• Typically defined as a widened alveolar-arterial oxygen gradient (A-a pO2) on room air (>15 mmHg, or >20 mmHg in patients >64 years of age) with or without hypoxemia resulting from intrapulmonary vasodilatation in the presence of hepatic dysfunction or portal hypertension.
• The hallmark of HPS is intrapulmonary vasodilatation of the precapillary and capillary vessels, impairing arterial oxygenation. A few pleural and pulmonary arteriovenous communications (shunts) and portopulmonary venous anastomosis are common findings as well.

Other key points

• Incidence is 15 to 20% in those with cirrhosis
• Can co exist with other cardiopulmonary abnormalities.
• A pO2 <70 mmHg is useful for clinically identifying those with significant HPS.
• There is no relationship between the presence or severity of the HPS and the severity of liver disease.
• Severity of hypoxemia appears to be directly related to the extent of intrapulmonary shunt, diffusion-perfusion impairment, or both.

Pathogenesis: current concepts

• Excessive vascular production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) causing vasodilatation.
• Other mediators may contribute to vascular tone i.e. heme oxygenase 1
• Hepatic endothelin-1 (ET-1) appears to be an important mechanism for triggering the increase in pulmonary eNOS and the onset of vasodilatation.
• Progression of HPS results in accumulation of macrophages in the pulmonary microvasculature, which produce inducible NOS & heme oxygenase 1. They respectively release NO and CO, causing further vasodilatation.
• TNF-a contributes to macrophage accumulation.

Clinical manifestations

• Insidious onset of exertional dyspnoea.
• Platypnea: shortness of breath exacerbated by sitting up and improved by lying supine.
• Orthodeoxia: hypoxemia exacerbated by going from supine to a upright position.
• Pulmonary AVMs are predominantly situated at the lung bases. Hence, dependent blood pooling occurs on sitting/standing with subsequent increased AV shunting.
• Clubbing, cyanosis and spider naevi in the presence of liver disease/portal hypertension should raise the suspicion of HPS.

Diagnosis

• Triad
  • Of liver disease or portal hypertension
  • Of intrapulmonary vasodilatation
  • Elevated age adjusted A-a pO2 gradient: [0.26age -0.43] + 10

Investigations

• ABG
  • Performed when SpO2 <97% or if history and exam strongly suggests HPS.
• CXR and pulmonary function tests to assess for other pulmonary disorders i.e. hepatic hydrothorax, COPD, pulmonary fibrosis.
• Transthoracic microbubble contrast ECHO
  • The left ventricle opacifies at least three cardiac cycles after the right (delayed shunting). Microbubbles do not pass through normal capillaries. This intrapulmonary shunting is characteristic of HPS.
• Macroaggregated albumin scan
  • This is useful to determine the contribution of HPS in patients with both intrapulmonary vasodilatation and intrinsic cardiopulmonary disease. Radiolabelled albumin macroaggregates (20um) are infused into the venous circulation. In significant intrapulmonary shunting, a fraction of the macroaggregates pass from the lungs into the systemic circulation. Normally, these particles would become trapped in the pulmonary microvasculature.
• Pulmonary function tests
  • Abnormal findings are of low specificity.
  • TLC and expiratory flow rates are generally normal in HPS.
  • Diffusion impairment for CO is common in HPS.
• Pulmonary angiography
  • Low sensitivity for detecting intrapulmonary vasodilatation. Should only be performed when pO2 <60mmHg which is poorly responsive to oxygen administration and when there is a strong suspicion of direct AV communications that may be amenable to embolisation.
• High resolution CT
  • Some evidence that quantitation of intrapulmonary vasodilatation is possible

Natural history/prognosis

• The natural history has yet to be fully established but most patients with HPS appear to have progressive intrapulmonary vasodilatation with worsening gas exchange.
• Reported median survival of 24 months and a 5-year survival rate of 23% in those not suitable for OLT.
• Survival and mortality rates are worse for patients with HPS, even after adjustment for the Child Turcotte Pugh classification of liver disease.
• Death is often due to hepatic complications rather than respiratory.

Treatment

• Orthotopic liver transplant is the only effective treatment for HPS. HPS with a pO2 <60mmHg is considered to be an indication for OLT. However, it may take up to a year post transplant for arterial hypoxaemia to normalise.
• Long term oxygen therapy is mainstay treatment for those with pO2 <60mmHg or exertional induced hypoxaemia.
• The role of TIPSS is uncertain and there are no established medical therapies.

Degree of severity

• Mild: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen ?80 mm Hg
• Moderate: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen ?60 to <80 mm Hg
• Severe: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen ?50 to <60 mm Hg
• Very severe: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen <50 mm Hg (<300 mm Hg while the patient is breathing 100% oxygen).

References
1.Hepatopulmonary Syndrome — A Liver-Induced Lung Vascular Disorder. Rodríguez-Roisin R, Krowka MJ, N Engl J Med 2008 May; 358:2378-2387.

2.The hepatopulmonary syndrome. Palma DT, Fallon MB. J Hepatol. 2006 Oct;45(4):617-25.

HE may be defined as a disturbance in central nervous system function because of hepatic insufficiency. It can be present in both acute and chronic liver failure. The neuropsychiatric manifestations are reversible.

Discuss the pathophysiology of HE?

• A large body of work points at ammonia as a key factor in the pathogenesis of HE.
• Portal ammonia is derived from both the urease activity of colonic bacteria and the deamidation of glutamine in the small bowel.
• The intact liver clears almost all of the portal vein ammonia, converting it into glutamine and preventing entry into the systemic circulation.
• Ammonia gain access to the systemic circulation as a result of decreased hepatic function or portal-systemic shunts.
• Once in brain tissue, they produce alterations of neurotransmission that affect consciousness and behaviour.
• In acute and chronic liver disease, increased arterial levels of ammonia are commonly seen. However, correlation of blood levels with mental state in cirrhosis is inaccurate.

Discuss the clinical presentation of HE?

• HE is a diagnosis of exclusion. Other metabolic and cerebral structural causes can have a similar presentation.
• Pre existing liver disease (acute or chronic), presence of a precipitating factor, and/or a prior history of HE are clinical elements needed for diagnosis.
• Measurement of venous ammonia blood levels may be helpful
• The most distinctive presentation is the development of an acute confusional state that can evolve into coma (acute encephalopathy).

Discuss the stages of HE?
West Haven criteria:
Stage 0. Lack of detectable changes in personality or behaviour. Asterixis absent.
Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria or
depression. Asterixis can be detected.
Stage 2. Lethargy or apathy. Disorientation. Inappropriate behaviour. Slurred speech. Obvious asterixis.
Stage 3. Gross disorientation. Bizarre behaviour. Semistupor to stupor. Asterixis generally absent.
Stage 4. Coma.

Discuss the management of HE?

Nutrition

In case of deep encephalopathy, oral intake is withheld for 24–48 h and i.v. glucose is provided until improvement. Enteral nutrition can be started if the patient appears unable to eat after this period. Protein intake begins at a dose of 0.5 g/kg/day, with progressive increase to 1–1.5 g/kg/day.

Precipitating factors

A precipitating factor can be found in most cases of cirrhosis with acute or chronic HE. These factors should be vigorously searched and eliminated. The precipitating factors are:

• GI bleed
• Infections- SBP or any other infection.
• Renal and electrolyte disturbances- renal failure, metabolic alkalosis, hypokalaemia, dehydration, and diuretic effects.
• Medication- benzodiazepines, narcotics, and other sedatives.
• Constipation
• Excessive dietary protein.
• Acute deterioration of liver function in cirrhosis- like superimposed alcoholic hepatitis, portal vein thrombosis etc.

Lactulose is a first-line pharmacological treatment of HE.

• Lactulose (galactosido-fructose) is not broken down by intestinal disaccharidases and thus reaches the colon, where bacteria will metabolize the lactulose to acetic acid and lactic acid. This lowers the colonic pH and thus favours the formation of the nonabsorbable NH4+ from NH3, trapping NH3 in the colon and effectively reducing plasma ammonia concentrations. Other effects like catharsis also contribute to the clinical effectiveness of lactulose.
• An excessively sweet taste, flatulence, and abdominal cramping are the most frequent subjective complaints with this drug.
• For acute encephalopathy, lactulose (ingested or via nasogastric tube), 45 ml p.o., is followed by dosing every hour until evacuation occurs. Then dosing is adjusted to an objective of two to three soft bowel movements per day (generally 15–45 ml every 8–12 h).
• Lactitol is more palatable and can be used instead of lactulose. Both are equally efficacious.

