Disorders of Bile Acid Synthesis and Biliary Transport

Abstract

Bile acids have well established roles as drivers of bile flow and as the catabolic end products of cholesterol metabolism, but bile acids and their metabolic precursors are increasingly recognised as important regulators of other pathways. Inborn errors have been identified in each of the main stages of bile acid synthesis (modification of sterol nucleus, side chain and conjugation) and also in a variety of steps in bile acid transport. Manifestations of these disorders reflect the lack of functional bile acids and build-up of their potentially toxic precursors. Examples include progressive liver dysfunction with fat soluble vitamin malabsoprtion, progressive neurological deterioration, hereditary spastic paraplegia and mild statin resistant hypercholesterolaemia.

Bile acids and there precursors can be detected in a variety of biological fluids including blood, urine, bile and CSF. They represent a considerable diagnostic challenge due to their natural heterogeneity. The characterisation of abnormal bile acids in these fluids has relied heavily on mass spectrometry. Single stage mass spectrometry of urine with minimal sample preparation can provide a rapid tool for the detection of abnormal patterns of bile acids sufficient to diagnose most inborn errors. Further characterisation of unusual bile acids can be achieved by gas-chromatography mass spectrometry or liquid chromatography linked to tandem mass spectrometry. Disorders of bile acid transport do not result in the production of abnormal bile acid patterns and require genetic characterisation.

Treatment for most of the disorders of bile acid synthesis is the replacement of the primary bile acids by oral administration of chenodeoxycholic and/or cholic acid. This supplies functional bile acids and has the benefit of negative feedback inhibition of potentially toxic bile acid intermediates. This is a highly effective treatment for those disorders presenting with hepatic impairment, as long as it is instigated prior to irreversible liver damage (which requires liver transplantation). Chenodeoxycholic acid has also been shown to improve neurological outcomes in patients with cerebrotendinousxanthomatosis.

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

1 Introduction

The primary bile acids produced in man are the taurine and glycine conjugates of cholic and chenodeoxycholic acid. They are synthesised in the liver from cholesterol via numerous modifications of the sterol nucleus and side chain. A number of physiological roles have traditionally been assigned to bile acids. These include the end products of cholesterol catabolism that account for approximately 90 % of cholesterol excretion, the facilitation of bile flow by activating bile solute pumps (via nuclear receptors such as the farnesoid X receptor) and driving the osmotic excretion of water into the bile canaliculi and as biological detergents within the gut lumen enabling the absorption of fat-soluble compounds. More recently a wider role of bile acids is becoming apparent as hormone regulators of metabolism, with postulated effects on diverse processes such as carbohydrate and fat metabolism and the regulation of energy expenditure by thyroid hormone (Hylemon et al. 2009).

The conversion of cholesterol to the primary bile acids can occur via different pathways, which are summarised in Fig. 34.1. The two commonly described pathways are the ‘neutral’ pathway, starting with 7α-hydroxylation and subsequent nuclear modification prior to side-chain modification, and the ‘acidic’ pathway that starts with side-chain modification. The majority of the enzymes involved in bile acid synthesis are shared between these pathways, with the notable exception being those involved in 7α-hydroxylation (cholesterol 7α-hydroxylase [neutral pathway] and the oxysterol 7α-hydroxylase [‘acidic pathway’]) and 12α-hydroxylation (Russell 2003). The neutral pathway is considered the most significant in human adult life, whereas the acidic pathway seems to play a more prominent role in early life. Alternative pathways that involve initial 24/25 hydroxylation are described and are postulated to play an important role in cholesterol metabolism in brain and lung. The common pathway for side-chain modification is completed via peroxisomal β-oxidation.

