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Year : 2016  |  Volume : 59  |  Issue : 3  |  Page : 339-347
Severe liver dysfunction in an infant with cystic fibrosis masquerading as metabolic liver disease

1 Department of Pediatric Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Advanced Pediatric Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

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Date of Web Publication10-Aug-2016


We present a rare presentation of cystic fibrosis with neonatal cholestasis. Histological features of mucoviscidosis were present in liver involving the biliary tract, intestinal mucosa, pancreas, and lung. Besides, there was a rare association with autosomal dominant type of polycystic renal disease.

Keywords: Autosomal dominant polycystic kidney disease, cholestatic liver disease, cystic fibrosis, mucoviscidosis

How to cite this article:
Srikanth K P, Panigrahi I, Thapa BR, Vaiphei K. Severe liver dysfunction in an infant with cystic fibrosis masquerading as metabolic liver disease. Indian J Pathol Microbiol 2016;59:339-47

How to cite this URL:
Srikanth K P, Panigrahi I, Thapa BR, Vaiphei K. Severe liver dysfunction in an infant with cystic fibrosis masquerading as metabolic liver disease. Indian J Pathol Microbiol [serial online] 2016 [cited 2022 May 18];59:339-47. Available from: https://www.ijpmonline.org/text.asp?2016/59/3/339/188137

   Clinical Protocol Top

The patient was a 4-month-old male who had been admitted two times in pediatric emergency. He was a full-term normal delivery who had normal perinatal events. He had developed neonatal jaundice on day 3 of birth and had required exchange transfusion and phototherapy. He was discharged from the hospital on day 5 of birth. There was no blood group incompatibility or G6PD deficiency. No history of consanguinity in the family. He had normal growth pattern. History of immunization was not cleared.

First admission

The child had presented at 3½ months of age with cholestatic symptoms of 3 weeks with pigmented stools. On examination, he was pale and icteric. His anthropometries were: Body weight was 4.75 kg (<3 z-score), occipito-forntal circumference was 38 cm (at − 3 z-score). His abdomen was soft, no free fluid but with hepatosplenomegaly. Liver was 5 cm below costal margin with the span of 9 cm, firm to feel with smooth surface but having irregular margin. Genitalia and hernia sites were normal. The spleen tip was just palpable. There was no evidence of sepsis, no lymphadenopathy. Other systems were within normal limits.


He had normal hemogram and normal range proteins, with conjugated hyperbilirubinemia and a total bilirubin of 4.5 mg/dL and mildly increased transaminases, normal alkaline phosphatase. In view of enlarged and firm hepatomegaly, the child was considered to have metabolic liver disease such as cholangitic variant of congenital hepatic fibrosis. Except for mild elevation of arterial lactate, other metabolic parameters were normal. Thyroid function tests were normal. Alfa-feto protein level was elevated. Liver biopsy was suggested to be progressive familial intrahepatic cholestasis (PFIC). After 10 days of hospital stay, the child was discharged from the hospital. He was started on ursodeoxycholic acid at 20 mg/kg/day along with multivitamins and minerals at age appropriate dose.

