Hepatitis D
Hepatitis D is a defective RNA virus infection that requires coinfection with hepatitis B virus (HBV) to replicate, causing either coinfection or superinfection that often leads to more severe liver disease and accelerated progression to cirrhosis.
Hepatitis D
Hepatitis D (also called delta hepatitis) is a liver infection caused by the Hepatitis D virus (HDV), a unique defective (or "satellite") RNA virus that absolutely requires the presence of Hepatitis B virus (HBV) for its replication and assembly. HDV cannot infect a person on its own — it needs HBV's surface antigen (HBsAg) to form its own viral envelope. This makes it the only known human pathogen that is an obligate satellite virus.
Breaking down the name:
- Hepatitis = "hepar" (Greek, liver) + "-itis" (inflammation) → inflammation of the liver
- Delta = the fourth letter of the Greek alphabet → it was the fourth hepatitis virus discovered (after A, B, C)
The clinical significance of HDV lies in the fact that it causes the most severe form of viral hepatitis in humans. When HDV is layered on top of chronic HBV, it accelerates progression to cirrhosis, increases the risk of hepatocellular carcinoma (HCC), and raises the mortality of acute hepatitis episodes.
Key Concept — HDV is Obligately Dependent on HBV
HDV cannot replicate without HBsAg. This is because HDV uses HBsAg as its outer coat to enter hepatocytes and to assemble new virions. Therefore, preventing HBV infection (e.g., through HBV vaccination) also prevents HDV infection. Conversely, HDV can only exist in individuals who are HBsAg-positive — either as a co-infection (acquired simultaneously with HBV) or a superinfection (acquired after established chronic HBV). [1][2]
2. Epidemiology
- Estimated 12–72 million people worldwide are infected with HDV (wide range reflects limited surveillance); the most commonly cited figure is approximately 15–20 million chronic HDV carriers [3].
- HDV prevalence is expressed as a proportion of HBsAg-positive individuals who are also anti-HDV positive. Globally this ranges from ~5% to > 20% of HBV carriers depending on the region.
- High-prevalence areas: Central and West Africa, the Amazon basin (South America), Central Asia (Mongolia, Pakistan), the Middle East, Eastern Europe (Romania, Moldova), and the Pacific Islands (including parts of Oceania).
- Low-prevalence areas: East Asia (including mainland China, Hong Kong, Japan, Korea), North America, Western Europe, and Australia.
- There has been a resurgence of HDV in Western Europe associated with immigration from endemic regions and among people who inject drugs (PWID).
HDV is very rare in Chinese populations, including Hong Kong [2]. In CL Lai's teaching, it is described as "very rare in Chinese" and mostly limited to intravenous drug users (IVDU) in Hong Kong [2].
- Hong Kong is a high-prevalence area for HBV (~8% of the population are chronic HBsAg carriers, with HBV accounting for ~64–75% of cirrhosis cases) [4], yet the prevalence of HDV co-infection among these HBV carriers is very low (< 2% in most local studies).
- Cases in HK are predominantly seen in:
- Intravenous drug users (IVDU) — the most important risk group locally
- Immigrants from HDV-endemic regions (e.g., Africa, Central Asia)
- Rarely, men who have sex with men (MSM) with high-risk behaviours
- 8 genotypes (HDV-1 to HDV-8) have been identified:
- HDV-1: Most globally widespread; predominant in Europe, North America, Middle East, and East Asia. Most studied. Associated with variable clinical outcomes.
- HDV-2 (formerly IIa): Predominant in East Asia (Japan, Taiwan). Generally milder disease.
- HDV-3: Found in the Amazon basin (South America). Associated with the most severe and fulminant hepatitis.
- HDV-4 (formerly IIb): Found in Japan and Taiwan.
- HDV-5 to HDV-8: Found predominantly in Africa.
- In Hong Kong, the rare cases are typically HDV-1.
Since HDV is an obligate satellite of HBV, all risk factors revolve around being HBsAg-positive AND having exposure to HDV:
| Risk Factor | Mechanism |
|---|---|
| Chronic HBV carrier status | Absolute prerequisite — HDV cannot infect without HBsAg |
| Intravenous drug use (IVDU) | Parenteral exposure; the most important risk factor in Hong Kong [2] |
| Blood transfusion (unscreened) | Parenteral exposure; now very rare in HK due to donor screening |
| Multiple sexual partners / MSM | Mucosal exposure to blood/body fluids |
| Healthcare workers (needle-stick injury) | Parenteral exposure |
| Migration from endemic regions | Higher background HDV prevalence (Africa, Central Asia, Amazon) |
| Lack of HBV vaccination | No HBV = no HDV; vaccination against HBV prevents HDV |
Exam Pearl — HBV Vaccination Prevents HDV
HBV vaccination is the single most effective prevention strategy for HDV because without HBsAg, HDV cannot replicate. There is no specific HDV vaccine. Therefore, universal HBV vaccination programmes (like Hong Kong's neonatal HBV vaccination programme since 1988) indirectly protect against HDV [1][5].
4. Anatomy and Function (Relevant Hepatic Anatomy)
Understanding HDV pathology requires understanding basic liver architecture:
- The functional unit of the liver is the hepatic lobule, with a central vein surrounded by radiating plates of hepatocytes.
- Hepatocytes are the target cells for both HBV and HDV.
- The liver parenchyma itself has no pain fibres — pain in hepatitis arises from distension of the Glisson's capsule (the fibrous capsule surrounding the liver) when the liver swells due to inflammation [6].
- Resident macrophages in the hepatic sinusoids that participate in immune surveillance.
- HDV infection triggers immune responses involving Kupffer cells, contributing to the inflammatory damage.
- Contain the hepatic artery, portal vein, and bile duct (the "portal triad").
- In chronic HDV, portal and periportal inflammation with interface hepatitis leads to progressive fibrosis, ultimately resulting in cirrhosis if unchecked.
- Located in the space of Disse.
- Activated by chronic inflammation → differentiate into myofibroblasts → deposit collagen → fibrosis → cirrhosis.
- HDV accelerates this process compared to HBV mono-infection.
5. Virology and Structure of HDV
- HDV is classified in the genus Deltavirus, the only member of the family Kolmioviridae (recently reclassified; formerly unassigned).
- It is the smallest known human pathogen that can replicate.
| Component | Detail |
|---|---|
| Genome | Single-stranded, circular, negative-sense RNA (~1.7 kb) — the smallest genome of any animal virus |
| Outer envelope | Composed entirely of HBsAg (all three forms: S, M, L) — this is "borrowed" from HBV, which is why HDV absolutely requires HBV |
| Inner nucleoprotein | Hepatitis delta antigen (HDAg) — the only protein encoded by HDV itself |
| Ribozyme activity | HDV RNA has intrinsic ribozyme (self-cleaving RNA) activity, which is critical for its replication — this is a feature shared with plant viroids |
HDV encodes only one protein — the hepatitis delta antigen — which exists in two forms:
-
Small HDAg (S-HDAg, 24 kDa, 195 amino acids):
- Required for HDV RNA replication
- Promotes genome replication in the nucleus
-
Large HDAg (L-HDAg, 27 kDa, 214 amino acids):
- Has an additional 19 amino acids at the C-terminus due to RNA editing (adenosine deaminase acting on RNA, or ADAR1, converts a stop codon UAG → UGG, allowing read-through)
- Inhibits replication but is essential for viral particle assembly (interacts with HBsAg)
- The farnesylation of L-HDAg is critical for its interaction with HBsAg
This is elegant: the small form replicates the genome, and once enough RNA editing occurs, the large form accumulates and shifts the balance toward packaging and secretion rather than further replication.
Key points about replication:
- HDV uses the host cell's RNA polymerase II (normally used for mRNA transcription from DNA) to replicate its RNA genome — this is remarkable because RNA Pol II usually only works on DNA templates. HDV RNA mimics a DNA template.
- Rolling-circle mechanism: similar to plant viroids.
- HDV shares the same hepatocyte entry receptor as HBV — the sodium taurocholate co-transporting polypeptide (NTCP) — because its envelope is HBsAg. This is why bulevirtide (a lipopeptide that blocks NTCP) can inhibit both HBV and HDV entry.
- HDV does not integrate into the host genome (unlike HBV DNA).
Why HDV Is Called a 'Defective' or 'Satellite' Virus
HDV genome encodes only one protein (HDAg) and has no genes for its own envelope proteins or polymerase for packaging. It must "borrow" HBsAg from a co-existing HBV infection to coat itself, exit the hepatocyte, and infect new cells. Without HBV, HDV RNA can replicate inside a cell but cannot form new virions or spread. This obligate dependence is what makes it "defective."
6. Etiology and Pathophysiology
This is arguably the most important clinical concept for HDV:
| Feature | Co-infection | Superinfection |
|---|---|---|
| Definition | Simultaneous acquisition of HBV + HDV | HDV acquired by a person who already has chronic HBV |
| HBV status at time of HDV acquisition | Acute HBV | Chronic HBV carrier |
| Clinical presentation | Biphasic acute hepatitis (two ALT peaks) | Severe acute hepatitis on background of chronic liver disease |
| Risk of chronicity of HDV | < 5% (because if HBV clears, HDV must also clear) | > 80% (because HBV is already chronic → persistent HBsAg supply → HDV persists) |
| Risk of fulminant hepatitis | ~5% (higher than HBV alone, which is < 1%) | ~5-20% |
| Risk of cirrhosis | Low (most co-infections resolve) | High — 70-80% within 5-10 years |
| Anti-HBc IgM | Positive (acute HBV) | Negative (chronic HBV) |
| HBsAg | Positive (may clear) | Persistently positive |
Superinfection of HDV on chronic HBV is clinically far more dangerous than co-infection because the pre-existing chronic HBV ensures a continuous supply of HBsAg, allowing HDV to persist indefinitely. This leads to chronic HDV, which is the most aggressive form of chronic viral hepatitis, progressing to cirrhosis in 70-80% of patients within 5-10 years [2][7].
The mechanism of hepatocyte damage in HDV is primarily immune-mediated (similar to HBV), but there is also evidence for direct cytopathic effects — this distinguishes HDV from HBV, which is almost entirely immune-mediated:
-
Immune-mediated injury (predominant mechanism):
- HDV antigens (S-HDAg and L-HDAg) are presented on hepatocyte surfaces via MHC class I molecules.
- Cytotoxic CD8+ T lymphocytes recognize these antigens and kill infected hepatocytes.
- The vigorous immune response is what causes the severe clinical hepatitis.
- NK cells and innate immune pathways also contribute significantly.
-
Direct cytopathic effect:
- Unlike HBV, there is evidence that HDV replication itself can be directly toxic to hepatocytes.
- S-HDAg accumulation in the nucleus may interfere with cellular functions.
- In some HDV genotypes (especially HDV-3 in the Amazon), the direct cytotoxicity is particularly pronounced, which may explain the higher rates of fulminant hepatitis.
-
HDV-HBV interaction (viral interference):
- HDV typically suppresses HBV replication — patients with chronic HDV often have low or undetectable HBV DNA despite being HBsAg-positive.
- This occurs because HDV interferes with HBV replication at the level of HBV RNA transcription.
- Clinically, this is important: the liver damage is primarily driven by HDV, not HBV, even though HBsAg is present.
- However, HBsAg levels remain high (as they are produced from integrated HBV DNA as well).
-
Accelerated fibrogenesis:
- The intense necroinflammation activates hepatic stellate cells → myofibroblast transformation → excessive collagen deposition → rapid progression to cirrhosis.
- HDV causes cirrhosis ~2-3 times faster than HBV mono-infection.
The combination of:
- Vigorous immune response (immune-mediated injury)
- Possible direct cytopathic effects
- Persistent HBsAg supply (in superinfection)
- Rapid fibrosis progression
...makes HDV the most aggressive of all hepatitis viruses. The 5-year mortality for chronic HDV cirrhosis without treatment is significantly higher than for HBV mono-infection.
7. Classification
As discussed above:
- Co-infection: Simultaneous HBV + HDV acquisition
- Superinfection: HDV acquired in a chronic HBV carrier
| Genotype | Geographic Distribution | Clinical Severity |
|---|---|---|
| HDV-1 | Worldwide (Europe, Middle East, N. America, East Asia) | Variable; can be severe |
| HDV-2 | East Asia (Japan, Taiwan) | Generally milder |
| HDV-3 | Amazon basin, South America | Most severe; high fulminant hepatitis rates |
| HDV-4 | Japan, Taiwan | Intermediate |
| HDV-5 to HDV-8 | Africa | Variable; less studied |
| Phase | Description |
|---|---|
| Acute HDV infection | Acute hepatitis with or without jaundice, may be co-infection or superinfection |
| Chronic HDV infection | Persistent HDV RNA positivity > 6 months, typically from superinfection |
| HDV-related cirrhosis | End-stage fibrosis with architectural distortion |
| HDV-related HCC | Hepatocellular carcinoma (risk lower than HBV mono-infection per some data, but controversy exists) |
8. Clinical Features
8.1 Symptoms (with Pathophysiological Basis)
The clinical presentation of acute HDV is largely similar to other acute viral hepatitides but tends to be more severe:
| Symptom | Pathophysiological Basis |
|---|---|
| Fatigue / malaise | Systemic cytokine release (TNF-α, IL-1, IL-6) from immune activation against infected hepatocytes |
| Fever | Pyrogenic cytokines released during acute hepatic inflammation; may also reflect the prodromal viraemic phase |
| Nausea / vomiting / anorexia | Cytokine-mediated central effects (nausea centre in medulla) + hepatocyte dysfunction leading to accumulation of toxic metabolites |
| Right upper quadrant dull ache | Distension of the Glisson's capsule due to hepatic swelling from inflammation — the liver parenchyma itself has no nerve fibres [6] |
| Jaundice | Hepatocyte necrosis → impaired bilirubin conjugation and excretion → accumulation of both conjugated and unconjugated bilirubin in the blood |
| Dark urine (tea/cola-coloured) | Conjugated (direct) bilirubin is water-soluble → filtered by kidneys → excreted in urine; also increased urinary urobilinogen due to inefficient hepatic clearance of reabsorbed urobilinogen [6][8] |
| Pale stools | Intrahepatic cholestasis → decreased bilirubin reaching the gut → decreased conversion to stercobilinogen/urobilinogen by gut bacteria → pale stools [8] |
| Pruritus | Cholestasis → bile salt retention in the skin → activation of itch receptors (possibly via lysophosphatidic acid pathway) |
| Arthralgia / myalgia | Immune complex deposition + circulating cytokines during the prodromal phase |
Biphasic pattern in co-infection: Because HBV and HDV may replicate at different rates, co-infection can produce two peaks of ALT — the first peak from HBV replication, the second from HDV replication peaking later. This biphasic pattern is a classic (though not always seen) feature.
