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

Rejection occurs most often in the first 3 months after transplant; it is less common in children under 6 months and in those receiving a living donor graft. The liver allograft is an ‘immunologically privileged’ organ, because rejection, especially if steroid sensitive, has no adverse effect on graft survival or even function. Further, some studies show that rejection itself may benefit patient survival. It seems that some rejection may be protective of graft function: a controlled amount of immune activation seems necessary (perhaps to delete clones of the recipient’s lymphocytes that can damage the graft). Most late graft losses are related to immunosuppression: either too much leading to sepsis, post-transplant lymphoproliferative disease (PTLD), lymphomas or other de novo tumours, or too little leading to graft loss, which is often a result of non-compliance (especially in teenagers). Chronic rejection is becoming rare, which some attribute to increased use of tacrolimus. Increased awareness of the adverse effects of immunosuppression is channelling interest into achieving just the right amount of immunosuppression: enough to prevent damaging rejection, but without the risks of unnecessary over-immunosuppression.

Graft rejection (60%)

• Rejection is the main cause of graft dysfunction following LTx.

• Late acute rejection can occur anywhere from 1 month to several years post-LTx. It can be associated with immunosuppressant non-compliance. It presents with increased transaminases, fever, malaise or jaundice; liver biopsy shows acute cellular rejection (ACR); it responds to pulse steroids, increased calcineurin inhibitors, and addition of another immunosuppressant such as mycophenolate mofetil; if unresponsive to these, treat with anti-T cell antibody preparations.

• Chronic rejection (also known as ‘ductopaenic rejection’), with the loss of over 50% of bile ducts, occurs 6 weeks to 6 months after LTx and can lead to biliary strictures, cholangitis and cholestasis. Treatment may include optimising immunosuppression, and dilatation of strictures. Severe allograft dysfunction could require re-transplantation.

• Autoimmune hepatitis can develop irrespective of initial disease process. It can occur months to years after LTx. It is treated with the addition of azathioprine and prednisolone to the immunosuppressive regimen.

Infection (50%)

• Earlier infections (up to 1 month after LTx) tend to be bacterial or fungal. Intra-abdominal and line infections are the most common early causes. Bacterial and fungal infections can be secondary to technical complications such as vascular thrombosis, bile leaks and strictures. Fungal sepsis, especially aspergillosis, can be seen with re-operation, bowel perforation and long stays in intensive care: prophylaxis is with antifungal agents such as itraconazole and fluconazole, or newer drugs (e.g. the caspofungins) and the lipid complex formulation of amphotericin (less nephrotoxic).

• Later infections (2–6 months after LTx) tend to be viral (e.g. cytomegalovirus [CMV], Epstein–Barr virus [EBV], herpes varicella-zoster virus [HVZ]) and have been reduced by prophylactic courses of ganciclovir, acyclovir and CMV hyper-immunoglobulin. Still later infections (>6 months) may be viral or fungal. Common respiratory viruses (adenovirus, parainfluenza, influenza) can produce necrotising pneumonitis.

• Fever in a young child in the first 12 months after LTx deserves assessment for sepsis, and depending on degree of immunosuppression, may need hospitalisation and intravenous broad-spectrum antibiotic cover.

Biliary complications (20%)

These can occur anywhere from 6 weeks to 6 years post-LTx and may present with cholangitis. There may be extrahepatic strictures (anastomosis site) or intrahepatic strictures (due to ischaemia). Treatment may include percutaneous balloon dilatation, surgical revision or retransplantation.

Hepatic vascular compromise (<10%)

This may be due to hepatic artery, hepatic vein or portal vein stenosis or occlusion. Hepatic artery thrombosis (HAT) can lead to urgent retransplantation, biliary leaks, peritonitis, relapsing septicaemia and biliary strictures. Portal vein stenosis can cause portal hypertension. Treatment may include ballooning, stenting, surgical reconstruction or retransplantation.

Post-transplant lymphoproliferative disorder (PTLD) (EBV-driven B cell proliferation; 5–25%)

This spectrum of disease ranges from lymphohyperplasia to true lymphoma, and may occur 3–12 months post-LTx. It can present with lymphadenopathy. Risk factors include: (a) primary EBV infection after transplant; (b) young age; (c) an EBV-negative recipient of an EBV-positive donor; (d) CMV infection; and (e) significantly immunocompromised children. The evolution of PTLD can be monitored by serial EBV polymerase chain reaction (PCR) determinations in peripheral blood: a rising EBV PCR is sensitive for PTLD. It may be treated by decreasing or stopping immunosuppression (usually successful, but this increases risk of LTx rejection), and starting ganciclovir, acyclovir and CMV hyper-immunoglobulin (has high levels of EBV antibodies). More recent therapies include anti-CD20 monoclonal antibodies (e.g. rituximab), and injection of in-vitro expanded autologous EBV-specific cytotoxic T cells. Mortality is around 20%; this has decreased due to EBV viraemia surveillance.

De novo autoimmune hepatitis (uncommon)

• This can occur in any graft, irrespective of the original disease.

• High transaminases, positive autoantibodies and hepatitis on biopsy.

• Addition of second-line immunosuppressant required; difficult to treat.

Recurrence of primary disease (uncommon)

• Recurrence of the original disease in the graft is uncommon, because liver diseases requiring transplantation are usually congenital or developmental, and LTx is curative.

• Primary sclerosing cholangitis can recur in an almost identical form to the original disease.

• Autoimmune hepatitis and viral hepatitis also can recur.

Chronic hepatitis (uncommon)

• This is a late complication in allografts; usually diagnosed by protocol biopsies, with portal inflammation (without bile duct or vascular changes), with normal transaminases.

• Only recognised recently; the optimal treatment has yet to be clarified.

Primary non-function (PNF) (rare)

• This is rare but catastrophic; probably related to ischaemia/reperfusion injury.

• High transaminases and creatinine, coagulopathy, progress to multisystem organ failure.

• Retransplantation urgently required.

Retransplantation (Re-LTx) (10-20%)

• Not uncommon; early (<30 days) or late (>30 days) after the original LTx date.

• Early re-LTx usually for PNF (see above) or HAT (see above).

• Late re-LTx usually for chronic rejection or biliary complications.

• Decreased survival versus original LTx.

Long-term toxicities of calcineurin inhibitors (CNIs): CSA and tacrolimus

Nephrotoxicity remains the most serious complication of CNIs. The glomerular filtration rate (GFR) is the best way to monitor its development. Early renal impairment can be reversible, and the dose of CNI can be reduced, but at some stage renal impairment can become irreversible. Hypertension that requires therapy occurs in around 20–30% of LTx recipients, and can be compounded by steroid use. Other effects include neurotoxicities and hyperlipidaemia. Some alternatives to CNIs have been used to address this problem, including the addition of either mycophenolate mofetil or sirolimus.

Bowel perforation

This is a feared complication, with high mortality. Previous abdominal surgery increases the risk. As the most common indication for LTx is EHBA with a failed Kasai, many children have a predisposing risk for perforation.

Improved outcomes

Improved immunosuppression has contributed to the improved outcomes of LTx. The main agents used, other than corticosteroids, are the calcineurin inhibitors (CNIs) tacrolimus (TRL) and cyclosporin (CSA). Both inhibit the production of cytotoxic T-lymphocytes and interleukin 2 (IL-2), and have similar side effects, although the former is more potent and does not cause hypertrichosis or gum hyperplasia. Levels of both TRL and CSA may be decreased by concomitant use of anticonvulsants and antituberculous drugs, and may be increased by calcium channel blockers, antibiotics (macrolides and quinolones) and antifungals. TRL is usually combined with steroids alone, whereas CSA is often combined with a third agent, such as mycophenolate mofetil or azathioprine (AZA). TRL is interesting in that its pharmacokinetic patterns retain the characteristics of the age of the donor, not the recipient. Most children may be weaned on to a single immunosuppressive agent. Most units now focus on minimisation of long-term maintenance immunosuppression, with steroid withdrawal as the first step. Some adult LTx protocols avoid steroids entirely and use either polyclonal or monoclonal antibody therapy, instead of steroids, given with TRL or CSA.

Evaluation for complications may include serial LFTs, tissue sampling and imaging, including Doppler ultrasonography for vascular patency, magnetic resonance imaging (MRI) and percutaneous transhepatic cholangiography (PTC).

Long term, there is significant improvement in nutritional status after LTx, with weight, fat stores and muscle mass (protein) recovering within 12 months and, of more importance, maintenance of psychosocial development, normal intellectual functioning, normal (if delayed) puberty, growth spurts with normal final height and participation in age-appropriate activities. Renal dysfunction occurs in around 30% of cases. Malignancy remains a long-term concern. A further concern is the supply of available donors.

Neonatal liver transplant recipients now have similar graft and patient survival rates to older children, and normal neurodevelopmental progress.

Survival rates are very high. Post-LTx death is unusual, and most commonly associated with recurrent malignancy, sepsis, PTLD or multisystem organ failure.

Malabsorption/maldigestion

Malabsorption presents as a diagnostic problem, not a specific disease. It is a state where there is inadequate digestion and/or inadequate absorption across the intestinal mucosa, related to digestive factors (e.g. pancreatic enzymes, bile) and/or absorptive factors (e.g. mucosal changes). The more common causes involve enzymes (cystic fibrosis [CF]) and mucosal surface area (coeliac disease). The presenting complaints may include failure to thrive, loose and frequent bowel motions, abdominal distension, short stature (e.g. coeliac disease), anaemia (folate, vitamin B₁₂ or iron malabsorption) or chest infection (CF).

Aetiology

The common causes in the developed world include:

1. Cystic fibrosis (CF).

2. Coeliac disease.

3. Post-gastroenteritis syndrome.

4. Giardiasis.

5. Bacterial overgrowth (usually associated with congenital gut anomalies or prior gastrointestinal surgery).

In contrast, in the developing world the most common cause of malabsorption is the combination of mucosal injury from repeated or persistent infections, plus poor hygiene and poor nutrition.

Other causes in the developed world include the following:

1. Inflammatory bowel disease (predominantly Crohn’s disease [CD]).

2. Syndromic causes of exocrine pancreatic insufficiency:

• Shwachman–Diamond syndrome (SDS; autosomal recessive). The abnormal gene is the Shwachman–Bodian–Diamond Syndrome (SBDS) gene located on 7q11; the SBDS protein is involved in ribosome biogenesis, stabilisation of the mitotic spindle and regulation of chromosome segration. Features include marrow failure (various cytopaenias, including cyclic neutropaenia, pancytopaenia), recurrent infections, increased risk for myelodysplasia and malignant transformation (especially acute myelogenous leukaemia, AML), short stature, skeletal anomalies.

• Johanson–Blizzard syndrome (JBS). The abnormal gene is located on 15q15–q21.1. Features include pancreatic insufficiency due to fatty replacement, gastrointestinal anomalies (e.g. imperforate anus), deafness, unusual whorls of tissue in scalp, absent nasal cartilage, hypothyroidism. Diabetes may also occur.