Second admission

Exactly 1 month later, the child 4½ months old was brought to the pediatric emergency on January 26, 2015 and the child expired on January 30, 2015. He had presented with the complaints of nasal discharge and dry nonproductive cough of 4 days. These symptoms were associated with continuous fever of 101°F for 2 days with 4–5 spikes per day. One day prior to the admission, the child was noted to have increased breathing efforts and chest in-drawing. The child also had multiple episodes of vomiting containing food materials and streaks of blood were noted for two times. He also had malena on day 2 of the present illness. There was deepening of the jaundice during the last 1 month. At the time of hospital admission, he was in severe respiratory distress. There was decreased air entry in left lower chest requiring nasal prong continuous positive airway pressure and subsequently mechanical ventilation. Chest X-ray carried out during this time showed bilateral infiltrates [Figure 1]. Abdominal examination showed massive hepatomegaly with span of 11 cm and palpable spleen. He was found to be hypoglycemic requiring dextrose bolus followed by continuous glucose infusion. Blood gas showed high anion gap metabolic acidosis with respiratory alkalosis (pH: 7.25, PaO2:133, PaCO2:12.8, HCO3:9.5, Base Excess: −2 mEq/L, SpO2: 98.4 and lactate: 26) for which he was started on bicarbonate infusion. Blood culture grew Streptococcus pneumonia, based on the report of sensitivity and he was continued on ceftriaxone and amikacin at appropriate doses. In view of severe lactic acidosis, gluconeogenic defects, mitochondrial disorder, organic acidemias, galactosemia, tyrosinemia etc., were considered. Routine investigations are shown in [Table 1] and [Table 2]. The child was continued on dextrose based fluids started along with mitochondrial cock tail comprising coenzyme Q, carnitine, riboflavin, thiamine, and biotin. In the hospital, there was worsening of the clinical condition of the child with deranged coagulation profiles [Table 1]. In spite of adequate cardiorespiratory support, the child expired on the day of hospital stay.
Figure 1: Plain chest X-ray showing bilateral infiltrates in both the lung fields

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Table 1: Rouitne Laboratory investigations

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Table 2: Blood gas parameters

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Unit's clinical diagnosis was severe metabolic crisis, severe pneumonia and sepsis, and refractory lactic acidosis. Underlying etiology of the disease could be either -? fatty acid oxidation defect or mitochondrial disorder.

   Discussion on Clinical Protocol Dr. Inusha Panigrahi Top

In an infant who presents with hepatomegaly, coagulopathy, and persistent high anion metabolic acidosis, in the differential diagnosis, various metabolic conditions need to be considered in this child. A definitive diagnosis will only be possible with the help of various laboratory investigations. High lactate can be due to various metabolic abnormalities including acute liver failure, shock and sepsis, and other organic acidemias such as propionic acidemia, methylmalonic academia, multiple carboxylase deficiency, glycogen storage disorder (GSD), fructose 1, 6-bisphosphatase deficiency, mitochondrial enzymes of gluconeogenesis such as pyruvate hydroxylase deficiency and mitochondrial enzymes of respiratory chain. Among these conditions, the likely condition will be one of the followings, i.e., galactosemia, tyrosinemia, hereditary fructose intolerance, mitochondrial DNA depletion syndrome, and GSD.


Most common cholestatic liver disorder in early infancy associates with early cirrhosis and decompensation. The child tends to have bleeding manifestation, ascites, and renal failure. The child will only respond to the withdrawal of galactose from dietary substances. Urine nonglucose reducing substance (galactosemia) would be positive. Galactose-1-phosphate uridyl transferase (GALT) assay in RBC will be confirmatory.

Hereditary hepatorenal tyrosinemia

Clinical presentation is usually in second half of infancy with less severe manifestation. Hypoglycemia is unusual and liver transaminases are mildly elevated. The child frequently has associated renal involvement in the form of renal tubular acidosis, which will help in diagnosing this condition. Elevated urine succinylacetone helps in the diagnosis.

Hereditary fructose intolerance

Clinical presenting feature is similar to galactosemia but is of lesser incidence. The child will have a catastrophic presentation when heavy load of fructose is introduced in the form of sweetened milk products, fruits, and fruit juices. Hypoglycemia along with hepatomegaly is the predominant manifestation.

Fructose 1, 6-bisphosphatase deficiency

The child usually presents by 4–6 months of age with seizures and hypoglycemia. Liver failure along with respiratory problems, metabolic acidosis, and raise lactic acid are the usual clinical problems in children with this condition.