Superinfection presentation: May present as a sudden severe flare in a known chronic HBV carrier, or as acute hepatitis in someone not previously known to have HBV (who turns out to have chronic HBV with HDV superinfection).
Chronic HDV is often clinically silent for years, similar to chronic HBV, until decompensation occurs:
| Symptom | Pathophysiological Basis |
|---|---|
| Fatigue | Chronic low-grade hepatic inflammation + cytokine release |
| Abdominal distension / bloating | Ascites from portal hypertension (once cirrhosis develops) |
| Peripheral oedema | Hypoalbuminaemia (decreased synthetic function) + portal hypertension → increased hydrostatic pressure |
| Easy bruising / bleeding | Decreased hepatic synthesis of clotting factors (II, VII, IX, X) + thrombocytopenia from hypersplenism |
| Confusion / altered mental state | Hepatic encephalopathy from inability to clear ammonia and other neurotoxins |
| Haematemesis / melaena | Variceal bleeding from portal hypertension |
8.2 Signs (with Pathophysiological Basis)
| Sign | Pathophysiological Basis |
|---|---|
| Jaundice (scleral icterus) | Bilirubin > 34 µmol/L → deposited in tissues with high elastin content (sclera binds bilirubin avidly) |
| Hepatomegaly (tender) | Hepatic inflammation → swelling of liver parenchyma → capsular distension → tenderness |
| Low-grade fever | Inflammatory cytokines; important to distinguish from bacterial cholangitis (which has high spiking fever) |
| Scratch marks | From pruritus due to cholestasis |
These are essentially the signs of chronic liver disease and portal hypertension:
| Sign | Pathophysiological Basis |
|---|---|
| Spider naevi | Hyperoestrogenism due to impaired hepatic oestrogen metabolism → arteriolar dilation in SVC distribution |
| Palmar erythema | Same hyperoestrogenism mechanism → vasodilation in thenar/hypothenar eminences |
| Gynaecomastia | Hyperoestrogenism in males |
| Dupuytren's contracture | Fibroblast proliferation; more associated with alcoholic liver disease but can occur in any cirrhosis |
| Ascites | Portal hypertension → increased hydrostatic pressure in splanchnic capillaries + hypoalbuminaemia → transudative fluid in peritoneum |
| Splenomegaly | Portal hypertension → back-pressure → splenic congestion |
| Caput medusae | Portal hypertension → portosystemic shunting via paraumbilical veins → visible dilated veins radiating from umbilicus |
| Hepatic encephalopathy (flapping tremor/asterixis) | Failure to clear ammonia → astrocyte swelling in the brain (osmotic theory) |
| Leukonychia | Hypoalbuminaemia → white nails |
| Muscle wasting | Decreased hepatic protein synthesis + catabolic state of cirrhosis |
| Hepatic fetor | Accumulation of mercaptans and dimethyl sulphide (not cleared by the failing liver) |
Clinical Pearl — HDV Superinfection as a Cause of Acute Hepatitis Flare in Chronic HBV
Superinfection by hepatitis D is listed as a recognised cause of hepatitis flare-up in chronic HBV carriers [2]. In a patient with known chronic HBV who presents with a sudden, unexplained, severe hepatitis flare (disproportionately elevated ALT, worsening jaundice, coagulopathy), always consider HDV superinfection — especially if the patient has risk factors such as IVDU or is from an endemic area. Test anti-HDV IgM and HDV RNA.
HDV is associated with a higher rate of fulminant hepatic failure than any other hepatitis virus:
- Co-infection: ~5% risk of fulminant hepatitis (vs. < 1% for HBV alone)
- Superinfection: up to 5-20% risk
- Clinical features of fulminant hepatitis include:
- Rapid onset of hepatic encephalopathy (within 8 weeks of symptom onset)
- Severe coagulopathy (INR > 1.5, often much higher)
- Markedly elevated bilirubin
- Paradoxically falling ALT/AST despite clinical deterioration — because there are fewer hepatocytes left to release enzymes (this is a sinister sign) [6]
- Hypoglycaemia (loss of hepatic gluconeogenesis)
- Cerebral oedema
- Multi-organ failure
For acute liver failure: a falling AST/ALT in the context of worsening clinical status (rising INR, deepening jaundice, encephalopathy) is an ominous sign — it means hepatocytes are being destroyed faster than they can release enzymes [6].
This table integrates information from the GC lecture slides and senior notes for rapid comparison:
| Feature | HAV | HBV | HCV | HDV | HEV |
|---|---|---|---|---|---|
| Family | Picornaviridae | Hepadnaviridae | Flaviviridae | Kolmioviridae | Hepeviridae |
| Genome | ssRNA | dsDNA | ssRNA | ssRNA (circular) | ssRNA |
| Incubation (weeks) | 2–4 | 4–20 | 2–26 | 6–9 (co-infection); 3–7 (superinfection) | 3–8 |
| Transmission | Faecal-oral | Blood, sexual, vertical | Blood (IVDU), rare sexual/vertical | Blood, sexual (requires HBV) | Faecal-oral, zoonotic |
| Chronic infection | Never | Yes | Yes (70-85%) | Yes (if superinfection > 80%) | No (except immunosuppressed) |
| Fulminant risk | Rare | Rare (< 1%) | Very rare | Highest (~5-20%) | Rare (but 20-25% in pregnant women 3rd trimester) |
| Serological Dx | Anti-HAV IgM | HBsAg, Anti-HBc IgM | Anti-HCV, HCV RNA | Anti-HDV IgM/IgG, HDV RNA | Anti-HEV IgM |
| Prevention | HAV vaccine | HBV vaccine | No vaccine | HBV vaccine (no specific HDV vaccine) | No vaccine (in HK) |
| Treatment (chronic) | N/A | NUCs (e.g., entecavir, TDF) | DAAs | PEG-IFNα; bulevirtide | N/A (ribavirin in chronic) |
All viral hepatitides (A, B, C, D, E) are notifiable diseases in Hong Kong [7]. Any confirmed case of hepatitis D must be reported to the Centre for Health Protection (CHP).
High Yield Summary
- HDV is a defective satellite virus that requires HBsAg (from HBV) for its envelope — it cannot infect without HBV.
- Two patterns: Co-infection (HBV + HDV acquired together → usually self-limited, < 5% chronicity) vs. Superinfection (HDV acquired by chronic HBV carrier → > 80% chronicity, rapid cirrhosis).
- Most severe viral hepatitis — highest rate of fulminant hepatitis among hepatitis viruses.
- Very rare in Hong Kong / Chinese populations — mostly seen in IVDU [2].
- HDV typically suppresses HBV replication (low HBV DNA despite positive HBsAg).
- HBV vaccination prevents HDV — no specific HDV vaccine exists.
- Chronic HDV accelerates cirrhosis (70-80% within 5-10 years) — faster than HBV mono-infection.
- HDV genotype 3 (Amazon) is associated with the most fulminant disease.
- Clinical features of acute HDV are similar to other acute viral hepatitides but more severe; chronic HDV presents with features of chronic liver disease/cirrhosis.
- Falling ALT with rising INR in acute hepatitis = ominous sign of fulminant liver failure [6].
Active Recall - Hepatitis D (Definition, Epidemiology, Pathophysiology, Clinical Features)
[1] GC 239. Viral hepatitis HAV_HBV_HCV_HEV.pdf (viral hepatitis overview, epidemiology, prevention) [2] Block A - I am a hepatitis B carrier.pdf (HDV superinfection as cause of hepatitis flare in chronic HBV; "very rare in Chinese") [3] Maksim Medicine Notes.pdf (p. 141, viral hepatitis overview table) [4] Block A - Abdominal distension_ ascites and cirrhosis.pdf (HBV as most common cause of cirrhosis in HK, 64-75%) [5] CFB (PAE03) Immunization.pdf (HBV vaccination programme) [6] Block A - Jaundice after raw oysters_ acute hepatitis.pdf (pathophysiology of RUQ pain, LFT interpretation in acute hepatitis, falling ALT as ominous sign) [7] MBBS Final MB (Medicine) (Felix PY Lai).pdf (hepatitis overview, clinical features, extrahepatic manifestations) [8] Ryan Ho GI.pdf (hepatitis D footnote, clinical features of acute hepatitis, HEV epidemiology)
Differential Diagnosis of Hepatitis D
When a patient presents with features suggestive of hepatitis D — be it acute hepatitis in an HBsAg-positive individual, a severe flare in a known chronic HBV carrier, or chronic liver disease with features of rapidly progressive cirrhosis — you need a structured approach to the differential diagnosis. The key challenge is that HDV rarely presents with pathognomonic features; rather, it overlaps clinically with many other causes of hepatitis and liver disease. Your job is to systematically work through the differentials using clinical context, risk factors, and serological/virological markers.
The differential diagnosis of hepatitis D can be framed from two clinical perspectives:
- A patient with acute hepatitis (who happens to be HBsAg-positive) — is this HDV, or something else?
- A chronic HBV carrier with a hepatitis flare — is HDV superinfection the cause, or is it one of the many other causes of flare?
1. Framework: Acute Hepatitis in an HBsAg-Positive Patient
When you encounter a patient with acute hepatitis (elevated ALT/AST, jaundice, malaise, etc.) and positive HBsAg, your differential must include all causes of acute hepatitis, not just HDV. The presence of HBsAg doesn't automatically mean the acute hepatitis is caused by HBV or HDV — HBsAg may be an incidental finding in a chronic carrier whose acute hepatitis is from an entirely different aetiology.
| Differential | Why it mimics HDV | How to distinguish |
|---|---|---|
| Acute HBV infection | Identical prodromal and icteric symptoms; both are HBsAg-positive | Anti-HBc IgM is positive and at high titre in acute HBV; HDV co-infection additionally shows positive anti-HDV IgM and/or HDV RNA. In co-infection, biphasic ALT pattern may occur [2][6] |
| HBV reactivation ("acute flare of chronic HBV") | Presents as sudden hepatitis flare in a known/unknown chronic HBV carrier — one of the most important differentials in Hong Kong | Anti-HBc IgM may be positive but at lower titre than in true acute HBV; HBV DNA typically rises dramatically; test anti-HDV to exclude superinfection. Triggers include immunosuppressant withdrawal, chemotherapy, steroid tapering [2][9] |
| Hepatitis A (HAV) superinfection | Enteric hepatitis can superinfect a chronic HBV carrier; more common than HDV in Hong Kong [2] | Anti-HAV IgM positive. History of shellfish consumption, travel to endemic area, or MSM [6][10] |
| Hepatitis E (HEV) superinfection | Also enteric; increasingly recognised as a cause of severe hepatitis in chronic HBV carriers in HK — "more important than HDV" in this setting [2] | Anti-HEV IgM positive ± HEV RNA by PCR. History of pork liver consumption, undercooked meat [1][6] |
| Hepatitis C (HCV) | Can co-infect with HBV; IVDU is a shared risk factor | Anti-HCV (may take 12 weeks to appear) ± HCV RNA [7] |
| CMV / EBV hepatitis | Both can cause hepatitis with fever, fatigue, lymphadenopathy, and deranged LFT — important differentials in acute hepatitis [11] | CMV IgM, EBV VCA IgM/IgG, heterophile antibody (monospot); atypical lymphocytosis on blood film; lymphadenopathy and splenomegaly more prominent than in HDV |
| HSV hepatitis | Rare but can cause fulminant hepatitis, especially in immunocompromised patients [11] | Vesicular skin lesions (may be absent); HSV PCR/culture; markedly elevated AST/ALT with leucopenia; liver biopsy shows haemorrhagic necrosis with viral inclusions |
High Yield — Superinfection by HAV/HEV on Chronic HBV Is More Important Than HDV in Hong Kong
Superinfection with other viral agents, especially HAV and HEV, is "more important than HDV" as a cause of hepatitis flare in chronic HBV carriers in Hong Kong [2]. HDV is described as "very rare in Chinese" and mostly limited to IVDU. In clinical practice, when a chronic HBV carrier presents with a hepatitis flare, always check anti-HAV IgM and anti-HEV IgM before thinking about HDV.
| Differential | Why it mimics HDV | How to distinguish |
|---|---|---|
| Drug-induced liver injury (DILI) | Can present with any pattern of liver injury (hepatitic, cholestatic, mixed) [12]; temporal relationship with drug initiation is key | Detailed drug history including TCM, herbal tea, supplements, paracetamol; improvement after drug withdrawal; Roussel-Uclaf Causality Assessment Method (RUCAM) score; DILI is a diagnosis of exclusion |
| Alcoholic hepatitis | Hepatitis with jaundice, hepatomegaly, fever; can co-exist with HBV | AST:ALT ratio > 2:1 (classic), AST usually < 500 U/L [9][13]; history of heavy alcohol use; elevated GGT disproportionately; neutrophilia; liver biopsy (Mallory-Denk bodies, neutrophilic infiltrate) |
| Autoimmune hepatitis (AIH) | Acute hepatitis, jaundice, fatigue; can even present with fulminant liver failure (25%) [12] | Elevated total IgG; autoantibodies (ANA, ASMA for Type 1; anti-LKM1 for Type 2); bimodal age (young and middle-aged females); associated autoimmune diseases (Graves', UC, SLE); diagnosis by exclusion + international scoring criteria [12] |
| Wilson's disease | Can present as acute hepatitis clinically indistinguishable from acute viral hepatitis [14]; also fulminant with Coombs-negative haemolytic anaemia [15] | Young patients (5–35 years); low serum ceruloplasmin, elevated 24-hour urine copper, Kayser-Fleischer rings on slit lamp; fulminant Wilson's has characteristic Coombs-negative haemolytic anaemia + disproportionately low ALP [14][15] |
| Ischaemic hepatitis ("shock liver") | Rapid massive rise in AST/ALT (often > 1000), followed by rapid fall [9][13] | Clinical context: hypotension, cardiac failure, sepsis, post-operative; massive LDH elevation; rapid fall in ALT/AST over days once perfusion restored; normal or near-normal ALP [13] |
| Paracetamol overdose | Massive ALT/AST elevation; acute liver failure | History of ingestion; paracetamol level at 4 hours; timeline: nausea/vomiting → asymptomatic → liver failure [12] |
"Different liver diseases have different patterns of abnormalities of the liver function test... Determining the final diagnosis requires history (drug history), clinical presentation, other investigations. Liver biopsy may be required" [9]
This is the more common clinical scenario relevant to HDV. A patient already known to have chronic HBV presents with a sudden worsening — jaundice, rising ALT, malaise, possibly encephalopathy. The question is: what triggered the flare?
