Term
Which of the following causes of viral hepatitis is a DNA virus?
1) A
2) B
3) C
4) D
5) E |
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Definition
Only Hep B is a DNA virus
B,C and D are parenteral routes
A and E are fecal-oral |
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Term
Which type of viral hepatitis is described by each of the following clinical features?
1) IV drug use, acutely asymptomatic and chronic 85% of time
2) Acute presentation without chronic phase, transmitted through feces
3) Acute presentation mostly transmitted sexually |
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Definition
Vaccine only available for A and B- prevention is key for C
1) Hepatitis C is chronic with IV drug use association
- ssRNA flavivirus
2) Hepatitis A is acute, transmitted through feces
- RNA picornavirus
3) Hepatitis B is acute in adults and transmitted sexually
- dsDNA virus (hepadnevirus) |
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Term
Patient presents with sudden onset fever, malaise, anorexia, nausea and abdominal discomfort.
They say that their urine has been dark in color and on PE you observe jaundiced sclera.
How would you work this patient up and treat them? |
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Definition
Sounds like Hepatitis A (incubation 15-50 days) transmitted through fecal-oral contact
Virus replicates in liver, excreted in bile and found in stool.
1) Diagnose with serum IgM (acutely) or total IgG/IgM against HAV
2) No good treatment (vaccine is now available), but may need transplant if liver failure occurs.
-pre-exposure prevention immune globulin also available
**common complications include fulminant, cholestatic and/or relapsing hepatitis (NOT chronic) and are more likely in elderly patients** |
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Term
| What are the 4 major proteins of hepatitis B? |
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Definition
Hepatitis B (dsDNA hepadnavirus with envelope) with 4 major proteins.
1. S (surface) gene (HBsAg)
Pre-S genes
2. C (core) gene (HBcAg)
3. P (polymerase) gene
4. X (x antigen) (HBxAg) |
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Term
| How does the major route of transmission of Hep B virus differ by region? |
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Definition
Hep B can be transmitted Sexually, Parenterally and Perinatally (SEx is biggest risk factor)
1) US (low risk)is generally sexual and only 5-10% remain infected
2) Asia/Africa (high risk) is at birth or early childhood and 80-100% remain infected |
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Term
| What are the important serological markers of acute and chronic hepatitis B infection? |
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Definition
Transition of HBcAb from IgM (acute) to IgG (chronic)
1) Acute
- HBsAg
- HBcAb-IgM
- HBeAg
2) Chronic
- HBsAg
- HBcAb-IgG
- HBeAg
**if disease is long-standing over 20-30 years, screen with scans and AFP every 6-12 months and treat symptoms with anti-virals |
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Term
| How can you distinguish, serologically, between a healthy carrier of Hepatitis B and acutely and chronically affected individuals? |
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Definition
If anti-HBsAb (+), they were vaccinated or have recovered from acute infection.
If you see IgM Ab against HBc, it is acute.
1) Healthy
- Evidence of HBsAg (+), but no evidence of replication (HBeAg (-) HBV DNA (-)
- evidence of prior infection: anti-HBc (+)
- Normal ALT
2) Acute
- HBsAg (+) and anti-HBc (+) with IgM
- Evidence of replication (HBV DNA and HBeAg)
- ALT elivation
3) Chronic
- HBsAg and HBeAg (+) for >6 months
- No evidence of HBeAg in precore cases
- anti-HBc IgG
- evidence of viral replication and inflammation (ALT) |
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Term
True or False:
Risk of fulminate hepatitis and chronic disease resulting from hepatitis B decreases with age. |
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Definition
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Term
| What are the 4 natural phases of Hepatitis B infection? |
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Definition
1) Immune tolerance- little inflammation despite high serum HBV DNA, HBeAg(+)
2) Immune clearance- hepatic inflammation and low serum HBV DNA level, ultimately loss of HBeAg
3) Inactive carrier- Low HBV DNA, HBeAg (-), normal ALT
4) Reactivation- high serum HBV DNA, hepatic inflammation (high ALT), may revert to HBeAg (+) or not |
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Term
8 year old child is asymptomatic, but on routine blood work you see high levels of anti-HBcAb-IgM.
Why are you so worried? |
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Definition
| Most children are asymptomatic, but will progress to chronic phase (complications include HCC, cirrhosis and liver failure), while most adults are symptomatic, but WILL clear the infection. |
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Term
| Who is at high risk for HCC in the context of Hepatitis B infection? |
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Definition
Old men with a positive family h/x, cirrhosis and/or co-infection with HCV.