Glycogen storage disorders

Usually GSD1 and GSD3 come with dominant liver related problems in the second half of infancy. GSD1: The child usually comes with massive hepatomegaly and recurrent bouts of hypoglycemia, at times with seizure due to hypoglycemia. Splenomegaly is not the presenting feature unless the patient develops cirrhosis. There will be elevated levels of lactate, urate, and triglycerides. GSD3: It is a rapidly progressive condition. The child may present with a cirrhotic liver and portal hypertension. Skeletal muscle involvement is the highlight of this subgroup of GSD and will manifest as muscle weakness and elevated creatine phosphokinase. In GSD, the child usually have a doll like faces with hepatosplenomegaly and increased transaminases. Abdominal ultrasonography may also show nephromegaly in GSD1.

Mitochondrial hepatopathy

Presentation may be at any age, from neonatal period to early adolescence. The child will have with multisystem involvement, in the form of liver failure, seizures, cardiomyopathy, skeletal myopathy, renal tubulopathy, cataract, deafness, and ophthalmoplegia. Hepatic manifestation will include jaundice, ascites, and coagulopathy. Gene sequencing will demonstrate mutation in POLG and MPV17 genes.

Congenital cytomegalovirus infection

This is one of the most common congenital infections. The child usually presents with multisystem involvement which will dominantly include hepatosplenomegaly, microcephaly, and recurrent respiratory infection. Infants and neonates acquire the infection from the mother during the time of delivery from an infected mother or may be by transfusion of infected blood products. Infection is best confirmed by the demonstration of the viral DNA by molecular technique and also by demonstration of the infected cells showing cytomegaly and nucleomegaly with characteristic inclusions.

Other investigations

  • Blood culture sensitivity (January 26, 2015): S. pneumonia
  • Urine for ketone bodies (January 26, 2015): Negative
  • Creatine kinase myocardial B fraction (January 26, 2015): 35
  • Urine routine examination (January 27, 2015) - Albumin: trace; sugar: Nil; pus cells: 1–2/HPF
  • Urine culture sensitivity (January 27, 2015): Sterile
  • Serum ammonia/lactate (January 28, 2015): 82/23.3
  • Ultrasonography of abdomen (January 10, 2015): Liver of 9 cm size, increased echotexture, no triangular cord sign. Normal portal vein and intrahepatic biliary radical. Distended gall bladder measuring 21 mm in length with mild periportal edema. Common bile duct and pancreas were obscured. Kidneys-increased echogenicity with mild splitting of left pelvicalyceal system
  • Trimethylsilyl ethers/chromatography/mass spectrometry (January 28, 2015): Elevated lactate and pyruvate
  • Serum biotinidase and homocysteine (January 28, 2015): Normal
  • Tandem mass spectrometry and capillary gas chromatography/mass spectrometry were carried out and there were increased in low free carnitine, ketones, lactate, and pyruvate
  • Urine for reducing substance (January 28, 2015): Negative
  • Urine routine examination (January 28, 2015): Normal.

Discussant's final clinical diagnosis

Acute metabolic crisis with very severe pneumonia with sepsis with refractory lactic acidosis, underlying etiology could be either fatty acid oxidation defect or mitochondrial hepatopathy.

   Comments on Clinical Protocol Top

Comments 1 (senior resident, treating unit)

Initial presentation was like intrahepatic cholestasis (sepsis, familial cholestasis, and metabolic liver disease). PFIC was the initial diagnosis based on HPE; however, this could be seen in any of the metabolic disease as well.


How it is possible that lactic acidosis with respiratory alkalosis in this case?

Comment 2 (consultant, treating unit)

Acute liver failure in the second admission is due to worsening of metabolic liver disease. GALT and urine succinly acetone were normal and infant was never exposed was sugar thus HFI is also unlikely. Thus the possibility of mitochondrial hepatopathy was considered.


This is a confusing case, but based on the available investigations, metabolic and mitochondrial hepatopathy is high on the list.

   Pathology Protocol (Dr. Kim Vaiphei, Pm No. 26456) Top

Partial autopsy was carried out in this grossly emaciated child who was also jaundiced and had distended abdomen. On opening the body cavities, there was 100 ml of blood clot in each pleural cavity and peritoneal cavity contained 500 ml of straw colored fluid. As the child had dominant liver related clinical problem, I will start with the findings in liver at autopsy.