Inborn errors of bile acid metabolism can present in a variety of ways. Most of the errors that effect transformation of the steroid nucleus (disorders 34.1–34.4) produce abnormal metabolites that are not substrates for active transport into bile and generally present with failure of bile flow (cholestasis) and malabsorption of fat and fat-soluble vitamins. Patients may present acutely with the effects of vitamin deficiency such as haemorrhage or hypocalcaemic seizures or more insidiously with prolonged neonatal jaundice, steatorrhoea and rickets. Transaminases are significantly raised with a conjugated hyperbilirubinaemia, but gamma-glutamyl transpeptidase (γGT) is characteristically normal. Notable exceptions include cholesterol 7α-hydroxylase deficiency, which presents with statin-resistant hyperlipidaemia and gallstones in later life. This presumably reflects the ability of the ‘acidic’ pathway to compensate for the deficit in the ‘neutral’ pathway. Also, oxysterol 7α-hydroxylase deficiency has been described in patients with neonatal cholestasis, but also in patients presenting with hereditary spastic paraplegia (HSP). The acidic pathway has been implicated in cholesterol catabolism in the central nervous system, and significantly elevated levels of 27-hydroxycholesterol have been found in the CSF of patients with HSP.

Inborn errors that effect the modification of the cholesterol side chain (disorders 34.5, 34.6 and the peroxisomal disorders) produce cholanoids (bile acids and alcohols) that, to some extent, can drive bile flow. Symptoms appear to be caused mainly by accumulation of intermediates proximal to the site of the block and conversion of these intermediates to a product which is deposited in various tissues of the body (Verrips et al. 2000). The deposition of cholestanol and cholesterol in CTX can lead to the formation of cataracts, mental retardation in the first decade and neurological regression with dementia and motor dysfunction in later life. The lipid deposition also produces tendon xanthomata and premature atherosclerosis. CTX can, however, also cause cholestasis in infancy. In several of the peroxisomal disorders, there is impaired bile acid synthesis and some impairment of liver function, although other pathways are often impaired and neurological disease usually predominates. These disorders are considered elsewhere. α-Methylacyl-CoA racemase deficiency (34.6) can present with neonatal cholestasis (Setchell et al. 2003) and is considered in this chapter, but is also mentioned in Chap. 24 on peroxisomal diseases.

In the defects of bile acid amidation (34.7, 34.8), the primary bile acids are synthesised but the final step of conjugation with glycine or taurine is defective. Bile acids synthesised de novo are produced as cholyl-CoA esters and require only the peroxisomal enzyme bile acid-CoA/amino acid N-acyltransferase (BAAT) to produce conjugated products (Pellicoro et al. 2007). Bile acids that are deconjugated by intestinal flora and returned to the liver via enterohepatic circulation require bile acid-CoA ligase to form the bile acid-CoA esters prior to reconjugation by BAAT. Deficiency of either enzyme leads to the production of unconjugated bile acids, which are substrates for active transport into bile thus driving bile flow, but are inefficient biological detergents. Thus, patients with BAAT deficiency can present with steatorrhoea and fat-soluble vitamin deficiency with mild or absent jaundice.

The clinical presentation of bile acid-CoA ligase deficiency is unclear as the only symptomatic child described had a possible concurrent diagnosis of TPN-related cholestasis and mutations in the bile salt export pump gene (Chong et al. 2012).

The simplest way to screen a symptomatic individual for inborn errors of bile acid synthesis is to analyse urine by a soft ionisation (usually electrospray) mass spectrometry technique (ESI-MS). Other methods are available for some of the individual disorders. Prompt and accurate diagnosis of inborn errors of bile acid metabolism is paramount, as many of these disorders are amenable to simple oral therapy if instituted before the onset of significant hepatic damage – treatment is further discussed in Sect. 34.10.

Defects in bile transporters are commonly identified in patients with inherited forms of cholestasis (e.g. conjugated hyperbilirubinaemia). The more severe protein defects manifest in early life, whilst milder abnormalities may become apparent only when the transport processes are under stress such as in pregnancy or after specific drug ingestion. Defects of at least six proteins that facilitate transport of different bile constituents are known (Fig. 34.2). Bile constituents that include bile acids, bilirubin, cholesterol, phospholipids and other products of metabolism are secreted into biliary canaliculi in an energy-dependent manner. Transmembrane transporter proteins mediate the secretory function of hepatocytes and biliary epithelial cells.