The causes of hepatitis flare in a chronic HBV carrier — as taught in the HBV carrier lecture — include [2]:
| Category | Cause | Distinguishing Features |
|---|---|---|
| HBV-related | "Spontaneous" reactivation | Anti-HBc IgM may rise (but not as high as acute HBV); fluctuating HBV DNA and ALT |
| Clearance of HBeAg (e-seroconversion) | Occurs during immune clearance phase; HBeAg → anti-HBe conversion | |
| e-Seroreversion | HBeAg negative/anti-HBe ± → HBeAg positive again | |
| Emergence of resistant variants / non-compliance during nucleoside analogue therapy | Rising HBV DNA despite antiviral treatment; resistance testing | |
| Immunosuppressant-related | Corticosteroid or other immunosuppressant withdrawal, especially anti-CD20 | Reactivation occurs during withdrawal, not during treatment [2]; massive immune reconstitution flare |
| Viral superinfection | Superinfection by HDV | "Very rare in Chinese" [2]; IVDU risk; anti-HDV IgM, HDV RNA |
| Superinfection with HAV or HEV | "More important than HDV" [2]; anti-HAV IgM, anti-HEV IgM | |
| Toxic/Drug | Drug-induced hepatic injury (including alcohol, TCM/herbal tea) | Drug history; temporal relationship; RUCAM score |
Exam Must-Know — Causes of Hepatitis Flare in Chronic HBV
This is a classic exam question. The list from the GC/Block A lectures includes [2]:
- Spontaneous reactivation
- HBeAg clearance (immune clearance phase)
- e-Seroreversion
- Resistant variants / non-compliance on NUCs
- Immunosuppressant (especially steroid and anti-CD20) withdrawal
- HDV superinfection (rare in HK)
- HAV / HEV superinfection (more important in HK)
- Drug-induced (alcohol, TCM, herbal tea)
If a patient with chronic HBV develops cirrhosis much faster than expected (e.g., within 5–10 years of documented HBV acquisition, particularly with low HBV DNA), consider:
| Differential | Rationale | Distinguishing Features |
|---|---|---|
| Chronic HDV infection | Most aggressive chronic viral hepatitis; 70-80% cirrhosis within 5-10 years; HDV suppresses HBV DNA so HBV DNA is paradoxically low | Anti-HDV IgG/total positive, HDV RNA positive; low/undetectable HBV DNA despite positive HBsAg |
| HBV + HCV co-infection | Dual viral infection accelerates fibrosis | Anti-HCV positive, HCV RNA positive |
| HBV + MASLD (MAFLD) overlap | "Dual liver disease — HBV cirrhosis and MAFLD — common in HK" [16] | BMI elevated; metabolic syndrome features; liver elastography showing both high stiffness (fibrosis) and high CAP score (steatosis) [16] |
| HBV + alcoholic liver disease | Alcohol synergises with HBV for accelerated fibrosis | Isolated elevated GGT (inducible enzyme); AST:ALT > 2:1; history of alcohol use; "anyone presenting with chronic liver disease and a history of alcoholism must exclude other causes" [17] |
| HBV + autoimmune hepatitis overlap | AIH can co-exist with HBV; steroid treatment risks HBV reactivation | Autoantibodies, elevated IgG; interface hepatitis on biopsy |
| HBV + haemochromatosis | Iron overload accelerates fibrosis | Elevated transferrin saturation > 45%, elevated ferritin; HFE gene testing |
The following algorithm shows how to approach the differential diagnosis when an HBsAg-positive patient presents with acute hepatitis or a hepatitis flare:
This table is particularly high-yield for exams — knowing which serological markers clinch which diagnosis:
| Diagnosis | Key Serological Marker(s) | Notes |
|---|---|---|
| Acute HBV (without HDV) | HBsAg+, anti-HBc IgM+ (high titre), anti-HDV negative | HBsAg clears within 6 months if truly acute [17] |
| HBV-HDV co-infection | HBsAg+, anti-HBc IgM+ (high titre), anti-HDV IgM+, HDV RNA+ | Biphasic ALT; < 5% chronicity of HDV |
| HDV superinfection on chronic HBV | HBsAg+, anti-HBc IgM negative or low titre, anti-HDV IgM+, HDV RNA+ | > 80% chronicity; often suppressed HBV DNA |
| HAV superinfection | Anti-HAV IgM+ | Shellfish, MSM; self-limited [6][10] |
| HEV superinfection | Anti-HEV IgM+ ± HEV RNA PCR | Pork liver, undercooked meat; dangerous in pregnancy [1][6] |
| HBV reactivation | Rising HBV DNA; anti-HBc IgM may be mildly positive | Steroid/immunosuppressant withdrawal [2] |
| Autoimmune hepatitis | ANA, ASMA, anti-LKM1; elevated total IgG | Female predominance; exclusion diagnosis [12] |
| Wilson's disease | Low ceruloplasmin; elevated 24h urine copper; KF rings | Age 5-35; Coombs-negative haemolytic anaemia in fulminant [14][15] |
In Hong Kong, HDV is extremely rare ("very rare in Chinese") and is largely confined to IVDU [2]. When approaching the differential diagnosis of a hepatitis flare in a chronic HBV carrier in HK, the following are statistically far more common causes:
- Spontaneous HBV reactivation — most common cause of flare
- HAV or HEV superinfection — "more important than HDV" [2]
- Drug-induced liver injury (TCM/herbal tea is culturally relevant in HK)
- MASLD overlap — very common, "dual liver disease" [16]
- Alcoholic liver disease overlap
- Immunosuppressant-related reactivation (steroids, anti-CD20 biologics)
HDV should be tested in the right clinical context (IVDU, immigrant from endemic region, unexplained severe hepatitis flare with low HBV DNA), but it is not the first-line diagnosis in the average Hong Kong chronic HBV carrier.
Common Exam Pitfall
Do not assume that a positive HBsAg with acute hepatitis = HBV-caused hepatitis. The acute hepatitis may be from HAV, HEV, DILI, ischaemic hepatitis, or any other cause — the HBsAg may simply reflect pre-existing chronic carriage. Always check the full viral panel (anti-HAV IgM, anti-HEV IgM, anti-HDV, anti-HCV) and take a thorough drug and alcohol history [9][17].
High Yield Summary
- HDV differential diagnosis spans two scenarios: acute hepatitis in an HBsAg+ patient, and hepatitis flare in a chronic HBV carrier.
- Co-infection (HBV + HDV simultaneously) vs. superinfection (HDV onto chronic HBV) — distinguish by anti-HBc IgM titre (high = co-infection, low/absent = superinfection).
- In Hong Kong, HAV and HEV superinfection on chronic HBV is "more important than HDV" [2].
- Always consider non-viral causes: DILI (including TCM), alcoholic hepatitis, autoimmune hepatitis, Wilson's disease, ischaemic hepatitis.
- Immunosuppressant withdrawal (especially steroids and anti-CD20) is a critical cause of HBV reactivation — the flare occurs during withdrawal, not during treatment [2].
- HDV characteristically suppresses HBV DNA — if a chronic HBV carrier has severe liver disease but paradoxically low HBV DNA, think HDV.
- Wilson's disease presenting as fulminant hepatitis has the hallmark of Coombs-negative haemolytic anaemia [14][15].
- Dual liver disease (HBV + MASLD) is common in HK [16] — always assess for metabolic factors contributing to accelerated fibrosis.
Active Recall - Hepatitis D Differential Diagnosis
References
[1] Lecture slides: GC 239. Viral hepatitis HAV_HBV_HCV_HEV.pdf (hepatitis overview, HEV clinical features) [2] Senior notes: Block A - I am a hepatitis B carrier.pdf (causes of hepatitis flare in chronic HBV, HDV superinfection "very rare in Chinese", HAV/HEV "more important than HDV") [6] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (acute hepatitis clinical features, HAV/HEV diagnosis, RUQ pain pathophysiology) [7] Senior notes: Ryan Ho GI.pdf (HCV transmission, clinical features, hepatitis D footnote) [9] Lecture slides: Gastroenterology Hepatology Introduction to GI/Hepatology investigations from the abnormal.pdf (LFT interpretation, differential diagnosis lists for acute hepatitis cases) [10] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf p.738 (HAV risk factors, differential diagnosis of hepatitis A) [11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf p.738, p.767 (CMV, EBV, HSV hepatitis as differentials) [12] Senior notes: Maksim Medicine Notes.pdf p.148-150 (AIH, DILI, paracetamol overdose) [13] Senior notes: Block A - Introduction to GI_Hepatology investigations (LFT, Endoscopy).pdf (ischaemic hepatitis, alcoholic hepatitis LFT patterns, GGT as inducible enzyme) [14] Senior notes: Adrian Lui Pediatrics Notes.pdf p.266 (Wilson's disease presentation, Coombs-negative haemolytic anaemia) [15] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (Wilson's fulminant hepatitis features, Coombs-negative haemolytic anaemia) [16] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (dual liver disease HBV + MAFLD in HK) [17] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (acute vs chronic HBV differentiation, HBsAg clearance in 6 months, alcoholic liver disease exclusion)
Diagnostic Criteria, Algorithm, and Investigations for Hepatitis D
Unlike many conditions (e.g., autoimmune hepatitis with its International Autoimmune Hepatitis Group scoring system, or rheumatic fever with the Jones criteria), there are no formal "diagnostic criteria" with a point-based scoring system for HDV. Instead, the diagnosis of hepatitis D is made by demonstrating:
- The prerequisite: Evidence of HBV infection — HBsAg must be positive (because HDV cannot exist without HBV) [3]
- Serological evidence of HDV exposure: Anti-HDV antibodies (IgM and/or IgG/total)
- Virological confirmation of active infection: HDV RNA by RT-PCR (the gold standard for confirming active, replicating HDV infection)
The diagnosis is then contextualised as either:
- Acute HDV (co-infection or superinfection) — based on clinical presentation + serology pattern
- Chronic HDV — defined as persistence of HDV RNA for ≥ 6 months (analogous to chronic HBV being defined by HBsAg positivity > 6 months [17])
Diagnostic Principle — HDV Diagnosis Requires Two Steps
Step 1: Confirm HBV infection (HBsAg positive). Step 2: Test for HDV markers (anti-HDV antibodies + HDV RNA). You cannot diagnose HDV in an HBsAg-negative patient — if HBsAg is negative, HDV is excluded by definition (rare exceptions: occult HBV with HBsAg below detection limits, but this is exceedingly unusual for clinically significant HDV).
2. HDV Serological and Virological Markers — Detailed Interpretation
Understanding each HDV marker from first principles:
- What it is: IgM antibody against hepatitis delta antigen (HDAg)
- What it means: Marker of acute or recent HDV infection
- When it appears: Typically detectable 2–8 weeks after HDV exposure; coincides with or shortly follows symptom onset
- Duration: In self-limited co-infection, anti-HDV IgM rises transiently and disappears within weeks to months. In chronic HDV (superinfection), anti-HDV IgM may persist at fluctuating levels — this is different from most other viral hepatitides where IgM is a purely acute-phase marker
- Why IgM can persist in chronic HDV: Ongoing viral replication continuously stimulates the immune system, maintaining IgM production. This is important because persistent anti-HDV IgM can be used as a surrogate marker of disease activity in chronic HDV
- What it is: IgG antibody against HDAg
- What it means: Marker of past or current HDV exposure
- When it appears: Follows IgM; rises during acute infection and persists
- Duration: In co-infection that resolves, IgG may eventually wane over years. In chronic HDV, IgG persists at high titres
- Limitation: A positive anti-HDV IgG alone does not distinguish active from resolved infection — you need HDV RNA to determine if the virus is still replicating
Most clinical laboratories report total anti-HDV (which captures both IgM and IgG combined) as the initial screening test. If total anti-HDV is positive, further characterisation with anti-HDV IgM and HDV RNA follows.