Liver weighed 250 g against the mean normal weight of 188 g for the age. The liver was deeply bile stain, firm to feel, and appeared vaguely nodular. On dissecting out the extra-hepatic biliary tract and the gall bladder, there was no stricture or impaction of mucous plug along the whole length. Multiple tissue blocks sampled at variable level of intra-hepatic and extra-hepatic biliary system were examined. Microscopically liver showed porto-porto bridging fibrosis resulting in incomplete nodule formation. Portal tracts were expanded by fibrosis and proliferating bile ducts with variable amount of moderately heavy mixed inflammatory cell infiltration along with periportal bile duct proliferation (CK7 positive). There were multiple foci of pericellular fibrosis. The bile ducts of variable sized showed dilation and contained eosinophilic material and the bile duct lining epithelial cells also showed mucinous metaplasia. Examination of these bile ducts in periodic acid-Schiff and alcian blue (PAS/AB) stained sections, the material present within dilated and nondilated biliary ducts and the metaplastic biliary mucosa were positive for PAS/AB. Hepatocytes showed extensive vacuolar and feathery degeneration. Hepatocytes also showed evidence of regeneration in the form of enlarged nucleas and prominent nucleoli, pseudo-rosette formation, and occasionally multinucleated giant cell transformation. There also extensive fatty changes dominantly macrovesicular. There was extensive intracytoplasmic, canalicular, and ductular cholestasis. Kupffer cells were prominent and contained bile pigment. Sections of the gall bladder and extra-hepatic biliary tree were within normal limits in microscopic examination. Electron microscopic examination of the hepatocytes did not show any feature to suggest diagnosis of mitochondrial disorder or any viral inclusions were noted. Hepatocytes were seen to contain fat globules and lamellar bodies entrapping irregular shaped electron dense possibly bile [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6].
Figure 2: Gross photograph of slices of organ complex comprising deeply bile stained liver, extra-hepatic biliary tract including gall bladder, and a lobulated firm pancreas along with C-loop of duodenum and a slice of spleen

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Figure 3: Close-up gross photographs of extra-hepatic biliary tract and gall bladder showing normal but mildly bile stained mucosa. Representative photomicrographs taken at different levels, and are shown side by side with the corresponding areas of the gross photographs depicting normal histology. There was no excess of alcian blue and periodic acid-Schiff positive cells along the lining mucosa

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Figure 4: Panel of photomicrographs of liver showing replacement of the normal parenchyma by ill-formed nodules separated by porto–porto bridging and pericellular fibrosis in different histochemicalstainings; (a) H and E; (b) Masson's trichrome stain; (c) Reticulin stain and (d) Smooth Muscle Actin in immunohistochemistry (peroxidase anti-peroxidase)

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Figure 5: Panel of photomicrographs of liver to show histological changes in varying sized portal tracts; (a) An expanded portal tract with variable degrees of bile duct proliferation including marginal bile ducts and inflammatory cell infiltration; (b) Intermediate sized portal tract with intermediate size dilated bile duct containing eosinophilic secretion; (c and d) Photomicrographs in periodic acid-Schiff and alcian blue stained sections to highlight positively stained intra-luminal secretions.

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Figure 6: Panel of photomicrographs of liver showing histological changes more in detail, (a) Diffuse macrovesicular fatty changes of hepatocytes intermixed with microvescicular fat globules, occasional giant multinucleated hepatocytes, and abundant hepatocytic and canalicular cholestasis; (b) prominent kupffer cells with intracytoplasmic bile pigments, which has been brought out better in Pouchet's stain; (c) medium power photomicrograph to show proliferating bile ducts in immunohistochemistry staining using CK7, separating the liver parenchyma into micronodules; and (d) electron microscopic picture of a hepatocyte to show normal mitochondria