1) Males
2) Family h/x
3) Old age
4) Cirrhosis (30-50% occur in its ABSENSE)
5) Co-infection with HCV
6) Presence of HBeAg |
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Term
| What therapies are available for the form of viral hepatitis that is most associated with sexual contact? |
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Definition
1) No treatment
2) Antiviral therapies:
- IFN-y
- Lamivudine
- Adefovir
- Entecavir
- Telbivudine
3) Liver transplant |
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Term
| How does HDV infection occur and what are its 2 major forms? How do you treat? |
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Definition
- Requires hepadnavirus (like HBV) to replicate
- acquired by IV drugs and sex and trated with IFN-y (deals with underlying HBV)
1) Co-infection with HBV produces fulminant hepatitis and presents as "severe, acute disease, with low chronic risk"
- prevent with pre or post-exposure prophylaxis to prevent HBV infection.
2) Super-infection with HBV produces chronic progressive disease (90%)
- Educate people with chronic HBV |
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Term
| What is the basic pathogenesis of Hep C infection? |
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Definition
Worry is chronic liver diseases and HCC!
ssRNA virus (Flaviviridae) with core (nucleocapsid) and E1 & E2 envelope proteins that is transmitted by IV drug use.
1) Virion enters hepatocyte and uses host and viral encoded enzymes for P synthesis and replication
2) Endogenously synthesized peptides are presented by HLA class I complexes at surface and recruit CD8 CTLs inducing necrosis/apoptosis
3) CD4+ T cells recognize HLA class-II complexes and lead to CTL stimulation and humoral response.
**Antibodies DO NOT protect against re-infection** |
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Term
| What factors increase the progression of HCV infection to chronic liver disease/cirrhosis and HCC? |
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Definition
10 years for chronic hepatitis, 20 years for cirrhosis and 30 years for HCC
1) Alcohol even modestly
2) Older age (>40) at exposure
3) Male gender
4) HCV genotype |
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Term
| What is the serological pattern of acute HCV infection and recovery? |
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Definition
Fluctuating elevations in ALT
15-25% resolve with absent HCV RNA and normalization of ALT
ALT is variable in chronic infection and can be misleading! |
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Term
| Describe the strategy for working up a patient with variable fluctuations in ALT levels and suspected HCV history (drug user)? |
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Definition
1) Test anti-HCV antibody
2) If positive
- HCV RNA level genotype (DOES NOT predict progression)
- Liver biopsy (degree of fibrosis is MOST important prognostic factor) |
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Term
| How is HCV treatment approached? |
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Definition
1) Does the patient need treatment?
“Significant” fibrosis (biopsy)
Other risk factors?
2) Can patient tolerate therapy?
Psychiatric side effects (interferon)
Cardiovascular risks (ribavirin/anemia)
Retinopathy, gout, thyroid disease (interferon)
Flu-like symptoms, body aches, fatigue
3) Choice of medication
4) Duration or treatment and how responsive will they be (viral load, fibrosis, genotype) |
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Term
| What is the current standard of care for a genotype 1 HCV infection? |
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Definition
| Three drug combination therapy (PegINF, ribavirin, Direct-Acting Agent) |
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Term
| How does HepE infection relate to other viral forms of hepatitis? |
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Definition
1) Feco-oral transmission
2) Self-limited virus treated with supportive care (similar to HAV)
3) Unknown efficacy of IG prepared from endemic areas. |
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Term
| What would you look for histologically do distinguish between alcoholic (ASH) and non-alcoholic (NASH) steatohepatitis? |
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Definition
Both have inflammation +/- fibrosis associated with fatty liver (vs. simple steatosis).
- Cannot be distinguished by histology alone!
- Both can proceed from steatosis....steatohepatitis....cirrhosis.....HCC |
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Term
| What are the common risk factors for NAFLD? |
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Definition
Directly proportional to body weight and higher in hispanics.
- considered to be the pro-inflammatory hepatic manifestation of Metabolic Syndrome (diabetes, dyslipidemia, obesity)
For MS, you need 3 or more
1. Increased waist (>102cm men and 88 women)
2. Hypertriglyceridemia (>150)
3. HTN (>130/80)
4. High fasting glucose (>110)
5. Low HDL (<40 men <50 women)
Also associated with DM, hyperlipidemia, TPN, acute starvation, inborn errors of metabolism, jejuno-ileal bypass surery, drugs/toxins |
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Term
| What is the basic pathogenesis of NAFLD? |
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Definition
Short: FFA accumulate, increasing TNF-a, which decreases adiponectin and leads to ROS signaling that causes hepatocyte death.
2-hit hypothesis (poorly understood)
1. first "hit" is hepatic steatosis
- FFA accumulate in skeletal muscle and toxic lipid metabolites cause defects in insulin signaling, which impair muscle glucose metabolism and cause hyperglycemia
- Increased circulating insulin activates SREBP, which increases de novo lipogenesis
2. second "hit" is lipid peroxidation and oxidative stress leading to inflammation and fibrosis.
