LIVER and GALL BLADDER

1927 De Lange C. Cirrhosis of pancreas and liver in infant. Am J Dis Child 1927; 34:372-383.
Cornelia de Lange, famous for her description of the syndrome of multiple congenital anomalies which bears her name, described the third child of healthy parents who was jaundiced from the 7th day of life and admitted to hospital aged six weeks weighing only 2200 gm. The child appeared atrophic with peeling skin and hepatosplenomegaly and died two days later. At autopsy the pancreas showed a great increase in connective tissue and round cells but “excretory ducts showed nothing of importance”. Some islets were of abnormal size and sclerotic. The liver showed bile thrombi and evidence of obstruction. The heart and lungs were normal.

–    It is difficult to accept that this infant definitely had CF, but there was neonatal obstructive jaundice and histological abnormalities of the pancreas and so CF would be a definite possibility.

1949 Pugsley HE, Spence PM. Case of cystic fibrosis of pancreas associated with chronic pulmonary disease and cirrhosis of the liver. Ann Int Med 1949; 30:1262-1272. [PubMed]
Cirrhosis of the liver in 17 year old white boy with CF and chronic pulmonary disease. At post mortem the liver was grossly nodular and microscopically the portal areas showed extensive irregular fibrosis with proliferation of the small bile ducts.

1953 Webster R, Williams H. Hepatic cirrhosis associated with fibrocystic disease of the pancreas: clinical and pathological reports of 5 patients. Arch Dis Child 1953; 28:343-350.[PubMed]
This is the first comprehensive paper on liver involvement in CF describing “an unusual type of multilobular portal cirrhosis”; three were identified at autopsy and two on liver biopsy. The authors considered that protein deficiency, due mainly to pancreatic dysfunction, was the cause of the liver damage.

However, di Sant’Agnese observed that CF was a generalised disease that could affect the liver as well as the pancreas, lungs and sweat glands. In commenting on this paper, he described six similar cases at the Babies Hospital New York – representing some two percent of the total CF clinic.

1955 Gatzimos CD, Jowitt RH. Jaundice in mucoviscidosis (fibrocystic disease of the pancreas). Report of four cases. Am J Dis Child 1955; 89:182. [PubMed]
In contrast to laboratory and pathological evidence of liver disease, clinical jaundice in people with CF is uncommon. From 1922 to 1954, 6741 autopsies were performed at Indianapolis University Medical Centre; 3517 were children. Fourteen had CF in four of whom jaundice had been the main complaint. The four of 14 with CF is a higher incidence of clinical jaundice than in previous series (Andersen, 1938 above; May & Lowe, 1949 above; Bodian, 1952 above). These authors suggested that CF should always be considered in the differential diagnosis of jaundice in infants.

–    Subsequent experience has confirmed the advice that CF should always be excluded particularly when an infant with obstructive jaundice is suspected of having congenital biliary atresia, as on occasion an infant suspected of having congenital biliary atresia has been treated with a Kasai operation (a major procedure anastomosing the underside of the liver to the bowel in an attempt to overcome biliary atresia) only to discover later that the infant had CF with severe neonatal cholestatic jaundice (Perkins WG. et al. Cystic fibrosis mistaken for idiopathic biliary atresia. Clin Pediatr 1985; 24:107-109. [PubMed]).

1956 Blanc WA, di Sant’Agnese PA. A distinctive type of biliary cirrhosis of the liver associated with cystic fibrosis of the pancreas: recognition through signs of portal hypertension. Pediatrics 1956; 18: 387-409. [PubMed]
Bodian (1952 above) recognised that foci of biliary fibrosis occurred commonly as a necropsy finding.

A liver removed from a 12 year old Leeds boy with CF who was in liver failure. He received a successful liver transplantation by the late Professor Geoff Giles at St James University Hospital Leeds around 1990.

Andersen (1938 above) reported three cases from the literature and one of her own where there was liver involvement. Here the progression of the early changes to a distinctive type of biliary cirrhosis (figure 1) accompanied by severe and at times fatal manifestations is reported.

Seven patients, aged four to 10 years, are reported; three died; four had raised portal pressures. The absence of jaundice was noted and the lack of consistency of “so-called” liver function tests. An infective or nutritional insult to an already abnormal liver was suggested. In these young patients the condition was first recognised by the appearance of signs of portal hypertension. The authors correctly predicted that “it is possible that symptoms due to failure of liver function may appear subsequently after prolonged survival”.(also Webster et al, 1953 above; Craig et al, 1957 below; Mieles et al, 1989 below).

1957 Craig J, Haddad M, Shwachman H. The pathological changes in the liver in cystic fibrosis of the pancreas. Am J Dis Child 1957; 93:357-369. [PubMed]
Description of the typical CF liver changes by Blanc and Craig (Blanc & di Sant’Agnese, 1956 above)

1957 Gibson JB, Rodgers HW. Portal hypertension in fibrocystic disease of the pancreas. Arch Dis Child 1957; 32:355-358. [PubMed]
Good results from removal of a large spleen which reached the level of the umbilicus and weighed 710 g in a boy aged nine years. The liver showed marked fibrosis and the authors considered the liver changes were not likely to be due solely to the pancreatic damage, but suggest that focal obstruction of the bile ductules was the prime lesion – an explanation which proved to be correct. They considered the main danger from liver disease in this condition was portal hypertension.

–   Subsequent reports confirmed the benefit of splenectomy where the size of the organ was an embarrassment in terms of abdominal space even interfering with respiration and the descent of the diaphragm.

In 1988 a Leeds boy aged 16 years with CF had a massive spleen (3.2 kg) removed by the late Prof. Geoff Giles after which his FEV1 improved by 30% and he returned to normal sporting activities (Gilbert J, et al. Scand J Gastroenterol 1988; 23 Suppl 143:177).

1958 Jones MD, Sakai H, Rogerson AG. Cholangiography in children with fibrocystic disease of the pancreas; a pilot study. J Pediatr 1958; 53:172-179. [PubMed]
Seventeen children with CF (aged 19 months to 11 years) had intravenous Cholografin and the bile ducts were visualised in 12; in 13 the gallbladder was opacified.

1961 Alagille D, Vinh Le Tan. Hepatic localizations of mucoviscidosis. Tijdschr gastro-enterol 1961; 4:435-454.
The incidence of hepatic cirrhosis varies in different reports but all agree the complication increases with age. In 200 people with CF cirrhosis occurred in 1% aged less than 3 months, 6% between three and 12 months, 11% one to three years, 37% over three years of age. Histologically there was a focal biliary cirrhosis, diffuse multilobular cirrhosis and/or portal hypertension.

The lesson the authors took from their findings was that “Investigation of the young cirrhotic patient is incomplete without a sweat test” – which is still sound advice today.

1962 Esterly JR, Oppenheimer EH. Observations in cystic fibrosis of the pancreas. I. The gallbladder. Bull Johns Hopkins Hosp 1962; 110:247-55. [PubMed]
First description of gall bladder abnormalities noted at autopsy that were present in 24 of 72 people with cystic fibrosis. “The cystic duct may be atretic or stenotic from inspissated mucus or mucosal hyperplasia. Mucus distends the gallbladder epithelial cells and fills the lumen with a colourless secretion. The gallbladder may atrophy or persist as a thin walled cyst lined with flattened mucosa”. Radiological appearances of the gall bladder and bile ducts had been reported by Jones et al, 1958 (above).

1966 Wilroy RS Jr, Crawford SE, Johnson W. Cystic fibrosis with extensive fatty replacement of the liver. J Pediatr 1966; 68:67-73. [PubMed]
An early description of fatty infiltration of the liver (steatosis), which can result in gross hepatomegaly and is, in part, reversible when the intestinal malabsorption is treated and the nutritional state improved. The child reported in this paper presented at two years five months with an enlarged liver which “extended to the pelvic brim” and marked generalised oedema – no manifestations of pulmonary disease were noted at the time.

1971 Valman HB, France NE, Wallis PG. Prolonged jaundice in cystic fibrosis. Arch Dis Child 1971; 46: 805-809. [PubMed]
Bernard Valman reviewed previous reports of early hepatic changes (Bodian, 1952; di Sant’Agnese & Blanc, 1956 both below) and of neonatal obstructive jaundice in CF (Gatzimos & Jowitt, 1955; Bernstein et al, 1960; Shier & Horn, 1963; Kulczycki 1967; Talamo & Hendren, 1968). Four new infants with CF and jaundice were reported – resolving in two survivors and one that died of other causes. Histology already showed established cirrhosis in the infant who died at 22 weeks.