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Pancreas almost normal size and firm to feel. There was no grossly visible dilated duct or evidence of fibrosis. Microscopy showed dilatation of the intra- and inter-lobular ducts and also the smaller main ductal system. All the dilated ducts were filled with thick inspissated PAS positive mucous and there was prominent periductal fibrosis. The lining epithelium of the dilated ductal system were showing denudation and degenerative changes along with focal neutrophil infiltration. The fibrosis was also seen in inter- and intra-lobular areas. There was prominent acinar dilatation containing PAS positive material. Sparse diffuse lymphomononuclear cell infiltration was present [Figure 2] and [Figure 7].
Figure 7: Panel of photomicrographs of pancreas from different areas showing - (a and b) inter and intralobular dilated ducts and acini which are filled with thick eosinophillic secretion; (c) there is disruption of the ductal lining epithelium along with periductal and periacinar fibrosis and mild to moderate lymphomononuclear cell infiltration; (d) Photomicrograph in alcian blue periodic acid-Schiff stained section to highlight alcian blue positive cells along ductal lining and periodic acid-Schiff positive material filling the dilated acini

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Intestine including duodenum

Duodenum was filled with the layers of thick mucus which could be removed and cleaned out with difficulty. Ampullary ostium was also impacted with similar thick mucus plug. Microscopically, there was a loss of Brunner's glands and replacement fibrosis with focal lymphoid aggregates. Duodenal mucosa showed dilated crypts filled with thick PAS positive mucus. Similar changes were also observed although out the length of small and large intestine [Figure 8].
Figure 8: (a) Gross photograph showing cut open C-loop of duodenum filled with thick mucus. (b) Photomicrograph to show replacement fibrosis of Brunner's gland and the remaining glands showing cystic dilatation and dilated duodenal mucosal crypts. (c) Replacement fibrosis of the Brunner's gland has been brought out better in Masson's trichrome staining as blue green color. (d) Medium power photomicrograph of alcian blue periodic acid-Schiff staining to highlight alcian blue and periodic acid-Schiff positive materials impacted deep into the crypts

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There flattening and loss of normal gastric mucosal folds. Microscopic examination showed denudation of the surface lining epithelium, and loss of specialized gastric glands. The intervening lamina propria was edematous and showed moderately heavy lymphomoonuclear cell infiltration [Figure 9].
Figure 9: (a) Gross photograph of cut open stomach showing loss of mucosal folds and mucosal edema. (b) Low power photomicrograph of H and E stained section to show superficial mucosal erosion and sub-mucosal edema. (c) Higher power photomicrograph of H and E stained section taken from gastric body showing mucosal thinning, loss of parietal cells and lamina propria edema

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Lungs weighed 120 g against the normal mean of 75 g. External examination showed discoloration of the pleura due to the focal areas of hemorrhagic congestion and fibrinous exudates. The lobes of the lung were felt solid. Slicing of the lung showed prominent bronchial markings. There was an evidence of aspiration. There were multiple enlarged carinal and hilar lymph nodes measuring up to 15 mm in size. In microscopic examination, the bronchi were dilated and irregular in shape due to the destruction of the bronchial cartilage. There was squamous metaplasia of the bronchial lining mucosa along with the destruction of the sub-mucosal glands. The bronchi were filled with aspirated material and AB positive thick mucus. More peripherally located bronchioles showed evidence of bronchopneumonia and multiple foci of breaking down abscess and necrosis. Surrounding these areas, there was an evidence of intra-alveolar edema and proliferation of the pale foamy looking alveolar macrophages containing lipid materials demonstrated by oil Red”O” staining on frozen section. There were also multiple foci showing evidence of diffuse alveolar damage where the alveolar ducts were lined by fibrinous membrane. E-membrane formation are seen and areas with abundant foamy macrophages [Figure 10] and [Figure 11].
Figure 10: (a) Gross photographs of lungs showing patchy congestion on pleural and cut surfaces, enlarged carinal and hilar lymph nodes and a clean tracheobronchial tree. (b) Low power photomicrograph showing dilated and irregular shaped main bronchus containing aspirated material, destruction of cartilage and a few cystically dilatated submucosal glands plugged with mucin. Partly sloughed off mucosa showed squamous metaplasia. (c) Alcian blue periodic acid-Schiff stained section showing alcian blue positivity along surface and submucosal glands