3. Short bowel syndrome (SBS): residual small bowel length less than 100 cm (e.g. post-necrotising enterocolitis).

4. Chronic liver disease (CLD) with cholestasis.

5. Others: immunodeficiency syndromes, intestinal lymphangiectasia, abetalipo-proteinaemia.

Infants may have congenital disorders of specific nutrient digestion or absorption/transport.

These include disorders involving the following:

1. Aminoacids: for example, enterokinase deficiency.

2. Fats: for example, chylomicron retention disease, intestinal lymphangiectasia; abetalipoproteinaemia.

3. Carbohydrates: congenital intestinal enterocyte brush border enzyme deficiencies or transport defects (e.g. glucose–galactose transporter deficiency, sucrase–isomaltase deficiency, lactase deficiency, microvillus inclusion disease).

4. Electrolytes, vitamins, trace elements: for example, congenital chloride diarrhoea, acrodermatitis enteropathica (zinc deficiency), selective B₁₂ deficiency.

Mechanisms of malabsorption

Candidates should refresh their knowledge of the physiology of digestive and absorptive processes. These are normally divided into phases: intraluminal digestion, mucosal absorption, venous transport phase and lymphatic transport phase. Most nutrient absorption occurs in the proximal small bowel, although vitamin B₁₂ and bile acids are absorbed in the terminal ileum. Malabsorbed bile acids irritate the colonic mucosa, having a detergent action that can lead to colitis and diarrhoea, especially in conditions such as CD and SBS with disorders of the terminal small bowel.

Hepatobiliary and pancreatic secretions mix with nutrients in the duodenum and jejunum to digest fat. Long-chain fatty acids are absorbed and repackaged into chylomicrons, transported sequentially via lymphatics, the venous circulation and finally the liver. Medium- and short-chain fatty acids are absorbed and transported directly to the liver via mesenteric venous blood flow.

Malabsorbed carbohydrates’ osmotic properties lead to intraluminal fluid accumulation and diarrhoea, plus fermentation by ileocolonic bacteria to simple sugars, organic acids and gases (methane, carbon dioxide and hydrogen—the basis for the hydrogen breath test). Generalised malabsorption usually does not cause azotorrhoea (excessive loss of nitrogen in the stool). Hypoproteinaemia in malnourished children with malabsorption is due to deficient dietary intake and excessive intestinal protein loss (protein-losing enteropathy [PLE]).

Digestive factors

1. Insufficient pancreatic enzymes (e.g. CF, SDS).

2. Lack of functioning bile salts:

• Insufficient supply (e.g. CLD, ileal resection, coeliac disease).

• Deconjugation (e.g. bacterial overgrowth).

3. Inadequate brush border enzymes (e.g. lactose intolerance).

Absorptive factors

1. Disordered mucosal villus function:

• Congenital defects in villus structure: for example, microvillus inclusion disease, tufting disease.

• Reduced mucosal surface area: for example, SBS, cytotoxic drug-induced epithelial injury, malnutrition.

• Inflammatory disorders of villus: for example, postinfectious diarrhoea (e.g. Shigella, Escherichia coli, Campylobacter jejuni, Giardia lamblia), coeliac disease (gluten-sensitive enteropathy), allergic enteropathies (e.g. to cow’s milk protein [CMP], soy, egg or gluten), acute infectious enteropathy, immunodeficiency syndromes, autoimmune enteritis.

2. Defective intracellular lipid transport: for example, abetalipoproteinaemia.

3. Inadequate lymphatic circulation of chylomicrons: for example, lymphangiectasia (primary, or secondary to CD), mycobacterial gut infection, radiation enteritis, forms of congenital heart disease with chronically elevated right-sided heart pressure (impeded flow from lymphatics [thoracic duct] into systemic venous circulation).

4. Abnormal water and electrolyte transport (e.g. giardiasis).

Coeliac disease

This is a systemic immune disease, including an enteropathy in which intestinal inflammation is due to ingestion of gliadin and associated prolamins (proteins with a high content of proline and glutamine), which are present in wheat (gluten), barley (hordeins) and rye (secalins), in genetically predisposed patients. The gold standard in diagnosing this condition remains findings on small bowel biopsy (obtained endoscopically from the post-bulbar duodenum) of partial or complete villous atrophy, crypt hyperplasia and increased intraepithelial lymphocytes, which resolve with a gluten-free diet. There is a strong association between coeliac disease and human leucocyte antigen (HLA) class II genes. Most patients with coeliac disease have particular pairs of allelic variants in two genes: HLA-DQA1 and HLA-DQB1; these are common: 30% of the general population has at least one of them, but only 3% of those have coeliac disease, and their absence effectively excludes the diagnosis. HLA-DQA1 encodes the alpha chain, and HLA-DQB1 the beta chain, of the HLA heterodimers associated with coeliac disease. The major histocompatibility complex (MHC) class II antigens are the DQ2 heterodimer (encoded by specific HLA-DQA1∗05 and HLA-DQB1∗02 alleles) and the DQ8 heterodimer (encoded by specific HLA-DQA1∗03 and HLA-DQB1∗0302 alleles). DQ2 and DQ8 molecules present peptides derived from gliadin to intestinal T-lymphocytes (some after deamination by tissue transglutaminase [tTG]). Activated Th1 T-cells produce pro-inflammatory cytokines that cause (probably) the gut lesions of coeliac disease.

Although celiac disease-associated antibodies serology may be useful, they have yet to replace biopsy. Most cases with positive tTG IgA antibodies and endomysial antibody (EMA) IgA have coeliac disease, and are HLA DQ2- or DQ8-positive. Measurement of the serum level of total IgA to evaluate for selective IgA deficiency (which occurs in 1 in 50 patients with celiac disease) is useful for accurate interpretation, as tTG IgA and EMA IgA will not be present, so in IgA-deficient patients testing for IgG antibodies should be performed: tTG IgG or anti-deamidated gliadin-related peptide (a-DGP) IgG, the latter being a newer test where both isotypes (IgA and IgG) are highly sensitive and specific for active coeliac disease.

History

Weight

Birth weight, progress of weight, timing of when weight gain started to diminish, current weight, rate of weight loss.

Chronology of symptoms

Age at onset of symptoms: for example, congenital villus dysfunction presents with intractable diarrhoea as neonate; coeliac disease may present between 3 and 9 months with severe diarrhoea, or later (9 months to late childhood) with moderate diarrhoea; inflammatory bowel disease is very rare before 8 years; it may present after a bout of known enteritis (e.g. Shigella).

Feeding

Dietary milestones, initial feeding, age at introduction of cow’s milk (CMP intolerance), age at introduction of first solids, age at introduction of first cereals and the type of cereal (gluten-containing [wheat, rye, barley] in coeliac disease), age at introduction of first fruits (sucrase–isomaltase deficiency), appetite, poor feeding with irritability (iron deficiency associated with coeliac disease), parent-devised dietary restriction (attempting to avoid diarrhoea), iatrogenic dietary manipulation (decreased caloric intake and chronic non-specific diarrhoea).

Stools

Appearance, volume, fluidity, offensiveness, difficulty flushing stools (steatorrhoea or excess gas in stool), frequency, associated blood (CD).

Symptoms of specific nutritional deficiencies

Pallor (anaemia), night-blindness (vitamin A), ataxia (vitamin E), bruising (vitamin K), rashes (zinc, various vitamins). See the short case on nutritional assessment for a comprehensive list of possibilities.

Specific diagnostic clues

Chest infections (CF), susceptibility to infections (immunodeficiency states or neutropenic episodes of SDS), arthralgia or rashes (e.g. erythema nodosum, erythema multiforme in CD), delay in pubertal development (CD), travel to giardia-endemic or exotic areas (giardiasis or other infestation), day-care (giardiasis).

Family history

CF, coeliac disease or other autoimmune disorders (e.g. type 1 diabetes, thyroid disorders, juvenile arthritis, autoimmune liver disease), disaccharidase deficiency, CD, infestations.

Social history

Beware of psychosocial causes of failure to thrive in the differential diagnosis.

Past medical history

Necrotising enterocolitis (NEC) as neonate, past bowel resections or other surgery.

Investigations thus far

The type and timing of investigations, the specialists involved, current thoughts on the diagnosis, planned future investigations.

Management

The current treatment approach (if any); plans for further treatment.

Examination

See the short case on nutritional assessment and suggested examinations for IBD and CLD long cases. Start with growth parameters—weight, height and head circumference—then perform a nutritional assessment, and look for underlying IBD, CLD and any suggestions of CF or immune deficiency. Carefully check for any abdominal distension, particularly with muscle wasting, as this can occur with an enteropathy. Perform a careful perianal examination. It is not necessary to perform a rectal examination, but this should be mentioned for completeness.

Investigations

Stool

1. Pus cells (colonic disease, e.g. CD).

2. Eosinophils (CMP intolerance).

3. Occult blood (IBD).

4. Cysts or trophozoites (e.g. Giardia lamblia).

5. Fat globules (CF or SDS-maldigestion [luminal] rather than malabsorption. (Note: lubricants or ointments can produce false-positive results.)

6. Fatty acid crystals (coeliac disease—malabsorption [mucosal]).

7. Reducing substances (carbohydrate maldigestion or malabsorption).

8. Faecal alpha-1-antitrypsin excretion test (FA1AT). This screens for PLE. An elevated FA1AT result suggests a mucosal disorder, as inflamed mucosa allows transudation of serum proteins. This is common in CD and occurs in coeliac disease, but not in CF or CLD, where there is an intraluminal maldigestive defect, which does not involve any mucosal damage.

9. Culture for pathogens (Cryptosporidium, Yersinia).

10. Three-day faecal fat assessment (more accurate than a qualitative stool stain).

11. Bile acids (in SBS with 40–80% ileal resection).

12. Colonic hydroxy fatty acids (in SBS with 80–100% ileal resection).

13. Ostomy output: electrolytes, osmolality (children with stomas).

Blood

1. Full blood count and film (anaemia, neutropenia [SDS], lymphopenia [lymphangiectasia], acanthocytosis [abetalipoproteinaemia, hypobetalipoproteinaemia, chylomicron retention disease]), megaloblastic anaemia (B12, folate malabsorption).

2. Erythrocyte sedimentation rate, ESR (chronic infection, IBD).

3. Liver function tests (albumin, total protein, transaminases) (CLD, CD with PLE).

4. Vitamins: folate (serum and red cell), vitamin B₁₂ (ileal disease), vitamins A, 25-OH D and E, and prothrombin time for vitamin K (fat malabsorption).

5. Minerals: calcium, magnesium, phosphate, iron, ferritin, zinc, copper, selenium.

6. Electrolytes, urea and creatinine (hydration, associated renal disease).

7. Fetal haemoglobin, HbF (SDS).

8. Pancreatic isoamylase (SDS).

9. IgA and coeliac disease serology (anti-tissue transglutaminase [tTG] IgA antibodies, EMA IgA). In addition, molecular genetic testing can be carried out: targeted mutation analysis can determine HLA-DQA1 and HLA-DQB1 genotypes to detect the presence or absence of coeliac disease associated alleles: HLA-DQA1∗0501, HLA-DQA1∗0505, HLA-DQB1∗0201, HLA-DQB1∗0202 and HLA-DQB1∗0302. Over 99.9% of these alleles will be detected by this test.