Enemas
Bowel cleansing is a rapid and effective method to remove ammoniagenic substrates.

Antibiotics
The goal of antibiotic therapy in the treatment of HE is to reduce the mass o f enteric bacteria that produce ammonia. Antibiotics are reserved for patients who respond poorly to disaccharides. So antibiotics are added to lactulose after 48 hours, if the response has been poor. Options are

• Neomycin (1-2 g/day) – concerns regarding oto and nephro toxicity limits its use.
• Metronidazole (250 mg bd) – neurotoxicity limits its use
• Rifaximin (400 mg t.i.d) is much better tolerated, but is expensive. The tolerability pro?le of rifaximin is comparable to placebo

Liver transplantation

The development of overt HE carries a poor prognosis with a 1-yr survival of 40%. Appropriate candidates should be referred to transplant centres after the first episode of overt encephalopathy of any type.

Ref
Blei AT, Córdoba J. Hepatic Encephalopathy. Am J Gastroenterol. 2001 Jul; 96(7):1968-76.
http://www.gi.org/physicians/guidelines/HepaticEncephalopathy.pdf

Steps:

1. Patient is placed on supine position and draped aseptically after cleaning the site
2. US probe is covered with aseptic plastic sheath and so is the image intensifier
3. Radiologist/interventionist  is also dressed aseptically with gown over lead apron (also leaded sterile gloves)
4. Patient is given both local anaesthesia +/- IV sedation (fentanyl/midazolam)
5. Anticipated needle tract is anaesthetized and a 3mm stab of the skin is made
6. Under US guidance a dilated left/right biliary radicle is punctured with a 22G Chiba needle ( part of Neff set – Chiba needle, dilator and .018 guidewire)  and the position is checked by injecting contrast (through a connecting tubing) with the patient breath holding in mid inspiration
7. Once position is confirmed a 0.018 guidewire (platinum tipped to ensure visibility on fluoroscopy) is advanced and then the Chiba needle is withdrawn a dilator is passed to dilate the tract through the liver capsule. Wire is changed to 0.038 guidewire and dilator is withdrawn

Cholangiogram showing a hilar stricture (above the coiled appearance of the cystic duct)

Same patient with an external-internal drain in situ beside a metal biliary stent across the stricture (also note distended gall bladder in the second picture)

1. A biliary manipulation catheter (BMC) is threaded over the guidewire and guidewire is changed to Hydrophilic Terumo wire to cross the stricture.
2. Once the stricture is crossed then guidewire is advanced to the distal duodenum followed by the BMC catheter- position confirmed by contrast in the small bowel.
3. Then BMC catheter is withdrawn and 7.5F angio sheath is introduced over the guidewire
4. Guidewire is changed to Amplatz superstiff/stiff guidewire.
5. Then a metal biliary stent is placed across the stricture and deployed
6. The metal stent may need to be further dilated with an angio balloon (inflated across the stricture).
7. Normally an 8F catheter is also kept to drain externally to ensure access and faster drainage.
8. The external drainage catheter can be closed off after 48hours (if LFT’s are improving and repeat imaging shows decompressed biliary system) and may be removed after a further period of observation. While removing the external catheter, the hole in the liver capsule is sealed of by injecting gel.
9. If in doubt about sepsis and cholangitis- before a stent is placed- biliary tree is decompressed thoroughly by placing an external-internal (EI) drain. An EI drain will have a loop in the duodenum outside ampulla and draining holes above the stricture (the technique to ensure that – a guidewire is passed through the EI drain- when it catches the hole on further pushing it buckles- on screening it ensures that buckle is above the stricture). Bile will collect in the external bag as well as will flow in the duodenum. Clipping the external drain ensures bile flows predominantly internally.
10. For biliary stone disease-Rendezvous procedure: After initial external-internal drainage, a guidewire is passed again in to the duodenum and EI drain is withdrawn. This is a very long guidewire- as it needs to come out through ampulla and then be able to be fed through the accessory channel of the ERCP scope (duodenoscope)
11. The duodenoscope is introduced and a snare is used to grab the tip of the guidewire and pulled back through the accessory channel.
12. Then the sphincterotome is passed over the guidewire into the biliary tree. Once position is secure- external guidewire is withdrawn and fresh guidewire is passed through accessory port into the biliary system.

What is A1AT?

A1AT is a serine protease inhibitor secreted primarily in liver parenchymal cells and to a lesser extent in macrophages.

It protects tissues from enzymes of inflammatory cells by inactivating especially neutrophil elastase (and also a variety of other proteases like collagenase, trypsin and chymotrypsin)

It has a reference range in blood of 1.5 – 3.5 gram/liter but the concentration can rise many fold upon acute inflammation.

In its absence, neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema, in adults and cirrhosis in adults or children. However the exact mechanism of liver injury is less precise compared to lung injury.

Discuss the phenotypes of A1ATD?

The gene coding for A1AT is located on chromosome 14 and there are more than 90 genetic variants producing different types of A1AT.

Serum AAT when allowed to migrate in a pH gradient gel (IEF or isoelectric focus gel)  travels at different speed according to the protein molecule property- the fastest are termed A and slowest Z.

As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing. The blood test results (i.e. IEF results) are notated as in PiMM, where Pi stands for protease inhibitor and “MM” is the banding pattern of that patient.

It has a reference range in blood of 1.5 – 3.5 gram/liter but the concentration can rise many fold upon acute inflammation.

The serum levels of some of the common genotypes are:

• PiMM: 100% (normal)
• PiMS: 80% of normal serum level of A1AT
• PiSS: 60% of normal serum level of A1AT
• PiMZ: 60% of normal serum level of A1AT
• PiSZ: 40% of normal serum level of A1AT
• PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)

M is the most common allele, accounting for 95% of those found in Caucasian people whereas S and Z are the most common mutant alleles.

How common is the condition?

It is the most common metabolic disease affecting the liver and the commonest cause of paediatric liver transplantation.

Prevalence is highest in northern European white population (incidence of homozygous deficiency is 1in 1500). Roughly one in ten in Northern Europe carry a deficiency gene. In USA the incidence is 1 in 1800-2000.

What does liver histology shows?

Periodic acid-Schiff (PAS) positive, diastase resistance globules are seen in periportal hepatocytes. These can be shown to be A1AT using specific antiserum. Fibrosis and cirrhosis can be present in some cases.

How many of the patient with abnormal allele will actually develop the liver disease according to the phenotype?

More than 90 phenotypic variants of alpha1-antitrypsin deficiency have been identified, but one phenotype, PiZZ, is responsible for nearly all cases of AAT deficiency emphysema and liver disease. PiZZ phenotype serum levels range from 3.4-7 µmol/L, about 10-20% of the reference range levels. Other phenotypes associated with alpha1-antitrypsin emphysema and liver disease include PiSZ and PiZ/Null. PiNull/Null is not associated with liver disease but is associated with alpha1-antitrypsin deficiency emphysema.

PiZZ phenotype is associated with development of liver disease in about 15-30% and affects both children and adults.

Prognosis of patients with liver disease presenting in infancy secondary to AAT deficiency (PiZZ) is variable- not all patients progress to end stage liver disease.

Approx 10-15% of the adult patients will develop cirrhosis, usually over 50yrs of age and 75% will have respiratory problems

Heterozygotes (PiSZ or PiMZ) may develop liver disease but the risk is small.

Discuss the clinical features of the condition?

Children and infant normally present with neonatal jaundice, unexplained hepatomegaly, elevated transaminase, failure to thrive.

Adults can present with abnormal LFT, Chronic hepatitis, cirrhosis and its complications or HCC.

Discuss the diagnosis of A1AT deficiency?

1. Low serum AAT level
2. Serum A1 phenotype determination (Pi typing)
3. Liver biopsy: to confirm, exclude other causes and determine prognosis

Discuss the mechanism of damage to liver and lungs in A1AT deficiency?

The most common pathologic form, which causes both lung and liver disease is the PiZZ variant which produces A1ATZ protein.

A1AT is produced in hepatocytes in rough endoplasmic reticulum and the secreted in the circulation via Golgi apparatus. Structural misfolding and polymerization of A1ATZ cause this protein to be retained in the ER but how that subsequently produces liver injury is not clear. However the lung injury is relatively straight forward by uninhibited damage by alveolar elastin fibres by neutrophil elastase present in the alveolar fluid.

Discuss the treatment of the condition?