–    This was an important paper showing a reasonably good prognosis for early prolonged obstructive jaundice in some CF infants. It is also important that this presentation of CF is recognised as infants with CF have been mistakenly thought to have biliary atresia only to be diagnosed as having CF after they had major surgery using a Kasai operation. In some of these CF infants the jaundice settles spontaneously over a few months; others have been reported to respond to treatment with ursodeoxycholic acid – the treatment introduced for older patients with liver disease in the early Nineties (Colombo et al, 1990 below).

1973 Weber A, Roy CC, Morin CL, Lasalle R. Malabsorption of bile acids in children with cystic fibrosis. New Engl J Med 1973; 289:1001. [PubMed]
Total faecal bile acid excretion had been reported to be increased (Leyland C. Arch Dis Child 1970; 45:714). This study of 26 children with CF aged two months to nine years from Professor Roy’s unit in Montreal confirmed that faecal bile acid levels may reach seven times the normal level.

1975 Feigelson J, Pecau Y, Cathelineau L, Navarro J. Additional data on hepatic function tests in cystic fibrosis. Acta Paediatr Scand 1975; 64:337-344. [PubMed]

  Jean Feigelson

An early contribution (of many over the years) from Jean Feigelson of Paris who must have attended every CF meeting since they

Jean Navarro

started and still does! Since the early Sixties Jean Feigelson has published on a wide range of CF topics, usually based on long personal experience, but unfortunately often in French journals! In this paper he describes 9 of 50 patients with CF reported who had multilobular cirrhosis observed for 3 years.

The last author on this paper Dr Jean Navarro  subsequently published many papers on CF, often in French, from Paris and became a leading researcher and clinician in both CF and paediatric gastroenterology and also in various roles in the French national CF organisation – Association Vaincre la Mucoviscidose.

1975 Goodchild MC, Murphy GM, Howell AM, Nutter SA, Anderson CM. Aspects of bile acid metabolism in cystic fibrosis. Arch Dis Child 1975; 50:769-777. [PubMed]
A detailed study by Mary Goodchild (who later moved to head the Cardiff Paediatric CF Unit) from Charlotte Anderson’s unit in Birmingham. Most children with CF had raised faecal bile acid levels which did not correlate with fat excretion but there was an inverse relationship with age. The authors suggested that chronic bile acid loss may eventually deplete the bile acid pool – which was in fact the case. Studies from Prof. Roy’s unit in Montreal also showed a greatly increased faecal loss of bile acids in children with cystic fibrosis (Weber et al, 1973; Roy et al, 1977 below).

1977 Roy CC, Weber AM, Morin CL, Combes JC, Nussle D, Megevand A, Lasalle R. Abnormal biliary lipid composition and cystic fibrosis. N Eng J Med 1977; 297:1301-1305. [PubMed]
Early description of the abnormal bile composition in CF from Prof. Roy’s unit in Montreal where there was a particular interest in paediatric liver disease. Cholesterol was similar to that of patients with cholelithiasis; also there were abnormal glycine/taurine ratios that improved with pancreatic enzymes (also Weber et al, 1973 above; Goodchild et al, 1975 above).

1977 Scott J, Elias E, Moult PJA, Barnes S, Wills MR. Rickets in adult cystic fibrosis with myopathy, pancreatic insufficiency and proximal renal tubular dysfunction. Am J Med 1977; 63:488-492. [PubMed]
One of the very few reports of rickets in a white man aged 19 years with CF in whom pancreatic and hepatic involvement was advanced. It was suggested that vitamin D malabsorption occurred due to gross bile salt deficiency due to the known increased bile acid loss in association with pancreatic steatorrhoea. There was evidence of secondary hyperparathyroidism with proximal renal tubular acidosis, aminoaciduria, phosphaturia and hypophosphatemia which may have accelerated the rachitic syndrome. Treatment with oral pancreatic and parenteral vitamin D supplements led to full recovery of the rachitic syndrome and the proximal renal tubular dysfunction.

1978 Schwarz HP, Kraemer R, Thurnheer U, Rossi E. Liver involvement in cystic fibrosis. A report of 9 cases. Helv Paediat Acta 1978; 33:351-364. [PubMed]
A report of 9 patients amongst the 204 seen at Professor Rossi’s clinic in Berne over the previous 20 years. Focal biliary cirrhosis was the main finding in three with non-specific nodular cirrhosis, an infant with prolonged obstructive neonatal jaundice and two others had steatosis. The authors review the previous literature.

1988 Gaskin KJ, Waters DL, Howman-Giles R, de Silva M, Earl JW, Martin HC, Kan AE, Brown JM, Dorney SF. Liver disease and common-bile-duct stenosis in cystic fibrosis. N Engl J Med 1988; 318:340-346. [PubMed]

Peter Cooper, Kevin Gaskin, Jim Littlewood, Peter Bye in Sydney 1990

This study from Sydney caused considerable interest. Hepatobiliary scans were performed on 50 of 61 patients with CF who had hepatomegaly, abnormal liver function, or both and also in 31 of 92 patients with CF who did not have hepatomegaly or abnormal liver function. Ninety-six percent of the patients with liver disease had evidence of biliary tract obstruction with a stricture of the distal common bile duct in the majority of cases. All the patients without liver disease had normal intra hepatic and common-duct excretion of tracer. The authors concluded that strictures of the distal common bile duct are common in patients with CF and liver disease. They said the association required further study, since surgical relief of common-duct obstruction may prevent or ameliorate the hepatic complications of cystic fibrosis.

–     If strictures of the common bile duct were an important cause of CF related liver disease this was a very important observation. However, the results were questioned and the findings were contested in later publications (Nagel RA, Westaby D, Javaid A, et al. Liver disease and bile duct abnormalities in adults with cystic fibrosis. Lancet 1989; ii: 1422-1425.[PubMed]; Brien S, Keogan M, Caseu M, et al. Biliary complications of cystic fibrosis. Gut 1992; 33:387-391. [PubMed]) who concluded “these results indicate that abnormalities of the bile ducts in patients with cystic fibrosis related liver disease are confined to the intrahepatic biliary tree and that common bile duct strictures do not contribute to either the progression or development of liver disease in these patients”. Subsequently bile duct obstruction was not considered to be an important cause of CF related liver disease.

1989 Mieles LA, Orenstein D, Teperman L, Podesta L, Koneru B, Starzl TE. Liver transplant in cystic fibrosis. Lancet 1989; i: 1073. [PubMed]

    Thomas Starzl

Liver transplantation has been used successfully in patients with CF and the results are surprisingly good. Lung function, far from deteriorating as a result of the long operation has improved in some patients (Noble-Jamieson et al, 1994). Successful heart-lung-liver transplantations (Noble-Jamieson et al, J R Soc Med 1996;89 (Suppl 27):31-37) and lung-liver transplantations have also been performed (Couetil et al, 1995; Couetil et al, 1997).

Figure shows the liver removed from a 12 year old boy in liver failure. This was the first CF patient who had a liver transplant in Leeds, by the late Professor Geoff Giles, soon after this first paper appeared from Starzl’s team in the United States. In fact we phoned the Starzl team and received helpful advice and encouragement before deciding on this transplant. The patient did very well after the operation.

1990 Colombo C, Battezzati PM, Crosignani A, Assaisso M, Ronchi M, Giunta A. Effects of taurine and ursodeoxycholic acid on liver function tests in patients with cystic fibrosis. Acta Universitatis Carolinae – Medica 1990; 36:148-151. [PubMed]
The report of a memorable presentation by Prof. Carla Colombo of Milan at the European CF Society meeting in Prague in

     Carla Colombo

1989 which I was fortunate to hear. This was the first report of the beneficial effect of oral ursodeoxycholic acid (URSO) in people with CF associated liver disease – before this there was no treatment for the liver disease.

In nine CF patients with clinical and biochemical evidence of liver disease, taurine (30 mg/kg/day) was administered one month before and during the successive treatment with ursodeoxycholic acid (10-15 mg/kg/day). Standard liver function tests were determined before and after each period of treatment. Taurine administration produced only inconsistent changes of liver function tests from baseline, whereas after the addition of ursodeoxycholic acid there was a substantial improvement in all abnormal liver function tests (details reported in J Pediatr 1990; 117:482-489 below).