- What it is: Direct detection of the viral genome in serum by reverse-transcription polymerase chain reaction
- What it means: Gold standard for confirming active HDV replication
- Clinical significance:
- Positive HDV RNA = active infection (the virus is replicating)
- Negative HDV RNA in a patient with positive anti-HDV = either resolved infection or very low-level replication below detection limit
- Used to monitor treatment response — the goal of therapy is HDV RNA negativity (analogous to HCV RNA negativity/SVR in HCV treatment [18])
- Quantitative HDV RNA: Increasingly available; allows monitoring of viral load kinetics during treatment. However, international standardisation of HDV RNA quantification assays has historically lagged behind HBV DNA and HCV RNA assays — the WHO International Standard for HDV RNA was established in 2013 to help harmonise results across laboratories
- What it is: Direct detection of hepatitis delta antigen in serum or liver tissue
- Serum HDAg: Transiently detectable in early acute infection, before antibodies develop. Once anti-HDV antibodies appear, serum HDAg becomes undetectable (immune complex formation)
- Liver tissue HDAg: Detected by immunohistochemistry on liver biopsy — can confirm HDV infection histologically
- Practical role: Rarely used in routine clinical practice; HDV RNA by PCR has largely replaced it
This table is the key to answering exam questions about distinguishing co-infection from superinfection:
| Marker | HBV-HDV Co-infection | HDV Superinfection on Chronic HBV |
|---|---|---|
| HBsAg | Positive (may clear if HBV resolves) | Persistently positive |
| Anti-HBc IgM | Positive, high titre (acute HBV) | Negative or low titre (chronic HBV) |
| Anti-HBc IgG | Develops later | Positive (established chronic HBV) |
| HBeAg | May be positive | Variable; often negative |
| HBV DNA | Variable; may be high initially | Often low/suppressed (HDV inhibits HBV replication) |
| Anti-HDV IgM | Positive (transient) | Positive (may persist) |
| Anti-HDV IgG/total | Develops; may wane if resolves | Positive, high titre, persistent |
| HDV RNA | Positive (transient if resolves) | Positive, persistent |
| ALT pattern | Biphasic (two ALT peaks: 1st from HBV, 2nd from HDV) | Single severe peak; may be fulminant |
| Chronicity of HDV | < 5% | > 80% |
High Yield Exam Point — The Single Most Important Distinguishing Marker
Anti-HBc IgM is the single most useful marker for differentiating co-infection from superinfection. In co-infection, anti-HBc IgM is positive at high titre (because HBV is also acute). In superinfection, anti-HBc IgM is negative or low titre (because HBV is chronic, already established). This principle is the same one used to differentiate acute HBV from chronic HBV with flare [17][19].
Not every HBsAg-positive patient needs HDV testing. International guidelines (EASL 2023, AASLD 2023) recommend testing for HDV in the following situations:
| Indication for HDV Testing | Rationale |
|---|---|
| All HBsAg-positive patients (at least once) | Current guideline shift — EASL 2023 recommends universal HDV screening for all HBsAg+ individuals, as selective screening misses cases |
| IVDU (past or present) | The most important risk group in Hong Kong [2] |
| Immigrants from HDV-endemic regions | Central/West Africa, Amazon, Central Asia, Eastern Europe |
| Chronic HBV with severe/rapidly progressive liver disease | Unexpectedly severe disease for HBV mono-infection suggests HDV |
| Chronic HBV with low HBV DNA but active liver disease | HDV suppresses HBV replication; if liver disease is active despite low HBV DNA, suspect HDV |
| Chronic HBV with unexplained hepatitis flare | HDV superinfection is a recognised cause of hepatitis flare in chronic HBV [2] |
| HIV-HBV co-infected patients | Higher risk of HDV co-infection, especially among IVDU and MSM |
| HBsAg-positive patients with HCC | To identify all aetiological factors |
5. Comprehensive Investigation Approach
The investigations for hepatitis D follow the same systematic approach used for any acute or chronic hepatitis, as taught in the GC lecture on viral hepatitis [1] and GI/Hepatology data interpretation [9][19]:
| Investigation | Key Findings in HDV | Interpretation |
|---|---|---|
| CBC | WCC usually normal [3]; may see mild lymphocytosis; thrombocytopenia if cirrhosis/hypersplenism | Leucocytosis would point toward bacterial infection (e.g., cholangitis, SBP) rather than viral hepatitis |
| Liver function tests (LFT) | Markedly elevated ALT and AST (often > 1000 in acute HDV); ALT typically > AST in viral hepatitis [13][20] | LFTs assess three aspects: cellular integrity (ALT/AST), synthetic capacity (albumin, PT/INR), and excretory function (bilirubin, ALP, GGT) [20] |
| Prothrombin time / INR | Elevated in severe/fulminant hepatitis; INR is the best marker for reflecting liver function because of the short half-life of Factor VII (~6 hours) [3][6] | A falling ALT with rising INR = ominous sign (fewer hepatocytes left to release enzymes, but insufficient synthetic function) [6] |
| Albumin | Low in chronic HDV with cirrhosis; may be normal in acute HDV (half-life ~21 days, so doesn't change quickly) | Reflects chronic synthetic dysfunction, not acute changes |
| Bilirubin | Elevated (mainly conjugated/direct) in icteric phase [6] | May remain elevated for weeks after clinical recovery (cholestatic phase) [6] |
| ALP and GGT | Usually only mildly elevated in hepatitis (much less than in cholestatic/obstructive causes) | If ALP/GGT markedly elevated with only mild ALT/AST elevation → think cholestatic pattern (biliary obstruction, PBC, drug-induced cholestatic injury) rather than HDV [13] |
"Liver function tests assess three distinct aspects of hepatic function: cellular integrity through ALT and AST levels, synthetic capacity via albumin and prothrombin time, and excretory function using bilirubin, ALP and GGT" [20]
The GC lecture on viral hepatitis provides a clear algorithm for investigating acute viral hepatitis [1]. Applying this to the HDV context:
| Test | Purpose | Expected Result in HDV |
|---|---|---|
| HBsAg | Must be positive for HDV to exist | Positive |
| Anti-HBc IgM | Differentiates acute HBV (co-infection) from chronic HBV (superinfection) [17][19] | High titre = co-infection; Low/absent = superinfection |
| HBeAg / Anti-HBe | Characterises HBV replication phase; HDV often suppresses HBV, so HBeAg may be negative | Variable |
| HBV DNA | Quantifies HBV replication; characteristically low/suppressed in chronic HDV | Often low or undetectable despite positive HBsAg |
| Anti-HAV IgM | Excludes HAV superinfection ("more important than HDV" in HK [2]) | Should be negative if HDV is the cause |
| Anti-HEV IgM | Excludes HEV superinfection | Should be negative |
| Anti-HCV | Excludes HCV co-infection | Should be negative (but can co-exist, especially in IVDU) |
| Anti-HDV (total or IgG) | Screening test for HDV exposure | Positive |
| Anti-HDV IgM | Marker of acute/active HDV infection | Positive |
| HDV RNA (RT-PCR) | Gold standard — confirms active HDV replication | Positive |
| ANA, anti-smooth muscle antibody, anti-LKM1 | Excludes autoimmune hepatitis [1] | Should be negative |
GC Lecture High Yield — Investigation Algorithm for Acute Viral Hepatitis
The GC 239 lecture slide presents the investigation algorithm as: markedly elevated ALT and AST → check HBsAg, anti-HAV IgM, anti-HCV, anti-HEV IgM, ANA/anti-smooth muscle/anti-LKM1, ultrasound, and toxicology screen [1]. If HBsAg is positive, further testing includes HBeAg, anti-HBc IgM, and HBV DNA [1][19]. For HDV, add anti-HDV and HDV RNA to this panel whenever HBsAg is positive, especially in high-risk patients.
| Investigation | Purpose | Key Findings |
|---|---|---|
| AFP (alpha-fetoprotein) | HCC screening in chronic HDV with cirrhosis; AFP can also be elevated in acute hepatitis with high inflammation — doesn't always mean cancer [17] | If persistently rising after acute phase resolves → suspect HCC; 20-30% of HCC is non-secreting (AFP-negative) [17] |
| Ammonia (NH₃) | Hepatic encephalopathy assessment | Elevated in liver failure; correlates with encephalopathy severity |
| Glucose (H'stix) | Liver failure can cause hypoglycaemia [3] | Monitor BD in acute hepatitis; the liver is the major gluconeogenic organ |
| Immunoglobulins | Elevated total IgG suggests autoimmune hepatitis; IgM elevation suggests PBC | Should be normal in HDV (unless co-existing autoimmune disease) |
| Ceruloplasmin, 24h urine copper | Excludes Wilson's disease (if age < 40 and unexplained hepatitis) | Low ceruloplasmin + high urine copper = Wilson's |
| Iron studies (ferritin, transferrin saturation) | Excludes haemochromatosis | Elevated ferritin + transferrin saturation > 45% = haemochromatosis |
| HDV genotype | Determines genotype (1–8); may have prognostic significance | Genotype 3 (Amazon) = most severe; genotype 2 (East Asia) = milder |
| Modality | Purpose | Key Findings |
|---|---|---|
| Ultrasound abdomen | First-line imaging — assess liver size, echotexture, portal vein patency, splenomegaly, ascites, biliary dilatation, liver masses | Acute: hepatomegaly with normal echotexture; Chronic: coarsened liver parenchyma, irregular surface, splenomegaly (cirrhosis); no biliary obstruction (rules out post-hepatic cause) [1] |
| Liver elastography (FibroScan) | Non-invasive measurement of liver fibrosis — standard of care replacing liver biopsy for fibrosis staging [17] | > 12 kPa suggestive of cirrhosis; CAP score assesses steatosis [16]; critical for staging chronic HDV |
| CT / MRI abdomen | HCC surveillance, further characterisation of liver lesions, assessment of portal hypertension | Arterial enhancement with portal venous washout = classic HCC pattern |
| Doppler ultrasound | Assess portal vein flow, hepatic vein patency | Excludes Budd-Chiari syndrome, assesses portal hypertension |
- Liver biopsy is generally not done anymore for routine diagnosis of chronic hepatitis — replaced by non-invasive methods (FibroScan) [17]
- However, liver biopsy may still be indicated in HDV when:
- Diagnosis is uncertain despite serological workup
- Need to assess degree of necroinflammation and fibrosis when non-invasive tests are equivocal
- Suspicion of co-existing liver disease (e.g., autoimmune hepatitis overlap)
- Research settings
Histological findings in HDV:
| Finding | Significance |
|---|---|
| Interface hepatitis (piecemeal necrosis) | Lymphocytic infiltration at the portal-parenchymal interface; indicates active chronic hepatitis |
| Bridging necrosis | Necrosis connecting portal tracts to central veins; indicates severe disease |
| Eosinophilic necrosis of hepatocytes | Cytopathic effect; more prominent in HDV than in HBV mono-infection |
| Nuclear HDAg by immunohistochemistry | Direct confirmation of HDV infection in liver tissue — S-HDAg stains in the nucleus |
| Morula cells (sanded nuclei) | Hepatocytes with granular-appearing nuclei due to HDAg accumulation — relatively specific for HDV (though also described in other settings) |
| Microvesicular steatosis | Can be seen in severe HDV, especially genotype 3 (Amazon) |
| Fibrosis staging (Metavir / Ishak) | Determines degree of fibrosis (F0–F4); HDV accelerates fibrosis compared to HBV alone |
"Liver biopsy generally not done anymore, rarely performed due to invasiveness... Non-invasive measurements → FibroScan, standard of care nowadays" [17]
This section integrates the LFT interpretation framework from the GI/Hepatology data interpretation lectures [9][13][20]:
| LFT Pattern | Typical Cause | How HDV Fits |
|---|---|---|
| ALT > AST, both markedly elevated (> 1000) | Acute viral hepatitis | Acute HDV (co-infection or superinfection) fits here |
| AST > ALT, ratio > 2:1, AST < 500 | Alcoholic hepatitis [13] | Not HDV; think alcohol |
| AST > ALT with massive LDH, rapid rise and fall | Ischaemic hepatitis ("shock liver") [13] | Not HDV; check haemodynamic context |
| AST > ALT | HCC, congestive heart failure [13] | Not typical for HDV hepatitis itself, but if HDV → cirrhosis → HCC, may see this |
| ALP/GGT markedly elevated, mild ALT/AST | Cholestatic pattern (biliary obstruction, PBC, drugs) [13] | Not HDV |
| Isolated elevated GGT, normal ALP | Alcohol, drugs (phenytoin, carbamazepine), fatty liver — GGT is an inducible enzyme [13] | Not HDV |
| Falling ALT/AST with rising INR | Fulminant hepatic failure [6] | Can occur in severe acute HDV — ominous sign |
Exam Pearl — Four Causes of AST > ALT
Four liver diseases where AST rise is greater than ALT [13]:
- Alcoholic hepatitis (ratio > 2:1, AST < 500)
- Hepatocellular carcinoma
- Congestive heart failure
- Ischaemic hepatitis (with disproportionate LDH elevation)
In viral hepatitis (including HDV), ALT is typically greater than AST.