10. IBD serology screening tests. None are routine, but they are included for completeness. Perinuclear anticytoplasmic antibodies (pANCAs) to neutrophil proteins may be elevated in UC. Anti-Saccharomyces cerevisiae (ASCA) antibodies may be present in CD (more sensitive and specific with elevated pANCA). Antibodies to E. coli (outer membrane porin C [anti-ompC] antibodies) may correlate with diagnosis of IBD.

11. Immunoglobulins (severe combined immunodeficiency syndrome and other primary immune defects).

12. Human immunodeficiency virus (HIV) serology in high-risk groups.

Imaging

1. Bone age (delay in skeletal development; abnormal in SDS syndrome with metaphyseal dysostosis; film will also show rickets).

2. Bowel contrast studies (anatomical lesions, CD).

3. Motility studies (nuclear medicine gastric emptying scan, upper gastrointestinal barium contrast study).

4. Liver scan (causes of CLD).

5. CT scan of liver and pancreas.

6. Radiolabelled Tc albumin lymphatic scan (lymphangiectasia).

Small bowel biopsy

This is the gold standard to diagnose villus injury. It is the standard test to diagnose coeliac disease, Giardia lamblia, intestinal lymphangiectasia and abetalipoproteinaemia (shows epithelial lipid). Severe villus atrophy occurs with coeliac disease and congenital microvillus inclusion disease. Less severe degrees of atrophy occur with giardiasis, immunodeficiency, allergic enteropathies and malnutrition. Biopsy can also determine mucosal enzyme deficiencies (e.g. disaccharidases).

Others

Other potentially useful investigations include the following:

1. Breath hydrogen test (carbohydrate malabsorption, bacterial overgrowth).

2. Urinary catecholamines and serotonin (carcinoid, neuroblastoma: causes of secretory diarrhoea).

Note that all these investigations can be performed as outpatient procedures. It is uncommon to need to admit a child to hospital for investigation of malabsorption, although a child with failure to thrive may require a period of hospitalisation for nutritional debilitation to resolve.

Short Cases

Gastrointestinal system

This is a reasonably common short case, and it is expected to be performed well. The introduction ‘Examine the gastrointestinal system’ is more detailed than ‘Examine the abdomen’, as it comprises not only abdominal but also nutritional assessment (which is a short case in itself), as well as a search for peripheral stigmata of various disease states. The most systematic method of approach, as in so many other cases, commences with inspection, followed by examining the hands, face, abdomen, lower limbs and then other systems depending on the findings.

The relevant findings sought are outlined in Figure 8.3. A more detailed listing of possible examination findings is given in Table 8.1.

Figure 8.3 The gastrointestinal system

Table 8.1 Additional information: details of possible findings on gastrointestinal examination

General inspection

Pallor (GIT blood loss, CLD, nutritional deficiencies in iron, folate, various vitamins)

Jaundice (CLD, vitamin B₁₂ deficiency with ileal resection or disease)

Bruising (CLD, thrombocytopenia in hypersplenism, HSP)

Petechiae (hypersplenism in portal hypertension)

Peripheral stigmata of CLD: spider naevi, scratch marks (pruritis with cholestasis), xanthomata (cholestasis)

Oedema (CLD, PLE)

Tachypnoea, cyanosis, cough, barrel chest (CF)

Irritability (iron deficiency, coeliac disease)

Mental state (hepatic encephalopathy)

Dysarthria (Wilson’s)

Involuntary movements: athetosis, chorea, tremor, dystonia or myoclonus (Wilson’s)

Access devices (venous ports used in CF for administering antibiotics; intravenous access for total parenteral nutrition, or hyperalimentation)

Nasogastric tube

Dysmorphic features

• Arteriohepatic dysplasia (Alagille)

• Zellweger syndrome (infants)

• Various other syndromes

Joint swelling (IBD) Evidence of rickets (bow legs, prominent wrists and ankles, rib rosary) (vitamin D deficiency) Abdominal distension, scars, access devices, stoma Skin

• Various rashes related to nutritional deficiencies

• Dermatitis herpetiformis (coeliac disease)

• Erythema nodosum (IBD, chronic active hepatitis)

Upper limbs Nails

• Clubbing (CLD, IBD, CF)

• Leuconychia (CLD)

• Koilonychia (iron deficiency)

• Cyanosis (CF)

Palms

• Crease pallor (anaemias)

• Erythema (CLD)

• Crease pigmentation (Addison’s)

Xanthomata (between fingers and on extensor surfaces) Dark brown spots on nails, hands (Peutz–Jeghers) Asterixis (liver failure, CO₂ retention in CF) Wrists: palpable epiphyseal enlargement (vitamin D deficiency) Joints: swelling (IBD) Head and neck Facial characteristics

• Cushingoid facies (steroid-treated IBD or chronic active hepatitis)

• Doll face ‘cherub’ (glycogen storage diseases types 1 and 3)

Eyes

• Pigmentation around eyes (2–3 mm brown–black spots in Peutz–Jeghers)

• Lids: xanthelasma (hyperlipidaemia)

• Conjunctivae: pallor (anaemias, with nutritional deficiencies, GIT blood loss [CLD, Wilson’s]), xerosis (vitamin A deficiency)

• Sclera: jaundice (note depth thereof)

• Iris: iritis (IBD)

• Cornea: xerosis, clouding, opacification (vitamin A deficiency), Kayser–Fleischer rings (brown/green pigmentation in limbic region, occur in Wilson’s disease)

• Lens: cataracts (congenital TORCH infections, steroid-treated IBD or chronic active hepatitis, Wilson’s)

• Retina: retinal pigmentation (abetalipoproteinaemia, Alagille), chorioretinitis (TORCH), retinopathy of prematurity (ex-premature with NEC)

Mouth

• Breath: hepatic fetor (liver failure)

• Lips: angular cheilosis (iron deficiency): pigmentation (Peutz–Jeghers)

• Buccal mucosa: areas of brown–black pigmentation (Peutz–Jeghers, Addison’s)

Abdomen—anterior aspect Distension

• Weak abdominal muscles (protein calorie malnutrition [PCM], coeliac disease)

• Ascites (CLD, PLE, PCM)

Operative scars (Kasai, colectomy, liver transplant) Access devices (e.g. venous port for antibiotics in CF) Injection sites (insulin in CF with diabetes, venous port site in currently treated CF) Stoma (colostomy, ileostomy, gastrostomy) Prominent abdominal wall veins (portal hypertension) Striae (Cushing’s syndrome in steroid treated IBD, chronic active hepatitis) Urine, stool, temperature chart Request inspection of

• Urine: dark (cholestasis)

• Stool: acholic (cholestasis); blood (portal hypertension)

Urinalysis

• Bilirubin (hepatobiliary disease)

• Urobilinogen (increased hepatic dysfunction)

Temperature chart (infectious hepatitis, chronic active hepatitis) Neurological system Infants Alertness (decreased in Zellweger, TORCH) Hypotonic posture (Zellweger) Choreoathetoid movements (kernicterus) Gross motor assessment (hypotonic with Zellweger, hypertonic with TORCH) Primitive reflexes: pathological persistence (TORCH, bilirubin encephalopathy) Hearing: deafness (congenital rubella, bilirubin encephalopathy, Zellweger) Older children (over 5 years) Gait examination

• Cerebellar ataxia (vitamin E deficiency)

• Peripheral neuropathy (vitamin E deficiency)

• Involuntary movements (Wilson’s)

• Antalgic gait (arthritis with IBD)

Romberg’s sign (vitamin E deficiency) Hold arms horizontally: wing beating tremor (Wilson’s) Diminished reflexes (vitamin E deficiency) Diminished sensation (vitamin E deficiency) Respiratory examination Full respiratory examination, including getting child to cough and inspecting any sputum (CF) Cardiac examination Full praecordial assessment (Alagille, congenital rubella, CF)

CF = cystic fibrosis; CLD = chronic liver disease; GIT = gastrointestinal tract; HSP = Henoch–Schönlein purpura; NEC = necrotising enterocolitis; PLE = protein-losing enteropathy; TORCH = toxoplasmosis, other (e.g. HIV, syphilis), rubella, cytomegalovirus, herpes (both simplex and varicella).

Start by introducing yourself to the patient and parent. Have the child adequately undressed for examination. Note the child’s parameters and visually assess the nutritional status. Request the percentile charts, as these are always helpful and often give a good indication of the underlying diagnosis before you examine the child. A good example of this is coeliac disease, where the weight percentile chart characteristically shows a falling-off of previously adequate weight gain, at the age that gluten-containing foods were introduced to the diet. The height chart can indicate disease chronicity and can suggest certain diagnoses that often present as short stature, such as Shwachman–Diamond syndrome (SDS) or Crohn’s disease. The head circumference is decreased in the congenital TORCH infections, which can present with poor growth and hepatomegaly.

Now, take 20 seconds or so to visually scan for those features outlined in the figure. After this, the child can be systematically examined, commencing with the hands, noting any clubbing, leuconychia or other peripheral stigmata of chronic liver disease (CLD). Move on to the head and neck, examining in particular the eyes and mouth. When examining the eyes, mention the relevance of examining the retinae, but defer actually doing it until you have completed the rest of your examination, as it is too time-consuming at this stage. This is followed by a thorough abdominal examination.

Next, inspect the lower limbs for erythema nodosum (inflammatory bowel disease [IBD], chronic active hepatitis [CAH]) and feel for ankle oedema (CLD). The findings noted to this point will determine whether further assessment of other systems, such as the following, is needed.

Neurological assessment

A neurological examination is appropriate in the following circumstances:

1. Any jaundice or other suggestion of liver disease in a child over 5 years (e.g. vitamin E deficiency causing cerebellar ataxia and/or peripheral neuropathy, Wilson’s disease causing ataxia, dysarthria, dystonia).

2. Any malabsorption or pigmentary retinopathy (e.g. abetalipoproteinaemia with vitamin E deficiency).

3. Dysmorphism in an infant (marked hypotonia in Zellweger syndrome).

4. Microcephaly (congenital TORCH infections, with developmental delay).

In older children, assess the gait and then formally test the lower limbs. In infants, a gross motor developmental approach, followed by lower limb assessment, is more appropriate.

Respiratory assessment

If there is any evidence of liver disease, respiratory distress or diabetes (think of CF), a full respiratory assessment is needed, including asking the child to cough and requesting inspection of a sputum specimen.

Cardiac assessment

If there is any evidence of jaundice or hepatomegaly in an infant (pulmonary arterial stenosis in Alagille syndrome, or in congenital rubella) or any suggestion of cystic fibrosis (for evidence of cor pulmonale), then a full praecordial assessment is warranted.

