Figure 8.2 shows complications (only) of CLD. For the approach to the examination for the aetiology (e.g. KF rings and neurological assessment for WD), refer to the short-case section.

Figure 8.2 Chronic liver disease

Investigations

These are outlined in the short-case section on jaundice. It is always worth discussing with the examiners the previous investigations in which you are particularly interested, showing your understanding of the significance of each. Furthermore, you must specify which investigations are important at present, which are likely to be important in future management and how often these should be checked. This may seem obvious, but is often not considered until the examiners put you ‘on the spot’, which is not optimal.

Principles of management of CLD

General

Monitor weight, serum albumin, serum bilirubin (total and conjugated), prothrombin time. Psychosocial support is important.

Nutrition

Deficiencies in nutrients are common in CLD. Patients require a high energy (120–150% of the recommended daily amount) and a moderately high protein intake (3–4 g/kg/day) for growth. Branched chain amino acid enriched formulations have been shown to be clearly advantageous in providing nutritional support and are the formulae of choice. Branched chain amino acids are metabolised in the periphery and do not require the liver for metabolism. Consider enteral feeding if the child is anorectic. Nocturnal nasogastric enteric feeding may be needed: parents can do this at home. Decreased bile flow leads to diminished intraluminal bile acids and fat malabsorption. The provision of adequate essential fatty acids, fat-soluble vitamins (A, D, E, K), zinc, iron and calcium is important. If enteral feeding is not tolerated due to ascites, variceal bleeding or recurrent hepatic complications, TPN may be needed.

Salt and water retention/ascites

The development of ascites is a poor prognostic sign. Management is by sodium restriction (less than 2 mmol/kg/day) and salt restriction to 0.3–0.5 g/day. Aim for a negative salt balance to lose water. A loss of 100–150 mEq of salt will result in a loss of 1 litre (1000 g) of water. Aim for 250 g weight loss per day. Spironolactone (aldosterone antagonist) may be used; salt-poor albumin and frusemide may be needed. An abdominal tap may be diagnostic with infected fluid, but is otherwise of little value. If acute renal failure or hepatorenal failure supervene, haemodialysis or haemofiltration may be necessary.

Encephalopathy

This can be difficult to detect, presenting with vague symptoms of lack of energy, drowsiness and regression in school work. The mainstays of therapy are decreasing the nitrogenous load to the bowel and reducing the bacterial production of ammonia in the colon. Review precipitating factors such as infection, large gastrointestinal bleed, excessive protein intake, electrolyte imbalance and diuretics. Restrict protein (to 2 g/kg/day); consider substitution with branch-chained amino acids. Use oral lactulose and neomycin.

Portal hypertension, varices and variceal haemorrhage

Oesophageal varices inevitably develop with portal hypertension. They can be evaluated endoscopically. Some centres suggest prophylactic sclerotherapy; this is a controversial point, and most centres do not recommend it. An acute episode of variceal bleeding can be life threatening, requiring intensive-care management, intravenous fluids and blood products, and therapy with intravenous vasopressin, octreotide or glypressin to reduce portal pressure. Once the patient is haemodynamically stable and the diagnosis has been confirmed by endoscopy, band ligation or sclerotherapy can be performed. Should these fail, balloon tamponade with a modified Sengstaken–Blakemore tube and intravenous vasopressin for 24–48 hours are useful. Complications of balloon tamponade can include pulmonary aspiration, oesophageal rupture and suffocation.

Endoscopic sclerotherapy has been replaced by band ligation, which ablates varices successfully in 70–100% of cases, has rebleeding rates of 15–30%, has fewer complications than sclerotherapy, except for dysphagia, which is more common with band ligation. In some children, bleeding may be controlled by insertion of a transjugular intrahepatic portosystemic stent shunt (TIPSS), which has success rates of 80–100%: complications include occlusion of stent, the development of encephalopathy and infection. TIPSS can be used to control portal hypertension in children with compensated CLD, such as in some children with CF.

Avoid splenectomy if possible. As well as the risk of infection after splenectomy, it may lead to increased bleeding from removal of good collateral vessels from the splenic capsule (azygos system) that bypass the lower oesophageal junction vessels. Haemorrhage can be exacerbated by deficiency of vitamin K dependent factors, thrombocytopenia secondary to hypersplenism and circulating fibrinolysins.

Coagulopathy

An adequate dose of vitamin K (2–10 mg/day) is needed. Fresh frozen plasma, cryoprecipitate and platelets (for hypersplenism) may be required during bleeding episodes.

Pruritus

Pruritus associated with CLD may cause significant morbidity and may be intractable in children with biliary hypoplasia. Ursodeoxycholic acid is widely used and is the treatment of choice. Often more than one drug is required, including rifampicin, cholestyramine, phenobarbitone, ondansetron and naltrexone.

Drugs

Certain drugs should be avoided in children with CLD. These include phenytoin, sulphonamides, erythromycin and paracetamol.

Sepsis

Infections are common in CLD, especially ascending cholangitis and bacterial peritonitis, and can precipitate encephalopathy, or acute or chronic liver failure.

