Hepatitis C: Virology, Cryoglobulinemia & DAA Drugs

Creator: Progress Note
Published: 2026-08-27
Keywords: hepatitis C, hepatitis c usmle, hcv flavivirus, hcv antibody vs rna, mixed cryoglobulinemia hcv, mpgn hepatitis c, porphyria cutanea tarda hcv, sofosbuvir mechanism, previr asvir buvir, no hcv vaccine

bolt The 60-second version

check_circleHCV is a flavivirus: enveloped, positive-sense single-stranded RNA.
check_circleIts RNA polymerase lacks proofreading, so the envelope proteins mutate constantly (hypervariable regions). This drives chronic infection in most patients and prevents an effective vaccine.
check_circleMain transmission is injection drug use; also transfusion before 1992, needlesticks, and less often sexual or perinatal spread.
check_circleAntibody (anti-HCV) shows exposure; HCV RNA by PCR shows current infection.
check_circleExtrahepatic disease: mixed cryoglobulinemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, lichen planus, B-cell lymphoma, and insulin resistance.
check_circleDAAs cure most patients: NS5B polymerase inhibitors (sofosbuvir), NS5A inhibitors (-asvir), and NS3/4A protease inhibitors (-previr).

target What you'll be able to do · aligned to USMLE Step 1 · Gastrointestinal; Microbiology

MICROExplain how HCV structure and error-prone replication lead to chronic infection and no vaccine.
MICROInterpret anti-HCV and HCV RNA results.
PATHRecognize cryoglobulinemia, MPGN, PCT, and other extrahepatic manifestations.
PHARMMatch DAA classes to their viral targets.

How hepatitis C is tested on Step 1

Expect a person who injects drugs with mildly elevated aminotransferases, or a patient with palpable purpura and kidney disease.

Natural history. Alcohol, HIV coinfection, and obesity speed progression to cirrhosis.

HCV vs HBV. Both cause cirrhosis and hepatocellular carcinoma.

Diagnosis

Antibody first, then RNA.

Anti-HCV	HCV RNA	Interpretation
+	+	Current infection
+	−	Past infection that cleared (or was cured)
−	+	Very early acute infection or immunosuppression
−	−	No infection

Antibodies to HCV are not protective; reinfection after cure is possible.

US guidance recommends one-time HCV screening for adults and testing in each pregnancy, plus periodic testing for ongoing risk.
Liver histology in chronic HCV often shows portal lymphoid aggregates and steatosis.

Extrahepatic manifestations

HCV stimulates B cells, producing immune-complex disease.

Extrahepatic HCV. Mixed cryoglobulins are immune complexes that precipitate in the cold and deposit in small vessels and glomeruli.

Direct-acting antivirals

Drug class names follow their viral targets.

Class	Examples	Target
NS5B polymerase inhibitor	Sofosbuvir	RNA-dependent RNA polymerase (nucleotide analog chain terminator)
NS5A inhibitors	Ledipasvir, velpatasvir, pibrentasvir (-asvir)	Replication complex assembly
NS3/4A protease inhibitors	Glecaprevir, grazoprevir, voxilaprevir (-previr)	Viral polyprotein cleavage
Ribavirin (older adjunct)	Ribavirin	Guanosine analog; hemolytic anemia, teratogenic

Combination DAA regimens achieve sustained virologic response (cure) in most patients. Check for HBV coinfection first, because HBV can reactivate during treatment.

Worked example

Connect skin, kidney, and liver.

functions Worked example — purpura and hematuria

A 52-year-old who injected drugs decades ago has palpable purpura on the legs, joint pain, hematuria with proteinuria, and low C4. Aminotransferases are mildly elevated. What links these findings?

Past injection drug use suggests chronic hepatitis C.
Palpable purpura, arthralgia, and low complement suggest immune-complex vasculitis.
Mixed cryoglobulinemia is the classic HCV-associated vasculitis.
Glomerular deposits produce membranoproliferative glomerulonephritis.

Answer. Chronic hepatitis C with mixed cryoglobulinemia and membranoproliferative glomerulonephritis.

Next in the roadmap

Cirrhosis

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3 real questions on Hepatitis C

Straight from the Progress Note question bank, each with a cited explanation. No account needed.

A 52-year-old man with a 15-year history of alcohol use disorder presents with jaundice, abdominal distension, and melena. Laboratory studies reveal elevated transaminases (AST 320 U/L, ALT 180 U/L), elevated bilirubin (5.2 mg/dL), coagulopathy (INR 2.8), and evidence of portal hypertension. Liver biopsy is shown below. Which of the following best explains the pathophysiology of alcoholic hepatitis and how the progression from steatosis through steatohepatitis to cirrhosis relates to the specific histologic findings observed in this patient?

Image for question 1 — Countincr at English Wikipedia., CC BY-SA 2.5 <https://creativecommons.org/licenses/by-sa/2.5>, via Wikimedia Commons.

A liver biopsy from a patient with chronic hepatitis B infection shows ground-glass hepatocytes on histology. Which intracellular process is most directly responsible for this appearance?

Image for question 2 — Mark ong, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons

A 52-year-old woman has fatigue and pruritus. Laboratory studies show an elevated alkaline phosphatase with normal transaminases and a positive antimitochondrial antibody. Liver biopsy is shown below. Which statement about the target of the antimitochondrial antibody and its relationship to the biopsy findings is correct?

Image for question 3 — Nephron, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons

Frequently asked questions

Why is there no vaccine for hepatitis C?expand_more

Its RNA polymerase lacks proofreading, so its envelope proteins vary constantly and escape neutralizing antibodies.

Does a positive HCV antibody mean active infection?expand_more

No. Current infection is confirmed by detecting HCV RNA.

What is the most common extrahepatic manifestation tested?expand_more

Mixed cryoglobulinemia, which can cause purpura, arthralgia, neuropathy, and MPGN.

How does sofosbuvir work?expand_more

It is a nucleotide analog that inhibits the NS5B RNA-dependent RNA polymerase.

References & further reading

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