At the completion of clinical examination, request inspection of any urine or stool specimens available, as well as the urinalysis, stool analysis and temperature chart.

The abdomen

This is a common short case, but it is often failed due to several simple errors. ‘Examine the abdomen’ is not the same as ‘Examine the gastrointestinal system’, but is often interpreted as such. The other common misconception is that the abdomen can be examined with the examiner standing up: this is inappropriate, as the hand and forearm should be at the same level as the abdomen, which can be achieved only by kneeling at the bedside or sitting on a chair. The other point worth noting is that after inspection, when initially palpating, you should look not at the abdomen or examining hand but at the face of the child, as that is the only way to assess if there is any abdominal tenderness.

First have the child fully undressed. Initial inspection can be performed with the child standing, as this is the best position from which to gain an overall impression of the child’s height and nutritional status, and also to assess abdominal distension. Then lie the child flat on the bed, with one pillow under the head, and, after completing an initial visual scan, sit on a chair or kneel next the bed so that the examining hand is at the same level as the abdomen for palpation.

Begin with general palpation, commencing in one or other iliac fossa and proceeding clockwise. Watch the child’s face throughout, to detect any abdominal tenderness. Then palpate for the liver, noting its size, consistency, surface, edge and vertical downward movement with inspiration. Percuss in the midclavicular line, from resonant to dull, first from above, then from below, and measure the span with a ruler or tape measure (in centimetres). Palpate for the spleen next, starting in the right iliac fossa so as not to miss massive splenomegaly. Note the movement towards the umbilicus with inspiration, and feel for the splenic notch; percuss and measure the span in centimetres.

Next, ballot for the kidneys, noting their size, and percuss for resonance above them. Percuss for ascites; if resonant to percussion to the flanks, there is no need to test for shifting dullness. If not, then check for the latter by rolling the patient away from you, waiting 20 seconds for any fluid to settle, and percussing again. Note any change in the site where the percussion note became dull. Measure this distance. Also check for a fluid thrill if there is evidence of any shifting dullness. An assistant (e.g. an examiner) is required to test for a fluid thrill.

Next, examine the inguinal regions for herniae or lymphadenopathy. Examine the genitalia: note the Tanner pubertal staging and the size of the external genitalia and, in a boy, the size, shape and consistency of the testes. If there is any mass here, then transilluminate it. After completion of palpation and percussion, auscultate over the liver, spleen, renal arteries and bowel. Finally, check the abdominal reflexes.

This completes the anterior abdominal examination. The posterior abdominal examination is also important, as many signs here may explain findings noted anteriorly (e.g. spina bifida associated with enlarged bladder or kidneys; bone marrow biopsy sites over the iliac crests, accompanying hepatosplenomegaly).

Roll the child over to inspect the posterior abdominal wall. Spring the pelvis and percuss the lumbar spine for any tenderness, and also auscultate over the kidneys for any bruits.

Next, roll the child on one side and, after asking the examiners for permission, inspect the perianal region, test for the anal wink, and mention performing a per rectal examination (you will not be expected to do this in the examination setting).

Always request the urinalysis, stool analysis and temperature chart at the completion of your examination.

Common findings in the examination setting include hepatosplenomegaly, ascites and enlarged kidneys.

In view of the large number of possibilities in this case, they are best enumerated in list form. Figure 8.4 shows several of the findings sought. For further details on the many possible signs on inspection, see Table 8.2.

Figure 8.4 The abdomen

Table 8.2 Additional information: details of possible findings on inspection of abdomen

Inspection

Anterior aspect of abdomen

Distension, best assessed standing (ascites, coeliac disease, PCM, organomegaly)

Operative scars (e.g. Kasai, renal transplant, peritoneal dialysis, exomphalos repair)

Access devices (e.g. Tenckhoff catheter, subcutaneous venous port)

Injection sites (e.g. insulin, desferrioxamine)

Stoma (colostomy, ileostomy, ileal conduit, gastrostomy)

Herniae (umbilical, paraumbilical, inguinal, incisional)

Prominent abdominal wall veins (portal hypertension)

Striae (Cushing)

Visible peristalsis (pyloric stenosis)

Inguinal lymphadenopathy (leukaemia, lymphoma)

Pubertal status (precocity)

External genitalia (ambiguous)

Enlarged testis (seminoma, teratoma)

Posterior aspect of abdomen

Purpura on buttocks (HSP)

Xanthomata on buttocks (cholestasis)

Buttock asymmetry (sacral tumour)

Gluteal wasting (malnutrition)

Midline anomalies related to spinal dysraphism

• Lipoma

• Midline hair tuft

• Myelomeningocoele

Midline scars (repaired spina bifida, resection spinal tumour) Needle marks over iliac crests (bone marrow biopsy site) Perianal fissures, fistulae (IBD) Patulous anus (spina bifida) Imperforate anus (congenital) Faecal soiling (habitual constipation)

HSP = Henoch–Schönlein purpura; IBD = inflammatory bowel disease; PCM = protein calorie malnutrition.

The abdominal findings will determine the remainder of the general physical examination.

• If the only finding is minimal tenderness, proceed to a gastrointestinal or renal examination, depending on the site of tenderness.

• If the finding is hepatosplenomegaly, proceed to a gastrointestinal and haematological assessment.

• If the finding is enlarged kidneys, proceed with a renal examination, after requesting the blood pressure and urinalysis.

• If the finding is lymphadenopathy and splenomegaly, examine the haematological system.

• If ascites is the finding, proceed as outlined in the short-case approach to the child with oedema.

• If ambiguous genitalia is the finding, request the blood pressure, look for hyperpigmentation and then proceed as in the short-case approach to ambiguous genitalia in Chapter 7.

Common findings on abdominal examination and their causes are outlined in the following sections.

Hepatomegaly

The following two lists give different classifications of hepatomegaly. The first is a mnemonic, SHIRT, which the author has found useful. The second describes the more common findings found in three different age groups: infant, preschool (less than 5 years) and school age (5 years and over), further subdivided into jaundiced or not jaundiced. This second classification is more practical than comprehensive.

Causes of hepatomegaly (mnemonic SHIRT)

S Structural

Extrahepatic biliary atresia (EHBA), choledochal cyst, intrahepatic biliary hypoplasia, polycystic disease, congenital hepatic fibrosis.

Storage/metabolic

1. Defective lipid metabolism—Gaucher disease, Niemann–Pick disease, hyperlipoproteinaemias, cholesteryl ester storage disease, carnitine deficiency, mucolipidoses.

2. Defective carbohydrate metabolism—diabetes mellitus, glycogen storage diseases (types 1, 3, 4 and 6), hereditary fructose intolerance (HFI), galactosaemia, Cushing’s syndrome, mucopolysaccharidoses.

3. Defective amino acid/protein metabolism—tyrosinaemia (type 1), urea cycle enzyme disorders.

4. Defective mineral metabolism—Wilson’s disease.

5. Defective electrolyte transport—CF.

6. Defective nutrition—protein calorie malnutrition (PCM), total parenteral nutrition (TPN).

7. Deficiency of protease—alpha-1-antitrypsin deficiency.

H Haematological

Thalassaemia, sickle cell disease (chronic haemolysis and transfusion haemosiderosis), acute leukaemia, chronic myeloid leukaemia.

Heart

Congestive cardiac failure (CCF), constrictive pericarditis, obstructed IVC.

I Infection

1. Viral infections—congenital rubella, cytomegalovirus infection, coxsackie virus, echovirus, hepatitis (A, B, C, D and E) viruses, infectious mononucleosis.

2. Bacterial infections—neonatal septicaemia, E. coli urinary tract infections, tuberculosis, congenital syphilis.

3. Parasitic infections—hydatid disease, malaria, schistosomiasis, toxoplasmosis, visceral larva migrans.

Inflammatory:

CAH, chronic persistent hepatitis, IBD associated liver disease.

Infiltrative:

Histiocytosis X, sarcoidosis.

R Reticuloendothelial:

Non-Hodgkin’s lymphoma, Hodgkin’s disease.

Rheumatological:

Systemic-onset juvenile idiopathic arthritis (SOJIA), SLE.

T Tumour/hamartoma

1. Primary hepatic neoplasms—hepatoblastoma, hepatocellular carcinoma.

2. Secondary deposits—neuroblastoma, Wilms’ tumour, gonadal tumours.

3. Vascular malformation/benign neoplasm—infantile haemangioendothelioma, cavernous haemangioma.

Trauma:

Hepatic haematoma.

Causes of hepatomegaly (practical classification)

Note that some diseases occur in both the ‘jaundiced’ and ‘not jaundiced’ lists. These are not misprints, but reflect the wide spectrum of clinical findings in these conditions.

School age (5 years and over)

Jaundiced

As above, plus Wilson’s disease and chronic active hepatitis.

Not jaundiced

As above, plus Wilson’s disease and chronic active hepatitis.

Hepatosplenomegaly

The causes of hepatosplenomegaly can be seen by persuing the preceding section and the following section for diseases on both lists. In general terms, the causes are as follows:

1. Congenital hepatic fibrosis.

2. Haematological—thalassaemia.

3. Infection—infectious mononucleosis, TORCH.

4. Malignancy—leukaemia, lymphoma.

5. Storage diseases—Gaucher (long term), Niemann–Pick, mucopolysaccharidoses.

Splenomegaly

A mnemonic (CHIMPS) is helpful to remember the causes of splenomegaly.

C Cardiac

Subacute bacterial endocarditis (SBE).

Connective tissue disease

SOJIA, SLE.

H Haematological

Chronic haemolytic anaemias—hereditary spherocytosis, glucose-6-phosphate dehydrogenase (G6PD) deficiency, thalassaemia.

I Infection

1. Viral infection—infectious mononucleosis, cytomegalovirus.

2. Bacterial infection—SBE, typhoid, septicaemia.

3. Protozoal infection—malaria, toxoplasmosis.

Injury

Haematoma.

M Malignancy

Leukaemia, lymphoma.

P Portal hypertension

1. Extrahepatic—post-neonatal umbilical vessel catheterisation or sepsis.

2. Hepatic—the various causes of cirrhosis, congenital hepatic fibrosis.

3. Suprahepatic—Budd–Chiari syndrome.

S Storage diseases

Gaucher’s, Niemann–Pick.

Splenic cyst or hamartoma

Renal enlargement

Bilateral flank masses

1. Polycystic kidney disease (infantile—autosomal recessive, adult type—autosomal dominant).

2. Hydronephrosis—posterior urethral valves, vesico-ureteral reflux, neurogenic bladder.

3. Tumour—Wilms’, leukaemia, lymphoma, tuberous sclerosis.

4. Metabolic—glycogen storage disease type 1 (A and B), tyrosinaemia type 1.

Ascites

1. Hepatic—cirrhosis and portal hypertension.

2. Renal—nephrotic syndrome.

3. Gastrointestinal—protein-losing enteropathy (e.g. coeliac disease, inflammatory bowel disease), nutritional (PCM, beri-beri), intestinal lymphangiectasia.