1. In absence of liver damage- patients are encouraged to avoid smoking (including passive smoking) and alcohol, maintain adequate nutritional intake and take oral fat soluble vitamins if needed.
2. Managing the complications of liver and lung disease once developed.
3. Patients with hepatic decompensation should be considered for liver transplant- donor liver synthesizes normal protein- so condition does not recur in the graft.
4. Experimental treatment for both pulmonary and hepatic disease are infusion/inhalation of purified AAT and gene therapy
5. Offering genetic counselling and phenotype identification of the relatives to determine those with high risk.

It is an autosomal recessive disease characterised by hepatic copper accumulation and injury. The gene ATP7B (on chromosome 13) encodes a transmembrane transporter of copper in hepatocytes. Absent or reduced function of ATP7B protein leads to decreased hepatic excretion of copper into bile. This results in hepatic copper accumulation and injury. Eventually copper is released into the bloodstream and deposited in various other organs, notably the brain, kidneys, and cornea.

Failure to incorporate copper into ceruloplasmin is an additional consequence of the loss of functional ATP7B protein. The hepatic production and secretion of the caeruloplasmin protein without copper (apocaeruloplasmin) results in the decreased blood levels of caeruloplasmin due to the reduced half-life of the apoprotein.

Discuss the copper cycle?

The average diet provides 2-5 mg/day (almost 3 times the recommended intake).
Most dietary copper ends up being excreted. Copper is absorbed mainly in the duodenum and proximal small intestine and transported to the liver, where it is avidly removed from the circulation. The liver utilizes some copper for metabolic needs and excretes excess copper into bile. Processes that impair biliary copper excretion can lead to increases in hepatic copper content

Discuss the clinical presentation of WD?

It can present clinically as liver disease, as a progressive neurologic disorder (hepatic dysfunction being less apparent or occasionally absent), or as psychiatric illness.
The type of the liver disease can be highly variable. It can be asymptomatic with only biochemical abnormalities or present with acute or chronic hepatitis or chronic liver disease with portal hypertension or with acute liver failure.

Discuss the eye manifestations of WD?

Kayser-Fleischer (KF) rings represent deposition of copper in Descemet’s membrane of the cornea. They appear as a band of golden-brownish pigment near the limbus. A slit-lamp examination is required to identify KF rings in most patients. They may also be found in patients with chronic cholestatic diseases. KF ring is present in up to 62% of patients with hepatic disease at the time of diagnosis. KF rings are almost invariably present in patients with a neurological presentation.
Sunflower cataracts, also found by slit-lamp examination, represent deposits of copper in the lens. These typically do not obstruct vision. Both KF rings and sunflower cataracts will gradually disappear with effective medical treatment or following liver transplant.

Discuss the diagnosis of WD?

WD should be considered in any individual between the ages of 3 and 55 years with liver abnormalities of uncertain cause. Age alone should not be the basis for eliminating a diagnosis of WD. Diagnosis of WD is confirmed, if 2 of the following 3 are present:

• Serum caeruloplasmin level <20 mg/dL
• Presence of KF ring
• Hepatic copper content > or =250 µg/g dry weight. (Normal < 50 µg/g).

A basal 24-hour urinary copper of more than 40 µg (>0.6 µmoles or >600 nmoles) suggests WD.

The serum noncaeruloplasmin-bound copper concentration is elevated above 25 µg/dL in most untreated patients (normal <15 µg/dL). Total serum copper (which includes copper incorporated in caeruloplasmin) in WD is usually decreased in proportion to the decreased caeruloplasmin in the circulation.

Mutation analysis by whole-gene sequencing is possible and should be performed on individuals in whom the diagnosis is difficult to establish by clinical and biochemical testing.

When should a diagnosis of WD be considered?

• Adult patients with atypical autoimmune hepatitis or who respond poorly to standard corticosteroid therapy.
• WD should be considered in the differential diagnosis of patients presenting with nonalcoholic fatty liver or who have pathologic findings of NASH.
• WD should be suspected in any patient presenting with fulminant hepatic failure with Coombs-negative intravascular hemolysis, modest elevations in serum amino transferases, low serum alkaline phosphatase, and ratio of alkaline phosphatase to bilirubin of less than 2.
• First-degree relatives of any patient newly diagnosed with WD must be screened for WD.

Discuss the therapeutic options in WD?

D-penicillamine – is the drug of choice.  It is a general chelator of metals and promotes urinary excretion of copper. Recovery from symptomatic liver disease occurs typically during the first 2-6 months of treatment. Penicillamine use is associated with numerous side effects i.e. sensitivity reactions, nephrotoxicity, lupus like syndrome, bone marrow toxicity, hepatotoxicity etc. Dose- 1000-1500 mg/day in 2-4 divided doses. Maintenance dose is usually 750-1000 mg/day.

Trientine – It is another chelator. Like penicillamine, trientine promotes copper excretion by the kidneys.   Trientine is an effective treatment for WD and is indicated especially in patients who are intolerant of penicillamine.  Dose- 750-1500 mg/day in 2-3 divided doses, with 750-1000 mg used for maintenance therapy.   As for penicillamine, trientine should be administered one hour before or two hours after meals.

Zinc – Zinc acts by interfering with the uptake of copper from the GI tract. Zinc induces enterocyte metallothionein, which binds copper present in the enterocyte and inhibits its entry into the portal circulation. Once bound, the copper is not absorbed but is lost into the focal contents as enterocytes are shed in normal turnover.  Zinc is currently reserved for maintenance treatment. Dose- 150 mg of elemental zinc per day in 2 divided doses.

How do you monitor adequacy of treatment?

Adequacy of treatment can be monitored by clinical and biochemical improvement and by measuring 24-hour urinary copper excretion while on treatment. This should run in the vicinity of 200 to 500 µg (3 to 8 µmoles) per day on treatment with chelators (less than 75 µg wit copper). Additionally, estimate of noncaeruloplasmin-bound copper may show normalization with effective treatment.  Urinary excretion of zinc may be measured from time to time to check compliance

Discuss the management of WD?

• Treatment is lifelong and should not be discontinued, unless a liver transplant has been performed.
• Foods with very high concentrations of copper (shellfish, nuts, chocolate, mushrooms, and organ meats) generally should be avoided, at least in the first year of treatment.
• Antioxidants, mainly vitamin E, may have a role as adjunctive treatment.
• Treatment should be initiated with a chelating agent in both symptomatic and asymptomatic or presymptomatic patients identified through family screening. Zinc may be used as the first agent in presymptomatic patients.
• Maintenance therapy – After adequate treatment with a chelator (usually for 1-5 years), stable patients may be transitioned to treatment with zinc. They will be clinically well, with normal serum aminotransferases and hepatic synthetic function, nonceruloplasmin-bound copper concentration in normal range, and 24-hour urinary copper repeatedly in the range of 200 to 500 µg (3 to 8 µmoles) per day on treatment. The advantages of long-term treatment with zinc include that it is more selective for removing copper than penicillamine or trientine and is associated with few side effects. Adequate studies regarding the timing of this change-over in treatment are not available. No matter how well a patient appears, treatment should never be terminated indefinitely. Patients who discontinue treatment altogether risk development of intractable hepatic decompensation.
• In pregnant women, treatment must be maintained throughout the course of pregnancy for all patients with WD. Interruption of treatment during pregnancy have resulted in fulminant hepatic failure.
• Liver transplantation is indicated for all WD patients with decompensated liver disease unresponsive to medical therapy, and it is the only effective option for those who present with fulminant hepatic failure.

Discuss the prognosis?

Long-term outcome is dependent on adherence to lifelong treatment. Patients with WD who commence treatment before onset of symptomatic hepatic or neurologic disease have an excellent long-term prognosis and rarely develop symptoms. Symptomatic patients may expect to stabilize or improve on treatment. A minority of patients with neurologic disease experience worsening with initiation of therapy: some stabilize but some worsen despite treatment. The prognosis for patients with liver disease who adhere to effective treatment is excellent, even if cirrhosis was present at the time of diagnosis.
Development of hepatocellular carcinoma is a rarely reported complication of WD. Screening for hepatocellular carcinoma has not been recommended for WD patients.

