useful radiology studies include abdominal ultrasound, abdominal CT scan, and abdominal MRI.

Staging and Classification of Cirrhosis

Child-Turcotte-Pugh Score

• Originally developed to estimate the risk of death after portacaval shunt surgery; this modified version was intended to assess the risk of nonshunt operations.
• The score is determined by assessing clinical (subjective) complications of cirrhosis and laboratory (objective) abnormalities indicative of liver dysfunction.

Child-Turcotte-Pugh Classification of Liver Disease

Model for End-Stage Liver Disease (MELD) Score

• The MELD score is a newer method for predicting 3-month survival. It is used for liver allocation (transplant) by the United Network for Organ Sharing (UNOS) and has been adopted for use in the nontransplant setting.
• It is used to determine how urgently a patient needs a liver transplant within the coming 3 months.
• It is the strongest predictor of mortality in HIV-infected patients with ESLD.
  • Used for patients ≥12 years of age
  • Expressed on a numerical scale, ranging from 6 to 40
  • Computed using 3 routine laboratory test results: bilirubin, INR, and CrCl:
    
    
    

    MELD = 3.78[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] + 9.57[Ln serum creatinine (mg/dL)] + 6.43

    A calculator for determining MELD scores is available on the Mayo Clinic website.

    • HCC and other complications of cirrhosis are ascribed additional MELD points.

Management

Goals: prevention of further liver damage, slowing progression of liver disease, management of cirrhotic complications

Prevention of further insults to the liver:

• HAV vaccination
• HBV vaccination
• Pneumococcus vaccination
• Influenza vaccination
• Avoid or minimize hepatotoxic drugs
• Maintain normal BMI (avoid obesity)
• For hepatically metabolized drugs, adjust dosages according to package insert instructions

Slow progression of liver disease:

• Abstinence from alcohol use for all, regardless of underlying disease process: counsel or refer for treatment, as appropriate (see Alcohol Misuse)
• Avoidance of hepatotoxic or nephrotoxic medications (eg, NVP, ddI, NSAIDs, aminoglycosides)
• Treatment of HIV, if coinfected with HBV or HCV: ARV therapy for HIV may slow progression of HBV and HCV
• Treatment of chronic HCV, if eligible: pegylated interferon-alfa in combination with ribavirin
• Treatment of chronic HBV, if eligible: currently FDA-approved medications for treatment of HBV include 3TC, TDF, telbivudine, entecavir, adefovir, and pegylated interferon-alfa. Another ARV, FTC, is also active against HBV, but is not approved for treatment of HBV.
  • It is very important to note that, when using HBV antiviral agents that are also active against HIV (eg, 3TC, FTC, TDF, or entecavir) in a patient coinfected with HIV and HBV, these agents should not be used as monotherapy. In coinfected patients, the HBV medications must be used as combination therapy within a multidrug, fully suppressive HIV regimen to avoid development of HIV resistance.
• Treatment of autoimmune hepatitis: can include prednisone or immunosuppressive agents

Management of Complications of Cirrhosis and Chronic Liver Disease: Detection, Prevention, Treatment

(Note: Patients with cirrhosis are best managed in collaboration with a GI specialist, particularly those with severe or recurrent complications, based on the 2009 VA Hepatitis C Resource Center recommendations on management and treatment of cirrhosis. A summary of these recommendations can be found in Cirrhosis Quicknotes.)

Ascites

Overview:

• The most common complication of cirrhosis
• 30% of patients with compensated cirrhosis develop ascites within 5 years
• 2-year survival rate of patients with ascites is 50%

Primary prophylaxis: none recommended, other a than low-salt diet (1-2 g Na/day); may liberalize salt intake if salt restriction results in poor food intake

Treatment:

• Diuretics (eg, spironolactone alone or together with furosemide)
  • Start with spironolactone 50-100 mg daily, then add furosemide 20-40 mg daily and sequentially increase as necessary and tolerated to maximum dosage of spironolactone 400 mg daily and furosemide 160 mg daily
  • Avoid NSAIDs because of risk of hepatorenal syndrome

• Patients with massive ascites may require therapeutic large-volume paracenteses, often with albumin supplementation; should be treated in consultation with a GI/hepatology specialist
• Refractory ascites may require placement of a transjugular intrahepatic portosystemic shunt (TIPS)

Spontaneous Bacterial Peritonitis (SBP)

Overview:

• Bacterial infection of ascitic fluid that occurs in the absence of an intraabdominal source of infection
• Diagnosis: Polymorphonuclear leukocyte (PMN) count of >250 cells/µL in the ascitic fluid, obtained via paracentesis
• Patients may be asymptomatic, may have very subtle clinical findings, or may have fever, abdominal pain, and altered mental status

Primary prophylaxis: Fluoroquinolone may be initiated in the hospitalized patient with severe liver disease and renal dysfunction