4. Cardiovascular—right ventricular failure, constrictive pericarditis, IVC obstruction, hepatic vein obstruction (Budd–Chiari syndrome).

5. Lymphatic—acquired chylous ascites (thoracic duct obstruction by enlarged lymph nodes or neoplasms).

6. Infection—chronic tuberculous peritonitis.

Jaundice

The approach to this case depends on the child’s age. In view of this, two separate diagrams of suggested approaches are included, one for the age group below 2–3 years, and one for those who are older. There is, of course, some overlap, but the author certainly found this division helpful.

The infant

Start by introducing yourself to the parent. Note the infant’s growth parameters and any obvious dysmorphic features. Alagille syndrome (arteriohepatic dysplasia) can be associated with a prominent forehead, a small pointed chin and hypertelorism. Zellweger syndrome, a peroxisomopathy, is associated with hypotonia, especially of the neck, a high forehead and huge anterior fontanelle, which may have metopic extension, and hypertelorism. Infants with a congenital TORCH infection may be small, microcephalic and neurologically abnormal, and infants with hypothyroidism can have coarse facial features and be relatively inactive. Note if the child looks well. Children with biliary atresia usually look very well despite the serious nature of their disease. Children with congenital TORCH or urinary tract infections or galactosaemia can look very sick. Listen to the infant’s cry, as it may be quite hoarse in hypothyroidism. Also note the infant’s posturing, which may be hypotonic (with ‘frog leg’ positioning of the lower limbs in Zellweger syndrome) or hypertonic (with signs of upper motor unit involvement in the TORCH group). Inspect carefully for any stigmata of chronic liver disease.

The systematic general examination of the infant commences with the hands, followed by the head and neck, the abdomen, a neurological assessment, cardiac and chest examinations and, finally, interpretation of the urinalysis, stool analysis and temperature chart. This approach is outlined in Figure 8.5. Note that the sequence outlined also includes assessing for complications of (unconjugated) hyperbilirubi-naemia itself (that is, kernicterus) or for bilirubin encephalopathy, and also examines for complications of cholestasis (if that is the underlying mechanism suspected); namely, deficiencies in the fat soluble vitamins A, D, E and K. All but vitamin E deficiency can manifest themselves clinically in this age group.

Figure 8.5 Jaundice in infants

In the examination of the abdomen, the presence or absence of hepatomegaly is particularly important. The most common four causes of an obstructive jaundice with hepatomegaly in an infant are as follows:

1. Extrahepatic biliary atresia (EHBA).

2. Alpha-1-antitrypsin deficiency.

3. Alagille syndrome.

4. Ex-premature graduate of neonatal intensive care (multiple mechanisms).

The other possibilities at this age include the following:

1. Metabolic—galactosaemia, tyrosinaemia, hereditary fructose intolerance (HFI), cystic fibrosis (CF).

2. Structural—choledochal cyst.

3. Infective—echovirus 11, TORCH.

Several clues can help differentiate between these. If a child is older than a few months and has no large surgical scars, it is unlikely that EHBA is the problem. Conversely, if the child has a large Kasai scar, then do not mention a metabolic disease as the most likely diagnosis! (Unless the scar is from a liver transplant—then it could be a metabolic disease, although again EHBA is the most likely diagnosis requiring liver transplant.) If the infant looks unwell, then infectious or metabolic causes are more likely. If the infant is only several weeks or a few months old, looks well and has acholic stools, then EHBA or choledochal cyst are the most likely diagnoses.

Associated splenomegaly can occur in chronic hepatic disease and in infective processes such as TORCH. Massive splenomegaly should lead to suspicion of a lysosomal storage disorder.

Ascites and jaundice occur with chronic liver disease, but can also coexist in spontaneous perforation of the bile duct, which stains the umbilicus and scrotum yellow–green.

The neurological examination is directed towards detecting underlying aetiologies, such as TORCH infection or Zellweger syndrome, as well as the complications mentioned above. Evidence should also be sought of malformations that cause hypopituitarism (e.g. septo-optic dysplasia).

In the cardiological assessment, there are several possible findings of relevance. In Alagille syndrome, there can be a congenital hypoplasia or stenosis of the pulmonary artery, and other cardiac anomalies. In congenital rubella, pulmonary artery stenosis, patent ductus arteriosus or septal defects can occur. Other less common associations linking jaundice and cardiovascular problems include the following:

1. Polysplenia/asplenia syndromes, in which biliary atresia indistinguishable from EHBA can occur in association with dextrocardia and congenital heart disease.

2. Arteriovenous malformation of the liver, which can lead to heart failure.

3. Congestive cardiac failure, which can cause hepatomegaly and jaundice.

In assessing urinalysis, as well as bilirubin and urobilinogen, ask whether any reducing substances are present (if the child is taking lactose in the diet) for galactosaemia, and whether there is blood or nitrites suggestive of a urinary tract infection. E. coli urinary tract infections, in particular, cause cholestasis and often occur in patients with galactosaemia.

The most important condition to identify early is EHBA, as its optimal treatment should be undertaken before 6 weeks of age. The examiners may therefore ask how you would investigate a child for whom this is the likely diagnosis. The following is a suggested approach.

1. Stool inspection—EHBA causes acholic stools.

2. Ultrasound of abdomen—EHBA is associated with a gall bladder less than 2.5 cm in diameter. Ultrasound can also identify choledochal cysts and exclude calculi.

3. Nuclear DISIDA scan—extrahepatic or intrahepatic biliary atresia and severe cholestasis can be indistinguishable. All are associated with lack of tracer in the gastrointestinal tract. For this test the patient should be primed with choleretic therapy with phenobarbitone and cholestyramine.

Exclude all other causes of cholestasis, as all can cause acholic stools. Investigations should include the following:

If all the above are normal, proceed as follows.

4. Liver biopsy (percutaneous)—EHBA shows extrahepatic biliary obstruction, and bile duct proliferation (discriminates EHBA from other diagnoses in 80% of cases).

5. Percutaneous transhepatic cholangiography (PTC), usually done with biopsy.

6. Operative cholangiogram—the ‘gold standard’ for diagnosing EHBA.

7. Wedge liver biopsy (if above inconclusive).

Table 8.3 gives details of the possible findings on examination of an infant with jaundice.

Table 8.3 Additional information: details of possible findings on jaundice examination (infant)

Inspection

Dysmorphic features

• Arteriohepatic dysplasia (Alagille)

• Zellweger syndrome (cerebro-hepato-renal syndrome)

Posture (hypotonic in Zellweger) Peripheral stigmata of CLD: bruising, bleeding, spider naevi Scratch marks (pruritis with cholestasis) Abdominal scars (Kasai) Hoarse cry (hypothyroidism) Head and neck Head Facial changes of syndromes

• High forehead, hypertelorism, large fontanelle (Zellweger)

• Prominent forehead, hypertelorism, small pointed chin (Alagille)

• Down syndrome

Coarse facial features (hypothyroid) Increased head circumference (extramedullary haematopoiesis in chronic haemolysis) Microcephaly (TORCH) Craniotabes (vitamin D deficiency) Very large anterior fontanelle (Zellweger) Large posterior fontanelle (hypothyroidism) Eyes: nystagmus (septo-optic dysplasia with hypopituitarism) Lids: xanthelasma Conjunctivae

• Pallor (haemolytic anaemia)

• Xerosis (vitamin A deficiency)

Sclerae: depth of jaundice Cornea: xerosis, clouding, opacification (vitamin A deficiency) Lens: cataract (galactosaemia, TORCH) Retina

• Chorioretinitis (TORCH)

• Retinal pigmentation (Zellweger)

• Optic atrophy (septo-optic dysplasia)

Midline defects (e.g. clefts): hypopituitarism Tongue: enlarged, protruding (hypothyroidism) Neck: goitre (hypothyroidism) Neurological Alertness (decreased in Zellweger, hypothyroidism, TORCH) Posture: hypotonic (Zellweger) Choreoathetoid movements (bilirubin encephalopathy) Gross motor assessment

• Hypotonic (Zellweger)

• Hypertonic (TORCH)

Primitive reflexes: pathological persistence (TORCH, bilirubin encephalopathy) Hearing: deafness (congenital rubella, bilirubin encephalopathy, Zellweger) Cardiac Palpate apex to exclude dextrocardia (polysplenia and asplenia syndromes) Auscultate praecordium for:

• Pulmonary artery stenosis (Alagille, congenital rubella)

• Patent ductus or septal defects (Zellweger, congenital rubella)

Other Urinalysis

• Bilirubin (hepatobiliary disease; its absence implies unconjugated hyperbilirubinaemia)

• Urobilinogen (increased in haemolysis and hepatic dysfunction)

• Blood (UTI)

• Nitrites (UTI)

• Reducing substances (galactosaemia)

Temperature chart (infection, e.g. UTI)

CLD = chronic liver disease; TORCH = toxoplasmosis, other (e.g. HIV, syphilis), rubella, cytomegalovirus, herpes (both simplex and varicella); UTI = urinary tract infection.

The older child

The examination of the older child is more like that of an adult. Again, commence by introducing yourself to child and parent. Listen to the child’s voice for any evidence of dysarthria, which can occur in Wilson’s disease (but is very rare in children under 10 years of age). Note the child’s growth parameters and whether the child looks sick or well. Look for dysmorphic features (Alagille syndrome) and any involuntary movements (Wilson’s disease). Visually scan the patient for any evidence of the peripheral stigmata of chronic liver disease. Also, assess whether there is any joint swelling, particularly in an adolescent patient (inflammatory bowel disease or chronic active hepatitis).

Systematic examination commences with the hands, followed by the head and neck, abdomen, heart and chest, neurological assessment and then interpretation of the urinalysis, stool analysis and temperature chart. This is outlined in Figure 8.6.

Figure 8.6 Jaundice in older children

As with the infant, the sequence also detects complications of cholestasis, and in children over 4 years signs of vitamin E deficiency can become manifest as cerebellar ataxia and peripheral neuropathy.

The diseases in this age group are somewhat different from those outlined in the section on the jaundiced infant. The main groups of disease that cause hepatomegaly and jaundice are as follows:

Choledochal cyst.

4. Autoimmune

Chronic active hepatitis.

Note that cystic fibrosis is the most common cause of liver disease in the 0–5 age group in Australia. There are few reports to date of Wilson’s disease occurring in a child under 5 years, so it is not wise to mention it early in the differential diagnosis of a 3-year-old with jaundice.

Important points regarding Wilson’s disease are as follows:

1. Neurological problems are extremely rare in children (although they are listed here for completeness).

2. If there is neurological disease, Kayser–Fleischer rings are usually present.

3. Cystic fibrosis often presents when screening an asymptomatic sibling of a child with Wilson’s disease.

4. It may present as a psychiatric problem or with deteriorating school performance.

5. It can present early in childhood, around 5 years, as a haemolytic anaemia, which can be associated with jaundice.

6. It is crucial not to miss the diagnosis, as it is one of the few curable causes of cirrhosis.

In the child over 10 years, chronic active hepatitis and Wilson’s disease are more likely to be seen in the examination setting. If chronic active hepatitis seems likely, then it is worthwhile mentioning, and examining for, associations of the autoimmune variety; namely, thyroiditis (feel for goitre), glomerulonephritis (request the blood pressure and urinalysis) and erythema nodosum (make a point of carefully inspecting the legs). In this age group, it is also worth assessing for evidence of inflammatory bowel disease, which can be complicated by liver disease, and may be associated with arthritis and erythema nodosum, as well as uveitis.