Progressive familial intrahepatic cholestasis (PFIC) is characterised by persistent conjugated hyperbilirubinaemia and in PFIC1 and PFIC2, low or normal serum γGT values and progressive liver damage that requires liver transplantation in childhood. Patients with PFIC1/2 have reduced concentrations of primary bile acids in bile. Mutations in ATP8B1 (PFIC1) and ABCB11 (PFIC2) were found to be the cause of disease in the majority of patients, although there is still a proportion of patients without mutations in either of the genes. There are some clinical differences in the presentation of ATP8B1 and ABCB11 disease; most notably patients with ATP8B1 have a range of extrahepatic manifestations such as diarrhoea and episodes of pancreatitis. Patients with ABCB11 mutations are at increased risk of hepatobiliary malignancy. In addition to the classical PFIC, some mutations in both ATP8B1 and ABCB11 cause the so-called benign recurrent intrahepatic cholestasis (BRIC), when cholestasis can completely resolve between relapses. It is now clear that a spectrum of severity between PFIC and BRIC exists. ABCB4 (PFIC3) deficiency results in impaired excretion of phosphatidylcholine (PC) into bile and can result in a spectrum of cholestatic disorders including neonatal hepatitis and biliary cirrhosis with patients typically having high serum γGT values.

Mutations in ABCC2 result in Dubin-Johnson syndrome, a condition characterised by recurrent episodes of cholestatic jaundice without other clinical/biochemical indications of hepatobiliary injury. Liver biopsy shows intrahepatocyte deposits of dark pigment but no other abnormalities. Rotor syndrome is phenotypically very similar to Dubin-Johnson syndrome and manifests with mild cholestatic jaundice that can be detected in the neonatal period or in childhood. It differs from Dubin-Johnson syndrome in that no intrahepatocyte pigment deposits can be found in Rotor syndrome patients and there is a delayed plasma clearance of unconjugated bromsulphthalein. Mutations in SLCO1B1 and SLCO1B3 genes, encoding organic anion-transporting polypeptides OATP1B1 and OATP1B3, have to be present simultaneously to cause Rotor syndrome.

2 Nomenclature

Disorders of peroxisome biogenesis and defects of peroxisomal β-oxidation (such as d-bifunctional protein deficiency) affect bile acid synthesis but are considered elsewhere. α-Methylacyl-CoA racemase is located both in peroxisomes and mitochondria; it is considered here because in common with other disorders of bile acid synthesis, it can present with neonatal cholestatic jaundice without neurological abnormalities. An identical argument can be made for BAAT deficiency. Both disorders can also be found in Chap. 24 on peroxisomal disease.

No.	Disorder	Alternative name	Abbreviation	Gene symbol	Chromosomal localisation	Affected protein	OMIM no.	Subtype
34.1	3β-Hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency	3β-Dehydrogenase deficiency	C27-3β-HSD	HSD3B7	16p11.2	3β-Hydroxy-Δ5-C27-steroid dehydrogenase/isomerase	607764	All forms
34.2	Δ4-3-Oxosteroid-5β-reductase deficiency	5β-Reductase deficiency	SRD5B1	AKR1D1	7q32-q33	Delta(4)-3-oxosteroid-5β-reductase	604741	All forms
34.3	Oxysterol 7α-hydroxylase deficiency	Spastic Paraplegia 5A	CYP7B1	CYP7B1	8q12.3	Oxysterol 7α-hydroxylase	603711	All forms
34.4	Cholesterol 7α-hydroxylase deficiency		CYP7A1	CYP7A1	8q12.1	Cholesterol 7α-hydroxylase	118455	All forms
34.5	Sterol 27-hydroxylase deficiency	Cerebrotendinous Xanthomatosis	CTX	CYP27A1	2q35	Sterol 27-hydroxylase	213700	All forms
34.6	α-Methylacyl-CoA racemase deficiency	AMACR deficiency	AMACR	AMACR	5q13.2	α-Methylacyl-CoA racemase	604489	All forms
34.7	Bile acid-CoA: amino acid N-acyltransferase deficiency	Bile acid amidation defect	BAAT	BAAT	9q31.1	Bile acid-CoA: amino acid N-acyltransferase	602938	All forms
34.8	Bile acid-CoA ligase deficiency		BA CoA LD	SLC27A5	19q13.43	Bile acid-CoA ligase	603314	All forms
34.9	ATP8B1 deficiency	Progressive familial intrahepatic cholestasis type 1	PFIC1	ATP8B1	18q21.31	ATP8B1 (type 4 P-type ATPase)	211600	All forms
34.10	ABCB11 deficiency	Progressive familial intrahepatic cholestasis type 2	PFIC 2	ABCB11	2q31.1	ABCB11 (bile salt export pump [BSEP])	603201	All forms
34.11	ABCB4 deficiency	Progressive familial intrahepatic cholestasis type 3	ABCB4	ABCB4	7q21.12	ABCB4 (MDR3)	602347	All forms
34.12	OATP1B1 and OATP1B3 disease	Rotor syndrome	OATP1B1 and OATP1B3	SLCO1B1 and SLCO1B3	12p12.2-p12.1 and 12p12.2	OATP1B1 and OATP1B3	237450, 604843, 605495	All forms
34.13	ABCC2 deficiency	Dubin-Johnson syndrome	ABCC2 or DJS	ABCC2	10q24.2	ABCC2 (cMOAT)	237500, 601107	All forms