- FFA activate TNF-a, which inhibits adiponectin and causes fat accumulation in hepatocytes
- Efforts to remove excess lipids generate ROS, which can lead to cell death. |
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Term
Patient presents with vague right upper quadrant pain and on PE you notice hepatomegaly.
How do you diagnose NAFDL and distinguish NASH vs. bland steatosis? |
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Definition
Most cases are asymptomatic anyways.
Distinction is key, because NASH may progress to cirrhosis, while bland steatosis most likely will not
1) Confirm etiology as fatty liver
- NO specific serological marker
- Metabolic syndrome (obese, type 2 DM, htn, dyslipidemia)
- Fatty liver on US (good for steatosis NOT steatohepatitis)
- Elevated AST/ALT
- "cryptogenic cirrhosis"
2) Specify type of fatty liver disease
- Alcohol or not?
3) Establish severity
- ASL/ALT ratio may help (elevated in cirrhosis)
- Thombocytopenia, decreased albumin and increased Bili can suggest cirrhosis
- Biopsy is gold standard (EXCEPT when cirrhosis has been established)
- Macrovesicular steatosis; parenchymal inflammation; necrosis, ballooning degeneration
- Fibrosis; mallory bodies; glycogenated nuclei |
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Term
| How do you manage a patient with established NAFLD? |
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Definition
If no evidence of NASH, DO NOT TREAT?
1) LIfestyle (most important)- 10% loss
2) Treat metabolic syndrome components (insulin, statins, bariatric surgery)
3) Insulin sensitizing agents (Pioglitazine) or VItamin E
If there is decompensated cirrhosis, transplant may be necessary, but will not treat metabolic syndrome. |
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Term
| How is iron normally stored/metabolized in the body? |
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Definition
No method of excretion, so it is absorbed in duodenum and stored 50% in hemoglobin (RBC) and 50% is muscle/heme-containing enzymes of liver/ferritin/hemosiderin
1) Ingested non-heme iron is usually oxidized Fe3+, and must be reduced to Fe2+ by brush-border ferrireductase (Dcytb), at which point it enters enterocytes by DMT1.
2) Once in enterocytes, iron is released from heme by heme oxygenase and stored or transported out via ferroportin 1 (Ireg1)
3) Fe2+ is again oxidized and then bound to plasma Transferrin to be transported to tissues.
2 models of regulation
1) "Crypt programming," where crypt cells sense body iron levels and regulate absorption.
2) "Hepcidin model", where liver HEPCIDIN is secreted into blood and interacts with villous enterocytes to regulate iron absorption (NEGATIVE regulator) |
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Term
| What is the genetic/pathophysiological basis of hereditary hemochromatosis (HH)? |
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Definition
AR condition where mutations (C282Y or H63D) in HFE protein on chromosome 6 (short arm) lead to excessive iron absorption
1) HFE is a GI protein expressed in duodenal crypt cells that regulates TfR expression and determined intestinal uptake of transferin-bound iron
2) Loss of HFE leads to increased DMT1 and FP1 expression, leading to increased dietary iron absorption
3) Inappropriately low expression of Hepcidin leads to aberrant sensing of iron.
Iron accumulation leads to cellular damage, fibrosis
Lipid peroxidation leads to ROS and cellular damage |
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Term
| What serological changes might you expect to find in hereditary hemochromatosis? |
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Definition
Elevated serum iron (>150), Transferrin saturation (>50), Ferritin (>300) and quantitative hepatic Fe (>5600)
Use Hepatic Iron Index!
Hepatic iron (umol/g) / age in years
If >1.9, you have homozygote for HH
If <1.9, you have Alcoholic liver disease of Heterozygote for HH |
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Term
| Describe the process of staging Hereditary hemochromatosis |
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Definition
1) Staging
- Stage 1 is genetic disorder with no increase in iron stores (susceptible)
- Stage 2 is genetic disorder and phenotypic evidence of iron overload, without tissue/organ damage
- Stage 3 has organ damage due to iron deposition |
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Term
| How do you diagnose/treat hereditary hemochromatosis? |
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Definition
1) Diagnose
1a) Step 1 is determine serum transferrin saturation and ferritin level
- If TS>45% and/or ferritin is elevated, check HFE genotype
1b) Step 2 is to to evaluate genotype
- If C282/C282 homozygous and ferritin is >1000 ug/L or their are elevated liver enzymes, DO A BIOPSY
- If homozygous, but ferritin is <1000 and liver enzymes are normal, do phlebotomy.
- If it is compound heterozygote or non-C282Y, you should exclude other liver or hematological diseases.
2) Treat
- Phlebotomy (acute and maintenance)
- won't reverse cirrhosis or risk of HCC, but will prevent clinical manifestations and reverse glucose intolerance, hepatomegaly and cardiac dysfunction. |
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