For a patient with acute HDV hepatitis, serial monitoring is essential to detect deterioration toward fulminant hepatic failure:
| Parameter | Frequency | Rationale |
|---|---|---|
| CBC, LRFT, INR | Daily [3] | Track hepatocyte damage (ALT/AST), synthetic function (INR, albumin), and excretory function (bilirubin) |
| NH₃ | Daily if encephalopathy suspected | Monitor for hepatic encephalopathy |
| H'stix (glucose monitoring) | BD (twice daily) [3] | Liver failure can cause hypoglycaemia — the liver is the major site of gluconeogenesis |
| Observations (vital signs) | Q4h [3] | Detect haemodynamic instability, sepsis |
| HDV RNA | Not needed daily; recheck to document clearance or persistence | Determines whether infection is resolving or becoming chronic |
Initial management for acute hepatitis: "DAT, Obs Q4h, H'stix BD (liver failure can cause hypoglycemia). Bloods × CBC, LRFT, INR, NH₃ daily" [3]
| Investigation | Frequency | Purpose |
|---|---|---|
| HDV RNA (quantitative) | Every 3–6 months (during treatment); every 6–12 months (off treatment) | Assess treatment response; detect relapse |
| HBV DNA, HBsAg quantitative | Every 6–12 months | Monitor HBV activity; HBsAg loss = functional cure of both HBV and HDV |
| LFT (ALT, bilirubin, albumin, INR) | Every 3–6 months | Assess ongoing liver inflammation and synthetic function |
| FibroScan | Annually | Non-invasive fibrosis assessment; track progression or regression |
| AFP + ultrasound abdomen | Every 6 months (if cirrhosis or meets HCC surveillance criteria) | HCC surveillance — same principles as for HBV [16] |
| Anti-HDV IgM | Periodically | Surrogate marker of disease activity in chronic HDV |
High Yield Summary
- Diagnosis of HDV requires: HBsAg positive + anti-HDV positive (screening) + HDV RNA positive (gold standard for active infection).
- Anti-HBc IgM distinguishes co-infection (high titre = acute HBV) from superinfection (low/absent = chronic HBV) [17][19].
- HDV characteristically suppresses HBV DNA — if a chronic HBV carrier has active liver disease but paradoxically low HBV DNA, suspect HDV and check anti-HDV/HDV RNA.
- LFT in acute HDV shows markedly elevated ALT > AST (hepatitic pattern); falling ALT with rising INR is ominous (fulminant hepatitis) [6].
- GC lecture algorithm for acute viral hepatitis: check HBsAg, anti-HAV IgM, anti-HCV, anti-HEV IgM, ANA/ASMA/anti-LKM1, ultrasound, toxicology screen [1].
- FibroScan is standard of care for fibrosis staging, replacing liver biopsy in most cases [17].
- HCC surveillance (AFP + ultrasound every 6 months) applies to all chronic HDV patients with cirrhosis or meeting HBV-specific criteria [16].
- Anti-HDV IgM can persist in chronic HDV — unlike other viral hepatitides where IgM is purely an acute marker.
- All viral hepatitides are notifiable diseases [3].
Active Recall - Hepatitis D Diagnosis and Investigations
References
[1] Lecture slides: GC 239. Viral hepatitis HAV_HBV_HCV_HEV.pdf (investigation algorithm for acute viral hepatitis, serological tests) [2] Senior notes: Block A - I am a hepatitis B carrier.pdf (HDV superinfection as cause of flare, "very rare in Chinese", "more important than HDV" for HAV/HEV) [3] Senior notes: Maksim Medicine Notes.pdf p.141 (viral hepatitis overview table, initial management including DAT/Obs/H'stix, daily bloods) [6] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (INR for monitoring, falling ALT with rising INR, bilirubin in cholestatic phase, conjugated bilirubin) [9] Lecture slides: Gastroenterology Hepatology Introduction to GI/Hepatology investigations from the abnormal.pdf (LFT patterns, conclusions for workshop cases) [13] Senior notes: Block A - Introduction to GI_Hepatology investigations (LFT, Endoscopy).pdf (AST vs ALT patterns, four causes of AST > ALT, GGT as inducible enzyme, cholestatic LFT pattern) [16] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (FibroScan, dual liver disease HBV + MAFLD, HCC surveillance criteria) [17] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (anti-HBc IgM in acute vs chronic HBV, HBsAg clearance in 6 months, FibroScan standard of care, AFP interpretation) [18] Senior notes: Maksim Medicine Notes.pdf p.146 (SVR definition in HCV, DAA treatment) [19] Lecture slides: Data Interpretation (M24 slides) LFT.pdf; 1213_DI_GI_Prof_WK_Leung.ppt.pdf (acute HBV vs chronic HBV with flare differentiation, viral hepatitis marker interpretation) [20] Senior notes: Learning_Points_All_Lectures.txt (LFT framework — three aspects of hepatic function)
Management of Hepatitis D
The management of hepatitis D follows a logical hierarchy based on the clinical scenario:
- Acute HDV (co-infection or superinfection) → predominantly supportive care (same as any acute viral hepatitis)
- Chronic HDV → antiviral therapy targeting HDV (and addressing HBV)
- HDV-related cirrhosis/decompensation → management of cirrhotic complications + consideration of liver transplantation
- Prevention → HBV vaccination prevents HDV (no specific HDV vaccine)
The overarching therapeutic challenge in chronic HDV is that HDV has no polymerase of its own — it hijacks host RNA polymerase II. This means that the nucleos(t)ide analogues (NUCs) used for HBV (e.g., entecavir, tenofovir) target HBV DNA polymerase but do not directly inhibit HDV replication. HDV requires entirely different therapeutic strategies.
3. Management of Acute HDV
The management of acute HDV hepatitis (whether co-infection or superinfection) is essentially the same as for any acute viral hepatitis — there is no specific antiviral treatment that hastens recovery from acute HDV [6][21]:
| Principle | Details | Rationale |
|---|---|---|
| No specific antiviral treatment | No drugs shorten the course of acute hepatitis [6] | Unlike chronic HBV/HCV where antivirals have clear roles, acute HDV is self-limited in co-infection and no antiviral has been proven to alter the acute course |
| Rest | Advised if symptomatic, but rest does not shorten the course of hepatitis [6] | Historical data from US soldiers in Vietnam showed no difference in duration of hepatitis between those who rested vs. those who continued active duty [6] |
| Diet | No solid diet modifications needed — eat normally [6] | "Glucose drip does not help — may actually induce fatty liver. Fatty diet is harmless" [6] |
| Alcohol abstinence | No alcohol for 6 months for acute hepatitis [3][6] | Alcohol is hepatotoxic and impairs hepatocyte regeneration |
| No drugs or herbs | "No known drugs or herbs that hasten recovery of acute hepatitis" [6] | "Definitely do not try TCM" [6] — unregulated herbal preparations can cause additional drug-induced liver injury |
| Monitoring | DAT, Obs Q4h, H'stix BD, Bloods × CBC, LRFT, INR, NH₃ daily [3] | Track for deterioration toward fulminant hepatic failure; H'stix because liver failure can cause hypoglycaemia [3] |
GC High Yield — Treatment of Acute Viral Hepatitis
The GC 239 lecture slide states: "No specific treatment. Supportive measures: maintaining hydration, electrolyte balance, nutritional balance. Long-term immunity after recovery from acute hepatitis A. Will not evolve into chronic viral hepatitis." [1] While this slide specifically addresses HAV, the principle of supportive care applies equally to acute HDV. The key difference is that acute HDV (especially superinfection) carries a much higher risk of fulminant hepatitis than HAV.
If acute HDV progresses to fulminant hepatitis (encephalopathy within 8 weeks, INR > 1.5, rising bilirubin), management follows the principles of acute liver failure [21]:
| Management Principle | Details |
|---|---|
| Supportive ICU care | Haemodynamic support, correction of metabolic abnormalities (hypoglycaemia, electrolytes, acid-base) |
| Identifying and treating the insult | In HDV context: NUCs (entecavir/tenofovir) may be given to suppress HBV (reducing HBsAg supply to HDV), though evidence for altering acute HDV course is limited. "Anti-HBV agents" listed as reversal strategy for HBV-caused liver failure [21] |
| Manage complications | Hepatic encephalopathy (lactulose; rifaximin controversial in acute liver failure [22]), raised ICP (mannitol, hyperventilation), seizures (phenytoin or short-acting benzodiazepines), AKI (CRRT), respiratory failure (mechanical ventilation) [22] |
| High-volume plasma exchange | "Wash away all the cytokines causing the liver failure — very expensive but very useful, combination treatment" [21] |
| Liver transplantation | "The final line — after exhausting all other treatments" [21]. Assessed by King's College Criteria or other prognostic scores |
"5 principles of management of acute liver failure: Supportive → standard ICU care; Identifying and removing/treating the insult; Manage complications; High volume plasma exchange; Liver transplantation" [21]
4. Management of Chronic HDV
Chronic HDV is the clinical scenario that matters most therapeutically, because it is the most aggressive form of chronic viral hepatitis with rapid progression to cirrhosis. Treatment aims to:
- Suppress or eliminate HDV replication (primary goal)
- Suppress HBV replication (secondary but important — removing HBsAg removes HDV's coat)
- Prevent progression to cirrhosis and HCC
- Achieve HBsAg loss (the ultimate "functional cure" that eliminates both HBV and HDV — occurs in < 10% [23])
| Indication | Rationale |
|---|---|
| All patients with detectable HDV RNA | Active HDV replication drives liver damage; unlike HBV where immune-tolerant patients may defer treatment, there is no "benign" phase of chronic HDV |
| Elevated ALT with positive HDV RNA | Active hepatitis confirmed biochemically and virologically |
| Evidence of fibrosis (any stage) with positive HDV RNA | Prevent progression; HDV causes rapid fibrosis |
| Cirrhosis (compensated) with positive HDV RNA | Slow or prevent decompensation |
Current guidelines (EASL 2023): Treatment should be considered for all patients with chronic HDV infection who have detectable HDV RNA and evidence of liver disease (elevated ALT, fibrosis, or cirrhosis). In practice, essentially all patients with chronic HDV and positive HDV RNA should be treated given the aggressive natural history.
4.2 Treatment Options
This has been the traditional backbone of HDV treatment for decades and remains a key treatment option:
| Feature | Detail |
|---|---|
| Drug | Pegylated interferon alpha-2a (PEG-IFNα-2a) |
| Mechanism | Immunomodulator — enhances innate and adaptive immune responses against HDV-infected hepatocytes; also has direct antiviral effects (upregulates intracellular antiviral pathways via JAK-STAT signalling). "Protein made by immune system to fight virus" [24] |
| "Pegylated" | PEG = polyethylene glycol — a polymer conjugated to IFNα to "allow interferon to stay in body much longer" [24]; PEG itself has "no activity against virus" [24] |
| Route | Subcutaneous injection [24] |
| Frequency | Once weekly (vs. 3× weekly for non-pegylated IFNα) [24] |
| Duration | 48 weeks (standard); some studies extend to 96 weeks for partial responders |
| Response rate | HDV RNA negativity at end of treatment: ~25–40%; sustained virological response (SVR) at 24 weeks post-treatment: ~25–30%; relapse is common (up to 50% relapse after stopping) |
| Treatment endpoint | Ideally: undetectable HDV RNA at 24 weeks post-treatment (SVR-24); ideal but rare: HBsAg loss |
| Why it works for HDV | Unlike NUCs that target viral polymerases (which HDV doesn't have), IFN boosts the host immune system to clear infected cells + has broad antiviral effects |
Side effects of PEG-IFNα — these are the same as for IFN use in HBV/HCV and are extensively covered in lectures [24]:
| Category | Side Effects | Mechanism |
|---|---|---|
| Flu-like symptoms | Fever, fatigue, myalgia, headache [24] | Direct interferon effect — IFN is a pyrogenic cytokine; induces prostaglandin synthesis |
| Myelosuppression | Anaemia, neutropenia, leucopenia [24] | IFN suppresses bone marrow progenitor proliferation |
| Neuropsychiatric | Depression (± suicidal), bipolar, schizophrenia [24] | IFN alters serotonin metabolism and induces tryptophan degradation via indoleamine 2,3-dioxygenase |
| Autoimmune reactivation | Autoimmune thyroiditis, autoimmune hepatitis [24] | IFN enhances immune surveillance → can unmask latent autoimmune tendencies |
| Hepatic decompensation | Decompensation of cirrhosis [24] | IFN-mediated immune enhancement → further killing of infected hepatocytes → can overwhelm a cirrhotic liver |
| Alopecia | Hair loss [24] | Antiproliferative effects on hair follicle cells |
| GI | Diarrhoea [24] | Direct mucosal effects |
| Tachyphylaxis | Rapid tolerance [24] | Downregulation of IFN receptors with prolonged exposure |
Contraindications to PEG-IFNα [24]:
| Contraindication | Rationale |
|---|---|
| Decompensated cirrhosis (Child-Pugh B or C) | Risk of fatal hepatic decompensation — IFN enhances immune-mediated hepatocyte killing in an already failing liver [24] |
| Pregnancy [24] | Teratogenic potential; antiproliferative effects |
| Severe psychiatric illness | Risk of worsening depression/suicidality |
| Severe cytopenias | IFN causes further myelosuppression |
| Autoimmune diseases (uncontrolled) | Risk of autoimmune flare |
| Epilepsy (uncontrolled) | IFN may lower seizure threshold |
Why NUCs Don't Work Directly Against HDV
Nucleos(t)ide analogues (entecavir, tenofovir) target HBV DNA polymerase (reverse transcriptase). HDV does not encode any polymerase — it uses host RNA polymerase II. Therefore, NUCs have no direct antiviral effect on HDV replication. However, NUCs suppress HBV replication and may gradually reduce HBsAg levels over very long periods, theoretically reducing the supply of envelope protein for HDV. In practice, NUCs alone do not clear HDV or significantly impact HDV RNA levels [23][25].