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Figure 11: Other areas of the lung parenchyma showing (a) bronchopneumonia with breaking down abscess; (b) alveoli and alveolar ducts lined by fibrinous membrane; (c) alveoli containing degenerated necrotic cells and foamy macrophages; (d) transmission electron microscopic picture to show a macrophage with fat globules; (e) photomicrograph of oil Red“O” stained frozen section using formalin fixed tissue showing positively stained alveolar macrophages

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Kidneys weighed 87 g against the normal mean of 50 g. The kidneys were enlarged with well-defined cortico-medullary junction. The cortex was bile stained and showed on closure look ill-defined linear stria present diffusely. Pelvi-calyceal system and ureters were well preserved. In microscopy, there was a diffuse dilatation of the cortical tubules possibly in the process of formation of varying size and shape cystic spaces in linear pattern. There was relatively sparing of the renal medulla. These dilated tubules were lined by flattened epithelium containing occasional hyaline and bile casts. The glomeruli, blood vessels, and interstitium were of normal morphology [Figure 12].
Figure 12: (a) Gross photograph of kidneys showing normal looking cut and capsular surfaces and mild greenish hue bile staining and normal pelvicalycex, cortex, medulla, ureters and bladder along with abdominal aorta exhibiting bile stained endothelium. (b) Low power photomicrograph showing many dilated tubules in cortex, normal medulla, glomeruli, blood vessels and interstitium

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Heart weighed 25 g which was within normal limit. The pericardium was shiny due to mucinous degeneration, which felt slimy to touch. There was enlargement of the right ventricle and concentric left ventricular hypertrophy. Microscopy confirmed the mucinus degeneration of the epicardial fat. Left ventricle myocardium showed anisonucleosis and disarray of myocardial fibers involving the inner third myocardium. Coronaries and cardiac veins were within normal limit [Figure 13].
Figure 13: (a) Anterior view of enlarged right ventricle along with prominent great cardiac vein, round left border and dull slimy epicardium. (b) Apical slice showing both ventricles at base of the papillary muscles showing concentric left ventricular hypertrophy. (c) Medium power photomicrograph of left ventricle showing disarray myocardial fibers dominantly involving inner half of left ventricular muscle

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Adrenal glands

Adrenal glands showed focal medullary and cortical necrosis. Section of the bone showed poorly mineralized trabeculae and mild megaloblastosis in erythroid series. Thymus was small and appeared shrunken. Histology showed depletion of the lymphoid tissue resulting in prominence of the thymic epithelial cells. There were degenerative changes of Hassle's corpuscles. Spleen weighed 25 g which was within the normal limit. Microscopy showed the depletion of the lymphoid tissue and hematopoietic cells within sinusoids. Lymph nodes showed reactive follicular hyperplasia [Figure 14]. Skeletal muscle was normal.
Figure 14: Panel of photomicrographs; (a) adrenal gland showing intact cortex with extensive cytolysis of medullary cells and fresh hemorrhage. (b) Thymus showing lymphoid depletion and approximation of Hassle's corpuscles with cystic degeneration. (c) Spleen showing depletion of lymphoid tissue with expansion of red pulp and sinusoidal fibrin deposition. (d) Lymph node showing depletion of lymphoid tissue

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   Final Autopsy Diagnosis Top

  • Mucoviscidosis of lungs, liver, pancreas, and intestine consistent with cystic fibrosis (CF)
  • Lungs – aspiration pneumonia with breaking down abscesses, pulmonary hemorrhage, and diffuse alveolar injury
  • Gastric erosion and parietal cell atrophy
  • Kidneys – autosomal dominant polycystic disease
  • Adrenal glands – necrosis
  • Left ventricular hypertrophy
  • Pleural hemorrhages and ascites.