3 Metabolic Pathways

Fig. 34.1

Simplified scheme of the known pathways for the synthesis of bile acids from cholesterol, including enterohepatic recycling. The ‘neutral’ pathway starts with conversion of cholesterol to 7α-hydroxycholesterol and the ‘acidic’ pathway with formation of 27-hydroxycholesterol. Defined inborn errors are highlighted with crossed arrows. Enzymatic steps thus far not associated with known deficiencies are numbered: (1) 12α-hydroxylase, (2) sterol 27-hydroxylase catalyses both 27-hdroxylation and further oxidation to a carboxylic acid, (3) 3α-hydroxysteroid dehydrogenase, (4) very long chain acyl-CoA synthase (VLCS)/di-/trihydroxycholestanoic acid-CoA ligase and (5) intraluminal bacterial deconjugation

Fig. 34.2

Diagram illustrating the transporters involved in the generation of bile. ATP8B1, a member of the type 4 subfamily of P-type ATPases, is present in the apical membrane of many epithelial cells including hepatocytes and enterocytes. ATP8B1 appears to translocate aminophospholipids such as phosphatidylserine (PS) from the outer to the inner leaflet of the plasma membrane bilayer but also has other functions such as facilitating polarised expression of other apical membrane proteins. ABCB11 encodes the bile salt export pump (BSEP), which is responsible for the ATP-dependent transport of taurine and glycine-conjugated primary BA across the canalicular membrane. BSEP is a member of the P-glycoprotein/multidrug resistance (MDR/ABCB) subfamily of transporters. ABCB4, or multidrug resistance protein 3 (MDR3), is a P-glycoprotein that translocates phospholipids from internal to external leaflet of the canalicular membrane. ABCB4 deficiency results in impaired excretion of phosphatidylcholine (PC) into bile and can result in a spectrum of cholestatic disorders including neonatal hepatitis and biliary cirrhosis. As PC is a major component of the mixed micelles into which salts of bile acids are emulsified, deficiency of ABCB4 leads to hepatocyte and cholangiocyte damage by bile acids. The protein encoded by ABCC2 (ABCC2 or MRP2) is a member of the multidrug resistance protein subfamily. It exports anionic glutathione and glucuronate conjugates (including bilirubin) from hepatocytes into canaliculi. ABCC2 is expressed on apical membranes of many epithelial cells including hepatocytes, proximal renal tubules, gallbladder, small intestine, bronchi and placenta. OATP1B1 and OATP1B3 localise to the sinusoidal membrane of hepatocytes and mediate sodium-independent cellular uptake of highly diverse compounds that include bilirubin glucuronide, bile acids, steroid and thyroid hormones, and numerous drugs