Ref

1. AASLD Practice Guidelines: Diagnosis and Treatment of Wilson Disease: An Update

• IV drug abuse is the principal mode of transmission of hepatitis C. Occasional users are likely to share needles because drug use is usually unplanned and with borrowed equipments.
• Sharing straws for snorting cocaine may be a route of infection due to nose bleeds.
• Blood or blood component transfusion or organ transplants before 1992 are other modes of transmission.
• People who received blood products such as haemophiliacs before 1985 will have at risk of infection.
• Sexual transmission of HCV between monogamous partners is uncommon.  Many authorities do not advise the use of barrier protection among monogamous couples. Nevertheless, between 1% and 5% of monogamous sexual partners of index HCV cases test positive for anti-HCV.
• HCV-infected persons should avoid activities that might result in blood exposure, such as sharing a razor or toothbrush.
• Maternal-foetal transmission- risk is about 6%. Unclear whether it happens in the uterus or during birth. Testing infant should be delayed until 8weeks as HCV PCR may be false negative earlier.
• Kissing/cuddling is fine. Breastfeeding is ok unless mother has cracked nipple and child has a cut in mouth. Breastfeeding is not recommended if there is co- infection with HIV..

Discuss the prevalence of Hep C

1. Hep C was discovered and cloned in 1989
2. Three percent of world population is infected- 180million are affected worldwide
3. 250,000 people infected in UK
4. 50% of active injectors will have hep C

Who should be screened for Hep C

1. IDU (intravenous drug users- past or present)
2. Dialysis
3. HIV infection
4. Transfusion or transplant prior to July 1992
5. Haemophiliacs who received factor clotting factor concentrates prior to 1987
6. Children born to HCV-infected mother
7. Current sexual partners of HCV infected persons
8. Health care worker after needle stick injury or mucodal exposure to HCV positive blood
9. People who have had tattoos or body piercings where infection control procedures are poor
10. People who have received medical or dental treatment in countries where infection control is poor and there is high prevalence of hep C eg Southeast Asia and subsaharan Africa

Discuss the natural history of hepatitis C?

• Hep C is described as chronic when infection persists beyond six months
• Up to 85% of individuals who develop acute hepatitis C will remain HCV-infected.
• The risk of developing cirrhosis ranges from 5% to 25% over periods of 25 to 30 years.
• HCC develops only in cirrhotic liver in hepatitis C (1-3% per year)
• Hepatitis C is the principal cause of death from liver disease and the leading indication for liver transplantation.

Discuss the diagnosis of hepatitis C?

The incubation period of acute hep C is usually between 6-9 weeks. The HCV antibody usually present three months after the initial infection and in some cases up to six months.Serologic assay that detect speci?c antibody to hepatitis C virus (anti-HCV) is used as a screening test. Confirmation is done with HCV RNA (highly sensitive PCR test)

• Anti HCV +ve HCV RNA +ve Diagnosis confirmed.
• Anti HCV +ve HCV RNA –ve This most likely indicates infection has resolved. However, HCV RNA may be falsely –ve in presence of intermittent or low level viremia. So recheck HCV RNA after 4-6weeks. If 2 tests for HCV RNA are negative, it means Hep C infection has resolved.
• In conditions associated with diminished antibody production such as HIV. Transplant recipients & chronic haemodialysis- negative anti-HCV does not exclude HCV – so HCV RNA may be needed.
• If acute infection is suspected then also HCV RNA is to be requested as it might take 8-12 weeks for anti-HCV to be positive, eg needle stick injury with hepC positive blood.
• If HCV RNA assay is positive- the HCV virus should be genotyped. There are 6 genotypes 1-6. Genotype 1 is the most common followed by genotype 2 and 3

Discuss the role of liver biopsy in hepatitis C?

Liver biopsy provides the stage of liver injury and hence the risk of progression. A liver biopsy was previously considered routine in HCV genotype 1 prior to treatment. However the issue is now in a state of flux. The procedure is not considered mandatory at present before deciding treatment.  However, if a liver biopsy is performed and the histology shows minimal to moderate fibrosis (i.e. portal fibrosis with no septa), treatment may be deferred. If performed and treatment is withheld, a common strategy is to repeat the liver biopsy 4 to 5 years later and to reconsider treatment should there be evidence of disease progression.

A liver biopsy may be unnecessary in persons with genotypes 2 and 3 HCV infection as there is high response to treatment. The need for liver biopsy is uncertain with genotype 4-6.

So in summary, a liver biopsy should be considered in patients if information is needed regarding ?brosis stage for prognostic purposes or to make a decision regarding treatment

Who should be treated for hepatitis C?

Characteristics of persons for whom therapy is widely accepted-

• At least 18 yrs of age and
• HCV RNA positive and
• Liver biopsy showing chronic hepatitis and significant fibrosis (bridging fibrosis or higher)&
• Compensated liver disease (bilirubin <1.5, INR < 1.5, Albumin >3.4, Platelets >75,000)&
• Acceptable haematological & biochemical indices (Hb- normal, neutrophil >1.5, creatinine <1.5)
• No contraindications of interferon or ribavirin
• Patient should be vaccinated against Hep B and Hep A

What are the contraindications for hepatitis C treatment?

• Major uncontrolled depressive illness
• Solid organ transplant (renal, heart, or lung)
• Autoimmune hepatitis or other autoimmune condition known to be exacerbated by peg interferon and ribavirin
• Decompensated liver cirrhosis
• Untreated thyroid disease
• Pregnant or unwilling to comply with adequate contraception
• Severe concurrent medical disease such as severe hypertension, heart failure, signi?cant coronary heart disease, poorly controlled diabetes, chronic obstructive pulmonary disease,epilepsy
• Age less than 2 years
• Known hypersensitivity to drugs used to treat HCV

Discuss the treatment for hepatitis C?

The optimal therapy for chronic HCV infection is the combination of peg interferon alfa and ribavirin.

Treatment of HCV genotype 1 and 4

• Treatment with peg interferon plus ribavirin should be planned for 48 weeks;
• Treatment may be discontinued in patients who do not achieve an early virological response (EVR; >2 log reduction in HCV RNA at week 12 of treatment). If an EVR is not seen, there is a less than 2% chance of achieving a SVR
• Patients who do not achieve a complete EVR (undetectable HCV RNA at week 12 of treatment) should be re-tested at week 24, and if HCV RNA remains positive, treatment should be discontinued.
• For patients with genotype 1 infection who have delayed virus clearance (HCV RNA test becomes negative between weeks 12 and 24), consideration should be given to extending therapy to 72 weeks.
• Patients with genotype 1 infection whose treatment continues through 48 to 72 weeks and whose measurement of HCV RNA is negative at the end of treatment should be retested for HCV RNA 24 weeks later to evaluate for a sustained virological response (SVR; HCV RNA negative 24 weeks after cessation of treatment)

Treatment of HCV genotype 2 and 3

• Treatment with peg interferon plus ribavirin should be administered for 24 weeks, using a ribavirin dose of 800 mg (Class I, Level A).
• Patients whose treatment continues through 24 weeks and whose measurement of HCV RNA is negative should be retested for HCV RNA 24 weeks later to evaluate for an SVR

NB:

• Patients with HCV-related cirrhosis who achieve an SVR, regardless of the genotype, should continue to be monitored at 6-12 month intervals for the development of HCC
• Patients with HCV-related compensated cirrhosis can be treated with the standard regimen of pegylated interferon and ribavirin but will require close monitoring for adverse events Patients with HCV-related decompensated cirrhosis should be referred for consideration of liver transplantation.
• Doses- the dose for peg interferon alfa-2a is 180g subcutaneously per week together with ribavirin using doses of 1,000 mg for those < 75 kg in weight and 1,200 mg for those > 75 kg; the dose for peg interferon alfa-2b is 1.5 g/kg subcutaneously per week together with ribavirin using doses of 800 mg for those weighing <65 kg; 1,000 mg for those weighing >65 kg to 85 kg, 1,200 mg for >85 kg to 105 kg, and 1,400 mg for >105 kg.
• Vaccinate against Hep A and B, if HBsAg and anti HAV negative Hep A on chronic C can cause fulminant hepatitis.
• Success with the treatment above: SVR of more than 80% in genotype 2 and 3 and 50% for genotype 1
• Presence of symptomatic cryoglobulinemia (extrahepatic manifestation) is an indication for HCV therapy- regardless of stage of liver disease.
• Achieving an SVR at 6m post treatment is likely to be maintained indefinitely in more than 98% of patients and a 2 year SVR represents a cure in all cases

Discuss the management of non responders and relapsers?

• Non-responders to peg interferon and ribavirin with advanced ?brosis should be screened for HCC and varices and be evaluated for liver transplantation. Patients with mild ?brosis should be monitored without treatment.
• In the majority of instances, virological relapse occurs within the ?rst 12 weeks and late relapse, beyond 24 weeks, is extremely uncommon. Patients with virological relapse are likely to respond to the same regimen given a second time but will still experience an unacceptable rate of relapse.
• Retreatment with peg interferon plus ribavirin can be considered for non-responders or relapsers who have previously been treated with non-pegylated interferon with or without ribavirin, or with peg interferon monotherapy, particularly if they have bridging ?brosis or cirrhosis

Discuss management of HCV patients with normal ALT?