Bulevirtide ("bule-" from its target, "-virtide" from its antiviral peptide nature) is a first-in-class entry inhibitor that was conditionally approved by the EMA in 2020 and is now the most important new drug for chronic HDV:
| Feature | Detail |
|---|---|
| Drug | Bulevirtide (formerly known as Myrcludex B) |
| Mechanism | Lipopeptide that blocks the sodium taurocholate co-transporting polypeptide (NTCP) receptor on hepatocytes — NTCP is the shared entry receptor for both HBV and HDV. By blocking NTCP, bulevirtide prevents HDV (and HBV) virions from entering hepatocytes |
| Why it works | HDV and HBV both use HBsAg to bind NTCP. Bulevirtide is a synthetic lipopeptide derived from the pre-S1 domain of HBsAg — it acts as a competitive antagonist at NTCP, occupying the binding site so that real virions cannot attach |
| Route | Subcutaneous injection, once daily |
| Dose | 2 mg SC daily (EMA-approved dose) |
| Duration | Long-term / indefinite — relapse is common upon discontinuation; optimal duration still being defined |
| Efficacy | Studies show HDV RNA decline > 2 log₁₀ in most patients; HDV RNA undetectable in 40–50% at 48 weeks; combination with PEG-IFNα may enhance responses |
| Key advantage | Can be used in decompensated cirrhosis (unlike PEG-IFNα, which is contraindicated) |
Side effects of bulevirtide:
| Side Effect | Mechanism |
|---|---|
| Elevated bile salts (dose-dependent) | NTCP normally mediates bile salt uptake into hepatocytes; blocking NTCP → bile salts accumulate in blood. Usually asymptomatic; mild pruritus in some patients |
| Injection site reactions | Local irritation from SC injection |
| Asymptomatic lipase elevation | Mechanism not fully understood; generally clinically insignificant |
Contraindications:
- Few absolute contraindications
- Use with caution with drugs that are NTCP substrates (e.g., certain statins)
- Not yet approved in all jurisdictions (available in EU; compassionate use programmes elsewhere)
| Drug | Dose | Role in HDV |
|---|---|---|
| Entecavir (ETV) | 0.5 mg daily PO (1 mg if lamivudine-refractory or decompensated) [25] | Suppress HBV replication; indicated if HBV DNA is detectable alongside HDV |
| Tenofovir disoproxil fumarate (TDF) | 300 mg daily PO [25] | Same; preferred in women of child-bearing age, pregnancy, and if resistance to prior NUCs [25] |
| Tenofovir alafenamide (TAF) | 25 mg daily PO [25] | Same; preferred if at risk of renal impairment or bone disease [25]; not recommended in decompensated (Child-Pugh B/C) hepatic impairment [25] |
Key point: NUCs do not directly treat HDV, but they are indicated whenever HBV DNA is detectable to prevent HBV-related disease progression. In many chronic HDV patients, HBV DNA is suppressed by HDV, so NUCs may not always be needed — but if HBV DNA is detectable, NUC therapy should be started [23][25].
| Feature | Detail |
|---|---|
| Mechanism | Farnesyltransferase inhibitor — blocks farnesylation of L-HDAg, which is essential for HDV virion assembly. Without farnesylation, L-HDAg cannot interact with HBsAg, so new HDV virions cannot be packaged |
| Route | Oral |
| Status | Phase 3 trials (DELTA trials); not yet approved |
| Efficacy | Shows HDV RNA decline; typically used with ritonavir boosting (ritonavir inhibits CYP3A4, increasing lonafarnib levels) |
| Side effects | GI side effects (nausea, vomiting, diarrhoea, weight loss) — dose-limiting; related to farnesyltransferase inhibition affecting GI epithelial cell signalling |
| Regimen | Indication | Duration | Notes |
|---|---|---|---|
| PEG-IFNα-2a monotherapy | Compensated chronic HDV (traditional first-line) | 48 weeks (up to 96 weeks) | ~25-30% SVR; high relapse rate |
| Bulevirtide monotherapy | Chronic HDV, especially if IFN-contraindicated or decompensated cirrhosis | Long-term / indefinite | Well-tolerated; relapse on stopping |
| Bulevirtide + PEG-IFNα-2a | Compensated chronic HDV (emerging preferred combination) | PEG-IFNα × 48w; bulevirtide possibly longer | Higher response rates than either alone |
| NUC (ETV or TDF/TAF) + PEG-IFNα and/or bulevirtide | Chronic HDV with detectable HBV DNA | NUC long-term; HDV-directed therapy as per above | NUC suppresses HBV; HDV therapy addresses HDV |
| NUC alone | HBV with resolved HDV (anti-HDV+, HDV RNA-) and detectable HBV DNA | Long-term (as per HBV indications) [25] | Only addresses HBV; no role in active HDV |
| Endpoint | Definition | Clinical Significance |
|---|---|---|
| HDV RNA undetectable at end of treatment | Negative HDV RNA by RT-PCR at treatment completion | Necessary but not sufficient — relapse is common |
| Sustained virological response (SVR) | Undetectable HDV RNA at 24 weeks post-treatment cessation | Analogous to SVR in HCV [18]; associated with improved long-term outcomes |
| ALT normalisation | ALT returns to normal range | Indicates resolution of hepatic necroinflammation |
| HBsAg loss | Loss of HBsAg (± anti-HBs seroconversion) | "Functional cure" of both HBV and HDV — occurs in < 10%, especially difficult for carriers acquiring disease early [23]; this is the ideal endpoint |
Once chronic HDV has led to cirrhosis, management follows the same principles as cirrhosis from any cause:
| Complication | Management |
|---|---|
| Ascites | Salt restriction, diuretics (spironolactone ± furosemide), therapeutic paracentesis + albumin replacement |
| SBP | High index of suspicion; diagnostic paracentesis — defined by checking neutrophils (PMN > 250/mm³) [17]; empiric antibiotics (IV cefotaxime or ceftriaxone) |
| Variceal bleeding | Endoscopic variceal ligation (EVL); vasoactive agents (octreotide/terlipressin); prophylaxis with non-selective beta-blockers (propranolol/carvedilol) |
| Hepatic encephalopathy | Lactulose (target 2-3 soft stools/day); rifaximin (add-on); identify and treat precipitants (infection, GI bleed, constipation, drugs) |
| Hepatorenal syndrome | Terlipressin + albumin [25]; renal replacement therapy is only a bridge to transplant [25]; liver transplantation |
| HCC surveillance | AFP + ultrasound every 6 months [16] |
| Staging cirrhosis severity | Child-Pugh score (5 parameters: albumin, bilirubin, INR, ascites, encephalopathy) and MELD score (3 parameters: creatinine, bilirubin, INR ± Na) — MELD used for transplantation prioritisation ("not first come first served") [17] |
5.1 Liver Transplantation
| Feature | Detail |
|---|---|
| Indication | Decompensated cirrhosis (Child-Pugh C), unresectable HCC meeting transplant criteria, acute liver failure not responding to medical management [21][27] |
| Age limit | ≤ 65 years [27] |
| Contraindications | Active uncontrolled infection, active alcohol/substance abuse [27] |
| HDV-specific consideration | Post-transplant HDV recurrence is lower than HBV mono-infection recurrence, because HDV suppresses HBV replication. With NUCs + HBIG post-transplant, recurrence of both HBV and HDV is rare |
| Post-transplant HBV prophylaxis | Antivirals × 2 months before transplant + long-term HBIG after transplant [27] |
| Scoring for prioritisation | MELD score — "the higher the score, the worse your short-term survival" and higher priority for transplant [17] |
Since there is no HDV-specific vaccine, prevention is entirely through preventing HBV:
| Strategy | Details |
|---|---|
| HBV vaccination | Prevents both HBV and HDV. Universal neonatal vaccination (HK programme since 1988): 3-dose schedule. Post-vaccination serologic testing recommended for babies born to HBV-infected mothers [1] |
| HBIG (hepatitis B immunoglobulin) | Passive immunisation for neonates born to HBsAg-positive mothers (given within 12 hours of birth alongside HBV vaccine) |
| Behavioural measures | Safe injection practices, harm reduction for IVDU, condom use, screening of blood products |
| HBV treatment of chronic carriers | Reducing HBsAg levels theoretically reduces HDV replication capacity; universal HBV treatment may indirectly reduce HDV burden |
The Hong Kong Viral Hepatitis Action Plan 2020-2024 includes: expanding access to treatment for hepatitis B, enhancement in laboratory/equipment/drug/model of care; providing antivirals for pregnant women with high viral load in the 3rd trimester; post-vaccination serologic testing for babies born to HBV-infected mothers [1]
Prevention Pearl — There Is No HDV Vaccine
No specific vaccine against HDV exists or is in advanced development. HBV vaccination is the only vaccine-based strategy to prevent HDV — by preventing HBV, you eliminate the reservoir of HBsAg that HDV needs. This makes universal HBV vaccination one of the most cost-effective interventions against HDV globally.
7. Special Situations
If an HDV-HBV co-infected patient requires immunosuppression (e.g., chemotherapy, anti-CD20, steroids):
- Start prophylactic antiviral therapy (entecavir or TDF/TAF) irrespective of baseline HBV DNA [23]
- "Superior and safer than monitoring for reactivation and treating when it occurs" [23]
- Duration: continue for 6-12 months after completion of immunosuppressive therapy (12 months if anti-CD20); lifelong if baseline HBV DNA > 2000 IU/mL [23]
- Monitor for both HBV reactivation AND potential HDV flare
- Common in IVDU
- Use TDF/TAF-based antiretroviral regimens (TDF/TAF treats both HIV and HBV)
- Add bulevirtide and/or PEG-IFNα for HDV as appropriate
- Complex drug-drug interaction considerations — use www.hep-druginteractions.org [1]
High Yield Summary
- Acute HDV: supportive care only — no specific antiviral hastens recovery; no alcohol for 6 months; no drugs or herbs [6]. Monitor for fulminant hepatitis with daily LFT/INR.
- Fulminant HDV: 5 principles — supportive ICU care, treat the cause, manage complications, high-volume plasma exchange, liver transplantation (final line) [21].
- Chronic HDV treatment options: PEG-IFNα-2a (48 weeks, ~25-30% SVR, many side effects, contraindicated in decompensated cirrhosis), bulevirtide (NTCP entry inhibitor, well-tolerated, long-term, usable in decompensation), NUCs (adjunctive for HBV suppression only).
- NUCs do not directly treat HDV — they target HBV DNA polymerase, which HDV does not have. NUCs are only adjunctive for co-existing HBV replication.
- Bulevirtide blocks NTCP — the shared entry receptor for HBV and HDV — preventing new hepatocyte infection. Key side effect: elevated bile salts (because NTCP normally imports bile salts).
- PEG-IFNα side effects: flu-like symptoms, myelosuppression, neuropsychiatric (depression), autoimmune reactivation, hepatic decompensation, alopecia, tachyphylaxis [24].
- HBV vaccination prevents HDV — no specific HDV vaccine exists.
- For immunosuppression in HBV-HDV patients: start prophylactic NUC irrespective of HBV DNA [23].
- Liver transplantation is the final line for decompensated cirrhosis/fulminant failure; HDV recurrence post-transplant is lower than HBV mono-infection.
- Treatment endpoints: HDV RNA undetectable (SVR-24); ALT normalisation; HBsAg loss (functional cure, < 10%) [23].
Active Recall - Hepatitis D Management
References
[1] Lecture slides: GC 239. Viral hepatitis HAV_HBV_HCV_HEV.pdf (supportive treatment for acute viral hepatitis, HK viral hepatitis action plan, DAA contraindications, prevention strategies) [3] Senior notes: Maksim Medicine Notes.pdf p.141 (initial management of acute hepatitis: DAT/Obs/H'stix/daily bloods, alcohol abstinence, viral hepatitis overview) [6] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (supportive management principles, "rest does not shorten course", "no drugs or herbs", alcohol abstinence × 6 months, "definitely do not try TCM") [16] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (HCC surveillance criteria, FibroScan) [17] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (Child-Pugh, MELD, SBP diagnosis, FibroScan standard of care, compensated vs decompensated cirrhosis) [18] Senior notes: Maksim Medicine Notes.pdf p.146 (SVR definition in HCV treatment) [21] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf (5 principles of ALF management, high-volume plasma exchange, liver transplantation as final line, anti-HBV agents for HBV-related ALF) [22] Senior notes: Ryan Ho GI.pdf p.207 (ALF management: NAC, complications management, King's College Criteria, dexamethasone NOT useful) [23] Senior notes: Block A - I am a hepatitis B carrier.pdf (aims of HBV treatment, HBsAg loss < 10%, prophylactic antivirals for immunosuppression, duration of prophylaxis) [24] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf p.751–753, 762–764 (PEG-IFNα mechanism, side effects, contraindications; ribavirin side effects and contraindications) [25] Lecture slides: Handbook of Internal Medicine 2024.pdf p.123 (NUC options: ETV, TDF, TAF indications and preferences; hepatorenal syndrome management) [26] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf p.769 (chronic HEV treatment: ribavirin, reduction of immunosuppression) [27] Senior notes: Maksim Surgery Notes.pdf p.125-127 (liver transplantation criteria: UCSF, Milan, MELD; contraindications; HBV carriers pre-transplant antivirals + HBIG)
Complications of Hepatitis D
Hepatitis D causes the most severe complications of any hepatitis virus. Every complication stems from the same fundamental cascade: HDV-driven hepatocyte destruction → inflammation → fibrosis → cirrhosis → portal hypertension and hepatic insufficiency. Understanding this cascade from first principles allows you to predict and explain every complication.
The complications of HDV can be organised into three temporal categories:
| Timing | Complication | Mechanism |
|---|---|---|
| Acute | Fulminant hepatic failure | Massive immune-mediated + direct cytopathic hepatocyte necrosis |
| Chronic → Cirrhosis | Liver cirrhosis, portal hypertension, hepatic insufficiency | Accelerated fibrogenesis from persistent necroinflammation |
| Chronic → End-stage | HCC, hepatorenal syndrome, death | End-stage liver disease + oncogenic milieu |
"6 associated complications of liver failure: Infections, Variceal bleeding, Ascites / Spontaneous bacterial peritonitis, Hepatorenal syndrome, Hepatic encephalopathy, (Coagulopathy), (Hepatocellular carcinoma)" [21]
2. Acute Complications
HDV is associated with the highest rate of fulminant hepatitis among all hepatitis viruses:
- Co-infection: ~5% risk (vs. < 1% for HBV alone)
- Superinfection: up to 5–20% risk
Why does HDV cause more fulminant hepatitis than HBV alone?