   Open House Forum After Autopsy Protocol Presentation Top

Comment 1

Once lung and gastrointestinal (GI) tract involvement then the CF would be one of the possibilities. CF has varied and manifestation and it should be one of the possibilities. COI is one of the presentations and it has been in past all many chronic liver disease undiagnosed turned out be CF. Acute manifestations in the lung are known and it need not be than they should always start with pulmonary manifestations. S. pneumonia in Indian setting would clue in predicting CF. However, severe lactic acidosis is unusual and took us away from CF. some time there would be respiratory alkalosis and it would be presenting as pseudo-bartter like presentation. When there is a doubt about the diagnosis, one should always look at the mutation and classical mutation del508 is seen only in about 30% of the Indian population and DNA sequencing would be helpful.

Comment 2 (consultant, treating unit)

Compliments for Prof. Kim. Retrospectively everyone is wise and it sometimes would be straight forward, but it is difficult when one is faced this situation in clinical day to day practice. It is very difficult to consider when there is no clue in form of respiratory involvement and malabsorption suggestive of pancreatic insufficiency. In CF, chest skiagrams were very classical, in the form of hyperinflation, atelectasis, and bronchiectasis, which was not seen in this patient so it made us difficult in diagnosing when the patient is alive.


Sometimes it is difficult to diagnose when it is.

Comment 3

It is very difficult to keep CF as initial diagnosis when a patient presents with cholestasis alone. Liver disease per se can cause severe lactic acidosis when there is severe shock and metabolic. Apart from metabolic liver disease there are other two differentials, one is CF and other is disseminated CMV which is brought out by the discussant. Use of PFIC is sometimes misleading as it indicates about a specific entity and blocks, we are thinking about other diagnosis, thus it would be rather cholestatic liver disease. Still CF would not be one of the first few diseases in clinical setting.

Comment 4

One should be careful while interpreting infantile liver biopsy. Based on the changes in the portal tract, one would classify PFIC.

Comment 5 (clinical discussant)

PFIC presents with diarrhea, cholestasis, and low GGT levels. GGT level was not done in this case. Presentation in this patient was clear cut of metabolic liver disease inform of acidosis, coagulopathy, and hypertriglyceridemia, which would be seen in GSDs and PAS positive material in GSD apart from CF.


Current phenotype fits into CF even though there were many oddities.

   Discussion on the Case by Dr Kim Vaiphei Top

CF is one the most common inherited channelopathies with defect in transport of either chloride or bicarbonate across various membranes in the body.[1] The defect in the function of the CF transmembrane conductance regulator CFTR gene dates to abnormality of processing and transport of protein at various sub-cellular levels in the affected organs. More than 2000 mutation are documented worldwide with predilection for particular mutation in affected subgroup of population. Respiratory system is most commonly involved organ followed by GI and hepatic tissue.[2] As per various series, liver disease accounts for around 17–25% in patients in CF. Most common liver manifestation is focal biliary cirrhosis due to defective flushing of the secretion into major biliary ducts and subsequently into intestine due decreased water content in the secretion. This leads to clogging of bile ducts at various levels and causing injury to cholangiocytes, fibrosis, and cirrhosis. This pathogenetic mechanism is a gradual process requiring at least a decade to have full-fledged disease and clinical manifestation.[3] Most patients present with cirrhosis and portal hypertension in the second decade of life. Acute liver failure and chronic liver disease with decompensation is the second most common presentation of CF related liver disease. Various risk factors for severe liver disease are male gender, severe CFRT gene mutation, associated pancreatic insufficiency, and meconium ileus.[4] Of the five known classes of CFTR gene mutations, mutation involving class I, class II, and class III genes result in complete lose of their respective function, and associate with severe clinical diseases. Manifestation of a severe clinical disease involves lung, pancreas, intestine, and liver.