Investigations

The examiners may ask what investigations you would perform. Obviously this depends on the findings in the particular child you see, but in general it is better to assess the severity of the problem before a long differential discussion about the cause, as this is what would apply in practice. Therefore, first mention basic investigations.

Liver function tests (LFTs)

1. Serum bilirubin (direct and indirect): total indicates severity of jaundice; fractional determination (conjugated or unconjugated) valuable in diagnosis.

2. Serum enzymes:

(a) transaminases—AST and ALT—indices of hepatocellular dysfunction;

(b) alkaline phosphatase (ALP)—indicates biliary tract disease;

(c) gamma-glutamyl transpeptidase (GGT)—confers specificity to an elevated ALP, as normal GGT activity occurs in children with bone disease.

3. Serum proteins: albumin—index of liver capacity for protein synthesis.

Clotting studies

Prothrombin time (PT) is not a sensitive indicator of hepatic disease, but has prognostic value (if response to vitamin K given parenterally, good prognostic value).

Assessment for deficiency of fat-soluble vitamins

1. Serum retinol level (vitamin A).

2. Serum calcium, phosphate, ALP (vitamin D).

3. Serum vitamin E level.

4. Vitamin K assessed by PT as above.

After these have been discussed, mention appropriate investigations to clarify the diagnosis.

The single most important disease that must not be missed is Wilson’s disease, as it is curable. Further important diagnoses include hereditary fructose intolerance and choledochal cyst, for similar reasons.

Table 8.4 gives an incomplete list of some of the more important possible investigations. Table 8.5 details the possible findings on examination of an older child for jaundice.

Table 8.4 Diagnostic investigations in the older child with jaundice

Disease	Investigations
Wilson’s disease	Reduced serum copper (usually) and caeruloplasmin
	Elevated urinary copper excretion
	Markedly elevated liver copper content on liver biopsy (most reliable)
Chronic active hepatitis
1. HBsAg negative	Markedly elevated serum gammaglobulin (over 90% of cases)
	Positive for antinuclear antibody (75%)
	High-titre smooth muscle antibody
	Positive direct Coomb’s test (75%)
2. HBsAg positive	Mildly elevated serum gammaglobulin
	Negative for antinuclear antibody (95%)
	Low-titre smooth muscle antibody
	Negative direct Coomb’s test
	Positive (often) HbsAb
3. HCAb positive
Alpha-1-antitrypsin (A1AT) deficiency	Pi phenotyping:
	• PiM allele; phenotype MM (normal level A1AT)

• PiZ allele; phenotype ZZ (5–15% of normal-level A1AT)

• PiMZ allele; phenotype MZ (60% of normal-level A1AT)

Hereditary fructose intolerance Fructose-1-phosphate aldolase assay on liver or jejunal biopsy specimen Sclerosing cholangitis in IBD Visualised on percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiography (ERCP)

Table 8.5 Additional information: details of possible findings on jaundice examination (older child)

Inspection

Dysmorphic features (Alagille)

Dysarthria (Wilson’s)

Involuntary movements: athetosis, chorea, tremor, dystonia or myoclonus (Wilson’s)

Peripheral stigmata of CLD: bruising, bleeding, spider naevi

Scratch marks (pruritis with cholestasis)

Abdominal scars (liver transplant, Kasai)

Joint swelling (IBD)

Head and neck

Head

Facial features of Alagille syndrome

Coarse facial features (hypothyroid)

Frontal and parietal bossing (thalassaemia)

Craniotabes (vitamin D deficiency)

Eyes

Lids: xanthelasma

Conjunctivae

• Pallor (haemolytic anaemia) (Wilson’s)

• Xerosis (vitamin A deficiency)

Sclerae: depth of jaundice

Cornea

• Xerosis, clouding, opacification (vitamin A deficiency)

• Kayser–Fleischer rings (Wilson’s)

Lens: cataracts (steroid-treated IBD)

Mouth

Poor state of dentition (vitamin D deficiency)

Palatal petechiae (infectious mononucleosis)

Tonsillar exudate (infectious mononucleosis)

Neck

Cervical lymphadenopathy (infectious mononucleosis)

Goitre (hypothyroidism)

Gait and lower limbs

Most of this section is only applicable to a child over 4 years of age, as vitamin E deficiency and Wilson’s disease do not exhibit neurological effects until later in childhood

Gait examination

• Cerebellar ataxia (vitamin E deficiency)

• Peripheral neuropathy (vitamin E deficiency)

• Involuntary movements (Wilson’s)

• Antalgic gait (arthritis with IBD)

Romberg’s sign (vitamin E deficiency)

Hold arms horizontally: wing beating tremor (Wilson’s)

Knee and ankle reflexes

• Diminished (vitamin E deficiency)

• Delayed return (hypothyroidism)

Sensation: diminished (vitamin E deficiency)

Other

Request inspection of:

• Urine: dark (cholestasis)

• Stool: acholic (cholestasis); blood (portal hypertension)

Urinalysis

• Bilirubin (hepatobiliary disease; its absence implies unconjugated hyperbilirubinaemia)

• Urobilinogen (increased in haemolysis, and hepatic dysfunction)

• Blood (UTI)

• Nitrites (UTI)

Temperature chart (hepatitis, UTI, chronic active hepatitis)

CLD = chronic liver disease; IBD = inflammatory bowel disease: UTI = urinary tract infection.

Nutritional assessment

The simplest approach to this case comprises three successive components:

1. Assessment of growth parameters.

2. Assessment of fat and protein stores.

3. Assessment of other nutrients, systematically.

First, introduce yourself to the child and the parent. Ensure that the child is fully undressed, then stand back and inspect the child carefully. Visually scan for subcutaneous tissue and muscle bulk. Comment on the child’s height and weight, request the percentile charts and interpret these. If only one measurement is given, request previous measurements to observe their progression. Work out the weight age and height age; compare these and comment. Next, if the child is underweight, work out the weight for height, to quantitate the difference in kilograms between this value and the child’s actual weight.

On interpretation of percentiles, the common finding is poor weight gain, but height can also be significantly decreased by chronic disease, protein calorie malnutrition (PCM), zinc deficiency and rickets. Head circumference can be decreased in PCM, but increased in vitamin D deficiency rickets.

After interpreting the percentile charts, demonstrate the amount of subcutaneous fat tissue by examining the skin fold thickness, between your thumb and index finger, at the mid-arm over biceps and triceps, the axillae, and the subscapular and suprailiac regions. Demonstrate muscle bulk at the arms, thighs and buttocks, muscle wasting being best demonstrated over these areas, particularly the buttocks (glutei). In infants, poor muscle bulk can be reflected by hypotonia on picking the child up.

The next step is a systematic general examination directed at detection of various deficiencies. It commences at the hands, continues up to the head, and then essentially moves from head to toe. Figure 8.7 outlines the order of examination, and Table 8.6 at the end of this section gives additional information. Each deficiency sought is given in parentheses after the relevant physical sign.

Figure 8.7 Nutritional assessment

Table 8.6 Additional information: details of possible findings on nutritional assessment

Inspection

Activity, awareness (PCM)

Irritability (vitamin C, iron, coeliac)

Nasogastric tube

Intravenous access for total parenteral nutrition

Posture

• ‘Frog leg’ (vitamin C)

• Bow legs (vitamin D)

Prominent wrists, ankles (vitamin D) Rib rosary (vitamin C, D) Harrison’s groove (vitamin D) Pot belly (PCM, coeliac, vitamin D) Skin Pallor (vitamins A, B₁, B₂, B₆, B₁₂, C, E; folate, iron, copper) Jaundice (CLD, vitamin B₁₂) Bruising (vitamins C, K) Poor wound healing (vitamin C, PCM, zinc) ‘Flaky paint’ dermatitis (PCM) Desquamation (linoleic acid, biotin) Dry (vitamin A, linoleic acid) Rough, scaly skin (pellagra) in sun-exposed areas (niacin) Seborrheic dermatitis (vitamin B₂) Eczematous scaling around mouth, elbows, knees, genitals, anus (zinc) Waxy (vitamin B₁, in wet beri beri) Dermatitis herpetiformis (coeliac) Erythema nodosum (IBD) Upper limbs Palms: crease pallor (anaemias), erythema (CLD) Nails: leuconychia (CLD), koilonychia (iron), brittle (iron, PCM) Pulse: bradycardia (iodine, PCM), tachycardia (vitamin B₁₂, hydration) Wrists: palpable epiphyseal enlargement (vitamin D) Forearms: tender (vitamin C) Joints: swollen (vitamin C) Blood pressure: hypotension (sodium, hydration) Trousseau’s sign (calcium) Head and neck Frontal and parietal prominence (vitamin D) Increased head circumference (vitamins A, D) Soft skull (craniotabes) (vitamin D) Fontanelle

• Large (vitamin D)

• Bulging (vitamin A)

• Depressed (hydration)

• Sutures separated (vitamin A)

Hair

• Alopecia (zinc, linoleic acid)

Eyes: sunken (hydration) Lids

• Ptosis (vitamin B)

• Blepharitis (vitamin B₂, zinc)

Conjunctivae

• Pallor (anaemias)

• Xerosis (vitamin A)

• Conjunctivitis (vitamin B₂, C)

• Bitot spots (vitamin A)

Scleral icterus (vitamin B₂, CLD) Cornea

• Xerosis (vitamin A)

• Cloudy (vitamin A)

• Keratomalacia (vitamin A)

• Opacification (vitamin A, zinc)

• Vascularisation (vitamin B₂)

Retina

• Optic neuritis (vitamin B₁₂)

• Optic atrophy (vitamin B₁)

Eye movements: ophthalmoplegia (vitamin E) Photophobia (vitamin B₂, zinc) Facial nerve: percuss for Chvostek’s sign (calcium) Mouth: angular cheilosis and stomatitis (iron, vitamin B₂, niacin) Teeth

• Caries (fluoride)

• Loose (vitamin C)

• Enamel defects (vitamin D)

Tongue

• Glossitis, reddening and ulceration (vitamin B group)

• Moisture (hydration)

• Cyanosis (CHD, vitamin B)

Buccal mucosa

• Reddened and ulcerated (vitamin B group)

• Petechiae (vitamin C)

Gums: swollen, bleeding (vitamin C) Contour of lower face

• Prominent salivary glands (vitamin C)

• Pendulous cheeks (PCM)

Neck: goitre (iodine) Gait and back Full gait examination, looking for:

• Cerebellar ataxia (vitamin E, zinc)

• Peripheral neuropathy (vitamins B₁, B₆, B₁₂)

• Romberg’s sign (vitamins E, B₁₂)

Examine back for scoliosis, kyphosis and lordosis (vitamin D) Lower limbs Palpate

• Muscle bulk (PCM)

• Ankle oedema (PCM, CLD)

• Long-bone tenderness (vitamin C, phosphate)

• Calf tenderness (vitamin B₁, selenium)

Power: decreased (PCM, vitamin C, sodium, potassium, phosphate) Tone: decreased (PCM) Reflexes

• Decreased (vitamins B₁, B₆, B₁₂, E)

• Increased (vitamin B₁₂ deficiency can cause decreased or increased reflexes)

• Slowed return (iodine)

Sensation

• Peripheral neuropathy (vitamins B₁, B₆, B₁₂, E)

• Posterior column dysfunction (vitamins B₁₂, E)

CHD = congenital heart disease; CLD = chronic liver disease; IBD = inflammatory bowel disease; PCM = protein calorie malnutrition.