1990 Colombo C, Setchell KD, Podda M, Crosignani A, Roda A, Curcio L, Ronchi M, Giunta A. Effects of ursodeoxycholic acid therapy for liver disease associated with cystic fibrosis. J Pediatr 1990; 117:482- 489. [PubMed]
The published report from Milan of data presented in 1989 at the European CF Society Meeting in Prague (1990 above) reporting the favourable effect of ursodeoxycholic acid (URSO) treatment 10-15 mg /kg day in 9 patients with CF who had chronic liver disease (presumably the same patients as reported in Prague in 1989). Liver function tests improved significantly (AST- by 34%, alanine aminotransferase – by 41%, gamma gutamyl transpeptidase – by 41% and alkaline phosphatase– by 19%).

–   Subsequently URSO was widely used in people with CF associated liver disease and represented one of the major advances in CF management. A further trail was published in 1996 (Colombo et al, 1996). Much information was published supporting URSO treatment at an early stage of liver involvement and eventually most people with evidence of liver involvement were treated with URSO.

However, a Cochrane Review updated in 2008/9 concluded “There is insufficient evidence to justify its (URSO) routine use in cystic fibrosis”. In this writer’s opinion this conclusion was unfortunate as it could influence clinicians to withhold treatment from people with liver involvement. The following statement would have been more appropriate – “There is a considerable amount of evidence that URSO improves liver function in people with CF particularly if used at an early stage; but, as yet, there is no clinical trial that conforms to Cochrane standards to show this”.

1991 Scott-Jupp R, Lama M, Tanner MS. Prevalence of liver disease in cystic fibrosis. Arch Dis Child 1991; 66:698-701. [PubMed]
A search for the presence of liver disease among 524 patients with CF in the UK by Dr Robert Scott-Jupp working with Prof. Stuart Tanner in Leicester; details of a further 576 patients were obtained from databases. The overall prevalence of overt liver disease as indicated by the presence of an enlarged liver or spleen (or both) was 4.2%. The age related prevalence rose to a peak in adolescence, and then fell in patients over 20 years old. The implied increase in mortality among those with liver disease was not explained by deaths from liver disease, which were rare. Male patients were significantly more affected than female, the ratio being 3:1 among adolescents. Increasing prevalence of liver disease in patients with cystic fibrosis was not just a result of longevity.

1996 Colombo C, Battezzi PM, Podda M, Bettinadi N, Giunta A. Ursodeoxycholic acid for liver disease associated with cystic fibrosis:a double blind multicenter trial. Hepatology 1996; 23:1484-1490. [PubMed]
A trial of ursodeoxycholic acid by Carla Colombo and colleagues from Milan who first reported the use in people with CF (Colombo et al, 1990 above). Fifty five patients from 12 CF centres over one year had either UDCA + taurine, UDCA + placebo, placebo + taurine or double placebo. The UDCA treated patients showed better clinical condition and improved biochemistry; also those treated with taurine had improved prealbumin levels.

Despite this trial, a Cochrane review, revised in 2008/9, considered “There is insufficient evidence to justify its (URSO) routine use in cystic fibrosis”. However, most clinicians consider there is clinical evidence and would disagree with the Cochrane Review and do use URSO at an early stage if there is any evidence of liver involvement.

1998 Lindblad A, Glaumann H, Strandvik B. A two-year prospective study of the effect of ursodeoxycholic acid on urinary bile acid excretion and liver morphology in cystic fibrosis-associated liver disease. Hepatology. 1998; 27:166-74. [PubMed]
The efficacy of 2 years of treatment with ursodeoxycholic acid (UDCA) in cystic fibrosis (CF)-associated liver disease was evaluated by liver biopsies and liver function tests in 10 patients aged 8 to 28 years. Blind evaluation of liver biopsies indicated improved liver morphology with less inflammation and/or bile duct proliferation than before treatment with UDCA in 7 patients. Only 1 patient had signs of progression of clinical liver disease. The secondary bile acids, such as lithocholic acid (LCA) and deoxycholic acid (DCA), did not increase significantly. The excretion pattern of glycosidic conjugates of UDCA and its metabolites was similar to that found in healthy individuals, UDCA and isoUDCA being mainly excreted in conjugation with N-acetylglucosamine.
This study shows that UDCA modulates inflammation in CF-associated liver disease and indicates improvement of liver morphology during 2 years of treatment.

1999 Sokol RJ, Durie PR. recommendations for the management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation hepatobiliary Disease Consensus Group. J Pediatr Gastroenterol Nutr 1999; 28 Suppl 1:S1-13.[PubMed]
Recommendations of an expert group on management of CF related liver disease.

2002 Colombo C, Battezzati PM, Crosignani A, Morality A, Costantini D, Padoan R, Giunta A. Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome. Hepatology 202; 36:1374-1382. [PubMed]
Incidence of liver disease (LD) associated with cystic fibrosis (CF) and its clinical characterization still is unsettled. The authors assessed prospectively the incidence and risk factors of this complication, and its impact on the clinical course of CF. Between 1980 and 1990, they enrolled 177 CF patients without LD in a systematic clinical, laboratory, ultrasonography screening program of at least a 10-year duration. During a 14-year median follow-up (2,432 patient-years), 48 patients developed LD, with cirrhosis already present in 5. Incidence rate (number of cases per 100 patient-years) was 1.8% (95% confidence interval: 1.3-2.4), with sharp decline after the age of 10 years and higher risk in patients with a history of meconium ileus (incidence rate ratio, 5.5; 2.7-11), male sex (2.5; 1.3-4.9), or severe mutations (2.4; 1.2-4.8) at multivariate analysis.

Incidence of cirrhosis was 4.5% (2.3-7.8) during a median period of 5 years from diagnosis of liver disease. Among the 17 cirrhotic patients, 13 developed portal hypertension, 4 developed esophageal varices, 1 developed liver decompensation requiring liver transplantation. Development of LD did not condition different mortality (death rate ratio, 0.4; 0.1-1.5) or higher incidence of other clinically relevant outcomes.

In conclusion, LD is a relatively frequent and early complication of CF, whose detection should be focused at the first life decade in patients with history of meconium ileus, male sex, or severe genotype. Although LD does not condition a different clinical course of CF, in some patients it may progress rapidly and require liver transplantation.

–   This was a major study from Carla Colombo, one of Europe’s leading authorities on CF liver disease.

2002 Williams SM, Goodman R, Thomson A, McHugh K, Lindsell DR. Ultrasound evaluation of liver disease in cystic fibrosis as part of an annual assessment clinic: a 9-year review. Clin Radiol 2002; 57:365-370. [PubMed]. 
To review 9 years of annual assessment data in cystic fibrosis (CF) and evaluate the frequency of hepatobiliary abnormalities and the correlation between ultrasound and biochemical findings. Over a 9-year period (1990-99), 168 children (age range 1-18 years) with CF have undergone an annual assessment which has included clinical, biochemical and ultrasonographic evaluation of the hepatobiliary system. We have retrospectively reviewed the sequential ultrasound reports and correlated them with the contemporaneous biochemical results. A total of 725 ultrasound examinations were performed over the review period. Sixty patients had at least one examination showing an abnormality of liver echo texture and in 39 patients this was a persisting finding. Seven patients (4.2%) developed frank cirrhotic change on ultrasound criteria, while 15 patients (8.9%) had evidence of persistent splenomegaly. Gall-bladder calculi were present in 4.8%. In 176 examinations (24%) there was disparity between the ultrasound findings and aspartate aminotransferase (AST) levels. In 3.0% of cases (five patients) there were persisting abnormalities of liver echo texture and persisting splenomegaly with a normal range AST value.

The authors concluded no perfect method of assessing hepatobiliary involvement in CF is currently available. Ultrasonographic and biochemical assessment may reflect different aspects of disease progression. Routine use of ultrasound in annual assessment allows identification of a minority of patients with liver changes but with normal biochemistry.