A normal ALT does not exclude advanced fibrosis or even cirrhosis. Thus, the decision to treat should be based on the severity of liver disease by liver biopsy, the potential for serious side effects, the likelihood of response, and the presence of co-morbid conditions rather than ALT levels

Discuss treatment of acute hepatitis C?

Acute hepatitis C can be diagnosed based on the clinical presentation: namely the presence of symptoms o r jaundice, and whether or not there was a prior history of ALT elevation and its duration. After acute infection, HCV RNA is usually detected in serum before antibody; HCV RNA can be identi?ed as early as 2 weeks following exposure whereas anti-HCV is generally not detectable before 8-12 weeks.

There is good evidence that treatment reduces the risk of chronic infection and the response rate to treatment is higher with acute than with chronic HCV. Thus patients with acute HCV infection should be considered for interferon-based anti-viral therapy.

Treatment can be delayed for 8 t o 1 2 weeks after acute onset of hepatitis to allow for spontaneous resolution. There is currently limited data on the duration of treatment and addition of ribavirin to the treatment of acute hepatitis C. However, it is reasonable to treat for at least 12 weeks and ribavirin should be considered on a case-by-case basis.

Discuss the side effects of HCV treatment?

Related to IFN

1. Flu-like symptoms
2. Marrow suppression (especially leukopenia and thrombocytopenia)
3. Emotional effects (irritability, difficulty concentrating, memory disturbances, and depression)
4. Autoimmune disorders (especially thyroiditis)
5. Hair loss, Rash, Diarrhea, Sleep disorders
6. Visual disorders (rarely retinal hemorrhages, especially in diabetic & hypertensive patients)
7. Weight loss, Seizures, Hearing loss, Pancreatitis
8. Interstitial pneumonitis, Injection site reactions

Related to ribavirin

1. Hemolytic anemia
2. Chest congestion, dry cough, and dyspnea
3. Pruritus, Sinus disorders
4. Rash, Gout, Nausea
5. Diarrhea, Teratogenicity (Contraception-very imp)

Discuss HCV and needle stick injury?

The likelihood of acute HCV infection after an accidental needle stick is only approximately 3% and because antiviral therapy initiated after the onset of hepatitis C viremia is so effective, treatment to prevent HCV infection need not be initiated prophylactically after needle stick exposure.

Discuss the terminology:

RVR- Rapid virological response- HCV RNA negative at treatment week 4- may allow shortened course for G2&3 and possibly G1 with low virological load

EVR- Early virological response- >= 2 log reduction (100fold decrease) in HCV RNA compared to baseline (Partial EVR) or HCV RNA negative at treatment week 12 (Complete EVR)

ETR- End of treatment response- HCV RNA negative at end of treatment either 23 weeks (for G2&3 or 48weeks for G1)

SVR- Sustained virological response- HCV RNA negative 24 weeks (6months) after cessation of treatment

Nonresponder- Failure to clear HCV RNA after 24 weeks of treatment

Relapse- Reappearence of HCV RNA after therapy is discontinued

Breakthrough- Reappearence of HCV RNA while still on therapy

Partial responder- Two log decrease in HCV RNA but still HCV RNA positive at week 24

Factors indicating favourable response:

1. Viral genotype- non G1
2. Low viral load- less than 600,000IU/ml
3. Dose of peginterferon and ribavirin
4. Female gender
5. Age less than 40yr
6. Non African-American race
7. Lower body weight <75kg
8. Absence of insulin resistance
9. Elevated ALT
10. Absence of bridging fibrosis or cirrhosis
11. Shorter duration of disease

The two different types of peginterferons:

Roche products:

Pegasys- Peginterferon alpha 2a

Copegus- ribavirin

• Doses- 180 micrograms subcutaneously per week together with ribavirin using doses of 1,000 mg for those < 75 kg in weight and 1,200 mg for those > 75 kg;

Schering Plough products:

Viraferon Peg- Peginterferon alpha 2b

Rabetol-ribavirin

• Dose for peg interferon alfa-2b is 1.5 micrograms/kg subcutaneously once a week together with ribavirin using doses of 800 mg for those weighing <65 kg; 1,000 mg for those weighing >65 kg to 85 kg, 1,200 mg for >85 kg to 105 kg, and 1,400 mg for >105 kg.

Duration of treament:

G2/G3- 24 weeks

G1/G4-6 48weeks

Stop treatment if no 2 log drop of HCV RNA at week 12 or HCV RNA detectable at week 24.

Extended duration:

1. G1/4-Cirrhotic patient, partial EVR at 12 weeks- consider 72 weeks provided HCV RNA is negative at 24 weeks
2. G2/3- Cirrhotic patient/partial EVR at 12 weeks – consider 48 weeks

Reduced duration:

1. G1/4 if RVR, young (<40yrs), BMI<25 and baseline HCV RNA <400,000IU/ml, fibrosis mild-moderate- consider 24 weeks.
2. G2/3- if RVR and complete EVR particularly if also young (<40yrs), BMI<25 and baseline HCV RNA <400,000IU/ml, fibrosis mild-moderate- consider 16 weeks

Special group of patients

1. Co-infection- peglylated interferon alpha -2a (180mcg weekly) plus weight based ribavirin for 48 weeks.. Treatment should be withheld if CD4 count is less than 200/ml until this is corrected with highly active antiretroviral therapy.
2. Post liver tranplant- start at low doses peglylated interferon alpha -2b 0.5microgram/kg and Rebetol 200-400mg od and increase every two weeks – duration 48 weeks
3. Renal dysfunction- peglylated interferon alpha -2a 135microgram weekly and copegus 200mg od and (if dialysis patient)- duration 48 weeks

Advise regarding sex:

sexual transmission is rare but does occasionally occur.

Risk is increased if there is history of sexually transmitted disease, anal/rough sex or sex during period or multiple partners.

Oral sex is low risk

Couples if one positive and other negative – if they are in stable relation- unnecessary to use condom. Advise to avoid sex during menstruation.

Advice regarding alcohol:

Patient should not drink alcohol. Research has shown that alcohol aggravates hepatitis C infection and progression from chronic hepatitis C to cirrhosis is hastened in those who drink alcohol. It also reduces the efficacy of combination treatment.

Assessment prior to treatment and monitoring during and after therapy:

1. All patients will have relevant blood tests, liver ultrasound and liver biopsy if clinically indicated
2. Vaccinated against Hep B and Hep A
3. Assess risk of coronary heart disease (ECG), uncontrolled diabetes (fasting glucose) and hypertension
4. Exclude thyroid disease (TSH normal)
5. Assess for depression- referral to liaison psychiatry need to be done if positive history
6. Advise regarding strict avoidance of pregnancy
7. Discussion of potential side effects
8. Active substance use is not a contraindication to treatment but is a factor that is taken into account when assessing the patient’s ability to tolerate therapy.

Monitoring during treatment:

1. Assessment for side-effects and depression-Peg interferon are subject to black triangle system. All suspected drug reactions should be reported to the CSM using a yellow card
2. A reasonable schedule would be monthly visits during the first 12 weeks and then every 8 weeks until the end of treatment
3. At each visit patient should be questioned about side effects, depression and adherence to treatment.
4. Hospital Anxiety and Depression Scale (HADS) is a self screening questionnaire for depression and anxiety. This tool may be a useful supplement to clinical judgement.
5. At each visit the blood test should include FBC, U/E, LFT, and HCV RNA at 4,12,24 weeks and 4-12 weeks interval thereafter , the end of treatment and 24 weeks after stopping the treatment.
6. Eye examination if any concern
7. CXR if any respiratory symptoms

Treatment of common side-effects

1. Flu like symptom and myalgia is very common. Injection should preferably taken in the evening and paracetamol should be given before the injection and for the rest of the day in recommended doses.
2. Mild depression can be treated with a SSRI like citalopram- psychiatric assessment or support might be needed.
3. Insomnia- Zopiclone 7.5mg od (not always prescribed in prison setting)
4. Itchy skin- piriton and E45
5. Sore mouth- Difflam mouthwash

Dose modification

1. If Hb drops to less than 10g/dl or drops by 2g/dl- reduce Ribavirin by 200mg decrement. Might consider erythropoitin injection. If still worsening anamia ? discontinuation of treatment. It is important to minimise ribavirin dose reduction in the first 12 weeks as this has the most effect on SVR
2. If more than one dose reduction is needed for ribavirin – treatment with erythropoietin should be considered (up to 40,000units weekly). Randomised controlled trials have shown this to be effective at preventing large dose reduction and/or discontinuation of treatment, thus increasing SVR. This is recommended by SIGN guidance.
3. If platelet <50,000/mm3, WBC < 1.5X109/L, neutrophil < 750/mm3, progressive increase in ALT- Reduce PEGASYS to 135microgram/week or VIRAFERON PEG to one half dose unit each week
4. Stop treatment if platelet <25,000/mm3, neutrophil <500/mm3, WBC <1x109/L,
5. Stop Ribavirin if Hb drops below 8.5g/L despite dose reduction

Newly licensed drugs for Hep C:

There are currently about 48 treatments in trial. Some are monotherapies (drugs or therapies taken on their own) and some are for use in conjunction with existing HCV treatments. Some of these developmental treatments have shown promising results in clinical trials.

