What are the potential complications of hepatitis C in a patient with a confirmed diagnosis and possible history of liver disease or other comorbidities?

Complications of Hepatitis C

Hepatic Complications

Chronic hepatitis C infection leads to progressive liver disease with a spectrum of complications ranging from fibrosis to cirrhosis, hepatocellular carcinoma, hepatic decompensation, and death. 1

Progressive Liver Disease and Cirrhosis

• Chronic HCV infection progresses to cirrhosis in 10-20% of patients over 20-30 years, with the rate of progression highly variable depending on individual factors 1, 2
• The long-term impact ranges from minimal histological changes to extensive fibrosis and cirrhosis with or without hepatocellular carcinoma 1
• Once cirrhosis is established, the annual risk of hepatocellular carcinoma development is 1-4% per year 1
• Patients with cirrhosis remain at risk for life-threatening complications including hepatic failure and portal hypertension even after viral clearance 1

Hepatocellular Carcinoma (HCC)

• HCC develops in 1-5% of chronic HCV patients, with cirrhotic patients at highest risk 2
• Even after achieving sustained virological response (SVR), cirrhotic patients have significantly reduced but not eliminated risk of HCC, requiring continued surveillance every six months 1
• The risk of HCC is increased by cirrhosis, long disease duration, and elevated bilirubin levels 3

Hepatic Decompensation

• Cirrhotic patients may experience hepatic decompensation and death when treated with alpha interferons, particularly those coinfected with HIV receiving HAART 4
• Decompensation manifests as jaundice, ascites, variceal hemorrhage, or encephalopathy 1
• In cirrhotic CHC/HIV coinfected patients on HAART, 11% developed hepatic decompensation resulting in death in clinical trials 4

Acute Hepatitis Exacerbations

• Chronic hepatitis B subjects treated with peginterferon experienced transient acute exacerbations (ALT elevation >10-fold above normal) in 12-18% during treatment and 7-12% post-treatment 4
• Marked transaminase flares may be accompanied by other liver test abnormalities and require close monitoring 4

Extrahepatic Manifestations

HCV is associated with numerous extrahepatic manifestations of immunologic origin that can affect multiple organ systems. 1

Hematologic and Immunologic Complications

• Cryoglobulinemia is a well-established extrahepatic manifestation that can lead to systemic vasculitis 1, 2
• Membranoproliferative glomerulonephritis occurs as an immune-mediated complication 1
• Thrombotic thrombocytopenic purpura and idiopathic thrombocytopenic purpura have been reported 4
• Pancytopenia with marked decreases in RBCs, neutrophils, and platelets can occur, particularly when peginterferon/ribavirin is combined with azathioprine 4

Autoimmune Disorders

• Development or exacerbation of autoimmune disorders including myositis, autoimmune hepatitis, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus have been reported during interferon therapy 4
• Seronegative arthritis, Sjögren syndrome, and lichen planus are associated conditions 1

Dermatologic Manifestations

• Porphyria cutanea tarda is a recognized extrahepatic complication of chronic HCV infection 1, 2

Cardiovascular Complications

• Chronic HCV infection is associated with increased risk of cardiovascular diseases, including carotid atherosclerosis and heart failure 5
• HCV is an independent risk factor for harmful cardiovascular manifestations and excess cardiovascular mortality 5
• HCV acts as a "metabolic virus" promoting insulin resistance and type 2 diabetes, which are pro-atherogenic conditions 5
• Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, even in those <45 years with few stroke risk factors 4

Endocrine Complications

• Peginterferon causes or aggravates hypothyroidism and hyperthyroidism 4
• Hyperglycemia, hypoglycemia, and diabetes mellitus develop in patients treated with peginterferon 4

Ophthalmologic Complications

• Decrease or loss of vision, retinopathy (including macular edema), retinal artery or vein thrombosis, retinal hemorrhages, cotton wool spots, optic neuritis, papilledema, and serous retinal detachment are induced or aggravated by interferon treatment 4
• All patients should receive baseline eye examination, with periodic exams for those with pre-existing ophthalmologic disorders 4

Pulmonary Complications

• Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis may be induced or aggravated by interferon therapy, some resulting in respiratory failure and death 4

Renal Complications

• Interstitial nephritis can develop as an autoimmune complication 4
• Membranoproliferative glomerulonephritis is an established extrahepatic manifestation 1

Factors Accelerating Disease Progression

Multiple cofactors and comorbidities profoundly influence the outcome of chronic hepatitis C and accelerate progression to cirrhosis. 6

Alcohol Consumption

• Alcohol intake ≥50 g/day increases fibrosis progression risk by 30% and accelerates disease progression 2, 6
• Even moderate alcohol intake (>10 g/day) may enhance disease progression in patients with chronic hepatitis C 1
• Among patients with alcoholic liver disease and HCV coinfection, liver disease progresses more rapidly and cirrhotic patients have higher risk of HCC 1

Age and Gender

• Being aged >40 years at infection and male sex are associated with more severe liver disease 1, 2
• Patients who acquire infection early in life have markedly increased mortality even when cirrhosis is absent at diagnosis 3

Metabolic Factors

• Metabolic syndrome and insulin resistance are the most important and frequent comorbidities influencing disease course, causing hepatic steatosis and accelerating fibrosis progression 6, 7
• Obesity combined with alcohol has an adjusted relative rate of liver-related death of 18.9 (versus 3.16 in lean individuals) with ≥15 drinks/week 2
• Diabetes and obesity independently predict more severe disease 1, 2

Coinfections

• HIV coinfection, particularly with CD4+ counts <100 cells/mm³, accelerates disease progression 4
• HBV coinfection complicates disease management and progression 1

Mortality and Long-Term Prognosis

• Chronic hepatitis C causes considerable mortality and morbidity when cirrhosis is present at diagnosis 3
• When compared with matched general population, hepatitis C increases mortality mainly when cirrhosis is present and in patients <50 years old at study entry 3
• More than 1 million patients could develop HCV-related cirrhosis, hepatic decompensation, or HCC by 2020 without effective therapies 7
• Even after achieving SVR, patients with advanced fibrosis or cirrhosis may still suffer from major risk of progressive liver damage, potentially leading to severe complications including liver decompensation, HCC, and death 8

Critical Monitoring Requirements

• Patients with advanced fibrosis (METAVIR F3) and cirrhosis require ongoing HCC surveillance every six months even after viral clearance 1
• Serial ALT measurements are more informative than single values, as patients may have fluctuating or intermittently normal ALT levels 9, 2
• Evaluation of disease severity should be performed regardless of ALT patterns, as significant fibrosis may be present with repeatedly normal ALT 1