4 Signs and Symptoms

Table 34.1 3β-Hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency

Table 34.2 Δ4-3-Oxosteroid-5β-reductase deficiency

Table 34.3 Oxysterol 7α-hydroxylase deficiency

Table 34.4 Cholesterol 7α-hydroxylase deficiency

Table 34.5 Sterol 27-hydroxylase deficiency

Table 34.6 α-Methylacyl-CoA racemase deficiency

Table 34.7 Bile acid-CoA/amino acid N-acyltransferase deficiency

Table 34.8 Bile acid-CoA ligase deficiency

Table 34.9 ATP8B1 deficiency

Table 34.10 ABCB11 deficiency

Table 34.11 ABCB4 deficiency

Table 34.12 OATP1B1 and OATP1B3 disease

Table 34.13 ABCC2 deficiency

Carriers for Mutations in Hepatocyte Transporter Proteins

Carriers of ATP8B1, ABCB11 and ABCB4 mutations are predisposed to intrahepatic cholestasis of pregnancy (ICP), which is a third-trimester disorder that is characterised by pruritus and elevated serum concentrations of bile acids (van der Woerd et al. 2010). It seems that the subtype with low serum γGT values occurs in ABCB11 and ATP8B1 mutation carriers, whilst carriers of ABCB4 typically have high γGT values. ICP is associated with fetal disease, fetal distress, premature birth and stillbirth. Cholestasis associated with the administration of oral contraceptives is also more frequent in carriers of ABCB11 mutations. Low-phospholipid-associated cholelithiasis (LPAC) is a form of gallstone disease that occurs in younger patients which is associated with ABCB4 mutations, recurs after cholecystectomy and appears to respond well to UDCA. Mutations in ABCB11 and ABCB4 have been associated with drug-induced cholestasis (DIC) following administration of amoxicillin, clavulanic acid and risperidone.

5 Reference Values

Table 34.14 Determination of urinary cholanoid (bile acid and bile alcohol) profile by ESI-MS (electrospray ionisation mass spectrometry)

The mass spectrometer scans negative ions over the range m/z 350–700, or sometimes 200–800, and draws a spectrum with the largest peak as 100 % intensity. In Table 34.14, indicates that the peak is not detectable above the background, ± indicates undetectable to 20 % of the largest peak and ↑ indicates 20–100 % intensity of largest peak. Daughter ions generated in a collision cell can be used to help confirm peak identities, e.g. m/z 74 for glycine conjugates, m/z 80 for taurine conjugates, m/z 97 for sulphates and m/z 85 for glucuronides.

Table 34.15 Urinary cholanoid excretions determined by GC-MS

Table 34.16 Plasma cholanoid concentrations

Table 34.17 Plasma cholestanol concentrations

The values below refer to total plasma concentration determined by GC-MS analysis following hydrolysis of cholestanol esters.

6 Pathological Values

Table 19 Urinary cholanoid (bile acid and alcohol) profile by ESI-MS

Table 20 Further analysis of plasma cholanoid profile by GC-MS

GC-MS analysis is used to confirm the identities of ions in the ESI-MS urine spectrum and to show that the excretion of abnormal cholanoids is >20 times normal. In the case of 5β-reductase deficiency GC-MS analysis should show that 3-oxo-Δ⁴ bile acids account for >70 % of the total urinary bile acid excretion. In the case of sterol 27-hydroxylase deficiency (CTX), GC-MS analysis should indicate that the major cholestane pentols in the urine are 3, 7, 12, 22, 25 and 3, 7, 12, 23, 25 pentols. Tandem mass spectrometry (e.g. liquid secondary ion tandem MS[LSI-MS/MS]) is an alternative method to GC-MS and can rapidly confirm the identity of a number of diagnostic ions that are found in the LSI-MS/ESI-MS spectrum of urine. These include sulphated and taurine-conjugated abnormal metabolites such as those observed in 3β-HSDH deficiency (34.1), 5β-reductase deficiency (34.2), oxysterol 7α-hydroxylase deficiency (34.3) and peroxisomal disorders.

7 Diagnostic Flow Charts

Fig. 34.3

Diagnostic flowchart for low γGT cholestasis

There are also some syndromes which include low γGT cholestasis as well as extrahepatic features, e.g. the arthrogryposis, renal dysfunction and cholestasis (ARC) and Åagenaes (cholestasis lymphoedema) syndromes.