Treatment: Third-generation cephalosporin, ampicillin/sulbactam, or fluoroquinolone, given IV for initial occurrence; avoid aminoglycosides

Secondary prophylaxis: Fluoroquinolone or TMP-SMX

Variceal Hemorrhage/GI Bleeding

Overview:

• ~25% of patients with cirrhosis and varices experience hemorrhage from gastroesophageal varices in the first year after diagnosis
• The bleeding-related mortality is around 30%

Screening: Upper endoscopy (EGD) is recommended for every patient with cirrhosis

Primary prophylaxis: Nonselective beta-blockers or endoscopic variceal ligation are recommended for prophylaxis in patients with medium or large varices, to prevent the first episode of variceal hemorrhage

• Recommendation: Propranolol; start 10-20 mg PO BID, increase as tolerated (goal is to titrate to a heart rate of 50-60 bpm, if tolerable)
• Starting beta-blockers is not recommended unless varices have been documented

Treatment: When a variceal bleed occurs, immediate hospitalization and GI consultation are needed for treatment

Secondary prophylaxis: After a variceal bleed, the combination of nonselective beta-blockers and endoscopic variceal ligation are recommended to decrease the risk of another bleed

Hepatic Encephalopathy

Overview:

• Variable abnormalities of neurological and psychiatric function, including insomnia, hypersomnia, irritability, confusion, disorientation, hyperactive deep tendon reflexes, and asterixis
• Diagnosis: Based on clinical picture rather than laboratory or imaging results

Primary prophylaxis: None

Treatment: Mainly consists of identification and treatment of precipitating factors

• Lactulose: start at 30 cc PO every 1-2 hours until bowel evacuation, titrate to 2-3 soft bowel movements per day, but avoid diarrhea as it will lead to volume depletion and dehydration
• Rifaximin: 400 mg PO TID is an alternative for patients who cannot tolerate lactulose

Secondary prophylaxis: None; once precipitating factors are eliminated, lactulose can be discontinued; in patients with chronic encephalopathy, chronic treatment with lactulose is warranted

• Sedatives and tranquilizers should not be used
• Constipation should be avoided

Hepatocellular Carcinoma (HCC)

Overview:

• Incidence varies widely according to geographic location, as well as among various ethnic groups within the same country
• In the United States, the incidence of HCC is rising and has almost doubled during the past 2-3 decades, chiefly among patients with cirrhosis secondary to HCV; in the VHA, the number of HCC cases nearly doubled between 2004 and 2007
• A study of 384 patients with HCV and compensated cirrhosis found that 1.4% per year developed HCC
• 20-56% of patients who develop HCC have previously undiagnosed cirrhosis
• In chronic HBV, HCC can occur before the development of cirrhosis, but in other chronic liver diseases, HCC typically does not occur until there is cirrhosis

Risk factors:

• Age
• Duration of liver disease
• Male sex
• HBV (can occur in patients with inactive, carrier HBV [HBsAg+, normal ALT, undetectable or low-level HBV DNA] and in those with chronic HBV [HBsAg+, elevated ALT, high HBV DNA])
  • Chronic HCV with cirrhosis
  • Hereditary hemochromatosis with cirrhosis, alcoholic cirrhosis
• Cirrhosis of almost any other cause

Screening: See below

Treatment: Potential indication for liver transplant; other treatment options include tumor resection, radiofrequency tumor ablation, transarterial chemoembolization, or chemotherapy; refer to Hepatology or Oncology

Screening for Hepatocellular Carcinoma

(based on American Association for the Study of Liver Diseases [AASLD] 2010 updated guidelines for management of HCC)

Patients who should be screened for HCC:

(Note that some patients with chronic HBV are at increased risk even in the absence of cirrhosis)

• HBsAg+ Asian males ≥40 years of age
• HBsAg+ Asian females ≥50 years of age
• HBsAg+ and cirrhosis
• HBsAg+ African/North American blacks
• HBsAg+ with a family history of HCC
• Cirrhosis resulting from alcohol use
• Cirrhosis resulting from HCV
• Cirrhosis resulting from hemochromatosis
• Cirrhosis resulting from primary biliary cirrhosis
• Patients on transplant waiting list
• Patients with cirrhosis resulting from alpha-1 antitrypsin deficiency
• Other cirrhosis

Recommended technique and time intervals for HCC screening

• Surveillance should be performed every 6 months using ultrasound. Because ultrasound is particularly operator dependent, some centers where ultrasound reliability is low may choose to use either CT or MRI for surveillance imaging.
• Alpha-fetoprotein (AFP) should not be used alone as a screening tool for HCC unless ultrasound is not available: it has poor sensitivity and specificity.
  • AFP measurement is recommended if a focal hepatic mass is detected with ultrasound or other abdominal imaging.
  • AFP level does not correlate well with other clinical features of HCC, such as size, stage, or prognosis.
  • Based on a systematic review, with a cutoff of 20 mcg/L, AFP has sensitivity of 41-65% and specificity of 80-94%.