Check the skin thoroughly before examining the patient. There are numerous dermatological manifestations of many deficiencies. Some of the relevant deficiencies include marked flakiness (PCM), dryness (linoleic acid, vitamin A), bruising (vitamin C, K), pellagra (niacin) or hyperpigmented hyperkeratosis (zinc deficiency).

Examine the child’s hands next. Look at the palms for crease pallor (anaemia associated with several deficiencies) or palmar erythema (chronic liver disease, CLD), and at the nails for koilonychia (iron), brittleness (iron, protein), leuconychia (CLD) or clubbing (cystic fibrosis [CF], CLD, Crohn’s disease).

Feel the radial pulse for bradycardia (PCM, iodine) or tachycardia (vitamin B₁, dehydration). Check the wrists for palpable epiphyseal enlargement (vitamin D), the forearms for tenderness (vitamin C) and the joints for swelling (vitamin C). Take, or request, the blood pressure, supine and standing (sodium, dehydration), and offer to look for Trousseau’s sign (cuff inflated to greater than systolic pressure for 3 minutes) at the end of the examination (calcium).

Next, examine the head and neck. Look for thinning of hair or areas of alopecia (linoleic acid, zinc), and for dyspigmentation of hair (PCM), and feel the hair for dryness (iodine) or excessive pluckability (PCM).

The eyes are the next area on which to focus, and many signs are possible here (see Table 8.6). In particular, look at the conjunctivae for pallor (iron, copper, B group vitamins, folate), or dryness and wrinkling (vitamin A), or Bitot’s spots (silver plaques of desquamated epithelial cells and mucus) on the bulbar aspect (vitamin A). Look for scleral icterus (vitamin B₁₂, CLD), corneal dryness, wrinkling or clouding (vitamin A) or opacification (vitamin A, zinc). Quickly assess the external ocular movement (vitamin E) and check for photophobia (riboflavin, zinc). Offer fundoscopy for optic nerve inflammation (vitamin B₁₂) or atrophy (vitamin B₁); usually this will not be required.

Next, percuss over the facial nerve, for Chvostek’s sign (calcium). Then, inspect the mouth for angular cheilosis (iron, riboflavin), the gums for swelling or bleeding (vitamin C), the teeth for caries (fluoride), enamel defects (vitamin D) or looseness (vitamin C), the tongue for moistness (hydration) or glossitis (B group vitamins), and the buccal mucosa for reddening, ulceration (B group vitamins) or petechiae (vitamin C). Examine the neck for goitre (iodine).

Examine the chest for sternal deformity (vitamins C, D), or any ‘rib rosary’ (vitamins C, D).

Next, examine the abdomen for evidence of pot belly (weak abdominal musculature, coeliac disease), hepatomegaly (PCM, linoleic acid), hepatosplenomegaly (CLD) or ascites (PCM, CLD). Assess Tanner staging for pubertal delay (zinc, Crohn’s).

Now, ask the child to walk, looking for evidence of cerebellar ataxia (vitamin E, zinc) or peripheral neuropathy (vitamins B₁, B₆, B₁₂). Check for Romberg’s sign (vitamins E, B₁₂). While the child is standing up, check the back for scoliosis, lordosis or kyphosis (vitamins D, C), and look again for any evidence of bow legs or knock knees (vitamin D).

Proceed with a lower limb examination; feel for ankle oedema (PCM, CLD) and test muscle tone (decreased in PCM). Check muscle power for weakness (PCM, sodium, potassium). Tap out the knee and ankle jerks, which may be decreased (vitamins B₁, B₆, B₁₂, E), increased (vitamin B₁₂) or have slowed return (iodine). Examine sensation for peripheral neuropathy (vitamins B₁, B₆, B₁₂, E) or posterior column dysfunction (vitamins B₁₂, E).

Examine the heart for cardiomegaly (vitamin B₁, phosphate, selenium) or congestive cardiac failure (vitamin B₁, phosphate, anaemia).

Finally, request the urinalysis for specific gravity (high with dehydration, low with chronic renal failure) and glucose (diabetes), and the stool analysis for evidence of malabsorption or giardiasis.

Failure to thrive

This is a very complicated short case and fortunately uncommon. The approach outlined is essentially a nutritional assessment modified to include relevant examination for chronic diseases of the main organ systems. To prevent unnecessary duplication, only aspects not mentioned in the nutritional short case are outlined in detail.

Commence with general inspection for obvious abnormalities, such as recognisable dysmorphic syndromes, central nervous system disease (e.g. cerebral palsy [CP]), neuromuscular disease (congenital myopathies, spinal muscular atrophy), tachypnoea (cardiac, respiratory, or renal—metabolic acidosis—in origin), cyanosis (congenital heart disease [CHD]) and any findings related to nutritional status. Next, request the child’s parameters. Failure to thrive as a term is used to describe failure of weight gain in particular, but—particularly if long-standing—may include lack of linear growth as well. If the head circumference is significantly affected, this suggests an intrauterine onset.

The percentile charts should be examined. The pattern of the height, weight and head circumference curves relative to each other may well give a valuable indication of the underlying pathology:

1. If all percentiles are equally affected, the possibilities include intrauterine TORCH infections or chromosomal abnormalities.

2. If height is most affected, possibilities include endocrinopathies and skeletal dysplasias.

3. The common pattern for malnutrition is that the weight is most affected, the height less affected and the head circumference relatively normal.

Demonstrate fat and protein stores, and then examine the skin fully; in particular, for dermatitis herpetiformis (coeliac disease), erythema nodosum (inflammatory bowel disease [IBD]) and pyoderma gangrenosum (IBD). Note any ichthyosis (Shwachman–Diamond syndrome, SDS).

Look next at the hands, noting any clubbing (chronic lung disease, chronic liver disease [CLD], IBD, CHD) and other nutrition-related signs. Examine the structure of the hands (dysmorphic syndromes), and take the radial and femoral pulses (CHD, coarctation). Check the blood pressure (renal disease, coarctation).

Proceed to the head and neck. As well as nutrition-related signs, look for dysmorphic features, macrocephaly, scars and shunts. In the eyes, look for cataracts or chorioretinitis (TORCH), retinitis pigmentosa (abetalipoproteinaemia, SDS) and papilloedema (intracranial tumours, hydrocephalus), and check the extraocular movements (neurological disease). At the mouth, check for thrush (can occur in cell-mediated immunity defects), check the palate for a cleft, note the quality of sucking and test the gag reflex. If a bottle or breast is available, the method of feeding should be observed.

Now, move to examination of the chest. Look for sternal deformity (syndromes), hyperinflation, Harrison’s sulcus, use of accessory muscles, intercostal recession (chronic lung disease), and scars of cardiac or pulmonary surgery. Palpate the tracheal position, apex beat and praecordium for thrills and heaves, percuss the chest, and auscultate the heart and lungs thoroughly to assess for chronic respiratory or cardiac disease.

Then, move on to the abdomen. Perform a full abdominal examination (see the short case on the abdomen). The findings sought include abdominal distension (ascites with CLD, coeliac disease, protein calorie malnutrition [PCM]), prominent veins (CLD), scars of previous surgery (e.g. bowel resection with necrotising enterocolitis [NEC], Kasai procedure for biliary atresia), hepatosplenomegaly (CLD, TORCH, metabolic and haematological diseases), enlarged kidneys (polycystic kidneys, hydronephrosis), anal anomalies (syndromes), rectal prolapse (cystic fibrosis [CF]) and excoriated buttocks (carbohydrate intolerance).

Next, have the child stand up and walk, checking the gait for primary neurological disease, as well as for nutritional deficiencies. Examine the back for midline defects or skeletal abnormalities such as kyphoscoliosis (syndromes, cerebral palsy), and then return the child to the bed and examine the lower limbs, again predominantly to detect primary neurological disease, as well as nutritional parameters. Note that if the patient is an infant, a gross motor developmental assessment is more appropriate at this point, and this may be combined with checking the primitive reflexes.

Request the urinalysis for specific gravity (low with chronic kidney disease [CKD], diabetes insipidus), glucose (diabetes), pH (renal tubular acidosis), protein (structural kidney disease, proximal tubular disease), blood (structural kidney disease, urinary tract infection), nitrites (urinary tract infection) and bilirubin (CLD). Request stool analysis, for evidence of steatorrhoea, fat crystals (coeliac disease) or globules (CF), low pH and reducing substances (carbohydrate intolerance), or giardia (cysts or vegetative forms). Mention inspection of any vomitus for bile (obstructive bowel lesions) or blood (portal hypertension) and the temperature chart for infection, as well as watching the mother feeding the child, noting their interaction, the feeding technique and any maternal anxiety.

The examiners may ask how you would investigate the problem. If undernutrition seems possible, then a common approach would be to admit the child to hospital and document whether the child can gain weight with adequate calories, which confirms undernutrition. If the child does not gain weight despite adequate calories, then investigation for malabsorption, or for any chronic disease, would be appropriate (see the long case on malabsorption).

Poor feeding

This is a very similar case to failure to thrive, but the problem may be of shorter duration, such that poor somatic growth has yet to occur. The approach is essentially the same in content, with some additions, but the order is changed.

Commence with general inspection, as outlined in the previous section, and comment on parameters and percentiles. The resting respiratory rate is a guide to a cardiac or respiratory cause, and obviously abnormal posturing and movements may indicate a neurological cause (e.g. cerebral palsy, spinal muscular atrophy).

Next, watch the child feed. This will help to clarify the nature of the feeding problem—whether it is local or general and, if general, which system is affected.

Start the examination with the head, looking for local causes first, if no initial clues are apparent after inspection. If there are suggestions of specific problems, such as an infant with an alert face but paucity of movement, then ‘go for the money’ and ‘chase’ all the relevant clinical signs for the diagnosis that you suspect (in this example, demonstrate all the findings recognised in Werdnig–Hoffmann spinal muscular atrophy).

Note whether there is any regurgitation of food through the nose, or any vomiting associated with feeding. Look for local structural problems, such as cleft palate. Check the gag reflex and note the quality of sucking. If the infant is breathless, check for nostril patency by holding a shiny metal object, such as one arm of a stethoscope, immediately below the nostrils, and inspect for condensation at the point underneath. The remainder of the head examination procedure suggested for failure to thrive is appropriate here.