Immunostaining can detect the absence of proteins involved in bile acid metabolism or biliary secretion in a liver biopsy.

Fig. 34.4

Diagnostic flow chart for disorders of bile acid synthesis

8 Specimen Collection

Test	Conditions	Material	Handling	Pitfalls
Urine cholanoid profile by LSI-MS or ESI-MS	No bile acid therapy	Urine ≥0.5 ml	Ambient temp. 12 h, 4 °C for 48 h, −20 °C for >6 months	Drugs and radiographic contrast media may produce large peaks on the LSI-MS spectrum
		Cholanoids from urine adsorbed on C18 cartridge (volume of urine and creatinine recorded)	Ambient temp. 48 h
Further analysis of urinary cholanoids by GC-MS	No bile acid therapy	Urine ≥2.0 ml (can be sent on C18 cartridge as above)	As above
Plasma bile acids	No bile acid therapy	Plasma/serum 0.5–2.0 ml	Ambient temp. 12 h, 4 °C for 48 h, −20 °C for >6 months
Plasma cholestanol	No bile acid therapy	Plasma/serum 0.2–1.0 ml	As above

9 Prenatal Diagnosis and DNA Testing

Routine specific DNA testing for the inborn errors of bile acid metabolism and biliary secretion is not generally available and is conducted on a research basis only. The advent of whole-exome sequencing will potentially increase the number of patients identified with these disorders. Prenatal diagnosis can be undertaken using DNA analysis.

10 Treatment

Summary

Treatment for most of the synthesis disorders is simple and, if instituted before the onset of significant hepatic damage, effective. Liver function tests and biopsy appearances can be normalised by treatment with oral chenodeoxycholic acid and/or cholic acid. These bile acids enter the enterohepatic circulation and drive bile flow and also inhibit the endogenous production of abnormal bile acids. In some, however, liver damage progresses requiring liver transplantation. Treatment of the consequences of acute vitamin K deficiency is important and can be immediately life saving, especially in the case of hypocalcaemic seizures and haemorrhage secondary to vitamin K deficiency. Not only can the treatment of cholestasis be successful, but the treatment can improve neurological sequelae in these conditions. In CTX, treatment with chenodeoxycholic acid reduces the rate of synthesis of cholestanol and the urinary excretion of bile alcohols and can reverse the patient’s neurological disability, with clearing of the dementia, improved orientation, a rise in intelligence quotient and enhanced strength and independence (Berginer et al. 1984).

Patients with PFIC usually require treatment for fat-soluble vitamin deficiency. They often have severe pruritus which is difficult to treat but may respond to drugs such as rifampicin, cholestyramine and ursodeoxycholic acid. Rifampicin has been shown to inhibit the expression of the enzyme autotaxin which is involved in the origin of pruritus (Kremer et al. 2012). No treatments are yet available that can correct the underlying transport defect. Ursodeoxycholic acid promotes bile flow and can probably protect biliary epithelial cells and hepatocytes from damage during cholestasis. It is of proven benefit in ABCB4 deficiency, but, in ATP8B1 and ABCB11 deficiencies, there are conflicting reports of any benefit. Some patients with ATP8B1 and ABCB11 deficiencies have benefitted from partial external biliary diversion or ileal exclusion surgery. However, in all three PFIC disorders, liver damage is progressive and most children ultimately require liver transplantation.

The Dubin-Johnson and Rotor syndromes generally produce mild (and often intermittent) conjugated hyperbilirubinaemia which has no important consequences and no progressive liver disease. So treatment is not required except for severe neonatal cases.