Other non-transplantation treatment options

There are several areas where there have been recent advances. Replacement of a deficient abnormal end product can be achieved, such as in patients with abnormal biosynthesis of bile acids, by oral administration of primary bile acids. Depletion of the substance stored is another strategy, as used in neonatal iron storage disease with chelation and antioxidant mixtures. Metabolic inhibitors may be used, such as NTBC in tyrosinaemia. Enzymes can be induced, such as with the use of phenobarbitone in Crigler–Najjar syndrome type II. Substrates can be restricted in the diet, as with galactose in galactosaemia. Molecular manipulation can be achieved, such as by inhibition of polymerisation of alpha-1-antitrypsin. Future treatment may incorporate gene therapy and receptor-based targeted enzyme replacement therapy.

Liver transplantation (LTx)

LTx is associated with a survival of 90% at 1 year and 80% at 5 years, and can be used as treatment for a multiplicity of liver diseases, many of which were considered incurable a decade ago. Recent improvements in LTx include refinements in immunosuppression, technical advances in the transplantation process, the use of reduced, split and living related donor organs, and improved management of infectious complications.

Timing of transplantation

The timing of LTx depends upon a variety of factors and may be hastened by any of the following:

1. A history of life-threatening variceal haemorrhage.

2. The development of: (a) a hepatorenal state; (b) hepatic encephalopathy; (c) refractory ascites; (d) reduction in psychosocial development; (e) intractable pruritus; (f) severe metabolic bone disease; or (g) a diminished quality of life.

Assessment occurs in specialist liver units, with preparatory education and counselling of the child and family, a multidisciplinary team that may include a psychologist and a play therapist (especially for children under 2 years), intensive nutritional support, completion of routine immunisation (especially hepatitis A and B) before commencement of immunosuppression, and management of CLD complications.

In the USA, organ allocation is assisted by the PELD (Pediatric End-stage Liver Disease) score, introduced in 2002, to enable the severity of the recipient liver disease to determine the priority list, so that the sickest children are transplanted first. The PELD score ranks children according to their likelihood of death and/or ICU admission within 3 months of listing; it is based on the INR, total bilirubin, serum albumin, age under 1 year, and height less than two standard deviations from the mean for age and gender. The PELD score is used for children up to 12 years. After this age, the MELD score is used. Since this system has been brought in, fewer patients have died waiting for a transplant.

Indications for LTx

As noted above, indications for LTx include failure of hepatic synthetic function, poor quality of life (e.g. intractable pruritis, lethargy, anorexia, recurrent infections), intractable malnutrition or failure to thrive, refractory ascending cholangitis, hyper-ammonaemia from certain inborn errors of metabolism (IEMs), encephalopathy, oesophageal varices from portal hypertension, and hypersplenism.

Specific diseases requiring LTx, in order of decreasing frequency, include the following:

1. Extrahepatic biliary atresia (EHBA): over 50% of LTx.

2. IEMs (10–15% of LTx) include AT deficiency, CF, galactosaemia, glycogen storage diseases (GSDs) type IA and IV, mitochondrial functional defects (e.g. defects of fatty acid beta-oxidation), some organic acidaemias, tyrosinaemia, urea cycle defects and WD.

3. Acute hepatic necrosis (around 10%).

4. Cirrhosis from chronic active hepatitis or primary biliary cirrhosis (under 10%).

5. Cholestatic liver disease, other than EHBA (under 5%).

6. Primary hepatic malignancy (2%).

The only absolute contraindication to LTx is irreversible extrahepatic disease (e.g. HIV, irreversible brain damage, incurable malignancy).

The following requirements must be met for a cadaveric donor for LTx:

1. Brain death prior to circulatory arrest.

2. The absence of sepsis, HBsAg and HBeAg, HIV, malignancy, drug abuse, liver or gallbladder disease, chronic hypertension.

3. Liver enzymes, serum bilirubin within three times normal values.

4. No period of hypoxia (PaO₂ < 60 mmHg) or hypotension (over 2 hours).

5. The absence of more than minimal pressor support to maintain normal blood pressure and peripheral perfusion.

6. To match a recipient, the suitable donor must have ABO compatibility with the recipient. Sex and HLA type compatibility are not necessary.

There have been many technical innovations in the LTx process. These include reduction hepatectomy (cutting an adult liver down, in an anatomical fashion, to fit one child, which wastes some of the adult liver), followed by the development of split-LTx (one donor liver offered to two recipients, usually an adult and a child) and then living related LTx (where the left lobe [occasionally the right lobe] or left lateral segment is removed from the parent/adult liver).

Transplant surgery procedure

The procedure itself has three main phases: (a) recipient hepatectomy, which can be complicated because of coexistent coagulopathy and portal hypertension (bleeding) and previous Kasai (adhesions); (b) the anhepatic phase, when the patient has the vascular anastomoses performed (vena cava, portal vein, hepatic artery), and then placement of the graft; (c) the neohepatic phase, where the liver graft is reperfused (cardiovascular instability can occur here, as the liver has been exposed to cold preservation techniques) and the biliary anastomosis performed—in patients with EHBA, the donor duct will be implanted into a Roux-en-Y loop, as there is no recipient biliary tree. This latter technique is also useful in small children who receive a segmental graft.

Complications of LTx

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