2003 Lenaerts C. Lapierre C. Patriquin H. Bureau N. Lepage G. Harel F. Marcotte J. Roy CC. Surveillance for cystic fibrosis-associated hepatobiliary disease: early ultrasound changes and predisposing factors. J Pediatr 2003; 143:343-350. [PubMed]
To investigate routine ultrasonography (US) as an early marker and to identify risk factors for the development of cirrhosis and portal hypertension (PHT) in cystic fibrosis (CF). 106 children with CF aged 5.9+/-2.3 years were followed for 10.4+/-0.2 years in a CF clinic. At enrollment, the US was normal, but biochemical and/or clinical disease was present in 10%. By the end of the study, 19 had developed US changes, eight with evidence of PHT. At the time of the initial US change, only 36.4% of those had, at the end of the study, either a heterogeneous or a nodular parenchyma, and only 50% of those with PHT had biochemical and/or clinical disease. Of the 30 patients treated with ursodeoxycholic acid for biochemical and/or clinical disease with (n=15) and without (n=15) associated US changes, PHT developed in six of the former and two of the latter. Univariate analysis and logistic regression showed that children with more severe disease in terms of forced expiratory volume in one second were at somewhat greater risk (P<.06) of PHT developing.

Ultrasound was an early marker of liver disease and more severe CF disease, a predictor of progressive liver disease. A controlled trial should be done to assess isolated US-detected disease as an indication for UDCA.

A record of experience and long follow up from a Montreal with extensive expertise in paedaitric liver disease

2003 Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, Walker C, Ricci R, Tsui LC, Durie PR, Zielenski J, Freedman SD. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet 2003; 113:286-292. [PubMed]
This complex study concludes that the data indicate that there is an increased prevalence of CFTR abnormalities in PSC as demonstrated by molecular and functional analyses and that these abnormalities may contribute to the development of PSC in a subset of patients with inflammatory bowel disease.

2005 Fridell JA, Vianna R, Kwo PY, Howenstine M, Sannuti A, Molleston JP, Pescovitz MD, Tector AJ. Simultaneous liver and pancreas transplantation in patients with cystic fibrosis. Transplantation Proceedings 2005; 37:3567-9. [PubMed]
Liver transplantation is the treatment of choice for end stage cirrhosis in this setting, but the addition of an isolated simultaneous pancreas transplant in patients with CF related diabetes had not been reported. Two female patients with CF underwent simultaneous pancreas and liver transplantation. Both patients recovered well with normal liver function, resolution of portal hypertension, and normal blood glucoses independent of insulin. As a result of the enteric exocrine drainage of the pancreas, the patients now also independent of supplemental pancreatic enzymes.

Simultaneous liver and pancreas transplantation in CF patients provides the advantages of normalization of glucose and improved nutrition for patients requiring liver transplantation and should be considered in CF patients with CF related diabetes who require liver transplants. This is one way to deal with both liver failure and CF related diabetes which is such a major additional problem for adults with CF.

2006 Robberecht E, Van Biervliet S, Vanrentergem K, Kerremans I. Outcome of total splenectomy with port systemic shunt for massive splenomegaly and variceal bleeding in cystic fibrosis. Pediatr Surg 2006; 41:1561-5.[PubMed]
Six patients with CF (median age 14 years) underwent splenectomy with a splenorenal shunt operation – 3 for massive splenomegaly and three to control variceal bleeding after several sessions of sclerotherapy. Lung function remained stable, and there was an overall reduction of respiratory tract infections. The youngest patient, however, died of overwhelming septicemia during treatment with steroids.

Sometimes the spleen is so large in people with CF that the size is a physical handicap causing respiratory embarrassment and considerable abdominal distension in addition to the systemic effects of hypersplenism. A boy with CF of 15 years in Leeds had a spleen weighing over 3 kg removed by the late Prof Giles with great improvement in his respiratory function and general health (Gilbert J et al. Splenectomy for massive splenomegaly in cystic fibrosis with improvement in pulmonary status. Scand J Gastroenterol 1987; 23 (Suppl 143):177).

2006 Melzi ML, Kelly DA, Colombo C, Jara P, Manzanares J, Colledan M, Strazzabosco M, DeLorenzo P, Valsecchi MG, Adam R, Gridelli B, Assael BM, EGSLTCF, European Liver Transplant Association (ELTA), European Cystic Fibrosis Society (ECFS). Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry. Transplant International 2006; 19:726-731. [PubMed]
A report of 57 CF patients, many of whom were in their teens, who had liver transplants. Post-transplant survival was high and poor respiratory function was the main risk factor for early death; in the short-term, respiratory function significantly improved in most patients. Transplantation was considered to be the appropriate treatment for patients with advanced CF-related liver disease and preserved pulmonary function and an FEV1 over 50% predicted.

Further more general European experience of liver transplantation in people with CF confirming the good results since the first report of Mieles LA et al.(1989 above).

2007 Corno V, Dezza MC, Lucianetti A, Codazzi D, Carrara B, Pinelli D, Parigi PC, Guizzetti M, Strazzabosco M, Melzi ML, Gaffuri G, Sonzogni V, Rossi A, Fagiuoli S, Colledan M. Combined double lung-liver transplantation for cystic fibrosis without cardio-pulmonary by-pass. Am J Transpl 2007; 7:2433-2438. [PubMed]
The authors performed sequential bilateral single lung-liver transplantation – a therapeutic option for patients with end stage lung and liver disease. They performed the operation in three young men with cystic fibrosis. All the recipients had respiratory failure and portal hypertension with hypersplenism. The three recipients are alive with a median follow-up of 670 days (range 244-1,533). The operation is a complex but effective procedure for the treatment of end stage lung disease due to cystic fibrosis.

2007 Desmond CP, Wilson J, Bailey M, Clark D, Roberts SK. The benign course of liver disease in adults with cystic fibrosis and the effect of ursodeoxycholic acid. Liver Int 2007; 27:1402-1408. [PubMed]
The authors concluded that liver disease in 6.7% of 278 adults with CF is commonly complicated by portal hypertension (67%), but morbidity and mortality associated with this in their patient population were low. Ursodeoxycholic acid treatment was associated with improvement in hepatobiliary symptoms and liver function tests (50%).

This is a useful record of experience in a large adult CF unit; similar conclusions also came from experience at the adult CF centre in Cambridge UK (Nash et al, 2008 above).

2007 Pall H, Zielenski J, Jonas MM, DaSilva DA, Potvin KM, Yuan XW, Huang Q, Freedman SD. Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function. J Pediatr 2007; 151:255-259. [PubMed]
Twenty children with primary sclerosing cholangitis (PSC) diagnosed in childhood had sweat chloride concentration, nasal transmembrane potential difference, and extensive genetic analysis of the CFTR gene. Disease control subjects consisted of 14 patients with inflammatory bowel disease alone and no liver disease.
In the PSC group, CFTR chloride channel function was markedly diminished at -8.6 +/- 8.2 mV (reference range: -24.6 +/- 10.4 mV). In contrast, disease control subjects had normal function, at -17.8 +/- 9.7 mV (P = .008). Sweat chloride concentration in subjects with PSC was greater than in disease control subjects (20.8 +/- 3.4 mmol/L vs 12.0 +/- 1.6 mmol/L, P = .045). Comprehensive CFTR genotyping revealed that 5 of 19 (26.3%) subjects with PSC had a CFTR mutation or variant, compared with 6 of 14 (42.9%) disease control subjects. The authors concluded there is a high prevalence of CFTR-mediated ion transport dysfunction in subjects with childhood PSC.

The presence of one CF mutation in 26.3% of people with primary sclerosing cholangitis is similar to the increased frequency of CF mutations in pancreatitis. This is the first report of this association with sclerosing cholangitis. It is not clear why the CF mutations are so frequent in the control group and this is not explained.

2008 Nash KL, Allison ME, McKeon D, Lomas DJ, Haworth CS, Bilton D, Alexander GJ. A single centre experience of liver disease in adults with cystic fibrosis 1995-2006. J Cyst Fibros 2008; 7:252-257. [PubMed]
Liver disease is an important cause of death in adults with cystic fibrosis. Ursodeoxycholic acid (UDCA) may slow progression. Managing varices and timely evaluation for liver transplantation are important. 154 patients attending the CF Centre at Papworth, Cambridge in the UK were followed for a median 5 years. 43 had significant liver disease. Only one patient developed chronic liver failure and none required liver transplantation. 27 underwent endoscopy; 1 required variceal banding, the others had insignificant varices. Ultrasound was normal in 97 patients while five had steatosis; nine further patients had splenomegaly but no other evidence of portal hypertension. Neither spleen size nor platelet count correlated with portal hypertension. So liver disease was common in adults with CF but disease progression was rare.

Thus liver disease detected and closely monitored in adults appeared to have a milder course than in childhood CF. Splenomegaly, unrelated to portal hypertension may be a consequence of the cystic fibrosis.