Two drugs that have already been approved for safety by the FDA and the European equivalent are Telaprevir (Janssen) and Boceprevir (Merck/MSD).

Both Boceprevir (Victrelis) and Telaprevir (Incivo, Invivek) have now been licensed but not NICE approved. This means that they can now be prescribed but the NHS may not fund it. Alternatively a patient may pay for it themselves. It is expected that these drugs will be approved by NHS between spring and summer 2012.

Both of these drugs are protease inhibitors, which are treatments that aim to prevent HCV from replicating.

Both Boceprevir and Telaprevir is for patients with Genotype 1. It is a protease inhibitor that helps target the virus and is added to the current treatment of Interferon and Ribavirin. It will mean the patient will be taking a combination of 3 drugs. It can boost the success rate of clearing the virus from 50% to 80% and in some cases will shorten the time that a patient needs to be on treatment.

If a patient has never done treatment before (Treatment Naive) then it is estimated that over 50% of them will only have to do 28 weeks treatment. However, all those who have done treatment before but not cleared the virus (treatment experienced) will still do 48 weeks.

Treatment time is calculated using a system called response guided therapy (RGT). This means that tests are done at various weeks into treatment that can tell how well a patient is responding to the treatment. This can help ensure that the patient does not stay on treatment longer than necessary.

Ref/Useful website

1. AASLD Practice Guidelines.  Diagnosis, Management, and Treatment of Hepatitis C: An Update 2009
2. Hep C trust

Although most carriers will not develop hepatic complications from chronic hepatitis B, 15% to 40% will develop serious sequelae (cirrhosis/HCC) during their lifetime.

Discuss the modes of transmission of HBV?

HBV is transmitted by perinatal, percutaneous, and sexual exposure, as well as by close person-to-person contact presumably by open cuts and sores, especially among children in hyper endemic areas.
HBV can survive outside the body for prolonged periods, and carriers who are HBeAg positive can shed large quantities of viral particles on environmental surfaces through open cuts or sores. The risk of developing chronic HBV infection after acute exposure ranges from 90% in newborns of HBeAg-positive mothers to 25% to 30% in infants and children under 5 and less than 10% in adults.

Who should be tested for HBV?

Persons born in hyper endemic areas, men who have sex with men, injecting drug users, dialysis patients, HIV-infected individuals, pregnant women, and family members, household members, and sexual contacts of HBV-infected persons. Testing for HBsAg and antibody to HBsAg (anti-HBs) should be performed, seronegative persons should be vaccinated.

Discuss the diagnostic criterion for chronic hepatitis B?

Chronic hepatitis B

• HBsAg + > 6 months
• Serum HBV DNA >20,000 IU/ml (>105 copies/ml)
• Persistent or intermittent elevation in ALT/AST levels
• Liver biopsy showing chronic hepatitis (necroinflammatory score more than equal to 4)

Inactive HBsAg carrier state

• HBsAg+ > 6 months
• HBeAg-, anti-HBe+
• Serum HBV DNA <2000 IU/ml
• Persistently normal ALT/AST levels
• Liver biopsy confirms absence of significant hepatitis (necroinflammatory score <4)

Discuss the serologic patterns of chronic HBV infection?

• Perinatal transmission- occurs mostly in Asia and the South Pacific Islands. Persistence of HBeAg is longer and seroconversion does not occur in most persons until later in adulthood. Among individuals with perinatally acquired HBV infection, a large percent of HBeAg-positive patients have high serum HBV DNA but normal ALT levels. These patients are considered to be in the “immune tolerant” phase. Many of these patients develop HBeAg-positive chronic hepatitis B with elevated ALT levels described as pattern 2 in later life.
• In sub-Saharan Africa, Alaska, and Mediterranean countries, transmission of HBV usually occurs from person to person in childhood, whereas perinatal transmission is less common. In these populations most children who are HBeAg positive have elevated ALT levels and seroconversion to anti-HBe is common near or shortly after the onset of puberty.
• The third pattern is usually observed in individuals who acquired HBV infection during adulthood. This is most common in developed countries where sexual transmission is the predominant mode of spread. Very little longitudinal data is available on the latter patients but liver disease is generally present in patients with high HBV DNA levels.

Discuss the natural history of HBV?

• The rate of clearance of HBeAg averages between 8% and 12% per year. HBeAg clearance may follow an exacerbation of hepatitis, manifested by an elevation of ALT levels.
• After spontaneous HBeAg seroconversion, 67% to 80% of carriers remain HBeAg negative and anti-HBe positive with normal ALT levels and minimal or no necroinflammation on liver biopsy. This has been referred to as the “inactive carrier state.”
• The course and outcome of the inactive HBsAg carrier state is generally but not invariably benign. Up to 20% of carriers in the inactive state can have exacerbations of hepatitis, as evidenced by elevations of ALT levels to 5 to 10 times the upper limit of normal, with or without seroreversion to HBeAg. Repeated exacerbations or reactivations can lead to progressive fibrosis.
• Approx 0.5% of HBsAg carriers will clear HBsAg yearly; most will develop anti-HBs.

Discuss HBeAg negative chronic hepatitis?

Most patients with HBeAg negative chronic hepatitis B harbour HBV variants in the precore or core promoter region. The most common precore mutation, G1896A, creates a premature stop codon in the precore region thus abolishing production of HBeAg.
Patients with HBeAg-negative chronic hepatitis B tend to have lower serum HBV DNA levels than those with HBeAg-positive chronic hepatitis B and are more likely to run a ?uctuating course. These patients are also older and have more advanced liver disease since HBeAg-negative chronic hepatitis B represents a later stage in the course of chronic HBV infection.

Patients with compensated cirrhosis who were HBeAg-negative had significantly better 5-year survival (97%) than those who were HBeAg-positive (72%).

Discuss the evaluation of patients with chronic HBV infection?

• History and physical examination
• Family History of liver disease, HCC
• Laboratory tests to assess liver disease—complete blood counts with platelets, liver screen, and prothrombin time
• Tests for HBV replication—HBeAg/anti-HBe, HBV DNA
• Tests to rule out viral coinfections—anti-HCV, anti-HDV and anti-HIV in those at risk
• Tests to screen for HCC–AFP at baseline and, in high risk patients, ultrasound
• Consider liver biopsy to grade and stage liver disease – for patients who meet criteria for chronic hepatitis.
• All persons with chronic hepatitis B not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6 to 18 months apart. Prevaccination screening for antibody to hepatitis A should be considered if the prevalence of infection in the population is likely to be greater than 33%.

Who would you consider for treatment?

The following patients should be considered for treatment:

• HBsAg+, HBeAg+ and ALT > 2 times the upper limit of normal
• HBsAg+, HBeAg- , HBV DNA > 20,000 IU/ml and ALT > 2 times the upper limit of normal.

Liver biopsy is optional in the above two groups. Also, HBeAg-positive patients with elevated ALT levels and compensated liver disease should be observed for 3 to 6 months for spontaneous seroconversion from HBeAg to anti-HBe prior to initiation of treatment.

A liver biopsy should be considered if the ALT in either of the above two groups is persistently more than 1-2 times the upper limit of normal (especially in age above 40). Consider treatment if biopsy shows moderate/severe in?ammation or signi?cant ?brosis.

Discuss follow up of patients not considered for treatment?

• HBeAg-Positive Patients with High Serum HBV DNA but Normal ALT Levels. These patients should be monitored at 3 to 6 month intervals.
• HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/mL (inactive carriers) should be tested for ALT every 3 months during the ?rst year to verify that they are truly in the “inactive carrier state” and then every 6-12 months.