The answer lies in the "double hit" mechanism:
- Vigorous immune response: Cytotoxic CD8+ T cells recognise both HBV antigens (HBsAg, HBcAg) and HDV antigens (HDAg) on infected hepatocytes → more targets = more immune-mediated killing
- Possible direct cytopathic effect: Unlike HBV (which is almost entirely immune-mediated), HDV may directly damage hepatocytes through nuclear accumulation of S-HDAg and interference with cellular processes
- In co-infection: The two viruses replicate at different rates, potentially causing two waves of hepatocyte destruction
- In superinfection: The pre-existing chronic HBV liver disease means the liver already has reduced functional reserve before the HDV onslaught
Clinical features of fulminant HDV hepatitis [6][21]:
| Feature | Pathophysiological Basis |
|---|---|
| Rapidly deepening jaundice | Massive hepatocyte necrosis → inability to conjugate and excrete bilirubin |
| Hepatic encephalopathy (within 8 weeks of symptom onset) | Loss of hepatic clearance of ammonia and other neurotoxins → astrocyte swelling (osmotic theory) → cerebral oedema |
| Severe coagulopathy (INR > 1.5, often much higher) | Loss of hepatic synthesis of clotting factors (especially Factor VII, half-life ~6 hours — hence INR/PT is the best marker for monitoring acute liver function) [6] |
| Paradoxically falling AST/ALT | "Reductions in AST/ALT as disease progresses" [6] — fewer hepatocytes remaining to release enzymes. "If AST/ALT is falling for a patient, along with worsening and prolongation of PT, have to keep fulminant hepatitis in mind" [6] |
| Hypoglycaemia | Loss of hepatic gluconeogenesis; the liver is the body's main glucose factory; hence H'stix monitoring BD is essential [3] |
| Cerebral oedema | Cytotoxic oedema from ammonia-induced astrocyte swelling; can lead to brainstem herniation |
| Multi-organ failure | Systemic inflammatory response → circulatory failure, renal failure (hepatorenal physiology), respiratory failure (ARDS) |
| Metabolic acidosis | Loss of hepatic lactate clearance + tissue hypoperfusion |
Ominous Sign — Falling ALT with Rising INR
A falling AST/ALT in the context of worsening clinical status (rising INR, deepening jaundice, encephalopathy) is an ominous sign — it means hepatocytes are being destroyed faster than they can release enzymes [6]. This paradox catches out many students who assume improving ALT = improving patient. Always interpret ALT trends in conjunction with synthetic markers (INR, albumin) and clinical state.
When HDV superinfection occurs in a patient with pre-existing chronic HBV (who may already have underlying cirrhosis), the result may be acute-on-chronic liver failure rather than pure acute liver failure:
- Definition: "Acute liver insult manifesting jaundice and INR > 1.5, complicating within 4 weeks by ascites and/or encephalopathy in patients with underlying chronic liver disease" [21][28]
- ACLF has much greater mortality than pure acute liver failure — 28-day mortality > 20% [21]
- Why? Because "now you have 2 insults instead of just 1" [21] — the acute HDV superinfection on top of the already-damaged chronic HBV liver
Prognostic factors for ACLF depend on 6 organ-specific factors [21]:
- Cerebral: hepatic encephalopathy grade
- Respiration: SaO₂/FiO₂
- Circulation: need for vasopressors
- Liver: bilirubin level
- Coagulation: INR level
- Kidney: creatinine level
"All 3 of the components of the MELD score are present here — SO MELD score still useful in prognosticating ACLF as well, not just for acute liver failure and transplant prioritisation" [21]
3. Chronic Complications
This is the most important chronic complication of HDV. Chronic HDV causes cirrhosis faster and more frequently than any other chronic viral hepatitis:
| Comparison | Chronic HBV mono-infection | Chronic HDV (superinfection) |
|---|---|---|
| Annual cirrhosis incidence | ~1.3–2.4% [2] | ~5–10% |
| Cirrhosis within 5-10 years | ~15-20% | 70-80% |
| Time to decompensation | Decades (often) | Years |
Why does HDV accelerate cirrhosis?
The pathophysiology follows a clear chain:
- Persistent necroinflammation: HDV drives continuous hepatocyte injury (immune-mediated + direct cytopathic)
- Stellate cell activation: Necroinflammation releases cytokines (TGF-β, PDGF) → hepatic stellate cells (in the space of Disse) activate → transform into myofibroblasts
- Collagen deposition: Myofibroblasts deposit excessive extracellular matrix (collagen types I and III) → progressive fibrosis
- Architectural distortion: Fibrous septa bridge portal tracts to central veins → regenerative nodules form → cirrhosis (F4)
- Portal hypertension: Fibrosis increases intrahepatic resistance to portal blood flow → portal pressure rises → complications ensue
Compensated vs. decompensated cirrhosis — this distinction is critical [17]:
| Compensated (Child A) | Decompensated (Child B/C) | |
|---|---|---|
| Symptoms | Often asymptomatic | Symptomatic (ascites, jaundice, encephalopathy, variceal bleeding) |
| Prognosis | Relatively preserved | "Poor survival once becomes decompensated" [17] |
| Management | Monitor + treat underlying cause | Manage complications + consider transplantation |
3.2 Portal Hypertension and Its Consequences
Once cirrhosis develops, portal hypertension (portal pressure gradient > 5 mmHg; clinically significant if > 10 mmHg) drives three major complications:
| Aspect | Detail |
|---|---|
| Mechanism | Portal hypertension → ↑hydrostatic pressure in splanchnic capillaries + ↓oncotic pressure (hypoalbuminaemia from impaired hepatic synthesis) + splanchnic vasodilation → activation of RAAS → Na and water retention → transudative fluid accumulates in the peritoneal cavity |
| Clinical features | Abdominal distension, shifting dullness, fluid thrill, weight gain, ankle oedema |
| Classification | SAAG (serum-ascites albumin gradient) ≥ 11 g/L → portal hypertension-related (transudative) |
| Management | Salt restriction (< 2g Na/day), diuretics (spironolactone ± furosemide), therapeutic paracentesis + albumin, TIPS (refractory cases) |
| Aspect | Detail |
|---|---|
| Mechanism | Bacterial translocation from the gut lumen across the intestinal wall (impaired mucosal barrier in cirrhosis + gut bacterial overgrowth) into the ascitic fluid, which has low opsonic activity (low complement, low protein) |
| Diagnosis | Requires high index of suspicion — "may actually not have a lot of abdominal signs, since no perforation" [17]. Defined by ascitic fluid PMN > 250/mm³, not by culture ("culture not useful, usually negative — defined by checking the neutrophils") [17] |
| Clinical features | Fever, abdominal pain/tenderness, worsening ascites, encephalopathy, or may be asymptomatic |
| Organisms | Usually Gram-negative (E. coli, Klebsiella); increasingly Gram-positive (Enterococcus, Streptococcus) |
| Treatment | Empiric IV cefotaxime/ceftriaxone; IV albumin (day 1 and day 3 — reduces hepatorenal syndrome risk) |
| Aspect | Detail |
|---|---|
| Mechanism | Portal hypertension → portosystemic collateral formation → oesophageal/gastric varices dilate → wall tension increases (La Place's law: tension = pressure × radius / wall thickness) → eventual rupture → massive upper GI haemorrhage |
| Clinical features | Haematemesis (fresh blood), melaena, haemodynamic instability, hypovolaemic shock |
| Prophylaxis | Primary: non-selective beta-blockers (propranolol/carvedilol) or endoscopic variceal ligation (EVL). Secondary: EVL + beta-blockers; TIPS if refractory |
| Acute management | Resuscitation, vasoactive agents (octreotide/terlipressin), urgent endoscopy with EVL, antibiotics (ceftriaxone — reduces infection and mortality) |
| Aspect | Detail |
|---|---|
| Mechanism | Hepatic failure → inability to clear ammonia (NH₃) and other gut-derived neurotoxins → ammonia crosses BBB → astrocytes convert NH₃ to glutamine (via glutamine synthetase) → glutamine is osmotically active → astrocyte swelling (osmotic/cytotoxic oedema) → cerebral dysfunction |
| Clinical grading | West Haven criteria: Grade 1 (mild confusion, disordered sleep) → Grade 2 (drowsiness, asterixis) → Grade 3 (somnolent but rousable, marked confusion) → Grade 4 (coma) |
| Signs | Asterixis (flapping tremor) — best elicited by asking the patient to extend the wrists with arms outstretched; represents a negative myoclonus (transient loss of muscle tone) due to impaired motor control from ammonia toxicity; hepatic fetor (musty, sweet breath — accumulation of mercaptans and dimethyl sulphide) |
| Precipitants | Infection (including SBP), GI bleeding (protein load → ↑ammonia), constipation, medications (sedatives, opioids), electrolyte imbalance (hypokalaemia, hyponatraemia), dehydration, excessive dietary protein |
| Treatment | Lactulose (target 2-3 soft stools/day — acidifies colonic lumen → converts NH₃ to NH₄⁺ which cannot be absorbed → promotes faecal excretion of nitrogen); rifaximin (poorly absorbed antibiotic → reduces ammonia-producing gut bacteria); identify and treat precipitants |
| Aspect | Detail |
|---|---|
| Definition | "Renal failure in a patient with acute liver failure or end-stage liver disease in the absence of an identifiable cause of renal failure" [25] — a diagnosis of exclusion |
| Mechanism | Cirrhosis → splanchnic vasodilation (due to excess NO, prostaglandins) → ↓effective arterial blood volume → compensatory renal vasoconstriction (via RAAS, sympathetic activation, ADH) → progressive renal hypoperfusion → functional renal failure (kidneys are structurally normal) |
| Precipitants | Sepsis (especially SBP), severe alcoholic hepatitis, upper GI bleeding [25] |
| Exclusion criteria | Must exclude: volume depletion (test with albumin challenge — 1 g/kg × 2 days + diuretic withdrawal), haemodynamic shock, nephrotoxic drugs (NSAIDs, aminoglycosides), structural kidney disease (proteinuria > 500 mg/day, haematuria, abnormal renal US) [25] |
| Management | Albumin (1 g/kg/day × 2 days, then 20-40 g/day) + terlipressin (vasopressin analogue → splanchnic vasoconstriction → ↑effective arterial blood volume → ↑renal perfusion) [25]; renal replacement therapy is only a bridge to liver transplant [25]; liver transplantation is definitive |
| Aspect | Detail |
|---|---|
| Mechanism | The liver synthesises most clotting factors (I, II, V, VII, IX, X, XI, XII, XIII) and anticoagulant proteins (protein C, S, antithrombin). In cirrhosis: ↓synthesis of both procoagulant and anticoagulant factors → a "rebalanced" but fragile haemostatic state. Additionally: thrombocytopenia from hypersplenism (portal hypertension → splenic sequestration of platelets) + impaired thrombopoietin production (liver makes thrombopoietin) |
| Clinical features | Easy bruising, prolonged bleeding from minor cuts, epistaxis, gingival bleeding, petechiae; risk of catastrophic bleeding with trauma or procedures |
| Monitoring | INR, platelet count, fibrinogen; note that standard coagulation tests may not fully reflect the "rebalanced" state |
| Aspect | Detail |
|---|---|
| Why are cirrhotic patients infection-prone? | "Reticuloendothelial dysfunction and reduced opsonization" [21] — the liver is the body's largest reticuloendothelial organ; Kupffer cells in the sinusoids normally clear bacteria and endotoxins from portal blood. In cirrhosis: ↓Kupffer cell function, ↓complement production, ↓opsonin production, portosystemic shunting bypasses the hepatic filter |
| Common infections | "Bacteria — especially from the respiratory and urinary tract. Staph, strep, gram-negative rods. Bacteraemia in up to 25% of fulminant hepatic failure patients. Fungal infection — especially Candida" [21] |
| SBP | As above — the most characteristic infection of cirrhosis |
| Clinical importance | Infection is a major precipitant of hepatic encephalopathy, variceal bleeding, hepatorenal syndrome, and ACLF; must have a low threshold for investigation and empiric treatment |
4. Hepatocellular Carcinoma (HCC)
The relationship between HDV and HCC is complex and somewhat controversial:
| Evidence for ↑ risk | Evidence for uncertain/↓ risk |
|---|---|
| Chronic HDV causes faster cirrhosis → cirrhosis is the strongest risk factor for HCC | HDV suppresses HBV DNA → less HBV-mediated direct oncogenesis (HBV DNA integration, transactivation by HBx protein) |
| Some epidemiological studies show ↑ HCC incidence in HDV vs. HBV mono-infection | Other studies show similar or even lower HCC rates when controlling for cirrhosis stage |
| HDV accelerates necroinflammation → regenerative nodule turnover → ↑ risk of dysplastic change | HDV does not integrate into the host genome (unlike HBV DNA) → no direct oncogenic mechanism |
Practical approach: All chronic HDV patients with cirrhosis (and those meeting HBV-specific surveillance criteria) should undergo HCC surveillance with AFP + ultrasound every 6 months [16][29]:
HBV-specific indications for HCC surveillance: Male 40+, Female 50+, or underlying cirrhosis, or family history of HCC [16]. "Since HBV can cause HCC without cirrhosis, jumps the barrier → have to be more stringent" [16].