2008 Mueller-Abt PR, Frawley KJ, Greer RM, Lewindon PJ. Comparison of ultrasound and biopsy findings in children with cystic fibrosis related liver disease. J Cyst Fibros 2008; 7:215-221. [PubMed].
The objective of this study from Brisbane was to determine if hepatic ultrasound findings in paediatric patients with cystic fibrosis and suspected liver disease are related to histopathological results derived from liver biopsies.

The authors concluded that the diagnosis of early liver disease in cystic fibrosis cannot reliably be made on the basis of ultrasound alone. A normal ultrasound does not preclude significant liver fibrosis in cystic fibrosis. An abnormal US that suggests cirrhosis predicts the presence of moderate to severe liver disease.

2009 Bartlett JR, Friedman KJ, Ling SC, et al. Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA 2009; 302:1076-1083. [PubMed]
A subset (approximately 3%-5%) of patients with CF develops severe liver disease with portal hypertension. The objective of the study was to assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF.

The authors concluded that the SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

2009 Perera E, Massie J, Phillips RJ. Treatment of acne with oral isotretinoin in patients with cystic fibrosis. Arch Dis Child 2009; 94:583-586.[PubMed]
Theoretical concerns about liver disease and vitamin A deficiency have limited the use of oral isotretinoin for troublesome acne in adolescents with cystic fibrosis. Oral isotretinoin was administered to nine patients with cystic fibrosis who had troublesome acne unresponsive to antibiotics. All patients were followed for 1-4 years after cessation of treatment. Isotretinoin treatment cleared active acne lesions in all patients. It was well tolerated, and no patient had significant side effects. All nine patients were pleased or delighted with the improvement in their skin. Adolescents with cystic fibrosis and acne can be treated with oral isotretinoin. Oral isotretinoin should be considered for adolescents with cystic fibrosis who have acne associated with scarring, acne not clearing with topical and antibiotic treatment, acne associated with depression or severe cystic acne.

This is a helpful paper for those considering the use of isotretinoin but who may have reservations regarding liver toxicity.

2011 Lewindon PJ, Shepherd RW, Walsh MJ, Greer RM, Williamson R, Pereira TN, Frawley K, Bell SC, Smith JL, Ramm GA. Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy. Hepatology 2011; 53:193-201. [PubMed]
Forty patients with cystic fibrosis (median age = 10.6 years) with abnormal clinical, biochemical, and US findings were subjected to dual-pass percutaneous liver biopsy. Clinical outcomes were recorded over 12 years of follow-up (median = 9.5 years for survivors). Logistic regression and receiver operating characteristic analyses were applied to predict hepatic fibrosis (which was assessed by fibrosis staging and quantitative immunohistochemistry) and the occurrence of PHT. PHT occurred in 17 of 40 patients (42%), including 6 of 7 (17%) who died during follow-up. Clinical examination, serum ALT levels, and US findings failed to predict either the presence of liver fibrosis or the development of portal hypertension (PHT). Fibrosis staging on liver biopsy, where the accuracy was improved by dual passes (P = 0.002, nonconcordance = 38%), predicted the development of PHT (P < 0.001), which occurred more frequently and at a younger age in those with severe fibrosis.

The authors conclude that although clinical modalities currently employed to evaluate suspected CFLD help to identify a cohort of children at risk for liver disease and adverse outcomes but do not predict an individual’s risk of liver fibrosis or PHT development. Liver fibrosis on biopsy predicts the development of clinically significant liver disease. Dual passes help to address sampling concerns. Liver biopsy has a relevant role in the management of patients with suspected CFLD and deserves more widespread application.

The following three papers (*) should be read in sequence as they concern the possibilty of UDCA toxicity. They are first the ECFS Best Pactice Guidelines for CF Related Liver Disease, then a letter commenting on the Guidelines followed by a response from the authors of the ECFS Guidelines

*2011 Debray D, Kelly D, Houwen R, Strandvik B, Colombo C. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. [Review] J Cyst Fibros 2011; 10 Suppl 2:S29-36. [PubMed] [Full version available on the ECFS website}
These are the European guidelines for the management of CF liver disease and are available on the ECFS website.

Approximately 5-10% of cystic fibrosis (CF) patients develop multilobular cirrhosis during the first decade of life. Most CF patients later develop signs of portal hypertension with complications, mainly variceal bleeding. Liver failure usually occurs later, after the paediatric age. Annual screening for liver disease is recommended to detect pre-symptomatic signs and initiate ursodeoxycholic acid therapy, which might halt disease progression. Liver disease should be considered if at least two of the following variables are present: abnormal physical examination, persistently abnormal liver function tests and pathological ultrasonography. If there is diagnostic doubt, a liver biopsy is indicated. All CF patients with liver disease need annual follow-up to evaluate the development of cirrhosis, portal hypertension or liver failure. Management should focus on nutrition, prevention of bleeding and variceal decompression. UDCA should be started as soon as a diagnosis if CF related liver disease is made. Deterioration of pulmonary function is an important consideration for liver transplantation, particularly in children with hepatic dysfunction or advanced portal hypertension.

See letter of comment from Dr Ooi CY et al. 2012 below.

2012 Ooi CY, Nightingale S, Durie PR, Freedman SD. J Cyst Fibros 2012; 11:72-73 Ursodeoxycholic acid in cystic fibrosis-associated liver disease.[PubMed]
This is a letter commenting on the Debray et al 2011 Best practice guidelines (above). Essentially the authors are concerned about the possible dangers of UDCA in view of the adverse effects reported in the 5 year trial of the drug in adults with primary sclerosing cholangitis (Lindor KD et al. 2009.[PubMed]) where the treated patients, although having improved liver function tests, had a significantly higher incidence of major adverse effects (death and liver transplantation) and no better survival. They state “Simply put at present there are no convincing data to demonstrate that UDCA is efficacious or harmful in CF related liver disease”.

Reply below from Carla Colombo and colleagues

*2012 Colombo C, Debray D, Kelly D, Houwen R, Battezzati PM, Strandvik. Response to the letter by Ooi et al 2012. J Cyst Fibros 2012; 11:74-75.
The authors of the Debray et al Best Practice Guidelines note that the concerns of Ooi et al are based mainly on the study of Lindor et al 2009 and they did not regard it pertinent to compare CFRL with PSC as they are of different aetiology, pathology, degree of cholestasis and prognosis. They do mention that UDCA can be epimerized to chenodeoxycholic acid and also transformed by bacterial flora to lithocholic acid which are both liver toxic. The higher doses used by Lindor et al may have increased the possibility of this transformation but they did not investigate the bile acid pattern.  Some of the European group are currently investigating the fate of this bile acid using mass spectrometry with stable-isotope dilution analysis.

They emphasise the lack of clinical ill effects after 20 years experience, request they be informed of any such ill effects but meanwhile state “we deem there are no compelling arguments for precluding CF patients to start UDCA early, before the liver disease has potentially progressed to a stage at which changing the course by any medical treatment is no longer possible”.

2012 Dowman JK, Watson D, Loganathan S, Gunson BK, Hodson J, Mirza DF, Clarke J, Lloyd C, Honeybourne D, Whitehouse JL, Nash EF, Kelly D, van Mourik I, Newsome PN. Long-term impact of liver transplantation on respiratory function and nutritional status in children and adults with cystic fibrosis. Am J Transplant 2012; 12:954-964. [PubMed]
Early liver transplant (LT) has been advocated for patients with cystic fibrosis liver disease (CFLD) and evidence of deterioration in nutritional state and respiratory function to prevent further decline. However, the impact of single LT on long-term respiratory function and nutritional status has not been adequately addressed. We performed a retrospective analysis of the outcomes of 40 (21 adult/19 pediatric) patients with CFLD transplanted between 1987 and 2009 with median follow-up of 47.8 months (range 4-180). One and five-year actuarial survival rates were 85%/64% for adult and 90%/85% for pediatric LT cohorts, respectively. Lung function remained stable until 4 years (FEV(1) % predicted; pretransplant 48.4% vs. 45.9%, 4 years post transplant) but declined by 5 years (42.4%). Up to 4 years post transplant mean annual decline in FEV(1) % was lower (0.74%; p = 0.04) compared with the predicted 3% annual decline in CF patients with co-morbidities including diabetes. Number of courses of intravenous antibiotics was reduced following LT, from 3.9/year pre transplant to 1.1/year, 5 years post transplant. Body mass index was preserved post transplant; 18.0 kg/m(2) (range 15-24.3) pre transplant versus 19.6 kg/m(2) (range 16.4-22.7) 5 years post transplant.