What is the goal of HBV treatment?

The aims of treatment of chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. The ultimate goal is to prevent cirrhosis, hepatic failure and HCC. Parameters used to assess treatment response include normalization of serum ALT, decrease in serum HBV DNA level, loss of HBeAg with or without detection of anti-HBe, and improvement in liver histology.

Discuss the drugs available for HBV?

Current therapy of chronic hepatitis B has limited long-term efficacy. Thus, careful balance of patient age, severity of liver disease, likelihood of response, and potential adverse events and complications is needed before treatment is initiated.
The ?rst-line drugs recommended for treatment of hepatitis B are pegIFN, entecavir or tenofovir. In view of the high rate of drug resistance during long-term treatment, lamivudine and telbivudine are not preferred. Since adefovir is less potent than other NA and is associated with increasing rate of antiviral resistance after the ?rst year of therapy, it is best utilized as a second line drug in treatment-naive patients.
The advantages of IFN- include a finite duration of treatment, more durable response, and the lack of resistant mutants. The disadvantages of IFN- are the costs and side effects.

Discuss the treatment of HBV?

• HBeAg+ chronic hepatitis- IFN?/PEG IFN? or one of the nucleoside analogues (NA) may be used as initial therapy. Entecavir or tenofovir is preferred.
  • Duration of therapy:
    • IFN? 16 weeks
    • PegIFN?- 48 weeks
    • NA’s- Treatment should be continued until the patient has achieved HBeAg seroconversion (at least 12 months)and undetectable serum HBV DNA and completed at least 6 months of additional treatment after appearance of anti-HBe.
  • Efficacy of treatment
    • IFN- Loss of HBeAg and HBV DNA in approx 1/3 rd of the cases. Response is durable in 80-90% of cases.
    • NA treatment for 48-52 weeks- loss of e antigen-around 30%. Loss of HBV DNA- 60-70% with entecavir and tenofovir. Response is durable in 50-80% of patients.
  • IFN non responders or contraindications to IFN- use NA’s
• HBeAg negative chronic hepatitis- treatment options are as above, however endpoint of treatment is not defined.
  • Duration of treatment
    • IFN- ?/pegIFN-?: 1 year
    • NA’s: more than 1 year. Treatment should be continued until the patient has achieved HBsAg clearance.
  • Efficacy of treatment
    • IFN- loss of HBV DNA 60-70%
    • NA for 48-52 weeks treatment- 90% or more with entecavir or tenofovir. However durability of response is only 10-20% with both IFN and NA
  • IFN non responders or contraindications to IFN- use NA’s
• Compensated cirrhotic patient with HBV DNA > 2000IU/ml with or without e antigen positivity- consider treatment with NA’s. These patients should receive long-term treatment. However, treatment may be stopped in HBeAg-positive patients if they have con?rmed HBeAg seroconversion and have completed at least 6 months of consolidation therapy and in HBeAg-negative patients if they have con?rmed HBsAg clearance. IFN should not be used because of the risk of hepatic decompensation associated with IFN- related flares of hepatitis.
• Decompensated cirrhosis- Treatment should be promptly initiated with a NA (coordinate care with the transplant centre). Life-long treatment is recommended.
  NB
• Patients who failed to achieve primary response as evidenced by <2 log decrease in serum HBV DNA level after at least 6 months of NA therapy should be switched to an alternative treatment or receive additional treatment.

Discuss the dose regimens?

• IFN- 5 MU SC daily or 10 MU thrice weekly. PEG IFN- 180mcg SC weekly.
• All NA’s are administered orally.

Discuss HCC surveillance in HBV infection?

HBV carriers at high risk for HCC such as Asian men over 40 years and Asian women over 50 years of age, persons with cirrhosis, persons with a family history of HCC, Africans over 20 years of age, and any carrier over 40 years with persistent or intermittent ALT elevation and/or high HBV DNA level >2,000 IU/mL should be screened with US examination every 6-12 months.

Discuss antiviral prophylaxis of HBV who receive immunosuppressive or cytotoxic therapy?

• Reactivation of HBV replication with increase in serum HBV DNA and ALT level has been reported in 20% to 50% of hepatitis B carriers undergoing immunosuppressive or cancer chemo therapies. In most instances, the hepatitis flares are asymptomatic, but icteric flares, and even hepatic decompensation and death have been observed.
• HBsAg and anti-HBc testing should be performed in patients who are at high risk of HBV infection, prior to initiation of chemotherapy or immunosuppressive therapy.
• Prophylactic antiviral therapy is recommended for HBV carriers at the onset of cancer chemotherapy or of a ?nite course of immunosuppressive therapy.
• Patients with baseline HBVDNA<2,000IU/mL level should continue treatment for 6 months after completion of chemotherapy or immunosuppressive therapy.
• Patients with high baseline HBV DNA (>2,000 IU/mL) level should continue treatment until they reach treatment endpoints as in immunocompetent patients.
• Lamivudine or telbivudine can be used if the anticipated duration of treatment is short (<12 months) and baseline serum HBV DNA is not detectable.
• Tenofovir or entecavir is preferred if longer duration of treatment is anticipated.
• IFN should be avoided in view of the bone marrow suppressive effect.

Discuss management of pregnant women with HBV?

Newborns of HBV-infected mothers should receive HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series. (With this strategy- a recent study showed no increased risk with breast feeding).

Discuss precautions for infected persons regarding prevention of transmission of HBV to others?

Persons who are HBsAg-positive should:

• Have sexual contacts vaccinated
• Use barrier protection  if partner not vaccinated or naturally immune.

• Not share toothbrushes or razors
• Cover open cuts and scratches
• Clean blood spills with detergent or bleach
• Not donate blood, organs or sperms

Children and adults who are HBsAg-positive:

• Can participate in all activities including contact sports
• Should not be excluded from day care or school participation and should not be isolated from other children
• Can share food, utensils, or kiss others

Discuss treatment of acute hepatitis B?

• Antiviral therapy is generally not necessary in patients with symptomatic acute hepatitis B because 95% of immunocompetent adults with acute hepatitis B recover spontaneously.
• Treatment is only indicated for patients with fulminant hepatitis B and those with protracted, severe acute hepatitis B (increase in INR and deep jaundice persisting for more than 4 weeks).
• Lamivudine or telbivudine may be used when the anticipated duration of treatment is short; otherwise, entecavir is preferred.
• Treatment should be continued until HBsAg clearance is con?rmed or inde?nitely in those who undergo liver transplantation.
• IFN is contraindicated.

Ref

1. AASLD Practice Guidelines. Chronic Hepatitis B: Update 2009

PVT was first described in 1868. PVT consists of two different entities, acute PVT and chronic PVT, which represent successive stages of the same disease.

What are the causes of PVT?

PVT is caused by a combination of local and general risk factors. A local risk factor can be identified in about 30% of patients, and a general risk factor in 70%.
Local risk factors: cancer of any abdominal organ, cirrhosis, inflammatory foci in the abdomen (diverticulitis, appendicitis, cholecystitis, pancreatitis, IBD etc), injury to the portal venous system at surgery
General risk factors: an inherited or acquired prothrombotic condition has been found in many patients with PVT. Thus general thrombophilic factors should be investigated, even when a local factor for portal vein thrombosis is evident.  30%-40% of patients with PVT are affected with chronic, Philadelphia-negative myeloproliferative diseases, usually polycythemia vera, essential thrombocythemia, or unclassified myeloproliferative diseases. Other causes- deficiencies in protein C, in protein S and in antithrombin, gene mutations in factor V Leiden (FVL) and factor II prothrombin. The acquired thrombophilic disorders include malignancy, myeloproliferative disorders, oral contraceptive pills, pregnancy and postpartum, antiphospholipid syndrome and paroxysmal nocturnal haemogobinuria.

Discuss the clinical features of acute PVT?

Diagnosis needs a high index of suspicion and very often radiologist is usually the first physician to suggest the diagnosis on the basis of imaging findings. The patients usually have abdominal pain. Ascites may occur transiently immediately after the thrombotic event. Patients may have abdominal tenderness. Other common complaints of patients with portal vein thrombosis include nausea, vomiting, anorexia, weight loss, diarrhoea and abdominal distension.  Liver function is preserved
in patients with acute PVT, however, a transient, moderate increase in serum aminotransferases can be observed in some patients.
The main complication of acute PVT is intestinal ischaemia when thrombosis extends to the mesenteric venules. When the ischaemic is prolonged for several days, intestinal infarction may follow.  Clinical features include severe
pain (beyond 5-7 days), bloody diarrhoea, acidosis and ascites. In the absence of treatment, intestinal perforation, peritonitis, shock, and death from multiorgan failure occur.