The remainder of the general examination can also follow the failure-to-thrive pattern; that is, assessing the cardiorespiratory system, abdomen and neurological system, as well as checking the blood pressure (renal disease), urinalysis and the temperature chart.

Weight loss—older child/adolescent

The easiest way to think about the differential diagnoses for this case is to go back to basic physiology—loss of weight can be due to any one or more of four groups:

1. Lack of caloric intake: voluntary (e.g. by desire in AN, to avoid nausea in Crohn’s disease) or involuntary (e.g. protein calorie malnutrition [PCM] in the third world, neglect, abuse, Münchausen’s syndrome by proxy [a specific form of abuse], local structural craniofacial problems), or neuromuscular and neuro-developmental disorders, making intake difficult.

2. Lack of calorie utilisation, from lack of food digestion (e.g. cystic fibrosis [CF], Shwachman–Diamond syndrome [SDS]) or food absorption (e.g. coeliac disease, severe Crohn’s disease, short bowel syndrome [SBS]).

3. Excessive use of calories in metabolic processes. Any child with ‘chronic [fill in the organ system here—any organ] failure’ can lose weight. Hence, numerous causes can be remembered easily: chronic kidney failure/disease (CKD), chronic liver failure (CLD), chronic respiratory failure (as in CF), congestive cardiac failure (various forms of congenital and acquired heart disease), chronic immune failure (immunodeficiencies such as HIV), chronic atopic dermatitis (‘skin failure’), chronic adrenocortical failure (Addison’s) or chronic pancreatic endocrine failure (type 1 diabetes mellitus [T1DM]). Any child with cancer will lose weight. Any child with an active inflammatory process can lose weight (e.g. juvenile idiopathic arthritis, IBD).

4. Excessive loss of calories/nutrients/water: various causes of diarrhoea (coeliac disease), various causes of polyuria (CKD, T1DM, diabetes inspidus), various causes of vomiting (AN patients with bulimic features, subacute bowel obstruction, intracranial pathology, malignancy).

Depending on the lead-in given, as alluded to above, malignancy may need to be considered. Leukaemia, intracranial tumours and solid tumours (lymphoma, neuroblastoma, Wilms’) thus all come into the differential diagnosis. The approach given in Table 8.7 includes selected findings only; the list is by no means complete. While it is unlikely that a child with a malignancy would be a short-case subject in an examination format, it is still worth learning a comprehensive approach that will be useful in day-to-day practice.

Table 8.7 Weight loss in the older child: list of possible findings on examination

1. General inspection

Position patient: fully undressed, standing then lying down

Parameters

• Weight age versus height age

• Weight for height (quantitate)

Sick or well Cachectic (malignancy, AN, AIDS) In pain (malignancy, IBD, JA) Activity, awareness (PCM) Irritability (hyperthyroidism, PCM, iron) Depressed affect (AN) Pigmentation (Addison’s, beta thalassaemia major) Nasogastric tube (AN) ‘Raccoon eyes’ (ecchymoses from neuroblastoma) Intravenous access port (chemotherapy in oncology patients, TPN in IBD) Chest AP diameter increased (asthma, CF) Pot belly (PCM, coeliac) Posture: bow legs (vitamin D) Hemihypertrophy (hepatoblastoma, Beckwith [e.g. with adrenal carcinoma]) 2. Demonstrate fat and protein stores Subcutaneous fat

Muscle bulk

3. Skin Pallor (deficiencies various vitamins, iron, CKD, ALL) Acrocyanosis (AN) Jaundice (CLD, vitamin B₁₂) Yellowish hue (from hypercarotenaemia in AN) Bruising (CLD, ALL, neuroblastoma) Petechiae: limited to SVC distribution (vomiting in AN) Petechiae, purpura: generalised distribution (leukaemia) Dry (atopic dermatitis, AN) Dermatitis artefacta (e.g. cigarette burns, other self-injury in AN) Scaling (AN) Excoriated acne (self-injuring AN) Hypertrichosis: lanugo-like, fine downy-like hair (AN) Eczematous scaling around mouth, elbows, knees, genitals, anus (zinc) Pigmented scars (Addison’s) Café-au-lait spots (NF-1 with associated tumours) Axillary freckling (NF-1 with associated tumours) Palpable non-tender subcutaneous nodules (neuroblastoma) Dermatitis herpetiformis (coeliac) Erythema nodosum (IBD) Pyoderma gangrenosum (IBD) Pretibial oedema (AN) Necrobiosis lipoidica diabeticorum (red-brown plaques on shins, in IDDM) 4. Head and neck Hair

• Loss of discrete areas (trichotillomania as self-injury in AN)

• Thinning (AN, PCM)

• Brittle, pluckable (AN, PCM)

Eyes: inspection (from above and from side, as well as in front) Mouth: angular cheilosis and stomatitis (iron) Tongue

• Glossitis, reddening and ulceration (vitamin B group)

• Cyanosis (CHD, CF)

Palate: scarring from self-induced vomiting (AN with bulimic features) Buccal mucosa

• Reddened and ulcerated (vitamin B group)

• Petechiae (leukaemia, vitamin C)

Gums: gingivitis (ALL) Teeth: erosion of enamel (AN who purge) Contour of lower face: prominent salivary glands (AN with bulimia) Neck

• Lymphadenopathy (lymphoma, ALL, CLL)

• Goitre (hyperthyroidism)

Full examination of cranial nerves, including motor cranial nerves (test first; for intracranial tumours) 5. Upper limbs Tremor (hyperthyroidism) Hands

• Russell’s sign (calluses, scars or erosions over dorsal surface of hands, especially metacarpophalangeal joints with self-induced vomiting in AN)

Palms

• Pigmented creases (Addison’s, beta thalassaemia major)

• Pallor (anaemias, CKD)

• Erythema (CLD)

Nails

• Clubbing (CF, IBD, CLD)

Fingers

• Fingertip prick marks (BSL testing in diabetes, CF)

• Hypertrophic pulmonary osteoarthropathy, HPOA (CF)

Pulse

• Bradycardia (AN, PCM)

• Tachycardia (thyrotoxicosis, phaeochromocytoma, vitamin B₁₂)

• Irregular (atrial arrhythmia in AN)

• Flap (hypercarbia in CF, liver failure)

Wrists: tender, palpable epiphyseal enlargement (vitamin D) Joints: swollen (juvenile arthritis, arthropathy with IBD, CF) Epitrochlear node enlargement (lymphoma) Blood pressure

• Hypotension: check for postural drop (Addison’s, AN)

• Hypertension (CRF, phaeochromocytoma, other neuroendocrine tumour)

Full neurological examination of upper limbs, looking for:

• Cerebellar ataxia (posterior fossa tumour)

• Peripheral neuropathy (vitamin B₁₂)

• Upper motor neurone signs (intracranial tumour, spinal tumour)

6. Chest Full chest and cardiac examination. Findings can include: Tachypnoea (CF, asthma, diabetic ketoacidosis, metabolic acidosis in AN) Scars (previous cardiac surgery with CHD, lung transplant with CF, venous access port with CF, malignancy) Chest deformity: pectus carinatum, increased AP diameter (asthma, CF) Harrison’s sulcus (CF) Subcutaneous emphysema (with pneumomediastinum in AN) Superior vena cava syndrome (malignancy) Praecordium: palpate, auscultate (various forms of CHD) Chest: ask to cough, palpate, percuss, auscultate (CF, secondary malignancy with effusion) Sacral oedema (PCM, CLD) 7. Abdomen Full abdominal examination. Findings can include: Prominent veins (CLD with portal hypertension, malignancy) Scars (gut surgery with IBD, hepatobiliary surgery, tumour removal) Needle marks (diabetes mellitus, DFO in beta thalassaemia major) Pigmented umbilicus, scars (Addison’s) Venous access port, below ‘bikini line’ (malignancy, CF) Distension

• Ascites (malignancy,CLD)

• Weak abdominal muscles (PCM, coeliac)

Striae (corticosteroid treatment in IBD, asthma, CF) Abdominal mass (Wilms’, neuroblastoma, lymphoma, germ cell tumour)

• Full examination of all aspects of a mass: location (site), size (measure), if crosses midline, consistency, surface, tenderness, mobility, relations to adjacent structures, associated bruit, venous dilatation, enlarged draining lymph nodes, percussion note, associated ascites, extension into pelvis

Hepatomegaly (hepatoblastoma, leukaemia, CCF, fatty liver: malabsorption) Hepatic bruit (hepatoblastoma) Hepatosplenomegaly (CLD, leukaemia) Splenomegaly (portal hypertension in CF, CLD) Renal mass (Wilms’) Genitalia/Tanner staging

• Pubertal delay (AN, Crohn’s)

• Pubertal precocity (adrenal tumour, NF-1 with tumour)

• Testicular enlargement (ALL, testicular tumour)

Perianal disease (Crohn’s) Perianal or buttock mass (malignancy) Rectal prolapse (CF) 8. Gait and back Full gait examination, looking for:

• Cerebellar ataxia (posterior fossa tumour)

• Upper motor neurone signs (intracranial tumour, primary or secondary)

• Peripheral neuropathy (vitamin B₁₂)

• Romberg’s sign (vitamins E, B₁₂)

Examine back for:

• Tenderness (spinal tumour)

• Scoliosis (NF-1 with tumour; spinal tumour, neuroblastoma)

• Kyphosis and lordosis (vitamin D)

9. Lower limbs Palpation

• Muscle bulk (AN, PCM)

• Ankle oedema (CHD, hypoproteinaemia in PCM)

• Tenderness (bone tumour, primary or secondary)

Full neurological examination of lower limbs, looking for:

• Cerebellar ataxia (posterior fossa tumour)

• Peripheral neuropathy (vitamin B₁₂)

• Upper motor neurone signs (intracranial tumour, primary or secondary)

10. Other Urinalysis

• Low specific gravity (CKD)

• High specific gravity (dehydration)

Stool analysis

Temperature chart

AIDS = acquired immune deficiency syndrome; ALL = acute lymphoblastic leukaemia; AML = acute myeloid leukaemia; AN = anorexia nervosa; AP = antero-posterior; BSL = blood sugar level; CF = cystic fibrosis; CHD = congenital heart disease; CLD = chronic liver disease; CLL = chronic lymphocytic leukaemia; CKD = chronic kidney disease; DFO = desferrioxamine; HPOA = hypertrophic pulmonary osteoarthropathy; IBD = inflammatory bowel disease; JA = juvenile arthritis; NF-1 = neurofibromatosis type 1; PCM = protein calorie malnutrition; SVC = superior vena cava; TPN = total parenteral nutrition.

For more detailed findings in the examinations for the various systems and their disorders, refer to the relevant sections (e.g. CF, IBD, CLD, CKD, oncology). Wherever a vitamin or trace element is noted in brackets, this refers to a deficiency of this, in the context of malnutrition.

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