In conclusion, liver transplantation is an effective treatment for selected patients with cirrhosis due to CFLD, stabilizing aspects of long-term lung function and preserving nutritional status.

A substantial number of these patients did well after liver transplantation with good survival rates, stable lung function and a slowing of FEV1 decline. Also there were nutritional benefits. Although clinicians have observed such benefits in individual patients since the first liver transplants in people with CF were reported (Mieles LA et al. Lancet 1989:i:1073. above) it is good to have the benefits of such a major procedure confirmed in a relatively large series.

2011 Lewindon PJ, Shepherd RW, Walsh MJ, Greer RM, Williamson R, Pereira TN, Frawley K, Bell SC, Smith JL, Ramm GA. Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy. Hepatology 2011; 53:193-201. [PubMed]
Cystic fibrosis liver disease (CFLD), which results from progressive hepatobiliary fibrosis, is an important cause of morbidity and mortality, but it is difficult to identify before portal hypertension (PHT) ensues. Clinical signs, serum alanine aminotransferase (ALT) levels, and ultrasound (US) are widely applied, but their value in predicting the presence of cirrhosis, the development of PHT, or adverse outcomes is undetermined. The potential gold standard, liver biopsy, is not standard practice and, notwithstanding sampling error considerations, has not been systematically evaluated. Forty patients with cystic fibrosis (median age = 10.6 years) with abnormal clinical, biochemical, and US findings were subjected to dual-pass percutaneous liver biopsy. Clinical outcomes were recorded over 12 years of follow-up (median = 9.5 years for survivors). Logistic regression and receiver operating characteristic analyses were applied to predict hepatic fibrosis (which was assessed by fibrosis staging and quantitative immunohistochemistry) and the occurrence of PHT. PHT occurred in 17 of 40 patients (42%), including 6 of 7 (17%) who died during follow-up. Clinical examination, serum ALT levels, and US findings failed to predict either the presence of liver fibrosis or the development of PHT. Fibrosis staging on liver biopsy, where the accuracy was improved by dual passes (P = 0.002, nonconcordance = 38%), predicted the development of PHT (P < 0.001), which occurred more frequently and at a younger age in those with severe fibrosis.

The authors conclude that although clinical modalities currently employed to evaluate suspected CFLD help to identify a cohort of children at risk for liver disease and adverse outcomes but do not predict an individual’s risk of liver fibrosis or PHT development. Liver fibrosis on biopsy predicts the development of clinically significant liver disease. Dual passes help to address sampling concerns. Liver biopsy has a relevant role in the management of patients with suspected CFLD and deserves more widespread application.

2012  Kappler M, Espach C, Schweiger-Kabesch A, Lang T, Hartl D, Hector A, Glasmacher C, Griese M. Ursodeoxycholic acid therapy in cystic fibrosis liver disease–a retrospective long-term follow-up case-control study.  Aliment Pharmacol Ther 2012; 36:266-273.[PubMed]
To assess the long-term effects of continuous ursodeoxycholic acid (UDCA) therapy in cystic fibrosis patients with constantly elevated serum liver enzymes.The primary endpoint was the incidence of overt liver disease. Between 1989 and 2005, UDCA treatment was started in 98 subjects from a cohort of 382 cystic fibrosis patients. These subjects were compared with a historic control group of 352 subjects who attended our centre between 1975 and 1989 before UDCA became standard treatment. For the long-term comparison of liver function and lung function tests, a group of 98 matched contemporary cystic fibrosis patients were compared with the 98 subjects treated with UDCA.

Overt liver disease developed in only one of the 382 patients who was treated with UDCA for increased serum liver enzymes compared with nine patients in the historic control group (P < 0.05). Serum liver enzyme levels declined in most patients receiving UDCA treatment during the 17-year follow-up (87/98, P < 0.05). No difference was seen in lung function between subjects with cystic fibrosis-related liver disease and the matched controls.

The authors concluded that regular and systematic screening for liver involvement enables early introduction of UDCA therapy in affected cystic fibrosis patients, reduces the development of severe liver disease and leads to a significant and persistent improvement in serum liver tests, without impairing long-term pulmonary outcome.

–   This is an interesting and reassuring record of experience in the use of UDCA over time in a large CF Centre in view of the concerns of Oii et al, 2012 above.

2014 Bruns F. Bremer M. Dettmer A. Janssen S. Low-dose splenic irradiation in symptomatic congestive splenomegaly: report of five cases with literature data. [Review] Oncology. 9:86, 2014.[PubMed]
Five patients (only 1 with CF) with symptomatic congestive splenomegaly received splenic irradiation with a total dose of 3 Gy (single dose: 0.5 Gy). One patient was re-irradiated after long-term failure with the same treatment schedule. Four patients obtained long term relief of splenic pain during the follow-up time of median 20 (range: 2-36) months. Four patients showed haematological response after irradiation with an increase of erythrocytes, leucocytes and/or platelets. A slightly decrease in spleen size was found in two patients.
The authors concluded low-dose splenic irradiation in symptomatic congestive splenomegaly is feasible and effective.

Splenic size in itself sometimes becomes a physical embarrassment to respiration and the space in the abdominal cavity. In such cases splenectomy has proved beneficial – radiation is obviously an alternative particularly if major surgery were to be contraindicated by the patient’s general condition.

Rowland M, Gallagher C, Gallagher CG, Laoide RÓ, Canny G, Broderick AM, Drummond J, Greally P, Slattery D, Daly L, McElvaney NG, Bourke B.  Outcome in patients with cystic fibrosis liver disease. J Cyst Fibros. 2015 Jan;14(1):120-6. doi: 10.1016/j.jcf.2014.05.013. Epub 2014 Jun 7 [PubMed]
Irish children with CF liver disease (CFLD), and their age and gender matched controls were enrolled at baseline and reviewed after 10 years to determine which characteristics predict mortality.
72/84 (85.71%) of participants were followed, (mean age Cases 21.71yrs SD 6.5, CF controls 23.62 SD 5.6, 22 (61%) males), with no difference in duration of follow-up. Nineteen participants (26.4%) died,
38.9% (14/36) with CFLD and 13.89% (5/36) CF controls (Odds Ratio (OR) 3.94 95% CI:1.23-12.56 p=0.005).
In logistic regression, liver disease (OR 4.28 95% CI 1.07-17.16) female gender (OR 12.25 95% CI 2.37-63.24), reduced pulmonary function, (OR 5.11 95% CI 1.09-23.81) were each independent risk factors for mortality in CF. The authors concluded liver disease is an independent risk factor for mortality in CF.

Colombo C, Crosignani A, Alicandro G, Zhang W, Biffi A, Motta V, Corti F, Setchell KD. Long-Term Ursodeoxycholic Acid Therapy Does Not Alter Lithocholic Acid Levels in Patients with Cystic Fibrosis with Associated Liver Disease.  J Pediatr. 2016 Jun 10. pii: S0022-3476(16)30216-5. doi: 10.1016/j.jpeds.2016.05.008. [Epub ahead of print][PubMed]

Fig 14. Carla Colombo

To evaluate the fasting and postprandial serum bile acid composition in patients with cystic fibrosis-associated liver disease (CFLD) after chronic administration of ursodeoxycholic acid (UDCA) (20mg/kg/day). The aim was to specifically focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid, because of recent concerns regarding the safety of long-term, high-dose UDCA treatment for CFLD.Twenty patients with CFLD (median age 16years, range: 2.4-35.0) prescribed UDCA therapy for at least 2years were studied. Total and individual serum bile acids were measured by stable-isotope dilution mass spectrometry, in fasting and 2-hour postprandial samples taken during chronic UDCA (20mg/kg/day) administration.During chronic UDCA administration (median duration 8years, IQR: 6-16), UDCA became the predominant serum bile acid in all patients (median, IQR: 3.17, 1.25-5.56μmol/L) and chenodeoxycholic acid concentrations were greater than cholic acid (1.86, 1.00-4.70μmol/L vs 0.40, 0.24-2.71μmol/L). The secondary bile acids, deoxycholate and lithocholate, were present in very low concentrations in fasted serum (<0.05μmol/L). After UDCA administration, 2-hour postprandial concentrations of both UDCA and chenodeoxycholic acid significantly increased (P<.01), but no significant changes in serum lithocholic acid concentrations were observed.

– These data do not support recent suggestions that enhanced biotransformation of UDCA to the hepatotoxic secondary bile acid lithocholic occurs when patients with CFLD are treated with relatively high doses of UDCA.