Neonatal presentation of CF related liver disease is uncommon. In one series of CF with infantile liver disease, the most common form of clinical presentation is incomplete cholestasis within the first 8 weeks of life.[5] Hepatomegaly, cholestatic jaundice, and poor nutritional status are the predominant features. Based on clinical features alone, it is almost impossible to differentiate CF induced cholestatic liver disease from other medical causes of cholestasis. Sweat chloride ion tophoresis is the initial screening investigation with very high sensitivity, and more recently serum immunoreactive trypsinogen is increasingly in use,[6],[7] especially in young children in whom acquisition of enough sweat for the test faces difficulties.

Cystic fibrosis and polycystic renal disease

Apical area of autosomal dominant polycystic kidney disease (ADPKD) cyst lining cells has strong CFTR expression. Functional studies have demonstrated role of CFTR in chloride secretion and cyst fluid accumulation. Hence, loss of CFTR function as in CF, will be expected to slow growth of the cysts and attenuate the ADPKD phenotype. However, such effect has not been observed in patients who have been documented to have co-existence of these two conditions, and protective effect of most common CF mutation-DF508 on renal ADPKD phenotype has been documented.[8],[9],[10]

To summarize, CF is one important chronic ailment involving lung and GI tract with varied clinical manifestation and disease onset at any time in first decade of life. High index of suspicion and appropriate metabolic and histopathological investigations will be of help to establish the diagnosis. Association of CF with ADPKD is seldom seen. Treatment is supportive in most of the patients except for newer therapies such as Ivacaftor, which may help in transporting CFTR protein to appropriate site.[11]

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Feranchak AP, Sokol RJ. Cholangiocyte biology and cystic fibrosis liver disease. Semin Liver Dis 2001;21:471-88.  Back to cited text no. 1
Cohn JA, Strong TV, Picciotto MR, Nairn AC, Collins FS, Fitz JG. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells. Gastroenterology 1993;105:1857-64.  Back to cited text no. 2
Colombo C, Battezzati PM, Crosignani A, Morabito A, Costantini D, Padoan R, et al. Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome. Hepatology 2002;36:1374-82.  Back to cited text no. 3
Efrati O, Barak A, Modan-Moses D, Augarten A, Vilozni D, Katznelson D, et al. Liver cirrhosis and portal hypertension in cystic fibrosis. Eur J Gastroenterol Hepatol 2003;15:1073-8.  Back to cited text no. 4
Lykavieris P, Bernard O, Hadchouel M. Neonatal cholestasis as the presenting feature in cystic fibrosis. Arch Dis Child 1996;75:67-70.  Back to cited text no. 5
Weintraub A, Blau H, Mussaffi H, Picard E, Bentur L, Kerem E, et al. Exocrine pancreatic function testing in patients with cystic fibrosis and pancreatic sufficiency: A correlation study. J Pediatr Gastroenterol Nutr 2009;48:306-10.  Back to cited text no. 6
Bates CM, Baum M, Quigley R. Cystic fibrosis presenting with hypokalemia and metabolic alkalosis in a previously healthy adolescent. J Am Soc Nephrol 1997;8:352-5.  Back to cited text no. 7
Hanaoka K, Devuyst O, Schwiebert EM, Wilson PD, Guggino WB. A role for CFTR in human autosomal dominant polycystic kidney disease. Am J Physiol 1996;270(1 Pt 1):C389-99.  Back to cited text no. 8
Brill SR, Ross KE, Davidow CJ, Ye M, Grantham JJ, Caplan MJ. Immunolocalization of ion transport proteins in human autosomal dominant polycystic kidney epithelial cells. Proc Natl Acad Sci U S A 1996;93:10206-11.  Back to cited text no. 9
Persu A, Devuyst O, Lannoy N, Materne R, Brosnahan G, Gabow PA, et al. CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2000;11:2285-96.  Back to cited text no. 10
Hayes D Jr., Warren PS, McCoy KS, Sheikh SI. Improvement of hepatic steatosis in cystic fibrosis with ivacaftor therapy. J Pediatr Gastroenterol Nutr 2015;60:578-9.  Back to cited text no. 11

Correspondence Address:
Prof. Kim Vaiphei
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.188137

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14]

  [Table 1], [Table 2]


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