Initial Management of the Cholestatic Infant with a Bile Acid Synthesis Defect

Fig. 34.5

Initial management of the cholestatic infant with a bile acid synthesis defect. ^aor cholic acid 7.5 mg/kg/day plus chenodeoxycholic acid 7.5 mg/kg/day. ^brapid healing of rickets may require more vitamin D (as 1,25-dihydroxycholecalciferol) and a calcium supplement

Treatment of the Consequences of Fat-Soluble Vitamin Malabsorption

Once coagulopathy has been corrected and rickets healed, bile acid replacement therapy should be adequate to prevent any manifestations of fat-soluble vitamin malabsorption; however, it is wise to continue for ca.3 months after starting treatment with a vitamin supplement containing all four fat-soluble vitamins, e.g. Ketovite tabs, iii daily (provides 15 mg α-tocopheryl acetate and 1.5 mg acetomenaphthone), plus Ketovite elixir 5 ml daily (provides 2,500 units of vitamin A and 400 units ergocalciferol).

Treatment for	Medication	Dose	Route	Target
Vitamin K deficient bleeding	Vitamin K (phytomenadione)	1 mg daily	i/v slowlya	Normal clotting times
Hypocalcaemia (fits, tetany)	10 % Calcium gluconate (plus 1,25-dihydroxycholecacliferol, see below)	0.1–0.3 ml/kg/dose	i/v slowly	Normal ionised calcium
Rickets	1,25-Dihydroxycholecalciferol	0.25–1.00 μg/day	Oral	Normal calcium, healing of rickets. Avoidance of hypercalcaemia
Vitamin E deficiency	Alpha-tocopherol acetate or water-soluble/miscible vit E preparation	50 mg	Oral	Normal plasma vitamin E
Vitamin A deficiency	Vitamin A or water miscible analogue	2,500 Units e.g. Ketovite elixir 5 ml daily	Oral	Normal plasma vitamin A
Basic defect	Chenodeoxycholic acid and/or cholic acid	See individual disorders	Oral	Normal liver function tests, etc.

1. ^aImmediate treatment of a coagulopathy caused by vitamin K deficiency may be life saving but intravenous phytomenadione can cause anaphylaxis

Specific Treatment Strategies

Table 23 3β-Hydroxysteroid-Δ⁵-C₂₇-steroid dehydrogenase deficiency

Table 24 Δ⁴-3-Oxosteroid-5β-reductase deficiency

Patients with 5β-reductase deficiency usually present with cholestatic liver disease in infancy. It is important to distinguish patients with mutations in the 5β-reductase gene from patients in whom excretion of 3-oxo-Δ ⁴ bile acids is secondary to severe liver damage caused by another genetic disorder (e.g. tyrosinaemia) or an acquired disorder (e.g. hepatitis B).

Table 25 Oxysterol-7α-hydroxylase deficiency

The three patients described initially were treated with ursodeoxycholic acid +/− liver transplantation, either as a result of initial severe liver disease or lack of chenodeoxycholic acid available for therapy. One recently described patient, postulated to have a deficiency of oxysterol 7α-hydroxylase, responded well to chenodeoxycholic acid therapy (Chong et al. 2010). If the liver disease does not respond to bile acid treatment, cholestasis will persist until liver transplantation can be undertaken (Mizuochi et al. 2011). Therefore, these children require forms of the fat-soluble vitamins that are water soluble or can be given by injection.

Table 26 Cholesterol 7α-hydroxylase deficiency

Table 27 Sterol 27-hydroxlase deficiency (CTX)

Table 28 α-Methylacyl-CoA racemase deficiency

Table 29 Bile acid-CoA: amino acid N-acyltransferase deficiency (BAAT deficiency)

Table 30 Bile acid-Co ligase deficiency

The requirement for treatment in this condition is unclear. Only two siblings have been described with a bile acid-CoA ligase deficiency, one of whom was asymptomatic and did not require treatment. Another sibling was treated with ursodeoxycholic acid for presumed TPN-related cholestasis, and only after resolution of cholestasis and termination of therapy was a diagnosis made. The patient remains well and has not required further therapy.

Table 31 ATP8B1 disease (PFIC1)

Table 32 ABCB11 disease (PFIC2)

Table 33 ABCB4 disease (PFIC3)

Table 34 OATPB1 and OATPB3 disease (Rotor syndrome)

Table 35 ABCC2 disease (Dubin-Johnson syndrome)

Alternative Therapies/Experiment Treatment

Table 36 Cerebrotendinous xanthomatosis