How to work up a hepatic mass found on screening ultrasound

• For a mass <1 cm in diameter found on ultrasound in a cirrhotic liver: repeat ultrasound in 3 months to look for stability versus a change in size.
• For a mass ≥1 cm in diameter found on ultrasound in a cirrhotic liver: CT scan with 4-phase dynamic vascular imaging.
• For evaluation, see Figure 1 below.

Figure: Algorithm for investigation of small nodules found on screening in patients at risk of HCC (MCDT = multidetector CT scan)

(See full figure )

Liver Transplantation

Note: Current information on VA transplantation policy and procedures can be found at the website for the VA National Transplant Program. See also Liver Transplant resources for providers.

Background

• Chronic hepatitis C with progression to ESLD or HCC is the most common reason for liver transplantation, both within the VA system and in the United States general patient population.
• VA patients may be referred for liver transplantation within the VA system or at affiliated academic medical centers.
• Currently, approximately 100 liver transplants are performed annually within the VA system, with survival rates that meet or exceed UNOS averages.
• HIV-infected patients are eligible for consideration for liver transplantation at selected VA transplant centers.
• Referral for liver transplantation involves submission of a transplantation package to the VA Central Office; if approved, the package is forwarded to one of the national VA liver transplant centers for further evaluation.
• For HIV-infected transplant candidates, the application package must contain an infectious disease evaluation using a template specified by the VA National Transplant Program.
• In cases of fulminant hepatic failure or other critical situations, emergency applications may be made by contacting the VA National Transplant Program.

Transplant referral

• The local VA Medical Center Transplant Referral Coordinator should be consulted as soon as referral for liver transplantation is under consideration.
• Update Child-Turcotte-Pugh and MELD scores regularly. For purposes of ESLD follow-up, patients should be seen as follows based on MELD scores (note: other factors may indicate more frequent follow-up):
  • ≤10: at least every 6-12 months
  • 11-18: at least every 3 months
  • 19-24: at least every month
  • ≥25: at least every week
• Refer for transplant evaluation if:
  • Child-Turcotte-Pugh score is ≥7 or MELD score is ≥15
  • MELD score is 11-13 and patient has refractory ascites or hyponatremia
  • Meets HCC criteria for transplantation (≤3 masses, all ≤3 cm in diameter; WHO performance status <3; Child-Turcotte-Pugh score ≤9)
• Patients must be abstinent from all substances, including tobacco. Active substance use of any kind, or <6 months' sobriety, is the most common reason for rejection or deferral of patients for listing for transplantation; see Alcohol Misuse, Substance Use, and Smoking Cessation.
• Patients also must have documented adequate social support for care during the peritransplant and posttransplant periods.

Posttransplant care

• Patients who have received liver transplants (whether inside or outside the VA system) will return to the referring VA Medical Center for care.
• 1-year survival rates are typically >80%.
• The major clinical issues in the posttransplant period are management of and toxicities from immunosuppressive agents required to prevent transplant rejection, drug interactions, and infectious complications of immunosuppression.
• More information on posttransplant care.

References

• Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011 Mar;53(3):1020-2. doi: 10.1002/hep.24199.
• Castellares C, Barreiro P, Martín-Carbonero L, et al. Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome. J Viral Hepat. 2008 Mar;15(3):165-72.
• Galvan FH, Bing EG, Fleishman JA, et al. The prevalence of alcohol consumption and heavy drinking among people with HIV in the United States: results from the HIV Cost and Services Utilization Study. J Stud Alcohol. 2002 Mar;63(2):179-86.
• Garcia-Tsao G, Lim JK; Members of Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. Am J Gastroenterol. 2009 Jul;104(7):1802-29.
• Ghany MG, Strader DB, Thomas DL, et al; American Association for the Study of Liver Diseases. Diagnosis, management and treatment of hepatitis C: an update. Hepatology. 2009 Apr;49(4):1335-74.
• Hooshyar D, Hanson DL, Wolfe M, et al. Trends in perimortal conditions and mortality rates among HIV-infected patients. AIDS. 2007 Oct 1;21(15):2093-100.
• Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med. 2007 Apr 5;356(14):1445-54.
• Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep;50(3):661-2.
• Merriman RB. Nonalcoholic fatty liver disease and HIV infection. Curr HIV/AIDS Rep. 2006 Sep;3(3):113-7.
• Rockstroh JK. Influence of viral hepatitis on HIV infection. J Hepatol. 2006;44(1 Suppl):S25-7.
• Sterling RK, Chiu S, Snider K, et al. The prevalence and risk factors for abnormal liver enzymes in HIV-positive patients without hepatitis B or C coinfections. Dig Dis Sci. 2008 May;53(5):1375-82.