Carla Colombo (figure 14) is Professor of Paediatrics in Milan and has pioneered the use of URSO for people with cystic fibrosis.

Drzymala-Czyz S, Jończyk-Potoczna K, Lisowska A, Stajgis M, Walkowiak J. Supplementation of ursodeoxycholic acid improves fat digestion and absorption in cystic fibrosis patients with mild liver involvement.  Eur J Gastroenterol Hepatol. 2016 Feb 12. [Epub ahead of print][PubMed]
Ursodeoxycholic acid (UDCA) supplementation is recommended for cystic fibrosis (CF) patients with associated liver disease. However, its effect on fat digestion and absorption is not known.In 23 patients with mild liver involvement, a C-mixed triglyceride breath test was performed on UDCA supplementation (with and without pancreatic enzymes – standard and increased dose) and after 1 month of UDCA withdrawal. Cumulative percentage dose recovery [CPDR; median (interquartile range)] has been considered to reflect lipid digestion and absorption.The enzyme supplementation resulted in a significant CPDR improvement [0% (0-0) vs. 4.6% (0.4-6.0); P<0.00046]. With the increased dose of enzymes in 16 patients with abnormal C-mixed triglyceride breath test results and lipase dose less than 3000 U/g of fat, higher CPDR values [8.6% (5.6-12.7); P<0.000027] were observed. However, a 1-month UDCA withdrawal resulted in a significant reduction in (P<0.000031) fat digestion and absorption [2.9% (0.7-5.8)].The authors conclude that UDCA supplementation seems to enhance lipid digestion and absorption in pancreatic insufficient CF patients with mild liver involvement. This finding points toward the potential impact of UDCA supplementation on nutritional status in CF patients with liver disease and underscores the often-overlooked role of factors other than pancreatic enzymes on digestion and absorption of fats in CF.

2016 Stonebraker JR, Ooi CY, Pace RG, Corvol H, Knowles MR, Durie PR, Ling SC.  Features of Severe Liver Disease With Portal Hypertension in Patients with Cystic Fibrosis. Clin Gastroenterol Hepatol. 2016 Apr 5. pii: S1542-3565(16)30016-7. doi: 10.1016/j.cgh.2016.03.041. [Epub ahead of print] [PubMed]
A retrospective analysis of data from 561 patients with CF (63% male, 99% with pancreatic insufficiency), liver disease.  All patients were enrolled in the Genetic Modifier Study of Severe CF Liver Disease at 76 international centers, from January 1999 through July 2013.Male patients were diagnosed with liver disease at a younger age than female patients (10 vs 11 years; P=.01). Splenomegaly was observed in 99% of patients and varices in 71%. Levels of liver enzymes were near normal in most patients. Thrombocytopenia affected 70% of patients and was more severe in patients with varices (88×109/L vs. 145×109/L; P<.0001). Ninety-one patients received liver transplants (16%), at a median age of 13.9 years. Compared to patients who did not receive liver transplants, patients who received liver transplants had lower platelet counts (78×109/L vs 113×100/L; P<.0001), higher international normalized ratios (P<.0001), and lower levels of albumin (P=.0002). The aminotransferase to platelet ratio index (APRI) and fibrosis index based on 4 factor (FIB4) values were above diagnostic thresholds for CF liver disease in 96% and 90% of patients, respectively. Patients who received liver transplants or who had varices had higher APRI and FIB4 values than patients who did not.In patients with CF, severe liver disease develops early in childhood (around 10 years of age) and is more common in boys than girls. Patients with varices and those who receive liver transplants have high platelet counts and APRI and FIB4 scores.

– A large series of patients the findings confirming, in particular, the fact that liver disease tends to develop early in childhood.

2016 van der Feen C; van der Doef HP; van der Ent CK; Houwen RH.  Ursodeoxycholic acid treatment is associated with improvement of liver stiffness in cystic fibrosis patients. J Cyst Fibros  2016 Jul 29. pii: S1569-1993(16)30566-5. doi: 10.1016/j.jcf.2016.07.009. [PubMed]
Ursodeoxycholic acid (UDCA) might prevent progression of cystic fibrosis liver disease, but objective parameters for its effect are lacking. The authors used liver stiffness measurements to evaluate the effect of ursodeoxycholic acid. Paired measurements of liver stiffness were done in 73 patients without UDCA and in 32 patients with UDCA. In the latter group, 6 patients had cirrhosis; in 15 patients, UDCA was started based on Colombo criteria, and in 11 patients for other reasons. In patients without UDCA, liver stiffness increased: 0.19 (-0.03 to 0.59) kPa/year. Liver stiffness also increased in patients with cirrhosis: 4.6 (0.67-12.4)kPa/year. In patients who had UDCA based on Colombo criteria, a decrease of liver stiffness was observed: 0.70 (-1.6 to 0.55)kPa/year (P=0.01). In patients on UDCA for other reasons, liver stiffness increased: 0.23 (-0.20 to 0.51)kPa/year.

The authors concluded UDCA reduced liver stiffness in patients with well-defined, mild liver disease.They noted that these data were the first objective evidence of the beneficial effect if UDCA therapy in this group of patients with mild liver involvement. They suggest that UDCA started before severe liver damage is present, might be able to prevent progression of CF related liver disease and may even induce a reversal of fibrosis

[*Carla Colombo’s criteria for URSO treatment in CF – At least two of the following criteria – hepatomegaly confirmed by ultrasound, other U/S abnormalities of liver parenchyma and persistently increased liver enzymes (ASAT, ALAT, GGT) – being abnormal for at least 12 months].

Dr Catherine van der Feen is a paediatrician at Jeroen Bosch Ziekenhuis in the Netherlands

2016 Woodruff SA; Sontag MK; Accurso FJ; Sokol RJ; Narkewicz MR. Prevalence of elevated liver enzymes in children with cystic fibrosis diagnosed by newborn screen.  J Cyst Fibros  2016 Aug 20. [PubMed
Prevalence and risks for elevated liver enzymes have not been studied systematically in children with CF identified by newborn screening by the team in Denver.  298 CF children had been identified by newborn screen since 1982. AST, ALT and GGT were tested at annual visits. The percent of children with 1 or >2 values of elevated AST, ALT and GGT determined. Relationship of liver enzymes to clinical factors or subsequent liver disease was analyzedAt least one abnormal value for AST (63%), ALT (93%) and ALT >1.5x ULN (52%) occurred by 21years of age. Liver enzyme elevations were not correlated with CFTR mutation, meconium ileus or ethnicity. AST and GGT >1.5x ULN were associated with later advanced liver disease HR (CI) 6.53 (2.02-21.1) and 4.03 (1.15-13.45), respectively.The authors concluded elevated liver enzymes are common during childhood in CF patients identified by newborn screening. Elevated AST and GGT may be markers for risk of advanced liver disease.

– A useful long-term study from Colorado, one of the first areas to introduce newborn CF screening in 1982 where Keith Hammond was the involved biochemist. The opportunity to undertake long-term follow-up, identifying findings that may indicate later significant liver involvement, is helpful. The finding raised AST, GGT would perhaps influence the earlier introduction of treatment with ursodeoxycholic acid?

2017 Cheng K, Ashby D, Smyth RL. Ursodeoxycholic acid for cystic fibrosis-related liver disease. Cochrane Database Syst Rev. 2017 Sep 11;9:CD000222. doi:10.1002/14651858.CD000222.pub4. [Epub ahead of print] [Pubmed]To analyse evidence that ursodeoxycholic acid improves indices of liver function, reduces the risk of developing chronic liver disease and improves outcomes. Twelve trials have been identified, of which four trials involving 137 participants were included; data were only available from three of the trials (118 participants) since one cross-over trial did not report appropriate data. The dose of ursodeoxycholic acid ranged from 10 to 20 mg/kg/day for up to 12 months. The complex design used in two trials meant that data could only be analysed for subsets of participants. There was no significant difference in weight change, mean difference -0.90 kg (95% confidence interval -1.94 to 0.14) based on 30 participants from two trials. Improvement in biliary excretion was reported in only one trial and no significant change after treatment was shown. There were no data available for analysis for long-term outcomes such as death or need for liver transplantation.

The authors of the review  concluded there were few trials assessing the effectiveness of ursodeoxycholic acid. The quality of the evidence identified ranged from low to very low. They consider there is currently insufficient evidence to justify its routine use in cystic fibrosis.