Discuss the diagnosis of acute PVT?

• CT scan or Doppler sonography
• Investigation of general thrombophilic factors must be extensive because an association of several factors is the rule rather than an exception

Discuss the treatment of acute PVT?

The goal of treatment of acute PVT is to recanalize the obstructed veins, which will prevent intestinal infarction and portal hypertension. Spontaneous repermeation is possible but uncommon, whereas complete or partial repermeation can be achieved with anticoagulant therapy in up to 90% of patients.

• Anticoagulation therapy is recommended for at least 3months in all patients with acute PVT. Anticoagulation therapy should be continued long term in patients with acute PVT and permanent thrombotic risk factors that are not correctable otherwise. Long term anticoagulation should also be considered in patients with acute PVT and thrombus extension distally into the mesenteric vein.
• Correction of the causal factors.
• Emergency laparotomy and resection is needed if intestinal infacrtion occurs.

Discuss chronic PVT?

• The natural history of portal vein thrombosis is not known. Portal hypertension develops when there is no repermeation of the portal vein. The proportion that progress to portal hypertension is not known.
• In patients with chronic PVT, also known as portal cavernoma, the obstructed portal vein is replaced by a network of collateral veins connecting the patent portion of the vein upstream from the thrombus to the patent portion downstream.
• Diagnosis is commonly made after a fortuitous finding of hypersplenism or portal hypertension.
• GI bleeding from varices is better tolerated than in other forms of portal hypertension   The occurrence of ascites or encephalopathy in patients with chronic PVT is uncommon.
• A diagnosis of cavernoma is readily made by abdominal imaging with ultrasound, CT or MRI which shows serpiginous structures while the main portal vein and/or its main branches are not visible.
• Consider long-term anticoagulation therapy (to prevent further thrombosis) in patients with chronic PVT, without cirrhosis, and with a permanent risk factor for venous thrombosis, provided there is no major contraindication. In patients with varices, do not initiate anticoagulation until after adequate prophylaxis for variceal bleeding has been instituted.
• Gastroesophageal varices- apply treatment for active variceal haemorrhage and for primary and secondary prophylaxis according to guidelines for patients with cirrhosis.

Discuss PVT and cirrhosis?

PVT is not uncommon in patients with pre-existing cirrhosis. The prevalence of PVT increases with the severity of the cirrhosis.  An underlying prothrombotic condition is difficult to detect in cirrhosis because of a nonspecific decrease in the plasma levels of coagulation inhibitors.
Thus, in patients with well-compensated cirrhosis and acute or chronic PVT, there are limited data on the utility of screening for an underlying prothrombotic condition,
and on the benefits of anticoagulation. However, it may be reasonable to consider anticoagulation in the setting of a known prothrombotic condition or in the setting of SMV thrombosis, but only after adequate prophylaxis for gastrointestinal bleeding has been instituted.

Ref-

AASLD Practice Guidelines. Vascular Disorders of the Liver

• Collection of anatomic and physiological changes brought about by reduction of hepatic venous outflow anywhere from right atrium to small hepatic venules.
• Classical BCS is near complete obstruction to flow of hepatic veins into the inferior vena cava or obstruction of the flow in IVC.
• Venoocclusive disease (VOD) and right heart failure are distinct subgroups with different management.

Discuss the causes of BCS?

Causes may be found in 80%

• Hypercoagulable states- myeloproliferative disorders, Factor V Leiden, Protein C or Protein S deficiency etc. Myeloproliferative disease is the commonest cause (between 20-50%)
• Infections(amoebic liver abscess, TB, Hydatid cyst, Schistosomiasis, Liver abscess, aspergillosis)
• Cancers(HCC, adrenal, Renal cell, Lung cancer, Leukaemia)
• Membranous obstruction of vena cava (MOVC) which can account for up to 40% in Asia.
• Gynaecological: OCP, PCOD, Pregnancy and OCP
• Others: Sarcoid, Crohn’s, Coeliac

Discuss the clinical features of BCS?

Presentation

• Median age at presentation is 34 yrs.
• 67% female
• Ascites in 84% and Hepatomegaly in 75%
• Hepatic vein occlusion in 62 % and IVC occlusion in 7 %. 31% has both.
• Associated Portal vein thrombosis in 34%

Fulminant: Generally pregnancy associated presentation. Severe pain, hepatomegaly, jaundice and ascites. May have hepatic coma. Prognosis is poor.

Acute: Generally present over weeks(less than 6 months). Hepatic coma usually not the presenting symptom.  Hepatitic picture more common.

Chronic: Commonest form of presentation. May be already cirrhotic. Often has large firm liver. Enzymes and bilirubin are less markedly elevated in subacute and chronic forms. Also caudate lobe hypertrophy is seen as blood supply is different.

Discuss the diagnosis of BCS?

• Ultrasound Doppler is the investigation of choice. CT and MRI can be done as well. Look for inability to visualise the hepatic veins to connect to IVC. In CT non or delayed filling of the hepatic veins and rapid clearance of the caudate lobe can be seen.
• IVC or percutaneous transhepatic hepatovenography to confirm in doubtful cases where suspicion is high and Doppler or MRI is negative.
• Arteriography to plan surgical intervention.
• Liver biopsy in doubtful cases and to assess for cirrhosis as cirrhotics will be candidates for transplant.

Discuss the management of BCS?

• Anticoagulation- Use in well compensated acute or chronic patients particularly if they are not for other form of therapies. Monitor for varices.
• Thrombolysis- can be used in acute presentations (less than 3-4 weeks) with good hepatic reserve. It does not work in extensive intrahepatic clot.
• Radiological intervention: Angioplasty, Stent and TIPS are the options. These are generally used in recent onset BCS as salvage procedures before transplant in fulminant cases.
• Shunts- Side to side splenorenal, mesocaval and portocaval shunts. It need patent IVC with not too much pressure difference between supra and infrahepatic portions. Shunts are used for clinically stable acute presentations and chronic presentation with good hepatic reserve.
• Liver transplantation- for patients with decompensated cirrhosis and fulminant hepatic failure.
• Treat the underlying cause.

• Symptoms- Fever, abdominal pain, nausea and vomiting, chest symptoms (cough, chest pain), weight loss, anorexia,
• Signs- abdominal tenderness, hepatomegaly, chest signs like consolidation,  jaundice

Discuss the investigations for liver abscess?

• Abnormal LFTs- raised alkaline phosphatase in majority. Transaminases and bilirubin may be raised too
• CT scan or Ultrasound is used to diagnose PLA. Imaging cannot distinguish amoebic from pyogenic liver abscess
• Gram stain and cultures (both aerobic and anaerobic) of the aspirate
• Blood cultures should be done in all as a significant number are positive in PLA

What are the causes of liver abscess?

• Biliary source of sepsis from gallstones, biliary stricture, ERCP and operation is the commonest cause
• Portal pyaemia from diverticular disease, Crohn’s disease, colon cancer, appendix abscess
• Haematogenous spread of infection
• Cryptogenic- no cause found

Discuss the microbiology of PLA?
Mostly poly microbial with both aerobes and anaerobes
Gram negative bacilli and streptococcus milleri group are important causes
Discuss the management of PLA?
Systemic antibiotics are the mainstay of treatment.  Ciprofloxacin plus metronidazole or augmentin (amoxicillin-clavulanate) may be used as the initial empiric treatment. The antibiotics are initially used IV. The regime should be changed based on the culture and sensitivity results. In the absence of drainage, antibiotics are given for 4-6 weeks. As usual the duration of therapy is guided by the clinical response and use of white cell count, CRP etc. In patients who have had drainage, the duration of therapy can be reduced to 2-4 weeks
Drainage- Large pyogenic abscesses (5 cms or more) usually need drainage, in addition to antibiotics for effective resolution. Drainage may also be needed in patients with poor response to antibiotics alone
There are currently two methods for drainage, namely:
Ultrasound or CT guided percutaneous drainage- a catheter is placed in the abscess cavity and left in place until drainage is minimal (5-7 days)
Surgical- open or laparoscopic drainage- may be required if there is inadequate response to percutaneous drainage.  Surgical drainage may also be preferred if there is an underlying disease requiring primary surgical management. Surgical drainage may also be considered if there are multiple abscesses or if the abscesses are loculated
Discuss the role of large bowel investigations in PLA?
A barium enema or colonoscopy is usually done to locate a source of infection in PLA unless a biliary or other source is apparent.