Key distinction between HBV and HCV regarding HCC [29][30]:
- "HCC that complicates hepatitis B usually presents on top of a non-cirrhotic liver since HBV has direct oncogenic effect" [30]
- "HCC that complicates hepatitis C usually presents on top of a cirrhotic liver" [30]
- HDV-related HCC: virtually always on a cirrhotic background (similar to HCV pattern), because HDV does not have direct oncogenic properties
AFP is not always a tumour marker [17]:
- "High inflammation in the liver can also cause marked elevation of AFP sometimes"
- "Key difference is to see whether it comes down after the symptoms disappear. If it doesn't, and keeps rising, then you start getting scared of cancer"
- "However, 20-30% of HCC is non-secreting, will have no AFP" [17]
- "HCC usually only causes symptoms such as abdominal pain or distension when its size exceeds 8 cm in diameter" [29] — which is why surveillance is critical
While less common than in HCV, chronic HDV can be associated with extrahepatic manifestations, likely immune-mediated:
| Complication | Mechanism |
|---|---|
| Membranoproliferative glomerulonephritis (MPGN) | Immune complex deposition (HDAg-anti-HDV complexes) in glomerular basement membrane → complement activation → glomerular inflammation |
| Polyarteritis nodosa (PAN) | Immune complex-mediated vasculitis; historically associated with HBV, but described in HBV-HDV co-infection |
| Aplastic anaemia | "Hepatitis well known to precede aplastic anaemia" [31] — T-cell mediated destruction of haematopoietic stem cells triggered by viral hepatitis (described for HBV, non-A-E hepatitis; can occur with HDV) |
| Autoimmune manifestations | Polyclonal B-cell activation → autoantibody production (LKM-3 antibodies have been described specifically in HDV) |
| Complication | Context |
|---|---|
| PEG-IFNα side effects | Flu-like symptoms, myelosuppression, neuropsychiatric (depression), autoimmune flare, hepatic decompensation (especially if used in cirrhosis — contraindicated in Child B/C) [24] |
| Bulevirtide-related bile salt elevation | Blocking NTCP → ↑serum bile salts; usually asymptomatic but may cause pruritus |
| HBV reactivation post-HDV treatment | If HDV is suppressed but HBV NUC coverage is inadequate, HBV may "rebound" since HDV no longer suppresses it; always ensure adequate HBV coverage |
| Relapse after stopping treatment | Extremely common with both PEG-IFNα and bulevirtide; up to 50% relapse after stopping PEG-IFNα; bulevirtide requires long-term/indefinite therapy |
This is a crossover complication worth emphasising, as it is heavily examined:
- "Corticosteroid or other immunosuppressants, especially anti-CD20, withdrawal → will cause reactivation of occult hepatitis B. During the steroid treatment actually fine, it is the withdrawal that activates a massive immune response" [2]
- "Anti-CD20 (rituximab) and anti-CD52 (alemtuzumab)" are the highest-risk agents [23]
- Reactivation can occur up to 11 months after the last cycle of rituximab — "profound depletion of B cells will take 1 year to recover, and once they do recover, these B cells will prime T-cells, which then damage the liver" [23]
- "Start entecavir when HBV DNA becomes detectable → studies show will completely control the reactivations. Cover for at least 1 year" [23]
- "Potentially dangerous and fatal, especially in: decompensated liver disease, abnormal immune system (lymphoma, leukaemia), and occasionally even in 'normal' patients" [23]
Must-Know — Why Does HBV Reactivation Occur During Withdrawal, Not During Immunosuppression?
During immunosuppression, HBV replicates freely (no immune check) but there is no immune-mediated liver damage — so the patient appears well. Upon immunosuppressant withdrawal, the reconstituting immune system recognises the now-heavily-infected hepatocytes and mounts a massive cytotoxic T-cell response, causing severe hepatitis flare or even fulminant liver failure. The damage is from the immune reconstitution, not from the virus itself. This is why prophylactic antiviral therapy is started before immunosuppression [2][23].
| Scenario | Outcome |
|---|---|
| Acute HDV co-infection | ~95% self-resolve; < 5% chronicity; ~5% fulminant hepatitis |
| Acute HDV superinfection | > 80% become chronic; 5-20% fulminant hepatitis |
| Chronic HDV without treatment | 70-80% develop cirrhosis within 5-10 years; 5-year survival with decompensated cirrhosis is poor |
| Chronic HDV with effective treatment | HDV RNA suppression associated with reduced fibrosis progression and improved survival; HBsAg loss (< 10%) = best outcome |
| Post-liver transplant | Good outcomes with NUC + HBIG prophylaxis; HDV recurrence is lower than HBV mono-infection recurrence |
High Yield Summary
- Fulminant hepatic failure is the most feared acute complication — HDV has the highest fulminant rate among all hepatitis viruses (up to 5-20% in superinfection). Look for the ominous sign of falling ALT with rising INR [6].
- Cirrhosis develops in 70-80% of chronic HDV within 5-10 years — faster than HBV mono-infection (~2-3× the rate).
- 6 complications of liver failure: infections, variceal bleeding, ascites/SBP, hepatorenal syndrome, hepatic encephalopathy, coagulopathy [21]. Add HCC for chronic disease.
- SBP diagnosis: high index of suspicion; ascitic fluid PMN > 250/mm³ (not culture-based) [17].
- Hepatorenal syndrome: diagnosis of exclusion; managed with terlipressin + albumin; RRT is only a bridge to transplant [25].
- HCC surveillance: AFP + US every 6 months for all cirrhotic patients; remember 20-30% of HCC is AFP-negative [17].
- HBV reactivation on immunosuppression: occurs during withdrawal, not during treatment; anti-CD20 highest risk; cover with NUC for at least 12 months post-rituximab [2][23].
- ACLF (acute-on-chronic liver failure) has 28-day mortality > 20% and is prognosticated using the same parameters as MELD [21].
Active Recall - Hepatitis D Complications
References
[2] Senior notes: Block A - I am a hepatitis B carrier.pdf (causes of hepatitis flare in chronic HBV, HDV superinfection, steroid/anti-CD20 withdrawal causing reactivation, annual cirrhosis incidence) [3] Senior notes: Maksim Medicine Notes.pdf p.141 (initial management of acute hepatitis, monitoring protocol) [6] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (falling ALT with rising INR as ominous sign, INR/PT as best monitoring parameter, supportive care principles, RUQ pain pathophysiology) [16] Senior notes: Block A - Gastroenterology Interactive Tutorial.pdf (HCC surveillance criteria, FibroScan) [17] Senior notes: Block A - Gastrointestinal Data Interpretation.pdf (compensated vs decompensated cirrhosis, SBP diagnosis by PMN count, AFP interpretation, MELD/Child-Pugh) [21] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf (6 complications of liver failure, infections in liver failure, reticuloendothelial dysfunction, ACLF definition and mortality, 5 principles of ALF management, MELD in ACLF) [23] Senior notes: Block A - I am a hepatitis B carrier.pdf p.68-70 (rituximab/anti-CD20 reactivation, entecavir prophylaxis, 11-month reactivation risk, duration of prophylaxis, screening before immunosuppression) [24] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf p.751-755 (PEG-IFNα side effects and contraindications, complications of HBV including HDV co-infection) [25] Lecture slides: Handbook of Internal Medicine 2024.pdf p.119 (hepatorenal syndrome definition, precipitants, exclusion criteria, terlipressin + albumin management) [28] Senior notes: Ryan Ho GI.pdf p.208 (ACLF definition, causes including HDV superinfection) [29] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf p.496 (HCC poor prognosis reasons, 8cm symptom threshold, surveillance intervals) [30] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf p.498 (HCC in HBV vs HCV — cirrhotic vs non-cirrhotic liver) [31] Senior notes: Block A - Hematology Data Interpretation.pdf (hepatitis preceding aplastic anaemia, T-cell mediated HSC destruction)
High Yield Summary
- HDV is a defective satellite virus that requires HBsAg (from HBV) for its envelope — it cannot infect without HBV.
- Two patterns: Co-infection (HBV + HDV acquired together → usually self-limited, < 5% chronicity) vs. Superinfection (HDV acquired by chronic HBV carrier → > 80% chronicity, rapid cirrhosis).
- Most severe viral hepatitis — highest rate of fulminant hepatitis among hepatitis viruses.
- Very rare in Hong Kong / Chinese populations — mostly seen in IVDU [2].
- HDV typically suppresses HBV replication (low HBV DNA despite positive HBsAg).
- HBV vaccination prevents HDV — no specific HDV vaccine exists.
- Chronic HDV accelerates cirrhosis (70-80% within 5-10 years) — faster than HBV mono-infection.
- HDV genotype 3 (Amazon) is associated with the most fulminant disease.
- Clinical features of acute HDV are similar to other acute viral hepatitides but more severe; chronic HDV presents with features of chronic liver disease/cirrhosis.
- Falling ALT with rising INR in acute hepatitis = ominous sign of fulminant liver failure [6].
High Yield Summary
- HDV differential diagnosis spans two scenarios: acute hepatitis in an HBsAg+ patient, and hepatitis flare in a chronic HBV carrier.
- Co-infection (HBV + HDV simultaneously) vs. superinfection (HDV onto chronic HBV) — distinguish by anti-HBc IgM titre (high = co-infection, low/absent = superinfection).
- In Hong Kong, HAV and HEV superinfection on chronic HBV is "more important than HDV" [2].
- Always consider non-viral causes: DILI (including TCM), alcoholic hepatitis, autoimmune hepatitis, Wilson's disease, ischaemic hepatitis.
- Immunosuppressant withdrawal (especially steroids and anti-CD20) is a critical cause of HBV reactivation — the flare occurs during withdrawal, not during treatment [2].
- HDV characteristically suppresses HBV DNA — if a chronic HBV carrier has severe liver disease but paradoxically low HBV DNA, think HDV.
- Wilson's disease presenting as fulminant hepatitis has the hallmark of Coombs-negative haemolytic anaemia [14][15].
- Dual liver disease (HBV + MASLD) is common in HK [16] — always assess for metabolic factors contributing to accelerated fibrosis.
High Yield Summary
- Diagnosis of HDV requires: HBsAg positive + anti-HDV positive (screening) + HDV RNA positive (gold standard for active infection).
- Anti-HBc IgM distinguishes co-infection (high titre = acute HBV) from superinfection (low/absent = chronic HBV) [17][19].
- HDV characteristically suppresses HBV DNA — if a chronic HBV carrier has active liver disease but paradoxically low HBV DNA, suspect HDV and check anti-HDV/HDV RNA.
- LFT in acute HDV shows markedly elevated ALT > AST (hepatitic pattern); falling ALT with rising INR is ominous (fulminant hepatitis) [6].
- GC lecture algorithm for acute viral hepatitis: check HBsAg, anti-HAV IgM, anti-HCV, anti-HEV IgM, ANA/ASMA/anti-LKM1, ultrasound, toxicology screen [1].
- FibroScan is standard of care for fibrosis staging, replacing liver biopsy in most cases [17].
- HCC surveillance (AFP + ultrasound every 6 months) applies to all chronic HDV patients with cirrhosis or meeting HBV-specific criteria [16].
- Anti-HDV IgM can persist in chronic HDV — unlike other viral hepatitides where IgM is purely an acute marker.
- All viral hepatitides are notifiable diseases [3].
High Yield Summary
- Acute HDV: supportive care only — no specific antiviral hastens recovery; no alcohol for 6 months; no drugs or herbs [6]. Monitor for fulminant hepatitis with daily LFT/INR.
- Fulminant HDV: 5 principles — supportive ICU care, treat the cause, manage complications, high-volume plasma exchange, liver transplantation (final line) [21].
- Chronic HDV treatment options: PEG-IFNα-2a (48 weeks, ~25-30% SVR, many side effects, contraindicated in decompensated cirrhosis), bulevirtide (NTCP entry inhibitor, well-tolerated, long-term, usable in decompensation), NUCs (adjunctive for HBV suppression only).
- NUCs do not directly treat HDV — they target HBV DNA polymerase, which HDV does not have. NUCs are only adjunctive for co-existing HBV replication.
- Bulevirtide blocks NTCP — the shared entry receptor for HBV and HDV — preventing new hepatocyte infection. Key side effect: elevated bile salts (because NTCP normally imports bile salts).
- PEG-IFNα side effects: flu-like symptoms, myelosuppression, neuropsychiatric (depression), autoimmune reactivation, hepatic decompensation, alopecia, tachyphylaxis [24].
- HBV vaccination prevents HDV — no specific HDV vaccine exists.
- For immunosuppression in HBV-HDV patients: start prophylactic NUC irrespective of HBV DNA [23].
- Liver transplantation is the final line for decompensated cirrhosis/fulminant failure; HDV recurrence post-transplant is lower than HBV mono-infection.
- Treatment endpoints: HDV RNA undetectable (SVR-24); ALT normalisation; HBsAg loss (functional cure, < 10%) [23].
High Yield Summary
- Fulminant hepatic failure is the most feared acute complication — HDV has the highest fulminant rate among all hepatitis viruses (up to 5-20% in superinfection). Look for the ominous sign of falling ALT with rising INR [6].
- Cirrhosis develops in 70-80% of chronic HDV within 5-10 years — faster than HBV mono-infection (~2-3× the rate).
- 6 complications of liver failure: infections, variceal bleeding, ascites/SBP, hepatorenal syndrome, hepatic encephalopathy, coagulopathy [21]. Add HCC for chronic disease.
- SBP diagnosis: high index of suspicion; ascitic fluid PMN > 250/mm³ (not culture-based) [17].
- Hepatorenal syndrome: diagnosis of exclusion; managed with terlipressin + albumin; RRT is only a bridge to transplant [25].
- HCC surveillance: AFP + US every 6 months for all cirrhotic patients; remember 20-30% of HCC is AFP-negative [17].
- HBV reactivation on immunosuppression: occurs during withdrawal, not during treatment; anti-CD20 highest risk; cover with NUC for at least 12 months post-rituximab [2][23].
- ACLF (acute-on-chronic liver failure) has 28-day mortality > 20% and is prognosticated using the same parameters as MELD [21].