–    Despite the conclusions of these Cochrane Reviewers, most experienced clinicians, including this writer when practising, would treat people with CF and early signs of liver abnormality with regular URSO. Before the introduction of URSO for children with CF by Carla Colombo in 1989, there was nothing one could do to halt the progression of liver involvement, which in some children had a serious outcome.   The latest text book advice (Cystic Fibrosis 4th Ed – Bush, Bilton & Hodson, 2016) on the use of URSO states that “it is likely that this less than objective use of UDCA in patients with CF liver disease will continue based on the evidence that is available and in the setting of a drug that is well tolerated and has very few associated adverse effects”.

2017 Colombo C; Crosignani A; Alicandro G; Zhang W; Biffi A; Motta V; Corti F; Setchell KD. Long-Term Ursodeoxycholic Acid Therapy Does Not Alter Lithocholic Acid. Levels in Patients with Cystic Fibrosis with Associated Liver Disease. J Pediatr 2016; 177:59-65.[Pubmed]
To evaluate the fasting and postprandial serum bile acid composition in patients with cystic fibrosis-associated liver disease (CFLD) after chronic administration of ursodeoxycholic acid (UDCA) (20mg/kg/day). The aim was to specifically focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid because of recent concerns regarding the safety of long-term, high-dose UDCA treatment for CFLD. During chronic UDCA administration (median duration 8 years, IQR: 6-16), UDCA became the predominant serum bile acid in all patient (median, IQR: 3.17, 1.25-5.56 mumol/L) and chenodeoxycholic acid concentrations were greater than cholic acid (1.86, 1.00-4.70 mumol/L vs 0.40, 0.24-2.71 mumol/L). The secondary bile acids, deoxycholate and lithocholate, were present in very low concentrations in fasted serum (<0.05 mumol/L). After UDCA administration, 2-hour postprandial concentrations of both UDCA and chenodeoxycholic acid significantly increased (P < .01), but no significant changes in serum lithocholic acid concentrations were observed.

The authors conclude these data do not support recent suggestions that enhanced biotransformation of UDCA to the hepatotoxic secondary bile acid lithocholic occurs when patients with CFLD are treated with relatively high doses of UDCA.

~ The possibility of UDCA toxicity had been raised (Ooi CY et al 2012) following the recommendation in the European Guidelines for starting UDCA as soon as the diagnosis CFRLD is made (Debray D et al, 2012). The details of the latter are concerns and Carla Colombo’s reply is detailed in the “Topics-Liver” section of this history (Colombo C et al, 2012). In summary of this reply Carla stated“we deem there are no compelling arguments for precluding CF patients to start UDCA early, before the liver disease has potentially progressed to a stage at which changing the course by any medical treatment in no longer possible”. (Please see “Topics – Liver” for the other relevant abstracts). Carla Colombo was the first to introduce UDCA for the treatment of CF liver disease in 1990 – before this there was no treatment.

2016 Sivam S; Al-Hindawi Y; Di Michiel J; Moriarty C; Spratt P; Jansz P; Malouf M; Plit M; Pleass H; Havryk A; Bowen D; Haber P; Glanville AR; Bye PT. Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre’s experience. Intern Med J 46(7):852-4, 2016 Jul.[Pubmed]A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants (the only fatality). Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation.

2017 Woodruff SA, Sontag MK, Accurso FJ, Sokol RJ, Narkewicz MR.  Prevalence of elevated liver enzymes in children with cystic fibrosis diagnosed by newborn screen. J Cyst Fibros. 2017 Jan;16(1):139-145. doi:10.1016/j.jcf.2016.08.002. Epub 2016 Aug 20.   [Pubmed] 

Samantha Woodruff

Prevalence and risks for elevated liver enzymes have not been studied systematically in children with CF identified by newborn screen. 298 CF children were identified by newborn screen since 1982. AST, ALT and GGT was tested at annual visits. The percent of children with 1 or ≥2 values of elevated AST, ALT and GGT was determined. Relationship of liver enzymes to clinical factors or subsequent liver disease was analysed.

At least one abnormal value for AST (63%), ALT (93%) and ALT ≥1.5× ULN (52%) occurred by 21years of age. Liver enzyme elevations were not correlated with CFTR mutation, meconium ileus or ethnicity. AST and GGT ≥1.5× ULN were associated with later advanced liver disease HR (CI) 6.53 (2.02-21.1) and 4.03 (1.15-13.45), respectively.

– The authors concluded that elevated liver enzymes are common during childhood in CF patients identified by newborn screening. They suggested that elevated AST and GGT may be markers for risk of advanced liver disease. The extent to which URSO was used in these patients was not known. Presumably the use of URSO would be indicated at an early stage in those with persistent elevation of these enzymes – most clinicians would agree that URSO is less effective as liver disease progresses. The authors’ protocol is to prescribe ursodeoxycholic acid after at least 2 elevations of AST, ALT or GGT N 1.5× ULN for more than 6 months. Thus while the continued persistence of elevated liver enzymes beyond 6 months may have been influenced by ursodeoxycholic acid treatment (from 2005), this would have not have had an effect on our definition of elevated enzyme prevalence.

Dr. Samantha Woodruff (figure) is a pediatric gastroenterologist in Aurora, Colorado and is affiliated with multiple hospitals in the area, including Children’s Hospital Colorado and Memorial Hospital.

Ayoub FTrillo-Alvarez CMorelli G, Lascano J.Risk factors for hepatic steatosis in adults with cystic fibrosis: Similarities to non-alcoholic fatty liver disease.World J Hepatol. 2018 Jan 27;10(1):34-40. doi: 10.4254/wjh.v10.i1.34.    Free PMC Article [Pubmed]
                                        To investigate the clinical, biochemical and imaging characteristics of adult cystic fibrosis (CF) patients with hepatic steatosis as compared to normal CF controls.   Data was collected on 114 patients meeting inclusion criteria. Seventeen patients (14.9%) were found to have hepatic steatosis on imaging. Being overweight (BMI > 25) (P = 0.019) and having a higher ppFEV1 (75 vs 53, P = 0.037) were significantly associated with hepatic steatosis. Patients with hepatic steatosis had a significantly higher median alanine aminotransferase level (27 vs 19, P = 0.048). None of the hepatic steatosis patients had frank CF liver disease, cirrhosis or portal hypertension. We found no significant association with pancreatic insufficiency or CF related diabetes.

The authors concluded hepatic steatosis appears to be a clinically and phenotypically distinct entity from CF liver disease. The lack of association with malnourishment and the significant association with higher BMI and higher ppFEV1 demonstrate similarities with non-alcoholic fatty liver disease. They suggest ong-term prospective studies are needed to ascertain whether CF hepatic steatosis progresses to fibrosis and cirrhosis.

Dr Fares Walid Ayoub is a physician in the Department of Medicine, University of Florida, Gainsville, Florida

Fawcett LKWidger JHenry GMOoi CY. Case report: Cholecystoduodenostomy for cholestatic liver disease in a premature infant with cystic fibrosis and short gut syndrome. 
BMC Pediatr.
 2019 Mar 11;19(1):78. doi: 10.1186/s12887-019-1443-5.[Pubmed] Free PMC Article
Cholecystoduodenostomy is a surgical procedure that bypasses the extrahepatic biliary tree and connects the gallbladder directly to the duodenum. This case describes the successful use of this procedure in a novel situation.

A premature (34 weeks gestation) female infant with cystic fibrosis required a laparotomy on day 1 of life due to an intrauterine small bowel perforation. Resection of small bowel and ileostomy formation resulted in short gut syndrome, with 82 cm residual small bowel and intact ileocaecal valve. Post-ileostomy reversal at 2 months old, she developed conjugated hyperbilirubinaemia. Despite conservative management including increased enteral feeding, ursodeoxycholic acid, cholecystostomy drain insertion and flushes, her cholestatic jaundice persisted. A liver biopsy revealed an “obstructive/cholestatic” picture with fibrosis. To avoid further shortening her gut with an hepatoportoenterostomy, cholecystoduodenostomy was performed at 3 months of age with subsequent post-operative improvement and eventual normalisation of her clinical jaundice and liver biochemistry.

This is the first reported case of a cholecystoduodenostomy being used successfully to treat an infant with persistent conjugated hyperbilirubinemia, cystic fibrosis and short gut syndrome. Cholecystoduodenostomy is a treatment option that with further study, may be considered for obstruction of the common bile duct in patients with short gut and/or where a shorter operating time with minimal intervention is preferred.